Neurologia Geriatrica (1).pdf

Geriatric Neurology edited by

anil k. nair | marwan n. sabbagh

Geriatric Neurology

I dedicate this book to my patients and mentors. This book would not be possible without my grandfather who carried me on his shoulders daily to an elementary school miles away and my very supportive family. AKN I dedicate this work to my mother and father, who nurtured my unquenchable thirst for knowledge. MNS

Geriatric Neurology EDI T ED BY

ANIL K. NA IR

MD

Director, Clinic for Cognitive Disorders and Alzheimer’s Disease Center Chief of Neurology, Quincy Medical Center Quincy, MA, USA

MARWAN N. SABBAGH Director, Banner Sun Health Research Institute Research Professor of Neurology University of Arizona College of Medicine – Phoenix Sun City, AZ, USA

MD, FAAN

This edition first published 2014 © 2014 by John Wiley & Sons, Ltd Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www .wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Geriatric neurology (Nair) Geriatric neurology/edited by Anil K. Nair and Marwan N. Sabbagh. 1 online resource. Includes bibliographical references and index. Description based on print version record and CIP data provided by publisher; resource not viewed. ISBN 978-1-118-73064-5 (ePub) – ISBN 978-1-118-73065-2 (Adobe PDF) – ISBN 978-1-118-73068-3 (cloth) I. Nair, Anil (Anil Kadoor), 1970- editor of compilation. II. Sabbagh, Marwan Noel, editor of compilation. III. Title. [DNLM: 1. Nervous System Diseases. 2. Aged. 3. Aging–physiology. 4. Nervous System Physiological Phenomena. WL 140] RC451.4.A5 618.97’68–dc23 2013038615 A catalogue record for this book is available from the British Library. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Cover images: top row - copyright Wiley; bottom - courtesy of Anil K. Nair Cover design by Andy Meaden Set in 9.25/12 pt Palatino by Aptara Inc., New Delhi, India

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Contents

About the Editors, vii List of Contributors, viii Preface, xii Acknowledgments, xiii

Part 1 The Aging Brain in Neurology, 1 1 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century, 3 Douglas F. Watt 2 Functional Changes Associated with the Aging Nervous System, 38 Julie A. Schneider and Chunhui Yang

Part 2 Assessment of the Geriatric Neurology Patient, 69 3 Approach to the Geriatric Neurology Patient: The Neurologic Examination, 71 Marwan N. Sabbagh and Anil K. Nair 4 Assessment of Cognitive Status in Geriatric Neurology, 85 4.1 Mental Status Examination in the Geriatric Neurology Patient, 87 Papan Thaipisuttikul and James E. Galvin 4.2 Neuropsychology in Geriatric Neurology, 98 Donald J. Connor and Marc A. Norman 5 Cognitive Reserve and the Aging Brain, 118 Adrienne M. Tucker and Yaakov Stern 6 Gait Disorders in the Graying Population, 126 Joe Verghese and Jessica Zwerling 7 Imaging of the Geriatric Brain, 136 7.1 Structural Neuroimaging in Degenerative Dementias, 138 Liana G. Apostolova

7.2 Functional Imaging in Dementia, 146 Adam S. Fleisher and Alexander Drzezga 7.3 Amyloid Imaging, 162 Anil K. Nair and Marwan N. Sabbagh 8 Clinical Laboratory Investigations in Geriatric Neurology, 170 Geoffrey S. Baird and Thomas J. Montine

Part 3 Neurologic Conditions in the Elderly, 181 9 Cognitive Impairment and the Dementias, 183 9.1 Mild Cognitive Impairment, 187 Ranjan Duara, Miriam Jocelyn Rodriguez, and David A. Loewenstein 9.2 Alzheimer’s Disease, 200 Martin R. Farlow 9.3 Dementia with Lewy Bodies, 208 Clive Ballard 9.4 Vascular Cognitive Impairment, 224 Helena C. Chui and Freddi Segal-Gidan 9.5 Frontotemporal Dementia, 239 David Perry and Howard Rosen 9.6 Primary Progressive Aphasia, 251 Maya L. Henry, Stephen M. Wilson, and Steven Z. Rapcsak 9.7 Prion Diseases, 267 Michael D. Geschwind and Katherine Wong 9.8 Normal Pressure Hydrocephalus, 281 Norman R. Relkin 10 Depression in the Elderly: Interactions with Aging, Stress, Chronic Pain, Inflammation, and Neurodegenerative Disorders, 287 Douglas F. Watt 11 Cerebrovascular Diseases in Geriatrics, 302 Patrick Lyden, Khalil Amir and Ilana Tidus

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vi

Contents

12 Movement Disorders, 313 12.1 Parkinson’s Disease, 315 Robert Fekete and Joseph Jankovic 12.2 Essential Tremor and Other Tremor Disorders, 325 Holly Shill 12.3 Progressive Supranuclear Palsy, 333 Virgilio Gerald H. Evidente 12.4 Corticobasal Degeneration, 344 Katrina Gwinn 13 Sleep Disorders, 347 Sanford Auerbach 14 Autonomic Dysfunction and Syncope, 358 Rohit R. Das 15 Geriatric Epilepsy, 370 David V. Lardizabal 16 Vertigo and Dizziness in the Elderly, 379 Terry D. Fife and Salih Demirhan 17 Disorders of the Special Senses in the Elderly, 396 Douglas J. Lanska 18 Nervous System Infections, 460 Ronald Ellis, David Croteau, and Suzi Hong

23.1 Evidence-Based Pharmacologic Treatment of Dementia, 557 Jasmeet Singh, Marwan N. Sabbagh, and Anil K. Nair 23.2 Immunotherapy for Alzheimer’s Disease, 574 Michael Grundman, Gene G. Kinney, Eric Yuen, and Ronald Black 24 Geriatric Psychopharmacology, 586 Sandra A. Jacobson 25 Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia, 615 Gary A. Martin and John Ranseen 26 Expressive Art Therapies in Geriatric Neurology, 630 Daniel C. Potts, Bruce L. Miller, Carol A. Prickett, Andrea M. Cevasco, and Angel C. Duncan

Part 5 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient, 645 27 Dietary Factors in Geriatric Neurology, 647 Yian Gu and Nikolaos Scarmeas

20 Headache in the Elderly, 486 Brian McGeeney

28 Exercising the Brain: Nonpharmacologic Interventions for Cognitive Decline Associated with Aging and Dementia, 669 Brenna A. Cholerton, Jeannine Skinner, and Laura D. Baker

21 Neuromuscular Disorders, 494 Heber Varela and Clifton Gooch

29 Driving Impairment in Older Adults, 682 Anne D. Halli-Tierney and Brian R. Ott

19 Delirium, 478 Alan Lerner, Stefani Parrisbalogun, and Joseph Locala

Part 4 Therapeutics for the Geriatric Neurology Patient, 519

30 Elder Abuse and Mistreatment, 699 Elliott Schulman, Ashley Roque, and Anna Hohler 31 Advocacy in Geriatric Neurology, 707 Glenn Finney and Anil K. Nair

22 Neurosurgical Care of the Geriatric Patient, 521 David Fusco, Rasha Germain, and Peter Nakaji 23 Treatment of Dementia, 556

Color plate section appears between pages 50 and 51

Index, 713

About the Editors

Anil K. Nair, MD, is the director of TheAlzCenter.org and chief of neurology at Quincy Medical Center. He is also the site director for clinical trials in neurology. He completed his fellowship from Mayo Clinic, Rochester, MN, and his neurology residency at the Cleveland Clinic and Temple University after graduation from JIPMER, Pondicherry, India. His interest area is early and preclinical detection, prevention, and treatment of Alzheimer’s dementia, and other neurocognitive disorders and dementias. Dr. Nair oversees the clinical and research facility called TheAlzCenter.org (The Alzheimer’s Center) serving the south shore of Boston. The center aims to advance the field of geriatric neurology and reduce the costs of debilitating diseases such as Alzheimer’s disease and other related dementias. In addition to providing preventive, diagnostic, and therapeutic services to patients with neurodegenerative and related diseases, Dr. Nair runs clinical trials in multiple indications, primarily in Alzheimer’s disease. He is dedicated to providing healthcare and referral services of the highest quality and is committed to building partnerships that increase the independence and quality of life for patients with dementia. Dr. Nair is also an investigator for the stroke and memory project at the Framingham Heart Study, which aims to identify the risk factors involved in such diseases as Alzheimer’s disease and related dementias.

Marwan N. Sabbagh, MD, FAAN, is a board-certified neurologist and geriatric neurologist. As the director of the Banner Sun Health Research Institute, Dr. Sabbagh has dedicated his entire career to finding a cure for Alzheimer’s and other age-related neurodegenerative diseases. Dr. Sabbagh is a leading investigator for many prominent national Alzheimer’s prevention and treatment trials. He is senior editor for Journal of Alzheimer’s Disease, BMC Neurology, and Clinical Neurology News, and has authored and coauthored more than 200 medical and scientific chapters, reviews, original research articles, and abstracts on Alzheimer’s research. Dr. Sabbagh has also authored The Alzheimer’s Answer—the book’s foreword was written by Justice Sandra Day O’Connor—and edited Palliative Care for Advanced Alzheimer’s and Dementia: Guidelines and Standards for Evidence Based Care and coauthored The Alzheimer's Prevention Cookbook: Recipes to Boost Brain Health (RandomHouse/TenSpeed, 2012). Dr. Sabbagh is research professor in the Department of Neurology, University of Arizona College of Medicine– Phoenix. He is also an adjunct professor at Midwestern University and Arizona State University. He earned his undergraduate degree from the University of California Berkeley and his medical degree from the University of Arizona in Tucson. He received his internship at the Banner Good Samaritan Regional Medical Center in Phoenix, AZ, and his residency training in neurology at Baylor College of Medicine in Houston, TX. He completed his fellowship in geriatric neurology and dementia at the UCSD School of Medicine.

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List of Contributors

Khalil Amir

Helena C. Chui

MD

Department of Neurology Cedars-Sinai Medical Centre Los Angeles, CA, USA

MD

Department of Neurology Keck School of Medicine University of Southern California Los Angeles, CA, USA

Liana G. Apostolova

MD, MS

Department of Neurology David Geffen School of Medicine University of California Los Angeles, CA, USA

Donald J. Connor

Sanford Auerbach

David Croteau

MD

PhD, PhD

Independent Practice Consultant in Clinical Trials San Diego, CA, USA MD

Departments of Neurology Psychiatry and Behavioral Neurosciences Boston University School of Medicine Boston, MA, USA

Department of Neurosciences and HIV Neurobehavioral Research Center University of California San Diego, CA, USA

Geoffrey S. Baird

Rohit R. Das

MD

Departments of Laboratory Medicine and Pathology University of Washington Seattle, WA, USA

MD, MPH

Indiana University School of Medicine Indianapolis, IN, USA

Salih Demirhan Laura D. Baker

PhD

Department of Medicine - Geriatrics Wake Forest School of Medicine Winston-Salem, NC, USA

Clive Ballard

MBChB MMedSci MRCPsych MD

Wolfson Centre for Age-Related Diseases King’s College London London, UK

Ronald Black

MD

Chief Medical Officer Probiodrug AG Halle, Germany

Andrea M. Cevasco

PhD, MT-BC

School of Music College of Arts and Sciences University of Alabama Tuscaloosa, AL, USA

Brenna A. Cholerton

Alexander Drzezga

PhD

MD

Department of Nuclear Medicine University Hospital of Cologne Cologne, Germany

Ranjan Duara

MD, FAAN

Wien Center for Alzheimer's Disease and Memory Disorders Mount Sinai Medical Center Miami Beach; Department of Neurology Herbert Wertheim College of Medicine Florida International University, Miami and University of Florida College of Medicine University of Florida Gainesville, FL, USA

Angel C. Duncan

Department of Psychiatry and Behavioral Science University of Washington School of Medicine and Geriatric Research, Education, and Clinical Center Veterans Affairs Puget Sound Health Care System Seattle, WA, USA

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MD

Marmara University School of Medicine Istanbul, Turkey

MA-MFT, ATR

Cognitive Dynamics Foundation Neuropsychiatric Research Center of Southwest Florida Albertus Magnus College American Art Therapy Association Fort Myers, FL, USA

List of Contributors

Ronald Ellis

Clifton Gooch

MD, PhD

Department of Neurosciences and HIV Neurobehavioral Research Center University of California San Diego, CA, USA

MD, FAAN

Department of Neurology University of South Florida College of Medicine Tampa, FL, USA

Michael Grundman Virgilio Gerald H. Evidente

MD

Movement Disorders Center of Arizona Ironwood Square Drive Scottsdale, AZ, USA

Martin R. Farlow

Yian Gu

PhD

Taub Institute for Research on Alzheimer’s Disease and the Aging Brain Columbia University Medical Center New York, NY, USA

MD

Department of Neurology Indiana University Indianapolis, IN, USA

Katrina Gwinn Robert Fekete

MD, MPH

President, Global R&D Partners, LLC San Diego, CA, USA

MD

National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, MD, USA

MD

Department of Neurology New York Medical College Valhalla, NY, USA

Anne D. Halli-Tierney Terry D. Fife

MD, FAAN

Barrow Neurological Institute and Department of Neurology University of Arizona College of Medicine Phoenix, AZ, USA

Glenn Finney

Maya L. Henry

PhD

Department of Communication Sciences and Disorders University of Texas at Austin and Memory and Aging Center Department of Neurology University of California San Francisco, CA, USA

MD

Department of Neurology McKnight Brain Institute Gainesville, FL, USA

Adam S. Fleisher

MD

Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, RI, USA

MD, MAS

Banner Alzheimer's Institute Department of Neurosciences University of California San Diego, CA, USA

Anna Hohler

David Fusco

Suzi Hong

MD

Department of Neurology Boston University School of Medicine Boston, MA, USA

MD

PhD

Division of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, AZ, USA

Department of Psychiatry School of Medicine University of California San Diego, CA, USA

James E. Galvin

Sandra A. Jacobson

MD, MPH

MD

Department of Neurology and Department of Psychiatry New York University Langone Medical Center New York, NY, USA

University of Arizona College of Medicine-Phoenix Banner Sun Health Research Institute and Cleo Roberts Center for Clinical Research Sun City, AZ, USA

Rasha Germain

Joseph Jankovic

MD

Division of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, AZ, USA

Michael D. Geschwind Memory and Aging Center Department of Neurology University of California San Francisco, CA, USA

MD

Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine Houston, TX, USA

MD, PhD

Gene G. Kinney

PhD

Chief Scientific Officer Prothena Biosciences, Inc. South San Francisco, CA, USA

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List of Contributors

Douglas J. Lanska

MD, MS, MSPH, FAAN

Neurology Service Veterans Affairs Medical Center Great Lakes Health Care System Tomah, WI, USA

Marc A. Norman

Brian R. Ott David V. Lardizabal

PhD, ABPP

Department of Psychiatry University of California San Diego, CA, USA MD

Epilepsy Program and Intraoperative Monitoring University of Missouri Columbia, MO, USA

Warren Alpert Medical School of Brown University and The Alzheimer’s Disease and Memory Disorders Center Rhode Island Hospital Providence, RI, USA

Alan Lerner

Stefani Parrisbalogun

MD

MD

Department of Neurology Case Western Reserve University School of Medicine Cleveland, OH, USA

David Perry Joseph Locala

MD

Department of Psychiatry Case Western Reserve University School of Medicine Cleveland, OH, USA

David A. Loewenstein

Gary A. Martin

MD

Cognitive Dynamics Foundation Veterans Affairs Medical Center The University of Alabama Tuscaloosa, AL, USA

Carol A. Prickett

PhD

Brian McGeeney

MD

Department of Neurology Boston University School of Medicine Boston, MA, USA

Bruce L. Miller

John Ranseen

PhD

Department of Psychiatry University of Kentucky College of Medicine Lexington, KY, USA

Steven Z. Rapcsak

MD

Department of Neurology University of Arizona Neurology Section Southern Arizona VA Health Care System Tucson, AZ, USA

MD

Memory and Aging Center University of California San Francisco, CA, USA

Thomas J. Montine

PhD, MT-BC

School of Music College of Arts and Sciences University of Alabama Tuscaloosa, AL, USA

Integrated Geriatric Behavioral Health Associates Scottsdale, AZ, USA

MD

Departments of Pathology and Neurological Surgery University of Washington Seattle, WA, USA MD

Clinic for Cognitive Disorders and Alzheimer’s Disease Center Quincy Medical Center Quincy, MA, USA

Peter Nakaji

Daniel C. Potts

MD

Department of Neurology Cedars-Sinai Medical Center Los Angeles, CA, USA

Anil K. Nair

MD

Memory and Aging Center Department of Neurology School of Medicine University of California San Francisco, USA

PhD, ABPP

Department of Psychiatry and Behavioral Sciences Miller School of Medicine University of Miami Miami, FL, USA

Patrick Lyden

MD

Rawson-Neal Psychiatric Hospital Las Vegas, NV, USA

MD

Division of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, AZ, USA

Norman R. Relkin

MD, PhD

Memory Disorders Program Department of Neurology and Brain Mind Research Institute Weill Cornell Medical College New York, NY, USA

Miriam Joscelyn Rodriguez

PhD

Wien Center for Alzheimer's Disease and Memory Disorders Mount Sinai Medical Center Miami Beach, FL, USA

Ashley Roque

MD

Boston University School of Medicine Boston, MA, USA

List of Contributors

Howard Rosen

Papan Thaipisuttikul

MD

Memory and Aging Center Department of Neurology School of Medicine University of California San Francisco, CA, USA

Ilana Tidus

BSc

Banner Sun Health Research Institute Sun City, AZ, USA

Department of Neurology Cedars-Sinai Medical Centre Los Angeles, CA, USA

Nikolaos Scarmeas

Adrienne M. Tucker

Marwan N. Sabbagh

MD, FAAN

MD, MSc

Taub Institute, Sergievsky Center Department of Neurology Columbia University New York, NY, USA and Department of Social Medicine, Psychiatry and Neurology National and Kapodistrian University of Athens Athens, Greece

Julie A. Schneider

MD, MS

Rush Alzheimer’s Disease Center Department of Pathology and Department of Neurological Sciences Rush University Medical Center Chicago, IL, USA

Elliott Schulman

MD

Lankenau Institute for Medical Research Lankenau Medical Center Wynnewood, PA, USA PA, PhD

Department of Neurology Keck School of Medicine University of Southern California Los Angeles, CA, USA

Heber Varela

MD

Department of Neurology University of South Florida College of Medicine Tampa, FL, USA

Joe Verghese

MD

Department of Neurology and Medicine Albert Einstein College of Medicine Bronx, NY, USA

Douglas F. Watt

PhD

Department of Neuropsychology Cambridge City Hospital, Harvard Medical School and Alzheimer’s Disease Center/Clinic for Cognitive Disorders Quincy Medical Center Quincy, MA, USA

Banner Sun Health Research Institute Sun City, AZ, USA

Jasmeet Singh

MD, MPHA

Alzheimer’s Disease Center Quincy Medical Center Quincy, MA, USA

Jeannine Skinner

PhD

Department of Neurology Vanderbilt School of Medicine Nashville, TN

Yaakov Stern

PhD

Cognitive Neuroscience Division Department of Neurology Columbia University Medical Center New York, NY, USA

PhD

Department of Speech Language and Hearing Sciences University of Arizona Tucson, AZ, USA

Katherine Wong MD

PhD

Cognitive Science Center Amsterdam University of Amsterdam Amsterdam, The Netherlands

Stephen M. Wilson Freddi Segal-Gidan

Holly Shill

MD

Department of Neurology and Department of Psychiatry New York University Langone Medical Center New York, NY, USA

BA

Memory and Aging Center Department of Neurology University of California San Francisco, CA, USA

Chunhui Yang

MD, PhD

Rush Alzheimer’s Disease Center and Department of Pathology Rush University Medical Center Chicago, IL, USA

Eric Yuen

MD

Clinical Development Janssen Alzheimer Immunotherapy Research & Development South San Francisco, CA, USA

Jessica Zwerling

MD

Department of Neurology Albert Einstein College of Medicine Bronx, NY, USA

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Preface

As scientific knowledge about the nervous system and neurological diseases explodes at an exponential rate, the ability to master all aspects of neurology becomes increasingly difficult. Because of this, neurology as a profession is fragmenting much the same way that internal medicine has, with many subspecialties of neurology emerging and establishing themselves as board-recognized subspecialties by the American Academy of Neurology and the United Council of Neurological Subspecialties (UCNS). Currently recognized subspecialties of the UCNS include autonomic disorders, behavioral neurology and neuropsychiatry, clinical neuromuscular disease, headache medicine, neural repair and rehabilitation, neurocritical care, neuroimaging, and neuro-oncology. Other recognized subspecialties include epilepsy, stroke, and movement disorders. For the past several years, the American Academy of Neurology’s Geriatric Neurology section has been advocating strongly for the creation of a boarded, recognized subspecialty in geriatric neurology. This recommendation was approved by the AAN and adopted by the UCNS. Subsequently, the UCNS drafted a course outline for examination purposes, convened an examining committee that drafted the exam questions, and has since proctored three exam sessions. This book mirrors the new board subspecialty of geriatric neurology within the larger field of neurology. This project is written as a textbook for an emerging field of neurology and provides evidencebased scientific review of the current thinking in the field. The content will be clearly articulated and summarized. Geriatric neurology is the field of neurology dedicated to age-related neurological diseases, including

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degenerative diseases (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis), gait and balance disorders, neuropathies, stroke, and sleep disturbances. Geriatric neurology is emerging as a subspecialty of neurology. This emergence reflects the growing understanding that geriatric patients have different neurological conditions that require different diagnostic evaluations and ultimately different features. Geriatric neurology is not adult neurology redux. The field has similarities to geriatrics and the approach to the geriatric patient is, by definition, different. As such, clinical syndromes can have features in common with younger patients but the etiologies are frequently different. Additionally, many neurodegenerative diseases are prevalent in the aged but less so in general neurology. This handbook is the summation of the field at present. It follows the UCNS examination outline to an extent in terms of topics covered. It covers all topics germane to geriatric neurology from disease-specific, neuroanatomical, diagnostic, and therapeutic perspectives. The good news is that we have made tremendous strides in understanding and managing the complications and challenges of diseases that are encompassed within geriatric neurology. We now understand the neurological changes that occur with age and the mechanisms that contribute to changes. We hope it will enhance practice skills and knowledge base for practitioners, residents, and students.

Anil K. Nair Marwan N. Sabbagh

Acknowledgments

This work would not exist without the exhaustive efforts of our contributors, who are the venerable authorities in their respective fields. We would also like to thank our assistants who were tireless and patient throughout— Bonnie Tigner, Myste Havens, Deborah Nadler, Nicole Chan, Roshni Patel, Sheela Chandrashekar, Ardriane Hancock, Krystal Kan, and Vishakadutta Kumaraswamy. We would like to thank the publishing team at

Wiley for their feedback, responsiveness, patience, and support. Finally, we would like to thank our spouses and children who endured our many late nights staying up writing and editing. Anil K. Nair Marwan N. Sabbagh

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Part 1 The Aging Brain in Neurology

Chapter 1 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century Douglas F. Watt Department of Neuropsychology Cambridge City Hospital, Harvard Medical School, and Alzheimer’s Center/Clinic for Cognitive Disorders, Quincy Medical Center, Quincy, MA, USA

Summary • Aging demographics, increasing penetration of diseases of aging, and the heightening expense of high technology health-care interventions are creating exploding costs that are becoming economically unsustainable. • Evolutionary theory suggests that aging is the fading out of adaptation once reproductive competence is achieved, and reflects the lack of selection for a sustained post-reproductive adaptation. • If extrinsic mortality is high in the natural environment, selection effects are less likely to promote organism maintenance for extended periods. Alternatively, aging is simply change of the organism over time, and is primarily under the control of the hypothalamic pituitary gonadotropin axis. Although traditionally viewed as opposing theories, these may be simply different perspectives on the same process. • Cellular and molecular theories attribute aging to a genetically modulated process, a consequence of “wear-and-tear”, or a combination of both types of processes. • Aging is probably a complex and recursive network of many changes. • Molecular and cellular models of aging include: nuclear and mitochondrial and even ribosomal DNA damage, including genomic instability, loss of epigenetic regulation, and mitochrondrial DNA deletion. • Oxidative stress (OS) and associated mitochondrial dysfunction and decline • Inflammation which is progressively disinhibited (‘inflammaging’) • Glycation • Declining autophagy • Dysregulation of apoptosis • Sarcopenia • Cellular senescence • Calorie or dietary restriction (CR/DR) has been shown to have positive effects in most but not all species on longevity and aging. • A network of interacting molecular pathways has been implicated in CR physiology. Sirtuins, a class of transcription factors, are thought to play an important role in cell signaling and aging, in concert with mTOR, AMPK, PGC-1a, and insulin signaling pathways. • The target of rapamycin (TOR) signaling network influences growth, proliferation, and lifespan. Rapamycin, an immunosuppressive macrolide, inhibits mammalian target of rapamycin (mTOR) and has been shown to increase lifespan. • CR mimetics are substances that potentially mimic the molecular effects and physiology of CR. Resveratrol is the most well known CR mimetic but only extends lifespan in obese animals. • Genetic manipulation of growth hormone, IGF-1, and insulin signaling pathways may mimic CR effects. • Lifestyle factors such as sleep, diet, exercise, and social support may affect a shared set of cellular and molecular pathways. • Exercise: elicits an acute anti-inflammatory response and inhibits production of proinflammatory cytokines. Protective against disease associated with low grade systemic inflammation. • Obesity: abdominal fat may contribute to the disinhibition of inflammation. • Polyphenols, often regarded as antioxidants, affect cell physiology and cell signaling in a wide variety of ways that are probably far more critical to their effects in mammalian physiology beyond any putative free radical scavenging. • Healthy lifestyle practices match those of ancestral hunter gatherers (HGs), suggesting that diseases of aging may be potentated by a mismatch between our genes and the modern environment.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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4

The Aging Brain in Neurology

Do not go gentle into that good night, Old age should burn and rave at close of day; Rage, rage against the dying of the light. Dylan Thomas Aging is arguably the most familiar yet least-well understood aspect of human biology. Murgatroyd, Wu, Bockmuhl, and Spengler (2009) Old age is no place for sissies. Bette Davis

Dedication: To my Dad, Richard F. Watt, who believed that the best scholarship and the best social values would eventually reveal each other.

Introduction Aging, now the focus of a rapidly expanding, if still immature, biological science, remains one of the most fundamental yet mysterious aspects of biology. The science of aging has explored the cellular and molecular basis of aging largely in three target organisms with fully sequenced genomes and short lifespans (yeast, roundworms, and fruit flies), as well as an increasing number of in vivo studies in mammalian animal models. Evidence argues that multiple pathways modulating aging in these three target organisms are well conserved in mammals, primates, and humans, although perhaps with additional modifications. The science of aging has made progress in describing and analyzing several critical phenotypes or components of aging, including sarcopenia, glycation, inflammation and oxidative stress (OS), endocrine dyscrasia, apoptosis, telomere loss and cellular senescence, genomic damage and instability, mitochondrial dysfunction and decline, and increasing junk protein and declining autophagy (removal of damaged or “junk” proteins). Although the relationships among these various aspects of aging remain incompletely mapped, evidence increasingly indicates that they are deeply interactive, perhaps reflecting the many linked “faces” or facets of aging. Increasing evidence links most, if not all, of these processes to the major diseases of aging and most neurodegenerative disorders. Evolutionary perspectives argue that aging must be a process against which natural selection operates minimally, in a postreproductive animal. In other words, basic selection processes ensure that enough members of the species (absent predation or other accidental death) survive to a period of maximum reproductive competence (otherwise, a species would not exist), but selection does not and indeed cannot ensure longevity much past a peak reproductive period. Aging is the result of this relative absence of selection for an extended postreproductive adaptation. In this sense, evolution “does not care too much about aging”, although partial exceptions to this principle in humans

may exist due to the likely contribution of tribal elders to an extended “group fitness,” possibly helping to explain why humans are longer lived than almost all other mammals. Such evolutionary perspectives also suggest that aging (and its deceleration) is likely to be highly polygenetic and not easily radically modified, arguing strongly against any wild optimism about improvements to maximum human lifespan beyond its documented maxima (about 120 years). Current thinking also suggests that aging clearly reflects an “antagonistic pleiotropy”—genes beneficial to and even critically necessary for growth and reproduction “backfire” in older animals and contribute to aging, in part through “unexpected” interactions. However, aging research has extensively probed highly conserved protective effects associated with dietary or calorie restriction (DR/CR), the gold standard in terms of a basic environmental manipulation that slows aging in virtually every species in which it has been closely studied, from yeast to mammals. CR/DR functions as a global metabolic “reprogramming” for most organisms, reflecting a shift of biological priorities from growth and reproduction toward stasis and conservation. CR physiology was presumably selected by allowing organisms to survive in times of nutrient shortage and then resume the critical business of growth and procreation when again in environments more supportive of fecundity. CR extends lifespan and reduces penetration of the diseases of aging significantly, if not dramatically, in almost every species in which it has been studied, but does not appear to be a viable health-care strategy for the vast majority of individuals (due to the intrinsic stresses of chronic hunger). CR mimetics (substances offering at least some of the physiology of CR without the stress of chronic hunger) may offer some or many of the benefits of CR, protective effects of enormous relevance to Western societies as they undergo progressive demographic shifts in the direction of a larger percentage of elderly citizens than at any point in human history, with an impending tsunami of diseases of aging. However, clinical and long-term data on CR mimetics is badly lacking beyond animal models, where they show

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

impressive protective effects. CR mimetics are currently being studied in multiple diseases of aging, including cancer, heart disease, Alzheimer’s disease (AD), diabetes, and several others. Last but not least, accumulating evidence also indicates that Western lifestyles and an associated pandemic of obesity, reflecting a radical departure from our evolutionary environment, will expose us to increased penetration by the diseases of aging, despite (or perhaps because of) increasing life expectancy. These multifactorial lifestyle changes (poorer sleep, little exercise, complex dietary shifts, increased social isolation) may increase many of the phenotypes or components of aging, including OS, inflammation, glycation, insulin resistance, telomere loss, disordered cell cycling and aberrant growth signals, increased junk proteins, and DNA damage. Fundamental shifts in health-care strategy and priorities will be needed in the coming decades, away from high-technology interventions aimed at an advanced disease of aging (often one at which little real prevention was ever aimed) and toward a reprioritizing of meaningful prevention via substantive lifestyle modifications. Such a shift in healthcare priorities is likely to be politically contentious, but the current (and unsustainable) escalation of health-care spending will eventually force basic changes in both health-care policy and clinical practice. The science of aging may eventually heuristically integrate much of our currently fragmented approach to the diseases of aging and thus merits much more attention and review not only in medical school curriculums, but also in basic biomedical research initiatives.

Aging and mortality All complex organisms age and eventually die1, with highly variable limits to their typical lifespans, a variability still poorly understood. The outer biological limit to the human lifespan is generally thought to be approximately 120 years. The oldest carefully verified human known was Jeanne Calment of France (1875–1997), who died at age 122 years, 164 days (Robine and Allard, 1995). As far as we know, we are the only species with a vivid awareness of and preoccupation with our own mortality (and perhaps, at other times, an equally great denial). Cultures from the earliest recorded history have been preoccupied with themes of dying and immortality, along with whether it would be possible to escape death or find a true “fountain of youth.” Wishes for and even expectations of immortality are a powerful driver in many

1

Only in organisms in which there is no real distinction between soma and germ line (such as hydra and most bacteria) is aging absent.

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organized religions and spiritual traditions. Yet despite such perennial and fundamental human wishes, no way of truly preventing aging or achieving any version of biological immortality has ever been achieved in human history. Aging and our eventual demise from it both seem as unavoidable as the next sunrise. Benjamin Franklin is credited with the famous quote, “The only thing certain in life are death and taxes.” More humorous perspectives on these existential challenges include George Bernard Shaw’s lament that youth was a wonderful thing and a shame that it had to be wasted on the young. When I was too young to fully appreciate the humor, my own father, who passed away during the writing of this chapter at the age of 93, offered, “Aging is vastly overrated, but most of the time, it beats the alternative.” But ultimately, aging is no joking matter, exposing humans to slow and inevitable degradation of virtually every organ system, progressive disability, and eventual outright physiological failure of one sort or another, with inevitably fatal consequences. Yet if we did not age and die, humans and their progeny would quickly overrun the planet and totally exhaust its ecology and resources, causing mass extinctions not only for many other species, but potentially for our own as well. Thus, any true “fountain of youth” for humans might prove to be a seductive but ultimately deadly Faustian bargain. Yet who does not want more life, particularly if in decent health and with preserved functional capacities? Such primordial motivation and longing was surely captured in Dylan Thomas’s haunting poem “Do Not Go Gentle into That Good Night,” tapping universal sentiments in the face of aging and mortality. In this context, one might ask why a chapter on the biology of aging appears in a textbook of geriatric neurology. Trivially, the obvious answer is that aging has everything to do with all things geriatric. However, less trivially and less obviously, one might argue that an understanding of the basic biology of aging could function as a “touchstone” or integrative “hub” around which much of the science of geriatric neurology might eventually be organized. Central questions here could include: What is aging? What drives the progressive deterioration of the human organism over time? Why does it lead to what have been called the “diseases of aging?” These diseases would include not just classic neurodegenerative disorders (most paradigmatically, AD, but also Parkinson’s disease (PD), frontotemporal dementias, and motor neuron diseases—all core clinical concerns for geriatric neurologists, neuropsychologists, and psychiatrists), but also coronary artery and cerebrovascular disease, other forms of age-related vascular disease, diabetes, cancers, macular degeneration and glaucoma, arthritis, failing immunocompetence, and perhaps many, if not most, forms of end-stage organ disease. Additional central questions potentially addressed by the science of aging include the following: what can we

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The Aging Brain in Neurology

do about slowing aging and extending the lifespan or, for that matter, protecting ourselves from the diseases of aging? Exactly how does aging lead to the various diseases of aging, and what determines which disease of aging an individual gets? Does someone truly die just from “old age,” or do we die of a disease of aging? What are the core biological processes responsible for aging? Are these a few biological processes or many dozens? What are the potential relationships (interactions) among various core processes implicated in aging? What is the relationship between aging in the brain and aging of the body in general? Can the brain be differentially protected from aging and age-related diseases? Would a slowing of aging itself potentially delimit the penetration by the diseases of aging in some or even all individuals? How radically? Is it possible to substantially slow aging, or perhaps even to arrest it? Even more radically, could aging ever be substantially reversed? Many of these questions do not have well-validated scientific answers yet. Most of these questions could be considered central biological questions for all the health-care disciplines and also questions around which there is now a rich and emerging, if still fundamentally young and incomplete, science of aging.

Implications of an aging demographic in Western societies for priorities in health care: prevention versus hightechnology medicine Unfortunately, very little of an emerging science of aging has trickled down into the health-care system and into the awareness of most health-care professionals, where a largely fragmented approach to the diseases of aging predominates theory, clinical research, and treatment. In addition, almost none of it seems to inform the way our health-care system currently works. Substantive prevention in relationship to the diseases of aging (let alone any concerted focus on potentially slowing aging) garners little substantive attention or meaningful share of fiscal resources; instead high-technology intervention, often aimed at an advanced disease of aging (at which little, if any, prevention was typically ever aimed), consumes an enormous fraction of medical resources and costs (Conrad, 2009). Recent estimates are that no more than 5% of health care is spent on prevention, broadly defined, whereas 75–85% is spent on an established illness, typically a disease of aging (Centers for Disease Control and Prevention (CDC), 2010). In 2010, at least $55 billion was spent on the last 2 months of life, and an enormous fraction of total medical costs was spent on end-of-life care (Social Security Advisory Board (SSAB), 2009), often with little evidence that this considerable expenditure improves the quality of life (and may even cause it to deteriorate, in some instances). If one were to extrapolate our current (average)

end-of-life care costs to the baby boomers (a demographic of roughly 60 million people), this could potentially yield a total price tag of about $6 trillion for end-of-life care for the baby boomer generation. Obviously, these trends are unsustainable, but there is little evidence of progress toward addressing, let alone reversing, them. The emerging and expanding science of the biology of aging, as a vigorous area of scientific inquiry, takes place at a time when the demographics of Western societies are tilting toward an increasingly high percentage of elderly citizens. At the beginning of the twentieth century, when life expectancy was about 47 years in the United States, until today, there has been a roughly 30-year increase in life expectation at birth (Minino et al., 2002). Roughly 25 years of this 30-year gain in lifespan can be attributed to one primary factor: lessening the impact from early mortality due to infectious diseases in children and young adults, in the context of better hygiene and the creation of effective antibiotics and vaccines (CDC, 1999). This has yielded a situation in which many Western societies are now for the first time in human history facing the prospect of having more people over the age of 60 than under the age of 15. Although currently roughly 13% of the United States is over the age of 65, within the next 20 years, this percentage is expected to increase by more than half again, to roughly 20%. By the end of the century, a whole one-third of the world’s population will be over the age of 60 (Lutz et al., 2008). These demographic shifts will centrally include a huge increase in the very old in the coming four decades. In 2010, more than an estimated 5.5 million Americans were 85 years or older; by the year 2050, that number is expected to almost quadruple to 19 million. Currently, the number of centenarians in this country (Americans 100 years and older) is estimated at roughly 80,000, but by 2050, there will be more than 500,000 Americans aged 100 years or older. This is unprecedented in human history. However, these significant increases in lifespan have not been accompanied by concomitant increases in “healthspan,” or in our ability to substantially prevent (or successfully treat and delimit) the disabling illnesses of later life, the major diseases of aging (centrally including diabetes, cardiovascular disease, stroke, AD, and cancers), which remain largely refractory to amelioration. Some evidence (summarized later in this chapter) argues that these diseases may be largely of Western civilization (primarily due to modern lifestyles) and relatively rare in elders from hunter gatherer (HG) societies, compared to Western societies, even when the younger mortality of HGs is taken into account (Eaton et al., 1988 a,b). The impact of these large demographic shifts and the associated increased penetration of diseases of aging on health-care economics, combined with the increasing costs of technology-driven health-care interventions, is quietly anticipated to be fiscally catastrophic, involving a steady annual escalation of health-care costs to unsustainable levels (US Government Accountability Office, 2007; Conrad, 2009). The impact on health-care economics of an

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

aging demographic, combined with an increasing emphasis on high technology, is increasingly penetrant and, frankly, worrisome, particularly in terms of its impact on health-care economics in this country. In 2010, health-care expenditures in the United States were approximately 18% of the gross domestic product (GDP), almost twice as much, in terms of percentage of GDP, as in any other Western society. Even just within the next several years, at a current rate of increase of between 4% and 8% a year (rates of increase moderated more by the recent recession than by changing practice), by 2018–2019, roughly 20% ($1 in every $5) of the US GDP could be spent on healthcare expenses, an unprecedented fraction of our national wealth and resources. The health-care expense as a proportion of GDP is projected (without substantive changes in practice trends or chronic illnesses) to rise to 28% in 2030 (more than $1 in every $4) and to 34% by 2040 (more than $1 in every $3; Council of Economic Advisers (CEA), 2009). These are frightening statistics, suggesting that the current rate of escalation in health-care expenditures is totally unsustainable. However, the demographic shifts toward an aging population are only one contributing factor in these accelerating expenditures and are paired with the escalating cost of first-line drugs and high-technology interventions and the high overhead associated with the burgeoning health-care and health-insurance bureaucracy itself (CEA, 2009). Evidence suggests that as much as threequarters of the increasing costs are due to factors other than an aging demographic (CEA, 2009). Despite these enormous and escalating financial outlays in health care, the overall health may be actually declining in the United States, as measured by several indices. Currently, the United States rank around 50th in life expectancy, while other indices, such as infant mortality, are also worrisome and rank 46th, behind all of Western Europe and Canada (CIA Factbook). Reflecting the major disease of aging with special relevance for this textbook, costs for AD in 2010 were roughly $170 billion in the United States alone (not counting an additional roughly $140 billion in unpaid caretaker costs, suggesting a real cost of over $300 billion in 2010 alone) (Alzheimer’s Association, 2010). These total costs of AD (assuming that current costs continue and no cure or highly effective treatment is found) are expected to potentially reach $2 trillion per year in the United States alone by 2050, with 65 million expected to suffer from the disease in 20 years worldwide, at a cost of many trillions of dollars (Olshansky et al., 2006). As the baby boomers enter the decades of greatest risk for cancers, heart disease, stroke, arthritis, AD, macular degeneration, and other diseases of aging, evidence indicates that the health-care system (as it is currently structured) will eventually undergo a slowly progressive but fundamental collapse in the context of these unsustainable cost escalations. Meaningful strategic options to prevent this fiscal implosion have not yet been developed.

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In addition to its financial impact on health-care economics, aging in the Western societies is anticipated to have a more generalized and severely deleterious impact on Western economies, as an increasing percentage of retired elderly severely strain basic social safety net and entitlement programs such as Medicare and Social Security, deteriorate tax and revenue margins, and stretch virtually every societal resource (McKinsey Global Institute, 2008). In this context, scientific work on the biology of aging, particularly if it might reduce or substantially delay penetration by the diseases of aging into an aging population and extend “healthspan” (as distinct from lifespan), appears vitally relevant, if not badly needed. Despite these considerations, the funding of research into all aspects of aging and age-related disease garners only 11% of the $31 billion NIH budget (Freudenheim 2010), and research into CR, our only well-replicated lifestyle intervention to slow aging and reduce diseases of aging, garners less than 1/100th of 1% of all biomedical research monies (Guarente, 2003).

Historical and basic evolutionary perspectives on aging Aging appears somehow woven into the very fabric of life itself; a still controversial question is whether this is accidental (in a sense, evolution did not worry much about aging, as postreproductive deterioration in a complex biological system is inevitable) or whether aging is selected (as nearly immortal organisms would destroy their environment and thus render themselves extinct). These may not be mutually exclusive perspectives. Aging is difficult to define and has no single pathognomonic biomarker, but to paraphrase a famous quote about obscenity, “You’ll know it when you see it.” Aging can be defined operationally as a progressive and time-dependent “loss of fitness” that begins to manifest itself after the organism attains its maximum reproductive competence (Vijg, 2009) but aging could also be seen as simply the change of the organism over time (Bowen and Atwood, 2004). Although this seems to conflate development with aging, it has other theoretical advantages (see discussion of endocrine dyscrasia). Aging consists of a composite of characteristic and often readily recognizable phenotypic changes and can be defined statistically as a point at which normal or expectable development shows an increasing probability of death from all-cause mortality (excepting traumatic injury, starvation, poisoning, or other accidental death) with increasing chronological age of the organism. Intrinsic to aging is that its characteristic phenotypic changes are progressive and affect virtually every aspect of physiology and every organ of the body, from the skin, to cardiac and muscle tissues, to the brain. Ontologically, aging may reflect “entropy’s revenge,” as fundamental aspects of life organization become increasingly disorganized,

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The Aging Brain in Neurology

presumably due to a complex composite of processes (Hayflick, 2007). Modern biological thought holds it axiomatic that purposeful genetic programs drive all biological processes occurring from the beginning of life to reproductive maturity. However, after reproductive competence is attained, current thinking is still divided on the question of whether aging is a continuation of some collection of genetic programs or whether it is the result of the accumulation of random, irreparable losses in cellular organization. Again, these may not be mutually exclusive. References to aging abound in the earliest human cultures’ writings and records, suggesting that humans have been keenly aware of aging for millennia. The Bible refers to aging and death as “the wages of sin,” at best, a colorful metaphor and, of course, totally scientifically inadequate. However, a modern biology of aging suggests that the metaphor of aging as a “wage” is both appropriate and heuristic: aging may readily reflect the “wages” of growth, metabolism, and reproduction (excess junk proteins, OS, glycation of proteins, and damage to both mitochondrial and nuclear DNA) and also to the “wages” of organism defense and repair (also known as inflammation). Additionally, one must accept evolutionary principles as fundamental here and grounding any discussion of biological phenomenon, suggesting that aging must, in a direct sense, reflect a relative absence of selection against aging itself. However, what this might mean is not clear. Initial evolutionary theories of aging hypothesized that aging was “programmed” to limit the population size (immortal organisms would destroy their environment and render themselves quickly extinct) and/or to accelerate an adaptive turnover of generations, thereby possibly enhancing adaptation to shifting environments. However, this argument has modest evidence for it, at best, as senescence typically contributes minimally to mortality in the wild (Kirkwood and Austad, 2000). Instead, mortality in wild populations (as opposed to that seen in protected populations) is mostly due to extrinsic factors, such as infection, predation, and starvation, and occurs mainly in younger animals (Charlesworth, 1994). As a general rule, many, if not most, wild animals simply do not live long enough to grow old, again due to these extrinsic factors and not to aging. In this sense, natural selection has a limited opportunity to exert any direct influence over the processes of aging. Even in species in which aging and senescence do make some contribution to mortality in the wild (for example, in larger mammals and some birds), any hypothetical “aging gene” would be clearly deleterious; thus, it is highly unlikely that it would be selected (Kirkwood and Austad, 2000). Indeed, the relative rarity of aged animals in the wild is an important clue about how fundamental evolutionary processes relate to aging. With extrinsic factors being the primary causes of mortality, there is invariably a progressive weakening in the force of selection with increasing age (Kirkwood and Austad, 2000). By the time an animal

in the wild reaches an age at which the percentage of a given population surviving has declined to very low levels, the force of selection is likely far too weakened (if not almost nonexistent, given the low probability of reproductive success in an aged animal) to effectively weed out the accumulation of genes with “late-acting” deleterious (in other words, pro-aging) effects. This constitutes a “selection gap” that allows any alleles with late deleterious (proaging) effects to accumulate over many generations, with little or no intrinsic “countermechanism” (referred to as the mutation accumulation theory of aging). A prediction emerging from this theory is that because the negative alleles are basically unselected mutations, there might be considerable heterogeneity in their distribution within a population of individuals. There is some evidence both for and against this (Kirkwood and Austad, 2000). A substantial modification of this basic idea is found in the notion of aging as “antagonistic pleiotropy” (Williams, 1957), that evolution would favor genes that have good effects early in development (for example, genes promoting growth and fecundity) even if these genes had clearly bad effects at later stages of life. A critical and heuristic modification of this basic idea has been provided by Bowen and Atwood (2004), who suggest that alterations in the hypothalamic–pituitary–gonadal (HPG) axis, characterized by increasing gonadotropins and declining sex steroids create aging and by implication its diseases, a process which is “paradoxically” under the control of the very same hormonal systems that regulate growth and reproduction (see Section “Endocrine Dyscrasia”). In this sense, a small but reproductively significant benefit early in life derived from particular genes or alleles would easily outweigh (in terms of selection effect) later deleterious effects, even if those later effects guaranteed eventual senescence and death, especially if those genes promote growth and reproduction. Aging is thus not the “wages of sin” but the wages of growth, reproduction, and metabolism. Of course, this suggests that aging expresses intrinsic trade-offs, a theme also echoed in the widely quoted “disposable soma” theory of aging (Kirkwood, 1977) which suggests a balance of allocation of metabolic resources between somatic maintenance and reproduction. Effective maintenance of the organism is required only for as long as it might typically survive in the wild. For example, because roughly 90% of wild mice die in their first year of life, biological programming for metabolically expensive body maintenance programs beyond this age benefits only 10% of the total population, at most (Phelan and Austad, 1989). Given that a primary cause for early mortality in wild mice is excessive cold (Berry and Bronson, 1992), the disposable soma theory suggests that mice would not benefit from developing body maintenance and repair programs that would slow aging nearly as much as investing metabolic resources into thermogenesis and thermoregulatory mechanisms.

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

Thus, longevity may be determined in large part by the level of “extrinsic” mortality in the natural environmental niche (Kirkwood and Austad, 2000). If this level is high (life expectancy thus is quite short), there is little chance that the force of selection would create a high level of protracted and successful somatic maintenance; the more critical issue is making sure that organisms either reproduce quickly before extrinsic mortality takes its toll or have high fecundity and reproduction rates to ensure that early mortality for many members of a species does not eliminate reproduction for all members of a species (rendering them extinct). On the other hand, if “extrinsic” mortality is relatively low over long periods of time, selection effects might well direct greater resources toward building and maintaining a more durable organism, by modulating genes that might otherwise contribute to rapid aging. If this set of assumptions is correct, one would predict that, in organisms in relatively safe environments (those with low extrinsic mortality), aging will evolve to be more retarded, while it would be predicted to be more rapid in hazardous environments (slowed aging in these environments would make little difference to procreative success and species survival)—and these predictions are generally well supported (Kirkwood and Austad, 2000). Additionally, evolutionary developments that reduce extrinsic mortality (for example, wings or other adaptations to reduce vulnerability to predation, highly protective armor (such as shells), or large brains (enabling transition from prey species to top predator status) are linked to increased longevity (as seen in birds, turtles, and humans), although mechanisms for this increased longevity are still debated and remain to be conclusively outlined (see Bowen and Atwood, 2004). However, disposable soma theory has been criticized (Blagosklonny, 2010b) as failing to account for many aspects of aging, most particularly the greater longevity of women and the role of specific genetic pathways (such as mammalian target of rapamycin (mTOR),–see later sections on mTOR) that may heavily modulate aging. Aging is increasingly thought to be not preprogrammed, but more likely the result of a relative absence of selection for “perfect” maintenance of the organism, past the period of reproductive competence. Another way of putting this is that aging is simply the “fading out of adaptation,” after achieving the age of reproductive success and moving into the postreproductive age (Rose, 2009). In other words, there is no basis for evolution to have selected against aging and for much better body maintenance, as these issues would escape selection, unless there was a specific selection pressure toward this. An example of a basic selection pressure that could reduce aging significantly might be progressively delayed reproduction (procreating at slightly later and later ages), which has been shown in animal models to result in significant enhancement of longevity, in complete concert with basic evolutionary principles

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(Teotônio et al., 2009). In animal models of aging, this is referred to as “experimental evolution” (Bennett, 2003). Intriguingly, experimental work with delayed reproduction has successfully developed longer lived species (for example, long-lived Drosophila, or fruit flies), but with the cost of depression of early life fecundity, suggesting again intrinsic trade-offs between slowed aging and growth and reproduction (Sgrò and Partridge, 1999). However, there is expert opinion (Johnson, Sinclair, and Guarente, 1999) that there could well be selection to slow the pace of aging, as such organisms could potentially have a more protracted period of reproductive fitness, conferring an adaptive advantage. Slower aging also appears intrinsically related to later age of reproductive fitness (Bowen and Atwood, 2004). Additionally, in hominid lines, evolutionary perspectives indicate that the existence of tribal elders, with greater accumulated wisdom and experience, would have improved evolutionary fitness for their tribal groups, despite being largely past a reproductive age, suggesting another potential selection mechanism driving “antiaging” (“group fitness” or “inclusive fitness” in highly social species such as hominids; Carey, 2003). Basic cellular and molecular theories of aging probably come in two fundamental forms: (1) aging as a genetically modulated process (under the control of discrete genes and molecular pathways—but not “preprogrammed”); (2) aging as an “error” or stochastic or “wear-and-tear” process (the best known of these being the oxidative damage/ stress theory). Neither “pure” type of theory is fully able to explain all aspects of aging, suggesting that aging is “quasiprogrammed” (Blagosklonny, 2009) and perhaps related to both growth programs (which are continued past the period of peak reproductive competence, as an example of antagonistic pleiotropy) and stochastic cellular damage/wear and tear aspects (such as emerging from disinhibited inflammation). CR, as the only conserved antiaging physiology yet discovered (see the later sections on CR and CR mimetics) may impact both of these (reducing growth programs and also attenuating factors such as OS and inflammation that may drive stochastic damage). Again, one has to assume that these issues do not contradict or replace a basic evolutionary perspective (in which aging reflects a relative absence of selection against wear and tear, stochastic damage, or failure of inhibition of many genes/pathways that might accelerate or drive agerelated decline). Kirkwood and Austad (2000) summarize these considerations for an evolutionary genetics of aging as three basic predictions (p. 236). 1 Specific genes selected to promote ageing are unlikely to exist. 2 Aging is not programmed but results largely from accumulation of somatic damage, owing to limited investments in maintenance and repair. Longevity is thus regulated by genes controlling levels of activities such as DNA repair and antioxidant defense.

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The Aging Brain in Neurology

3 In addition, there may be adverse gene actions at older ages arising either from purely deleterious genes that escape the force of natural selection or from pleiotropic genes that trade benefit at an early age against harm at older ages. Thus, aging could reflect the species-variable interactions and intrinsic “tug-of-war” between deleterious and degrading changes (and the declining influence of selection/adaptation in a postreproductive animal), with many of these pro-aging factors intrinsic to growth, reproduction, metabolism, inflammation, and other aspects of physiology (“antagonistic pleiotropy”), versus various (and presumably selected) counterbalanced repair, protection, and maintenance programs. Of course, if aging itself potentially deteriorates those counterbalanced cellular repair and maintenance programs, this suggests that aging is a losing tugof-war between forces of cellular protection and forces of cellular degradation, and that (as the tug-of-war metaphor suggests), as one side loses, it may lose at an accelerating rate. There is indeed some evidence, although it is hardly conclusive, that aging may actually accelerate (Guarente, 2003). Few elderly would find this possibility surprising. Cellular and molecular aspects of aging that might map onto these various considerations about the evolutionary basis for aging suggest a dizzying composite of phenotypic changes, including changes in mitochondrial, nuclear, and ribosomal DNA; subsequent genomic and chromatin changes and instability; increasing levels of OS (including pleiotropic and differential expression of OS on membranes and lipids, proteins, and nucleic acids, particularly mitochondrial); increasing systemic inflammation (“inflammaging”), paradoxically concomitant with declining immunocompetence; increasing glycation of proteins (and increasing amounts of advanced glycation end products (AGEs), which potentiate inflammation); increasing cellular senescence and loss of telomeres; dysregulation of apoptosis (programmed cell death is over- or under-recruited); and increasing junk proteins, combined with impaired protein turnover and declining removal of damaged (and glycated) proteins (declining “autophagy”). Last but certainly not least, even our stem cells age and reach senescence, preventing rejuvenation of many organ systems and structures. A clear sense of what are leading versus trailing edges in this process (in other words, clearly distinguished “causes” vs “effects”) are still unclear and biology is clearly a place where causes become effects and effects become causes. However, there is evidence for each of these various aspects of cellular change as direct contributors to all the manifestations of aging, including evidence linking virtually all of these processes (“phenotypes of aging”) to all the diseases of aging. Like many aspects of biological regulation, and indeed life itself, recursive interactions among these various processes may be essential; in other words, the many mechanisms of aging may be highly interactive, suggesting that there cannot be a single pathway into aging (see the discussion of the network of molecular pathways in CR effects), and that instead aging probably reflects a

complex and recursive network of (still incompletely understood) changes. This is consistent with the severe limitations of all “linear causality” models in biological systems, where causality is intrinsically more recursive, circular, and multifactorial (Freeman, 2000). As critical examples of this principle of reciprocal interaction, inflammation and OS are increasingly linked and seen as mutually reinforcing (Jesmin et al., 2010), OS is thought to drive DNA damage (both mitochondrial and nuclear), glycation promotes inflammation, and declining removal of junk (including glycated) proteins may be related to increased OS (Kurz, Terman, and Brunk, 2007) and mitochondrial decline, while senescence promotes inflammation, as does endocrine decline, as does increasing junk protein while chronic inflammation and OS contribute to senescence. All of these phenotypes may thus be interlinked aspects of declining biological organization and increasing entropy, as basic phenotypes of aging with positive feedback loops between these phenotypes; new interactions seem to be emerging regularly in research into aging and its diseases. Such interaction may explain how processes involved in a modest departure from an ideal youthful physiology gives rise to a process that, over time, deterministically kills the organism without exception. Aging in other words may emerge from a deadly ‘recursion matrix’ of these interactive phenotypes. This is consistent with overwhelming evidence that nothing in biology truly emerges from single factors, but from the concerted crosstalk and feedback between multiple partners. At the same time, several molecular pathways (such as mTOR, and many molecular and cell-signaling pathways with which mTOR interacts) may be particularly critical to aging and the modulation of age-related change. At the end of this chapter, we also summarize evidence that lifestyle factors modulate risk for diseases of aging (and perhaps aging itself), possibly accelerating or retarding it at least to some degree. We also examine the difference between the current Western technological environment and our original evolutionary environment, in terms of the impact that multiple lifestyle variables may have on the cellular mechanisms and the physiology of aging and the diseases of aging.

Basic molecular and cellular perspectives on aging: phenotypes of aging Although popular conceptions of the molecular basis of aging center around reactive oxygen species (ROS), hard evidence for this as the prime driver of aging is actually very mixed, and increasing evidence argues against it, as least as the central process driving aging. However, OS may interact with many of the other phenotypes of aging, particularly inflammation, as well as disinhibited growth factors/programs, suggesting that a softer form of OS theory (that ROS may contribute to aging) may still be valid.

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

Oxidative stress and associated mitochondrial perspectives A basic assumption about aging is that it must have a fundamental cellular basis, and cellular and molecular perspectives on aging have dominated the scientific landscape of aging research and theory. The oldest and most widely quoted molecular theory about aging was provided by Harman, 1956, who postulated that oxidizing “free radicals” damaged and degraded cells over time, causing aging. Harman’s early work on radiation with experimental animals demonstrated that aging had important similarities to the aftereffects of massive exposure to radiation, particularly cancer, inflammation, apoptosis, and other tissue changes not dissimilar to classic phenotypes of aging in older animals and humans. Harman’s hypothesis emerged from his familiarity with work on radiation exposure and early findings that large doses of ionizing radiation generated enormous quantities of free radicals. Harman subsequently published what may be the first dietary antioxidant study (1957), studying the effects of dietary 2-mercaptoethylamine, the most potent radioprotective compound known at the time, and demonstrating a modest 20% increase in average lifespan, although the mechanism of action of this compound is still debated. In 1972, Harman published an important extension to the free radical theory, suggesting that the mitochondria were the primary source for OS, as well as the primary site for oxidative damage, and that the mitochondria therefore represented a kind of “biological clock” that he argued determined maximum lifespan. He concluded that his inability to extend maximum lifespan with dietary supplements must derive from the fact that most exogenous antioxidants do not get into the mitochondria. He hypothesized that OS in the mitochondria (vs its endogenous antioxidant defenses) set an outer limit on a given species longevity. Some work has suggested that OS is mostly generated by mitochondrial complex 1 (Mozaffari et al., 2011). This led to a second “vicious circle hypothesis” about OS in relation to the mitochondria: that OS caused deterioration in mitochondrial antioxidant defense systems and mitochondrial function in general, leading to more OS and, in turn, driving more damage and increasing age-related deterioration. Although this is clearly the most widely quoted and accepted molecular theory of aging, particularly in the popular media and product advertising, the most comprehensive and wide-ranging review of this theory to date (Van Remmen, Lustgarten, and Muller, 2011) concludes that hard support for it is actually quite mixed. Therefore, the authors conclude that this theory remains unproven (but also not clearly falsified either), at least in the original “hard” form of the hypothesis (that OS in the mitochondria was the driver of aging. It has also been known for some time that OS markers increase with aging, although debate still rages about how much of this is cause or effect of aging (Sohal and Weindruch, 1996). There are many data points both for and against the oxidative-stress-in-the-mitochondria theory

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of aging, which might readily lead even the advanced student of aging to a sense of confusion and frustration. On the other hand, a softer form of the hypothesis—that OS in the mitochondria may significantly contribute to aging—may be better supported, particularly in view of the interaction between ROS and other molecular pathways that clearly have been shown to contribute to aging, and to the diseases of aging, such as inflammatory signaling, and growth signaling (see Blagosklonny, 2008) (see Section “Mammalian target of rapamycin”). Much experimental work to test the basic hypothesis has focused on genetic manipulations of antioxidant enzyme systems in short-lived species. Support for the hypothesis can be drawn from the results of knockouts of superoxide dismutase (SOD) 2 (Perez et al., 2009) and glutathione peroxidase 4 (Ran et al., 2007), both of which show lethal effects. Other primary data points in favor of the hypothesis emerge from work correlating species longevity with lowered rates of mitochondrial DNA mutation (Sanz et al., 2006) and with other experimental manipulations of OS and mitochondrial function (Hagen et al., 1999). Additionally, longer lived rodents (white-footed mouse (Peromyscus leucopus)) exhibit lower levels of ROS (superoxide and hydrogen peroxide), compared to the shorter lived house mouse (Mus musculus), and show higher cellular concentrations of some antioxidant enzymes (catalase and glutathione peroxidase) and lowered markers for protein oxidative damage (Sohal et al., 1993). Schriner et al. (2005) generated transgenic mice that overexpressed human catalase localized to peroxisome, nucleus, or mitochondria (MCAT). Median and maximum lifespans were maximally increased (averages of 5 months and 5.5 months, respectively) in the MCAT group. Cardiac pathology and cataract development were both delayed, markers for oxidative damage were reduced, peroxide production was attenuated, and mitochondrial DNA deletions (perhaps the most serious form of mitochondrial damage) were also reduced. These results offer strong support for the free radical theory of aging and also argue that the mitochondria are indeed the most biologically relevant source of these free radicals. In general, there is also broad, although occasionally inconsistent, correlation among OS in the mitochondria, rates of mitochondrial DNA damage, and longevity (Sanz et al., 2006;Barja and Herrero, 2000). However, there is equally compelling data against this classic hypothesis. The naked mole rat (NMR) demonstrates an unusual phenotype of significantly delayed aging and the longest lifespan of any rodent (about 30 years), five times the expected lifespan based on body size, and exceptional cancer resistance, despite elevated markers for OS and short telomeres (Buffenstein et al., 2011). Additionally, the lack of a significant lifespan decrease or accelerated aging phenotypes in SOD 2−/+ mice (missing one copy of the gene), despite evidence for increased OS (Mansouri et al., 2006), and increased mitochondrial DNA damage (Osterod et al., 2001) are data points against this classic theory. Further complicating the picture is the evidence that although oxidation

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The Aging Brain in Neurology

of mitochondrial DNA is elevated in SOD 2−/+ mice, mitochondrial DNA deletions (thought to reflect the most serious form of mitochondrial DNA damage) are not increased (Lin et al., 2001). This suggests that this particular partial knockout model may not adequately probe the question of the relationship between mitochondrial OS and longevity. Other animal models demonstrate that increased expression of the major antioxidant enzymes involved in protection from mitochondrial OS, including upregulation of the two isoforms of SOD (MnSOD and Cu/ZnSOD) and catalase, individually or in various combinations, does not extend maximum lifespan in mouse models (see Van Remmen, Lustgarten, and Muller, 2011 for detailed review). Mice with genetically reduced individual components of the antioxidant defense system have also been extensively studied, including knockouts of two isoforms of SOD (MnSOD and Cu/ZnSOD), glutathione peroxidases (Gpx-1, Gpx-2, and Gpx-4), catalase, thioredoxin, and peroxiredoxin. Complete ablation of individual components of antioxidant defense can often be embryonically lethal (specifically, homozygous knockout of thioredoxin 2, glutathione peroxidase 4, or MnSOD), but simply a loss of one allele (generating about 50% loss in activity) in heterozygous knockout mouse models (SOD1+/−, SOD2+/−, and Gpx4+/−) does not result in reduced lifespan (Van Remmen, Lustgarten, and Muller, 2011). Lastly, recent work shows that combining a heterozygous knockout of MnSOD and homozygous glutathione peroxidase 1 knockout clearly results in increased OS, indexed through several classic markers (both protein carbonyls and oxidized nucleic acids), but not in a decrease in lifespan (Zhang et al., 2009). At face value, such negative results might suggest that the “hard” form of the mitochondrial OS hypothesis (OS is the primary driver of aging and mortality) is not well supported. However, some very recent work argues that antioxidant defense in the mitochondria involves factors beyond these classic antioxidant enzyme systems and requires activation of one of the seven sirtuins (SIRT3), which promotes acetylation of antioxidant enzymes, significantly enhancing their effectiveness. Hafner et al. (2010) show that SIRT3-/- knockout mice show accelerated aging phenotypes, including classical mitochondrial swelling. Although earlier work on OS and CR emphasized the role of SIRT1 and its homologs (Sinclair, 2005), recent work has demonstrated that SIRT3 appears essential for CRmediated reduction in OS (Qiu et al., 2010), as homonymous knockout of SIRT3 prevents the expected reduction of OS during CR. SIRT3 reduces OS by increasing activity of SOD2 through deacetylation (Tao et al., 2010; Qiu et al., 2010). In addition to regulating SOD2, SIRT3 reduces OS by modulating the activity of isocitrate dehydrogenase 2 (IDH2), a mitochondrial enzyme generating nicotinamide adenine dinucleotide phosphate (part of antioxidant defense in the MITO; Someya et al., 2010). Thus, there may be many players in the defense against OS in the MITO,

arguing that a comprehensive test of the OS hypothesis of aging may be challenging to design and that single or even combined manipulations of antioxidant enzyme systems may be insufficient to fully probe Harman’s original and provocative idea. In general, however, there is increasing skepticism that the OS emerging from mitochondrial respiration is the driver of aging or any version of a sole “prime mover” in aging organisms. Additionally, many of the data points supporting a classic OS hypothesis can potentially be reinterpreted in light of evidence that ROS are a secondary driver for mTOR (Blagosklonny, 2008) (see Section “Mammalian target of rapamycin”); antioxidant interventions may therefore reduce overall drive or activation of mTOR (which may slow aging). Additionally, cellular senescence, another fundamental phenotype of aging, may be hinged to DNA damage detection (Chen et al., 2007), damage caused by ROS, suggesting that ROS concepts have to be seen not as operating in etiological isolation, but more as interactive with other phenotypes of aging. A major practical challenge to test the basic hypotheses of OS perspectives on aging and also explore therapeutic implications of this idea has been the question of how to deliver antioxidants into the mitochondria (as the primary cellular nexus for OS vs antioxidant protection). Most organic compounds conventionally regarded as antioxidants (particularly the so-called “antioxidant” vitamins A, E, and C) do not get into the mitochondria in meaningful quantities, nor do others common in the diet, such as many polyphenols. Work by Skulachev et al. (2009) however, suggests that one can design molecules that do materially affect OS (SkQs, in this case, comprising plastoquinone, an antioxidant moiety, and a penetrating cation and a decane/pentane link). In vitro work indeed confirms that SkQ1 accumulates almost exclusively in mitochondria. In several species of varying phylogenetic complexity (the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, Drosophila, and mice), SkQ1 prolonged lifespan, especially at the early and middle stages of aging. In mammals, SkQs inhibited development of age-related diseases and involutional markers (cataracts, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, hypothermia, torpor, peroxidation of lipids and proteins). SkQ1 manifested “a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia.” With eye drops containing 250 nM SkQ1, vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy. Moreover, SkQ1 pretreatment of rats significantly decreased hydrogen peroxide or ischemia-induced arrhythmia of the heart, reducing the damaged area in myocardial infarction or stroke and preventing the death of animals from kidney ischemia. In p53 (−/−) knockout mice, 5 nmol/kg/day of SkQ1 decreased ROS levels in spleen and inhibited lymphomas. Thus, such “designer antioxidants” show promise

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

in slowing aging and in both preventing and potentially treating diseases of aging. Intriguingly, of the many common dietary supplements regarded as “antioxidant” (see Section “Polyphenols”), only melatonin has evidence for consistent mitochondrial localization (Srinivasan et al., 2011), with some evidence suggesting that it may function as a significant mitochondrial protectant and regulator of MITO bioenergetic function. Intriguingly, and underlining the intrinsic connections among the many biological phenotypes of aging, in recent years, the OS theory of aging has forged increasing connections to disinhibited inflammation and inflammatory signaling, with many positive feedback loops between the two processes, such that neatly separating these two processes is difficult (see Section “Inflammation”). Recent work on gene interactions (Jesmin et al., 2010) suggests that OS is perhaps the critical common denominator underpinning the intimate associations between obesity, type II diabetes, and hypertension, and that obesity itself may increase OS (Fernàndez-Sànchez et al., 2011). Evidence also indicates that cancers and AD are hinged to OS, suggesting that the long-term reduction of OS in aging may have significant health benefits and may offer protection against many diseases of aging, even if the hard form of the OS hypothesis (that ROS are the driver of aging) is unsupported. Further evidence for critical interactions among these various phenotypes of aging is suggested in the landmark study by Sahin et al. (2011) which shows that telomere dysfunction causes repression of mitochondrial biogenesis regulatory enzymes (PGC-1α/PGC-1β) through activation of p53, leading to increased OS and impaired mitochondrial biogenesis and bioenergetic function. Suggesting another dimension to these dynamic relationships among phenotypes of aging, recent work has suggested that telomere loss may be directly related to lifetime inflammation and OS burden, and that rate of telomere loss in leukocytes predicts cardiovascular mortality in men (Epel et al., 2009).

Inflammation Increasing evidence argues that aging centrally involves changes in both innate and adaptive immunity (in the direction of declining adaptive immunity and compensatory upregulation of innate immunity), combined with increasing systemic inflammation, recently dubbed “inflammaging” (Franceschi et al., 2007), even in the absence of obvious pathological consequences or lesions. While traditional perspectives on inflammation emphasize acute and local inflammatory processes and the classic cardinal signs of localized inflammation (rubor et tumor cum calore et dolore—redness and swelling with heat and pain) involving many “acute phase” proteins, recent work on “inflammaging” emphasizes a different side of inflammation that is more systemic, chronic, and often (at least initially, if not over the long term) asymptomatic.

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Of course, inflammation is also a highly adaptive and selected process, central to both organism defense and tissue repair; without it, we could not survive long at all, and it operates at virtually all levels of biological organization, from the small molecular level all the way to the level of behavioral organization (see Chapter 21, “Depression in the Elderly: Interactions with Aging, Stress, Chronic Pain, Inflammation, and Neurodegenerative Disorders”). Yet it is centrally implicated in many, if not virtually all, of the major diseases of aging, particularly atherosclerosis (see Section “Diseases of Aging with Relevance to Neurology”), AD, PD, most cancers, arthritis, and type II diabetes (see Finch, 2011 for a detailed review). This profoundly Janus-faced nature of inflammation may be one of the most striking examples of “antagonistic pleiotropy,” suggesting that aging and its acceleration may be at least partially one of the “wages” of successful organism defense and tissue repair. From the perspective of aging and its diseases, the immune system may be simultaneously a best friend and a worst enemy. Blood levels of proinflammatory cytokines (such as C-reactive protein and interleukin-6) are now widely understood to be primary risk factors for vascular disease and predictors of mortality/morbidity in cardiovascular events. Underlining intimate relationships between proinflammatory and anti-inflammatory signaling, the adaptive up-regulation of IL-6 due to exercise appears critical to the anti-inflammatory production of IL-10 (Walsh et al., 2011) and IL-1ra while inhibiting production of a cardinal proinflammatory cytokine, TNF- . IL-6 was suggested to be a “myokine,” defined as a cytokine that is produced and released by contracting skeletal muscle fibers; it is responsible for the anti-inflammatory effects of exercise, part of increasing evidence that systemic inflammatory signaling and “tone” are highly plastic and perhaps highly responsive to diet and lifestyle issues (see the last sections on lifestyle and dietary factors.). Indeed, many if not most important lifestyle variables appear to modulate systemic inflammatory tone directly, including classic dietary factors such as fiber consumption (Galland, 2010), omega-3 intake (Mittal et al., 2010), and polyphenol intake (Zhou et al., 2011); sleep quality versus sleep deprivation (Motivala, 2011); aerobic exercise (Walsh et al., 2011); and even social stress (social isolation vs social comfort; Slavich et al., 2010). This suggests that Western lifestyles (sedentary and with typical Western diet patterns) may be, in toto, seriously proinflammatory and may significantly increase the risk of the diseases of aging most related to chronic and systemic inflammation (many cancers, cardiovascular disease, AD and PD, diabetes, and arthritis).

Glycation, advanced glycation end products, and AGE receptors Glycation of proteins is a fundamental mechanism in aging and in the deterioration of both organ structure

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and function, and is probably neglected in many treatments of aging relative to its importance (Semba et al., 2010; Bengmark, 2007). Glycation appears implicated in almost every disease of aging, and not simply diabetes, with glycation as a primary contributing cause and not simply as a secondary effect. Additionally, AGEs interact with receptors (rAGE) to upregulate inflammation, another primary factor in the biology of aging (see Section “Inflammation”), potentially contributing to another critical dimension of aging. The creation of AGEs involves bonding two or more proteins, a process known as “cross-linking,” typically by the creation of sugar–protein bonds. While some AGEs are relatively short lived and fluctuate in response to diet and metabolic state, other AGEs are long lived and virtually impossible for the body to break down. The creation and accumulation of these AGEs, particularly in essential tissues such as coronary arteries and the brain, can have serious effects on function and constitute a major risk factor for a disease of aging in those organs (Semba et al., 2010). For example, areas of arterial glycation are much more likely to eventually become regions of atherosclerosis and plaque accumulation, while glycation of CNS tissue is associated with increasing inflammation and the classic plaque and tangle pathology of AD (Srikanth et al., 2011; Lue et al., 2010), with AGEs a major facilitating cofactor in the creation of both amyloid oligomers and tangles (Gella and Durany, 2009). On the other hand, rAGE activation may also increase autophagy as a protective response, and may reduce apoptosis after oxidative injury (Kang et al., 2011), suggesting yet another layer of interactions between these phenotypes of aging (see Sections “Autophagy” and “Apoptosis”). Glycation of tendons and other connective tissue may form important foundations for loss of flexibility in aging. Obviously, diabetes provides a classic model for the acceleration of glycation and generates a more rapid accumulation of AGEs, with hemoglobin A1C a direct measure of glycation of hemoglobin molecules (an example of a relatively short-lived form of glycation). rAGE receptors are also implicated in AD as a channel for amyloid oligomers to enter cells where the oligomers potentially wreak havoc with multiple cellular compartments, particularly mitochondria and lysosomes (LeFerla, 2008). Glycation can be inhibited by AGE breakers, which includes the amino acid l-carnosine, and also blocked by multiple polyphenols particularly ellagic acid. Green tea extract (Babu et al., 2008), curcumin (Pari and Murugan, 2007), and many flavonoids (Urios et al., 2007) have shown at least some antiglycation functionality, along with alpha lipoic acid (Thirunavukkarasu et al., 2005). This suggests that a diet high in polyphenols and relatively low in free sugars might prevent or reduce long-term glycation of tissues (although this is never been proven in a human clinical assay to our knowledge).

Autophagy Autophagy is an essential catabolic process through which existing proteins and other cellular components are degraded and recycled, supporting the adaptive function of removal and potential repair of damaged, dysfunctional, or even toxic proteins and cellular organelles. This function is dependent on “autophagosomes” (an intracytoplasmic vacuole containing elements of a cell’s own cytoplasm), typically fused with lysosomes to facilitate the digestion of target proteins by lysosomal proteases. Autophagy, like glycation, is perhaps one of the more neglected critical storylines in aging in many popular treatments of the subject, and its importance in aging appears central. Indeed, it appears that aging can be slowed significantly by simply improving this critical process—or, alternatively, perhaps aging itself causes degradation of this process (Madeo et al., 2010). Antiaging effects from improved autophagy are robust (Petrovski and Das, 2010) and include lifespan extension. Severe dysfunction in the various autophagy pathways (typically caused by mutations) can correspondingly generate severe progeroid pathology, affecting multiple organ systems, including muscle, the liver, the immune system, and the brain. Defects in autophagy have shown accelerated aging phenotypes in classic yeast, worm, and fruit fly model organisms (primary models for aging in terms of unraveling its basic cellular and molecular mechanisms). In mammals, autophagy appears essential to life and survival, as genetic knock-out of proteins required for the process is lethal, suggesting a basic role in homeostasis and development. More limited knock-out of genes involved in autophagy in mice results in accelerated aging phenotypes. While the precise underlying mechanisms driving autophagy-related pathology remain obscure, the study of Finkel and colleagues (Wu et al., 2009) suggests that mitochondrial dysfunction is likely a critical factor. Underscoring important reciprocal relationships among the many phenotypes of aging, recent work suggests that disruption of autophagy may manifest itself physiologically in terms of mitochondrial dysfunction and increased OS (Wu et al., 2009). Growing evidence links declining autophagy to all the neurodegenerative disorders, with their characteristic protein aggregations (often ubiquitinated, suggesting that they are being tagged for removal), although pathological changes can result from excessive or disinhibited as well as deficient autophagy (Cherra and Chu, 2008). Experimental animals genetically defective in autophagy develop neurodegeneration accompanied by ubiquitinated protein aggregates, demonstrating that basic autophagy function is essential for long-term neuronal health. Additionally, both age- and disease-associated (with AD) reductions in the autophagy regulatory protein beclin 1 have been found in patient brain samples (Cherra and Chu, 2008), while treatments that promote autophagy

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

have been shown to reduce levels of pathological proteins in several in vivo and in vitro models of neurodegeneration. Rapamycin, lithium, and several polyphenols have been shown to enhance degradation and also possibly reduce synthesis of proteins that may contribute to toxic oligomer formation, as well as larger extracellular aggregates of toxic protein seen in several neurodegenerative diseases. Quercetin, several other polyphenols, and vitamin D all appear to increase autophagy, suggesting important but incompletely mapped roles for diet and lifestyle in modulating this critical aging-related process (Wang et al., 2010b; Wu et al., 2011). These considerations suggest that many neurodegenerative disorders (which are all primary proteinopathies) may have future effective treatments based at least in part on the improvement of autophagy function.

Apoptosis Apoptosis, originally thought to be a deleterious and primarily negative process, now is appreciated to have a critical role in adaptation and longevity. Apoptosis must balance regulation of the potential benefits of eliminating damaged cells against the pathogenic impact of more maladaptive forms of cell death (such as progressive cell loss in postmitotic tissues, a major mechanism driving atrophy in neurodegenerative disorders and contributing to endstage organ disease in postmitotic tissues.). Thus, a delicate balance must be struck, and dysfunction in the regulation of programmed cell death can mean that, on one hand, apoptosis potentially contributes to atrophy and a senescent cell phenotype, while, on the other, its failure potentially leads to neoplastic cell proliferation. Apoptosis is thus an important cellular defense for maintaining both genetic stability and physiological function. An intriguing question is whether centenarians may be more or less prone to apoptosis and whether longevity may slightly favor an excessive trimming of still possibly viable cells over allowing an increased percentage of potentially rogue cells to survive–or the reverse (Monti et al., 2000). Additional data points underscoring the importance of a finely tuned apoptosis equation include that cells that avoid apoptosis, particularly proliferating vascular smooth muscle cells, participate centrally in atherosclerosis. Cancer could be thought of as the paradigmatic failure of apoptosis, and several lines of evidence suggest that cellular senescence and apoptosis (both of which contribute to aging) are primary defenses against cancer (Chen et al., 2007). On the other hand, accelerated apoptosis in postmitotic tissues such as the brain clearly contributes to virtually all neurodegenerative disorders. This suggests that adaptive regulation of apoptosis and its tuning and modulation may be highly protective in relation to the diseases of aging and, conversely, that disregulated apoptosis may contribute to both aging and the diseases of aging. Just as future modulators of autophagy may be treatments for

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neurodegenerative diseases, similar prospects may apply for regulators of apoptosis, although promotion of cancers and perhaps obesity also would be potential concerns. However, promoting apoptosis in senescent cells could be highly desirable and might slow aging significantly (see discussion in later section on Cellular Senescence).

Sarcopenia Sarcopenia, the loss of both muscle mass and function, is a universal feature of aging that has a major impact on individual health and quality of life, predisposing people to falls and eventual frailty, also often neglected in treatments of aging and its phenotypes. Although the term sarcopenia was first coined in 1989, its etiology is still incompletely understood and its precise definition is still debated. It centrally includes losses in muscle fiber quantity and quality, alpha-motor neurons, protein synthesis, and several anabolic and sex hormones (Waters et al., 2010). Other factors may include altered basal metabolic rate, increased protein requirement, and chronic inflammation and OS. These changes lead to decreased overall physical functioning, increased frailty, falls risk, and, ultimately, the loss of independent living. Sarcopenia is a critical aging phenotype. All elderly show evidence of it, particularly after the seventh decade, with a roughly 40% decline in muscle mass by the age of 80 (Evans, 1995). Mechanisms leading to this are multifactorial and include mitochondrial dysfunction and decline, altered apoptotic and autophagic processes, and even altered trace metal homeostasis (Marzetti et al., 2009). Like virtually every other aspect of aging, CR mitigates this process in a variety of species studied, again via pleiotropic effects of CR, including mitochondrial biogenesis, reduction of OS, and improved apoptotic regulation and autophagic processing. To our knowledge, reduction of sarcopenia has not been demonstrated in humans with CR mimetics. Cellular senescence No discussion of aging would be complete and without at least a basic review of cellular senescence, first discovered by Hayflick in vitro (Hayflick, 1965). Evidence argues that cellular senescence probably evolved as a defense against cancer and as a response to DNA damage and genomic instability (Chen et al., 2007), and has to be seen as sitting, like apoptosis, as a critical adaptive checkpoint on all cell cycling. In this important sense, the cell cycle, apoptosis, senescence and carcinogenesis have to be all seen as intimately related biological processes. Although cellular senescence is popularly understood mechanistically as driven by a simple loss of telomeres, evidence argues that like all other phenotypes of aging, its true derivation is complex and highly multifactorial, and additionally, that loss of telomeres is not simply due to the total number of replication events, as originally assumed by

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Hayflick. Instead, evidence suggest many factors, particularly those related to chronic OS, chronic inflammation and even chronic emotional stress (perhaps as proxy for inflammation but perhaps reflecting other effects in addition to this) determine the rate of telomere loss, suggesting a critical role for lifestyle in protecting against loss of telomeres (Falus et al., 2010). Specifically, recent work has shown that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short telomere length in leukocytes (O’Donovan et. al., 2011). Emotional regulation may play an underappreciated role in protection of telomeres, and consistent with this, lifestyle interventions that reduce stress, such as mindfulness meditation, have even been shown to enhance both telomerase (Jacobs et al., 2011) and preserve telomeres (Epel et al., 2009). Additionally, recent work makes a principled distinction between cellular quiescence (cell cycle arrest) and cellular senescence (Blagosklonny, 2011), with the former reversible, and paradoxically, with activation of the progrowth mTOR pathways increasing the likelihood of senescence, while inhibition of TOR saves cells from this biological “dead-end” and shifts them into quiescence. Thus, cell signaling pathways involved in aging also have a critical role as well, suggesting that conjoined activation of DNA-damage sensing systems such as p53 and p21 (which orchestrate blocks on cell cycling) and growth pathways simultaneously helps to select senescence. Additionally, and perhaps critically important in many clinical situations, senescent cells develop a large cell morphology and become hypersecretory in a proinflammatory direction. This is part of the evidence that aging is a kind of a dysregulated “hyper-functional” state, driven in part by disinhibited growth signals (mTOR acting as a central integrator of those signals). As Blagosklonny states, “cellular functions are tissue-specific: contraction for smooth muscle cells, secretion of lipoproteins for hepatocytes, aggregation for platelets, oxidative burst for neutrophils, bone resorption for osteoclasts and so on. These hyperfunctions lead to age-related diseases, such as atherosclerosis, hypertension, macular degeneration, increasing the probability of organismal death” (Blagosklonny, 2011. p 95). Thus, as Blagosklonny notes, senescence reflects a biological version of cells responding simultaneously to “pressing the gas pedal” (growth drive) and “getting on the brakes” at the same time (cell cycle blocks driven by DNA-damage sensing systems). Additionally, senescence both promotes inflammation and is promoted by it, further underscoring recursive relationships between these phenotypes of aging, and offering further evidence of the Janus-faced nature of inflammation, as an example of antagonistic pleiotropy (Blagosklonny, 2011; Figure 1.1).That removing senescent cells slows aging in a progeroid mouse model demonstrates that senescence is not simply an aging phenotype

(an effect or component of aging), but a driver of aging itself (Baker et al., 2011). This is consistent with much other evidence that most if not all the phenotypes of aging reciprocally reinforce one another, consistent with a circular/ recursive causality model of biological causation.

Endocrine dyscrasia It has been only in the last 10 years or so (since the seminal paper of Bowen and Atwood, 2004) that evidence has accumulated for a primary role in aging for changes in the hormonal-reproductive (HPG) axis potentially characterized as an “endocrine dyscrasia”. Although many are aware of the more famous components of this dyscrasia (age-related declines in classic sex steroids with the decline in male testosterone more gradual but starting earlier than the steep menopausal decline of estrogen and progesterone in females), Bowen and Atwood have argued persuasively that the less appreciated upregulation of luteinizing hormone and follicle stimulating hormone from the pituitary and the associated increase in gonadotropin-releasing hormone (GnRH) from the hypothalamus to the pituitary (along with associated down regulation of inhibins and upregulation of activins—as peripheral modulators of HPG axis function) may play a central role in aging and its phenotypes. As Atwood and Bowen (2011) summarize, this theory is a clear extension of basic antagonistic pleiotropy concepts of aging: “hormones that regulate reproduction act in an antagonistic pleiotropic manner to control aging via cell cycle signaling—promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence. Since reproduction is the most important function of an organism from the perspective of the survival of the species, if reproductive-cell cycle signaling factors determine the rate of growth, determine the rate of development, determine the rate of reproduction, and determine the rate of senescence, then by definition they determine the rate of aging and thus lifespan.” (p.100). As support for the theory, HPG axis dysregulation may be a primary factor in AD, with elevation of luteinizing hormone and FSH, and decline of sex steroids as etiological, and as contributing to an exaggerated mitogenic signal that promotes beta-amyloid pathways, hyperphosphorylation of tau, synaptic retraction, and drives dysfunctional neurons into the cell cycle and from there into programmed cell death (Atwood et al., 2005; Casadesus et al., 2006). Challenges to this novel and heuristic theory of aging include relatively its undeveloped linkages to classic mTOR and insulin signaling pathways, as well as links to other classic aging phenotypes, such as mitochondrial decline, OS, and “inflammaging”. However, recent updates (Atwood and Bowen, 2011) summarize data linking evidence for endocrine dyscrasia with multiple diseases of aging, suggesting that an endocrine dyscrasia

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

(a)

(b)

UPS dysfunction

Normal DA content (%)

Unknown factors

Compensatory mechanisms

Stochastic interaction between multiple factors

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Normal aging

DA metabolism

DA neuron dysfunction and death Oxidative and nitrative stress

Inflammation PD (accelerated DA loss) Mitochondrial damage Threshold for PD

Time (yrs)

Accelerants • Genetic predispositions • Environmental toxins • Cellular predispositions • Prenatal infections • Unknown factors

Figure 1.1 Cell cycle factors related to aging based on the stochastic acceleration hypothesis of Collier, Kanaan & Kordower (2011). A revised

hypothesis of the relationship between aging and Parkinson’s disease (PD) as they affect the biology of midbrain dopamine (DA) neurons. The hypothesis incorporates evidence that supports the involvement of common cellular mechanisms in dopamine neuron dysfunction in ageing and degeneration in Parkinson’s disease. (a) The effects of these altered cellular mechanisms as they accumulate during normal ageing result in Parkinsonian dopamine neuron dysfunction, either very late in life or not at all (shown by the light gray line). However, when these same cellular mechanisms are accelerated by specific, individually determined factors, Parkinsonism emerges earlier in the lifespan (shown by the dark gray line). (b) The hypothesis contends that the cellular mechanisms that threaten dopamine neuron function are identical, but are not linked in an orderly cascade of cause and effect; instead, they can contribute to varying degrees and combine in patient-specific patterns, thus fulfilling the definition of a stochastic interaction: incorporating elements of randomness with directionality toward dopamine neuron dysfunction. Light gray double-ended arrows show cellular events in normal ageing. Thicker, dark gray doubleended arrows show accelerated cellular events in PD. UPS, ubiquitin-proteasome system. Similar mechanisms are implicated in cancer pathogenesis also. Source: Blagosklonny (2011). Reproduced with permission from US Administration on Aging.

may interdigitate with and generate reciprocal synergies with many other core phenotypes of aging mentioned in this chapter, particularly disinhibited particularly inflammation via promotion of TNF-α (Clark and Atwood, 2011). Novel approaches to antiaging therapies from this theory would centrally include efforts to normalize HPG axis function, not just through classic supplementation of sex steroids, but also intercepting other aspects of altered cell signaling, particularly overactivation of activins and an undersupply of inhibins, although these two latter manipulations are currently unavailable and represent highly appealing targets for future technologies.

The slowing of aging: dietary or calorie restriction and lifestyle interventions Calorie restriction: evolutionary and animal models Although the effects of CR on longevity were described more than 115 years ago (Jones, 1884), and its protection against the diseases of aging has been appreciated for

almost a century (Rous, 1914), only more recently have we begin to unravel the molecular mechanisms by which CR extends lifespan and protects the organism from agerelated change. CR functions as a kind of global metabolic reprogramming for virtually all organisms, extends lifespan, and reduces penetration of the diseases of aging significantly, if not dramatically, in most species in which it has been studied. Although the precise molecular pathways and cellular effects of CR are still being studied and debated, in general, it is viewed as a selected and phylogenetically conserved trade-off between reproductive fecundity and physiological conservation/preservation, and consistent with ideas in the previous section, results in a downregulation of the gonadotropic axis (Bowen and Atwood, 2004). A basic speculation has been that some version of a basic CR mechanism arose relatively early in evolution, during common periods of nutrient shortfalls, to allow organisms to trade off reproduction for conservation (when major energy shortages would have made reproductive efforts too metabolically costly), allowing an adaptive shift back to growth and reproduction at a time when nutritional supplies were more abundant.

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Recent work has confirmed that CR effects are conserved virtually throughout the entire animal kingdom, starting with organisms as primitive as yeast and extending into insects and other invertebrates, lower vertebrates such as fish, mammals (Fernandes et al., 1976), primates (Lane et al., 2001; Roth et al., 2001), and even humans (Rochon et al., 2011), although long-term studies on CR effects in humans are still lacking. (Short-term studies clearly demonstrate that the basic physiology of CR is well conserved in humans, but life extension—confirming that aging is indeed slowed—has not yet been empirically confirmed. Most researchers, however, anticipate that this will be eventually demonstrated.) CR/DR lacks a precise quantitative definition but might be considered to reflect a roughly 30% reduction in calories from eating freely until satiation (Richardson, 1985). CR effects for many species might begin at around a 25% to 30% reduction and extend to a 50% to 65% reduction, at which point CR transitions into starvation, a process that does not demonstrate any of the protective effects of CR and actively destroys global health. CR also requires that basic macro- and micronutrients be obtained (vitamins, minerals, fatty acids, and at least some protein). CR/DR is probably not a simple “homogeneous” issue, and can include differential restriction of proteins, carbohydrates, and fats, with these different forms of DR probably activating different cellular pathways involved in nutrient sensing and, therefore, having somewhat different physiological effects. However, protein and amino acid restriction clearly appears to be the more critical component, as protein restriction without CR elicits a significantly more robust profile of CR effects (Simpson and Raubenheimer, 2009) than the reverse (CR but without protein restriction; Kim et al., 2010a). Reasons for this may hinge on the importance of protein restriction for downregulation of mTOR, which is required for maximal CR benefits (see Section “Mammalian target of rapamycin”). Protein restriction may cause downregulation of growth factors and growth hormones (particularly GH, but also IGF), as well as provide downstream inhibition of TOR pathways (Figures 1.2, 1.3 and 1.4), improving autophagy and decreasing protein synthesis, among other effects, and may be particularly protective in relation to carcinogenesis (Anisimov et al., 2010); CR without protein restriction may not be nearly as protective in relation to cancers (Baur et al., 2006). Carbohydrate and glucose restriction, on the other hand, may more directly modulate insulin pathways and their several downstream targets. Intriguingly, evidence indicates that single amino acid restriction (specifically limiting dietary methionine or tryptophan) can yield CR effects (Caro et al., 2009), with subsequent reduced ROS in the mitochondria, lowered insulin and blood sugar levels, improved insulin sensitivity, and more (in other words, a CR physiology). This suggests an intriguing and perhaps less burdensome

Glucose Testosterone

Amino acids

Insulin

Fatty acids

IGF-1

TOR

Growth Hyperfunction

Aging Diseases of aging Life time

Figure 1.2 A simple schematic for the molecular pathway of mTOR

as “antagonistic pleiotropy”–that, in some sense, aging is simply the flip side of a protracted growth process that is not sufficiently turned off after a peak reproductive period. Source: Blagosklonny (2009). Reproduced with permission from US Administration on Aging.

option to classic CR approaches, without at least some of the aversive effects of classic CR diets (foods high in methionine include eggs, fish, soy, and many seeds, especially sesame seeds). CR without protein restriction, on the other hand, may not produce lifespan extension, probably because of a blunting of the CR protective effects against carcinogenesis, as well as perhaps a more limited downregulation of IGF (and other growth factors) and lessened overall inhibition of mTOR (Anisimov et al., 2010; see the next sections on mTOR).

Calorie restriction

Insulin IR S1/2

GF

PI-3K

LKB1 AMPK

Metformin

TOR S6K

Environmental factors

Aging Age-related diseases

RAPA Other genetic factors

Figure 1.3 A simple schematic of some of the cellular pathways

implicated in calorie restriction, aging, and the slowing of aging. Nutrients, growth factors (GF), and insulin activate the TOR pathway, which is involved in aging and age-related diseases. Other genetic factors and environmental factors (such as smoking, sedentary lifestyles, and obesity) contribute to age-related diseases. Several potential antiaging modalities (metformin, calorie restriction, and rapamycin and several polyphenols particularly resveratrol) all directly or indirectly (via impact on AMP kinase) inhibit the TOR pathway. Source: Blagosklonny (2009, 2010a). Reproduced with permission from US Administration on Aging.

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

Low P:C diet

Levels of glucose

AMPK activity

Levels of glucose

TOR activity

Levels of amino acids

High P:C diet

Levels of amino acids

Leptin; insulin/IGF; etc.

Stress factors; sirtuins; etc

High aa:glu

Insulin resistance; autophagy and repair inhibited

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Nutrients

TOR

Low aa:glu

AMPK Eat less

Insulin sensitivity; autophagy and repair promoted

Eat more

Anabolic responses

Catabolic responses

Protein synthesis, lipogenesis, cell proliferation, growth, reproduction

Cell cycle arrest, inhibition of growth and reproduction, lipolysis, proteolysis

Vicious cycle to obesity Overeat on low %P diets Live longer Obesity and insulin resistance Die early Lipolysis, elevated FA, lean muscle breakdown, enhanced hepatic gluconeogenesis Figure 1.4 A schematic summarizing the hypothesis

for how diet balance might affect lifespan via the TOR and AMPK signaling pathways. Source: Simpson and Raubenheimer (2009). Reproduced with permission from US Administration on Aging.

Calorie restriction: genes and pathways Many genes and molecular pathways are implicated in CR effects, consistent with the previous discussion. Indeed, many researchers and theorists at this point believe that CR involves a whole family or network of interacting molecular pathways. These would include insulin signaling 1/2, IGF and other growth factors, PI3 kinase, AKT (protein kinase B), forkhead transcription factors, PGC1- , AMP kinase, sirtuins, and mTOR (Figures 1.3 and 1.4). This network of pathways argues against any version of a single primary pathway being responsible for CR effects, and suggests a highly pleiotropic phenotype, consistent with other evidence that adaptive growth processes must be, by necessity, sensitive to a host of signals (see Section Mammalian Target of Rapamycin). Thus CR as a protective and antiaging intervention, probably operates through a network of linked molecular pathways, where recursive interactions and relationships may be incompletely understood at present. Although a class of transcription factors called sirtuins, particularly SIRT1, were initially conceptualized as the critical regulators of CR effects (Sinclair, 2005),

Depleted muscle mass and aa pool; reduced lean signal (IL15?); low aa:glu; high AMPK

recent work suggests that SIRT1 may operate on and influence some, but not all, of the CR network, while SIRT3 may also be critical as well. However, research suggests that CR (if it includes significant protein restriction) downregulates mTOR while also upregulating AMPK (Baur, 2006), up-regulates several sirtuins (Sinclair 2005), promotes mitochondrial biogenesis, and significantly reduces inflammation (Figures 1.3 and 1.4). Effects from inhibition of TOR are increasingly thought to be critical to mediating lifespan extension and slowing the aging process with DR. As a result, this TOR pathway has supplanted the sirtuins as the most studied and most intriguing cell-signaling group of pathways in aging (and antiaging) science. As such, it merits a detailed overview.

Mammalian Target of Rapamycin Target of rapamycin (TOR) belongs to a highly conserved group of kinases from the PIKK (phosphatidylinositol) family, increasingly conceptualized as core and essential integrators of growth signaling. Knockout of mTOR is consistently embryonically lethal across several species,

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The Aging Brain in Neurology

suggesting a strong antagonistic pleiotropy affect for this particular gene (Blagosklonny, 2010a). Rapamycin, an immunosuppressive macrolide, was first discovered as the product of a soil bacteria from Easter Island. It directly and potently inhibits the activity of TOR (TOR complex 1 (TORC1), but not until recently did we understand that it also impacts TOR complex 2 (TORC2)). TOR was first identified in yeast but subsequently has been found to exist in all eukaryotic organisms. TORC1 (rapamycin sensitive) is thought to be the central element of the TOR signaling network, monitoring and integrating a large set of intra- and extracellular processes and controlling growth, proliferation, and lifespan with a host of complex downstream effects (Kapahi et al., 2010). TORC2 is also rapamycin sensitive, but contributes to the full activation of AKT, an upstream and critical signaler of TORC1; it also mediates spatial control of cell growth by regulating the actin cytoskeleton (Hall, 2008) and disruption of TORC2 by rapalogs appears to drive the “paradoxical” insulin resistance seen in chronic administration (Lamming et al., 2012). TOR plays a highly conserved and central role in coupling nutrient sensing to growth signals, integrating signals from wnt-β-catenin signaling pathway (growth factors involved in stem cell differentiation and regulation), glucose and lipid availability (signaled by AMP kinase), protein and amino acids deficiency or availability (growth resources), signals from multiple other growth factors and hormones, and even oxygen availability and hypoxia signals to dynamically determine the envelope of growth versus conservation signaling in the cell. TORC1 is thus thought to act as a growth “checkpoint” and signal integrator, determining whether the extra- and intra cellular milieu is favorable to growth and, if not, producing effects consistent with a CR phenotype. TORC1 has many output targets, altered in either CR or CR mimetic effects from rapamycin, including messenger RNA translation (inhibited in CR), autophagy (increased in CR), transcription and ribosome biogenesis (inhibited in CR), proliferation and growth (inhibited in CR), and several other key cellular processes, including stress resistance (increased by CR); for a fine technical review of TOR research, see Kapahi et al. (2010). Inhibition of mTOR by rapamycin has been shown experimentally to increase lifespan, even when given to mice in late middle age (Harrison et al., 2009). This finding suggests that rapamycin is a more powerful CR mimetic than resveratrol, which has failed to extend lifespan outside of obese animals (Baur et al., 2006; Miller et al., 2011). On the basis of age at 90% mortality, rapamycin led to increased lifespan of 14% for females and 9% for males. Intriguingly, patterns of mortality and disease in rapamycin-treated mice did not differ from those of control mice, suggesting that treatment with rapamycin globally delays aging and age-related disease in a nonspecific and fairly “even” fashion (Harrison et al., 2009),

arguing for at least some involvement of mTOR in virtually all age-related disease that might cause or contribute to mortality (at least in mice). Inhibition of TOR’s major downstream targets, such as S6K, a kinase involved in ribosome biogenesis, appears to be important to the protective (antiaging) effects of TOR inhibition, and a knockout of this gene (S6K) also increases lifespan in mice and, intriguingly, generates activation of AMP kinase; this suggests dynamic relationships between mTOR and AMP kinase (Selman et al., 2009) that are probably incompletely mapped at this time (as two core primary mediators of CR/DR effects). Figure 1.4 (from Simpson and Raubenheimer, 2009) schematically summarizes relationships between AMP kinase and mTOR. These two kinases are increasingly viewed as possibly integrating much of CR physiology, with an upregulation of AMP kinase and a downregulation of mTOR potentially orchestrating the entire range of CR effects through their conjoint activity. These two kinases are differentially involved in nutrient sensing, with TOR activated by high amino acid/glucose ratios (in other words, plenty of amino acids and proteins to build new tissue, thus releasing a “go” signal to anabolic processes and growth) and AMP kinase activated by low amino acid/glucose ratios. Thus, protein/carbohydrate dietary ratio may influence differential activation/inhibition of TOR and of AMP kinase (and these two integrators of CR physiology are also interactive, with AMP kinase inhibiting mTOR). These differential nutrient-sensing systems may help explain why CR without at least some protein restriction may not be as effective as a general antiaging strategy (Blagosklonny, 2010a, 2010b), particularly in relation to the prevention of cancers, because such a diet does not maximally downregulate mTOR. Additionally, Figure 1.4 may help explain why resveratrol by itself (a primary activator of AMP kinase, but not a primary or direct inhibitor of mTOR) does not produce a lifespan extension in animal models (outside of obesity) because it does not inhibit mTOR sufficiently.

Calorie-restriction mimetics Given the intrinsically stressful and unpleasant nature of basic CR approaches (for example, CR animals typically cannot be housed together because they are too irritable and will fight), most believe that CR is simply not a viable health-maintenance strategy for most people. If anything, the recent pandemic of obesity has underlined that most individuals, when given ready access to tasty and addicting high-calorie-density foods, are simply not going to restrict their calorie intake voluntarily, regardless of the well-known and widely appreciated negative consequences. This has led to increasing interest in CR mimetics, defined as any substance that potentially mimics the molecular effects and physiology of CR (without the stress of making a person hungry much of the time). There are probably many substances that cause

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

mild nausea, visceral upset, or other GI distress and that subsequently inhibit food intake, but although these can show CR effects in sustained administration in animal models, they cannot be considered CR mimetics. Additionally, drugs that may directly modulate appetite (such as Rimonabant, an endocannabinoid-1 receptor blocker) might also show CR effects in sustained administration by modulating consumption and hunger drive at central levels, but they also cannot be considered true CR mimetics. One emerging prediction might be that CR mimetics will occupy an increasingly central role in primary prevention in relation to the diseases of aging in the coming decades, but an enormous amount of basic research remains to be done before widespread implementation of CR mimetics would be advisable or feasible; long-term data in both preclinical and clinical populations also is lacking (although data collection and trials of CR mimetics are underway in relation to many diseases of aging). There are actually a number of CR mimetics with accumulating research supporting CR effects, but the most famous of these is clearly resveratrol, a molecule that has received enormous research attention in the last 15 years. In addition, metformin is a true CR mimetic (a drug commonly used to treat type II diabetes and rarely categorized in conventional medical literature as a CR mimetic) and 2-deoxyglucose are CR mimetics (2-deoxyglucose was actually the first described CR mimetic and interferes with glycolysis, preventing glucose utilization by cells even when abundant glucose is available, but it is cardiotoxic in chronic administration). Fisetin, derived from Fustet shrubs, is a flavonoid polyphenol that has also demonstrated CR mimetic effects. Rapamycin (as a primary inhibitor of TOR) is also a potent CR mimetic; to date, only rapamycin has demonstrated lifespan extension when given to older mammals (many CR mimetics have demonstrated lifespan extension in other target species, such as yeast, fruit flies, fish, and worms). Other polyphenols (a very large group of compounds found in fruits and vegetables, totaling perhaps as many as 6000 substances) may have mild CR effects, particularly quercetin, resveratrol, and its first cousin, pterostilbene (Belinha et al., 2007). However, single-polyphenol regimens, particularly resveratrol, have not shown lifespan extension (Pearson et al., 2008)2, except in obese animals (protecting mice from premature mortality and the undesirable physiology of obesity (Baur et al., 2006) or cases in which resveratrol was combined with every-other-day dieting (EOD) as a

2

Given that AMP kinase inhibits mTOR, resveratrol might have some modest indirect effects on this critical pathway. Studies on resveratrol reviewed in later sections (see the section on CR mimetics) suggest that mTOR inhibition is likely to be modest, given the absence of lifespan extension in mammalian animal models, outside of obese animals, where its AMPK promotion may be protective and promote similar aging trajectories to non-obese animals.

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mild CR alternative (also demonstrated in a mouse model in Pearson et al., 2008). Although resveratrol was initially assumed to have its protective effects through SIRT1 activation, recent work has clarified that AMP kinase is probably the necessary and sufficient target for the protective effects of resveratrol (Um et al., 2010). Recent work has suggested that pterostilbene may be a more effective CR mimetic, with better bioavailability than resveratrol, and also a better activator of PPAR-α (Rimando et al., 2005), with more beneficial effects on lipid profiles, while still showing extraordinarily low toxicity (Ruiz et al., 2009). Evidence suggest that resveratrol and its analogs, like pterostilbene (along with metformin and quercetin, two other CR mimetics), are probably only partial CR mimetics; even moderately high-dose resveratrol (20–30 mg per kilogram) does not appear to protect mice against latelife cancers (particularly a form of virally induced lymphoma, a very common cause of death in aged laboratory mice; Pearson et al., 2008) and does not extend lifespan outside of obese animals. Intriguingly, a nutraceutical combination of resveratrol and quercetin appeared to provide better mimicking of CR physiology than resveratrol alone (Barger et al., 2008; although longevity was not indexed specifically). This suggests that combinations of partial CR agents may get us closer to mimicking a full CR physiology than a single compound particularly a combination of rapamycin and an AMPK modulator such as resveratrol or metformin -- a logical combination that has yet to be tested, and where AMPK modulation might help reduce the insulin resistance seen on chronic administration of rapalogs (associated with its TORC2 disruption). These considerations (Figure 1.4, by Simpson and Raubenheimer 2009) suggest that a complete or ideal CR mimetic might both activate AMP kinase and directly inhibit mTOR (not simply indirectly through increased AMPK activity), without toxicities or major side effects, a design target that no single known compound at this time yet achieves. Inhibition of mTOR (via rapamycin) has shown promising protection against diseases of aging in mammalian animal models (Stanfel et al., 2009). Perhaps a combination of low-dose rapamycin and resveratrol or pterostilbene might achieve the desirable targets of mTOR inhibition and AMPK activation, and thus function as a full CR/DR mimetic. To prove this in a mouse model, one would have to show further protective benefits from those achieved with rapamycin alone if resveratrol or pterostilbene were added in late middle age. This intriguing hypothesis has never been probed or tested even in a mammalian animal model. Full testing of these ideas in humans appears even further away, underlining an enormous gap between research promise and clinical reality in this vital area of biological science. Given the potential impact that a full, robust, and safe CR mimetic could have on aging and the diseases of aging (particularly the potential extension of “healthspan”), there is remarkably little

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research into this area, relative to its potential biological promise. Indeed, conventional medicine still sees CR/DR and CR mimetics largely as biological “fringe” subjects, instead of appreciating their potentially enormous protective functions and central and paradigmatic insights. Large pharmaceutical firms have just recently begun to pay more attention to this area of CR and its mimetics (see the recent GSK acquisition of Sirtris, www.gsk.com/ media/pressreleases/2008/2008_us_pressrelease_10038 .htm).

Calorie-restriction variants and mutants There are many ways to generate CR effects, beyond classic CR approaches. One of the most basic of these is simply intermittent fasting (which may not result in nearly as much weight loss as full CR but still activates a CR physiology), along with methionine restriction (as noted earlier). In addition, there is manipulation of growth hormone (such as growth hormone knockout) and IGF-1 and insulin signaling manipulations (consistent with overwhelming evidence that insulin-signaling pathways are primary targets for CR effects; Figures 1.3 and 1.4). A dwarf mouse implementing a growth hormone knockout shows a roughly 60% life extension (and won a recent Methuselah prize; Bartke and Brown-Borg, 2004). This animal showed reduced hepatic synthesis of IGF-1, reduced secretion of insulin, increased sensitivity to insulin actions, reduced plasma glucose, reduced generation of ROS markers, upregulated antioxidant defenses, increased resistance to OS, and reduced oxidative damage, all quite consistent with CR physiology. Probably many dozens of genes can be modified to yield some variation of a CR physiology and at least some increase in longevity (and therefore slowing of aging), consistent with the evidence that CR/DR activates a complex and highly interactive network of cell signaling and regulatory pathways (Yuan et al., 2011; Lorenz et al., 2009).

Lifestyle and dietary factors There is increasing, if not collectively convincing, evidence that core lifestyle factors such as exercise and diet (as well as sleep quality and social stress vs social comfort) potentially influence many aspects of aging, thus constituting a complex collection of negative and positive risk factors for all the diseases of aging. This collection of lifestyle variables are also presumably interactive with a small group of known polymorphisms and a likely much larger group of unmapped polymorphisms that collectively may have a large effect on longevity (Yashin et al., 2010) and risk for specific diseases of aging. Future mapping of those polymorphisms (and their likely complex interactions with lifestyle variables) may allow much better prediction of risk, and eventually allow for more effective and tailored early interventions, to reduce specific

risk for a particular disease of aging. As but a small example of these issues, IL-10 endowment may affect risk for AD. Although a good night’s sleep, a healthy and more balanced diet, regular aerobic exercise, and social support are generally regarded as having nothing to do with each other biologically, recent work in relationship to all of these lifestyle factors suggests that they impact a broad but fundamentally shared set of cellular and molecular pathways. These shared effect pathways include multiple if not most aspects of cell signaling (internal cellular regulation): regulation of cell cycling, regulation of inflammatory, stress, defense and growth pathways, including mTOR. Although our understanding of diet, exercise versus sedentary lifestyle, sleep, and stress versus social comfort is still evolving, evidence suggests that basic lifestyle factors either promote or inhibit inflammation, protect insulin sensitivity versus generating insulin resistance, and create more OS versus protect against it, while promoting (or inhibiting) autophagy, cellular senescence, and apoptosis in aging, thus modulating virtually every known phenotype of aging. Additionally and rarely appreciated within traditional medicine, all the individual components of so-called healthy lifestyle practices appear to be part of our ancient evolutionary environment and reflect HG lifestyle characteristics. This suggests the possibility of a version of a “unified field theory” in relationship to long-term health versus chronic disease, and that healthy living may reduce complex and still poorly understood “mismatches” between our genome and our current biological environment in Western societies. In general, such ideas have little current visibility within conventional medical circles (although a reprioritizing of prevention is now being widely emphasized), but a nascent awareness of these more global biological perspectives on health versus chronic disease is slowly emerging, energized by increasing research into lifestyle and its complex biological impact.

Exercise Regular aerobic exercise is widely recognized as an essential component of a healthy lifestyle, yet fewer than 15% of individuals living in the United States engage in adequate amounts of aerobic exercise; a majority of people in the United States are almost completely sedentary (Roberts and Barnard, 2005). Sedentary lifestyles are thought to contribute to risk for all diseases of aging, particularly cardiovascular disease, metabolic syndrome, and type II diabetes, especially when combined with a Western diet. Exercise has an extremely complex biological footprint, but among its many effects, exercise offers protection against all-cause mortality, particularly against atherosclerosis, DMII, and several but perhaps not all cancers, notably colon and breast cancer. It also significantly reduces frailty and sarcopenia. Regular exercise appears specifically protective against diseases associated

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

with chronic low-grade systemic inflammation (Peterson and Peterson, 2005), perhaps due the anti-inflammatory response elicited by an acute bout of exercise, largely mediated by muscle-derived IL-6. IL-6 stimulates production of anti-inflammatory cytokines (such as IL-1ra and IL-10) and inhibits subsequent (postexercise) production of the key proinflammatory cytokine TNF-α. In addition, IL-6 stimulates lipolysis and fat oxidation and metabolism (see Peterson and Peterson, 2005 for a detailed review). These anti-inflammatory effects also inhibit insulin resistance, which is partly modulated by TNF-α and by NFκ-B/AP-1, transcription factors centrally involved in inflammatory signaling. Exercise may also upregulate antioxidant defenses (Kaliman et al., 2011), while OS actually initially increases during a bout of exercise, with subsequent upregulation of endogenous defenses (referred to as mitochondrial hormesis or “mitohormesis”). Some work on the effects of exercise calls into question the conventional wisdom of blocking OS, as evidence suggests that this actually impairs exercise benefit and even may prevent beneficial effects of CR (Ristow and Schmeisser, 2011). Exercise may also increase neurotrophins, improve stress resistance, improve mood, increase emotional and stress resilience, and enhance cognitive function and learning (Ratey, 2009), and consistent with these effects, at least some preventative/protective effects against most neurodegenerative disorders, particularly AD, have also been demonstrated.

Obesity One of the most worrisome public health trends over the last 20 years has been a steady and dramatic increase in the prevalence of overweight and obese individuals. Current statistics suggest that roughly one-third of the United States is obese (with a body mass index (BMI), greater than 30), with another one-third of the population overweight (BMI over 25 but less than 30; Wang et al., 2007). Additionally some evidence suggests that the rate of obesity is still increasing despite much attention to this public health issue, and may reach 50% penetration in the United States by 2025. Equally worrisome is the emerging evidence that the rates of obesity in the United States are actually higher in children than in adults, perhaps due to a highly undesirable combination of increasingly sedentary gameplay (in which video games have largely supplanted more physical activity), increasing fast food consumption, and overconsumption of sugary beverages. Obesity is increasingly appreciated as a risk factor for virtually every disease of aging, beyond its popular link to risk for cardiovascular disease. Obesity contributes significantly to risk for hypertension, dyslipidemia, insulin resistance and type II diabetes, multiple cancers, and even AD. Evidence suggests that increased abdominal fat (vs subcutaneous fat) is a more significant risk factor than generalized obesity, and this relationship is potentiated,

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curiously enough, in otherwise leaner subjects (Pischon et al., 2008), as abdominal fat may have a particularly potent effect on dysregulation of inflammation (Fontana et al., 2007) via promotion of proinflammatory cytokines. Aging itself decreases subcutaneous fat while increasing abdominal fat, and simply reducing abdominal fat surgically has a prolongevity effect in animal models. Increased visceral fat is independently associated with all-cause mortality, insulin resistance and diabetes, cardiovascular disease, cerebrovascular disease, AD, and disability in the elderly (Florido et al., 2011). Additionally, there is evidence for intrinsic relationships between obesity and upregulated inflammation (in part as compensatory and a way of using more energy) and, on the other hand, CR and reduced inflammation (Ye and Keller, 2010).

Polyphenols Although conventionally regarded as “antioxidants”, polyphenols are an enormous class of substances (constituting perhaps as many as 6000 distinct compounds) found in plants, principally fruits and vegetables, that have enormously pleiotropic effects on human and mammalian physiology. Some of these effects may be more biologically significant than any direct “free radical scavenging” done by any polyphenol; they include many effects on cell signaling, the regulation of growth factors and apoptosis, the regulation of cell cycling, the regulation of inflammation, the modulation of many (if not most) cellular stress pathways, an impact on multiple transcription factors (including those involved in energy homeostasis), and (consistent with their conventional designation) the management of OS (Virgili and Marino, 2008). Many of these effects on aspects of cell signaling require much lower levels of polyphenol than any direct free radical scavenging in serum or tissues. Indeed, from this perspective, polyphenols look less like “antioxidants” and more like complex cell physiology and cell signaling modulators. However, it seems unlikely that such a designation will replace the catchy title of “antioxidant,” even in the context of increasing evidence that such a title may be fundamentally if not profoundly misleading. Many, if not most, of the phenotypes of aging (OS, mitochondrial dysfunction, inflammation, and declining autophagy, among others) appear to be partially modulated by various polyphenols. From this perspective, if our ancestors consumed more plants than we do and did so over tens of thousands of years (if not much longer), the relative removal of polyphenols from the human diet (in those eating minimal fruits and vegetables) would be predicted to have complex but potentially profound effects on physiology and on the biological trajectories of aging. Conversely, those eating a rich variety of plants may be more protected against accelerated aging and the diseases

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of aging. Of these two predictions, the second has been better studied, and is generally supported, while the first has some evidence for it as well, but is not well elucidated. Polyphenols consist of several classes of chemical substances, including nonflavonoid compounds (such as resveratrol, other stilbenes, and curcuminoids), and classic flavonoids (consisting of two large classes, anthocyanins, which are colorful and pigmented, and anthoxanthins, which are colorless). Resveratrol and its first cousin, pterostilbene, are both naturally occurring phytoalexins produced by plants in response to fungal infection (phytoalexins are all “plant defense” compounds). Of the anthoxanthin family, quercetin is one of the best-known and best-studied members, along with EGCG (a member of the catechins family, with catechins constituting a large group of polyphenols in tea and wine). Dietary sources for polyphenols include many foods that have been ancient components of the human diet for many hundreds and even thousands of years: fruits and their juices (typically containing both anthocyanins and anthoxanthins), tea (catechins), coffee (chlorogenic, caffeic and ferulic acids), red wine (anthocyanins, resveratrol, and quercetin), vegetables (many anthoxanthins and anthocyanins), some cereals, chocolate (multiple flavonoids, including catechins and proanthocyanidins), and various legumes, particularly soy (isoflavones) and peanuts. In this context, there are multiple challenges to any emerging science that might explain the roles polyphenols could play in health maintenance and the slowing of at least some aspects of aging and/or age-related disease. First, there are many thousands of different bioflavonoids in toto, but only a handful with much in vivo research (resveratrol, curcumin, green tea extract, and quercetin are perhaps best studied). Most of the studies of polyphenols use in vitro approaches; although there are increasing numbers of in vivo studies in animal models, very few clinical studies have taken place in humans. As an additional major challenge to potential therapeutic use, virtually all bioflavonoids have relatively poor bioavailability, which may be part of their extraordinarily nontoxic biological footprint. Most polyphenols are rapidly conjugated (typically sulfated and glucuronided), and variably metabolized, often with an uncertain biological status of their multiple metabolites. The proper study of any polyphenol in potentially slowing or preventing any disease of aging is methodologically challenging and also expensive (long time frames are needed and it is difficult to control for many other positive and negative lifestyle risk factors). With all these scientific and methodological challenges, there is little financial incentive to study polyphenols in humans in relation to the diseases of aging or aging itself, given the poor return on investment with inexpensive agents that cannot be patented. This collection of factors has generated the current situation, where one finds much promising animal-model data for

multiple polyphenols in relation to a disease of aging, but a dearth of good human clinical studies. This is changing slowly, and several polyphenols are in clinical trails related to several diseases of aging. One of the few completed studies of a polyphenol in a human clinical population demonstrated that resveratrol is effective at higher doses in treating diabetes (Patel et al., 2011). Clinical studies are underway related to cancer, AD, and heart disease. Curcumin is also being increasingly studied for its anti-inflammatory, antiproliferative, and antiaging effects. Curcuminoids are thought to affect many dozens of cellular pathways and, like many polyphenols, block NF kappa-B, a transcription factor involved in the regulation and activation of inflammatory responses (Aggarwal, 2010). Curcumin is also one of several polyphenolic inhibitors of mTOR, a critical nutrient-sensing and growth factor integrative pathway that is increasingly implicated as a molecular target of CR; if inhibited, it may slow aging and also inhibit or delay diseases of aging (Beevers et al., 2009), but curcumin has notoriously poor bioavailability and rapid metabolism (Bengmark, 2006).

Diseases of aging (with particular relevance to neurology) This list of diseases is truncated due to space considerations, and does not include many important illnesses, including motor neuron diseases, frontotemporal lobar degenerative disorders, and various brain cancers. Cardiovascular disease Although “cardiovascular disease” technically refers to any disease that affects the heart or blood vessels, the term has become increasingly synonymous over the last 20 years with atherosclerosis. This disease of aging is directly responsible for more deaths than any other in Western societies, killing twice as many individuals as all cancers combined and probably more than all the other diseases of aging put together (Minino et al., 2006). Thus, it clearly merits a summary review. Evidence argues that lifestyle and cultural factors have to be considered as primary etiological issues here. As Kones pointedly states “Americans are under assault by a fierce epidemic of obesity, diabetes, and cardiovascular disease, of their own doing. Latest data indicate that 32% of children are overweight or obese, and fewer than 17% exercise sufficiently. Over 68% of adults are overweight, 35% are obese, nearly 40% fulfill criteria for metabolic syndrome, 8–13% have diabetes, 34% have hypertension, 36% have prehypertension, 29% have prediabetes, 15% of the population with either diabetes, hypertension, or dyslipidemia are undiagnosed, 59% engage in no vigorous activity, and fewer than 5% of the US population qualifies for the American Heart Association (AHA) definition of ideal cardiovascular health. Health, nutrition, and exercise illiteracy is prevalent, while misinformation and unrealistic expectations are the norm. Half of American

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

adults have at least one cardiovascular risk factor. Up to 65% do not have their conventional risk biomarkers under control. Of those patients with multiple risk factors, fewer than 10% have all of them adequately controlled. Even when patients are treated according to evidence-based protocols, about 70% of cardiac events remain unaddressed. Undertreatment is also common. Poor patient adherence, probably well below 50%, adds further difficulty in reducing cardiovascular risk. Available data indicate that only a modest fraction of the total cardiovascular risk burden in the population is actually now being eliminated. A fresh view of these issues, a change in current philosophy, leading to new and different, multimechanistic methods of prevention may be needed. Adherence to published guidelines will improve substantially outcomes in both primary and secondary prevention. Primordial prevention, which does not allow risk values to appear in a population, affords more complete protection than subsequent partial reversal of elevated risk factors or biomarkers” (Kones, 2011, p. 61). Consistent with these statements, recent research demonstrates that the underlying process of atherogenesis is a complex and long-term process involving many players, including endothelial cells, cytokines and immunoglobulins, immune cells, growth factors, extracellular matrix molecules, and lipids, but with a primary role for OS and inflammation. Atherogenesis requires a cascade of processes, starting with a maladaptive, sustained proinflammatory reaction to oxidized lipid deposition in the arterial wall. The initiating event appears to be the deposition of apoB-containing lipids, typically oxidized low-density lipoproteins. Oxidation of these lipids dramatically increases the likelihood that the deposition process will irritate the vessel, promoting increased proinflammatory cytokine release; this suggests that plasma redox balance may be a critical variable (Maharjan et al., 2008). Hyperlipidemia is also associated with declining endothelial nitric oxide synthase (eNOS) and increasing nitroxidative stress in the endothelium (Heeba et al., 2009). These inflammatory cascades lead to accumulation and swelling in arterial structures, mostly from macrophage cells combined with lipids (principally, oxidized low-density lipoprotein (LDL), VLDL, and other fatty acids), calcium (particularly in advanced lesions), and a certain amount of fibrous connective tissue. Glycation of proteins (an intrinsic component or phenotype of aging), as well as foreign antigens, can also promote these fundamental inflammatory changes (Milioti et al., 2008), with regions of more glycated tissue and AGEs promoting and accelerating the formation of these plaque structures (Kim et al., 2010b). These slowly developing structures (atheromatous plaques) are found at least to some degree in most individuals in Western societies, and early asymptomatic stages of this process are found in many young adults; however, they are rare in HGs (Eaton et al., 1988 a,b). LDL is the most common ApoB plasma lipoprotein, but ApoB-containing VLDL,

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remnant VLDL (depleted of triglycerides), intermediatedensity lipoprotein (IDL), and LP(a) have also been shown to be atherogenic, along with ApoB from chylomicron remnants; this suggests that many forms of lipid contribute to risk. These lesions actually begin in childhood and develop slowly over many, many decades. The early stages of deposition are called “fatty streaks,” but they are not composed of adipose cells; instead, they consist of white cells, especially macrophages, that have taken up oxidized LDL. After these cells accumulate large amounts of cytoplasmic membranes (and high cholesterol content), they become “foam cells.” When foam cells undergo apoptosis, the contents are deposited into the surrounding tissue, attracting more macrophages and inflammation, and causing a positive and self-sustaining feedback loop. Upon activation by proinflammatory stimuli, macrophages and lymphocytes release proinflammatory cytokines that stimulate the migration of smooth muscle cells (SMCs) from the medium of the vessel wall. SMCs then contribute to more foam cell and fibrous cap formation, also under the influence of proinflammatory cytokines (for example, IFN-γ and TNF-α secreted by T helper cells, and IL-12 secreted by macrophages and foam cells; Milioti et al., 2008). Eventually, foam cells die via apoptosis, dumping nondegradable cholesterol crystals that form the lipid core of the plaque structure. Plaque structures can be either stable or unstable, with vulnerable plaque tending to be faster growing and with higher macrophage content, suggesting that autoinflammatory processes not only contribute to the early, more silent stage of the process, but also drive the deadly late stages of the process well. Recent work by Wang et al., 2011 suggests a potentially pivotal role by immunoglobulins (IgE) as a critical player in the activation of macrophages, and with high correlations between IgE levels and degree of plaque instability. Although popularly viewed as a disease of cholesterol (a perspective that dominated the earlier conceptualizations of vascular disease in the 1960s and 1970s), increasing scientific opinion favors atherosclerotic vascular disease as a disease of inflammation and OS. Consistent with this, increasing evidence shows that statins actually impact both inflammatory and OS issues (Heeba et al., 2009), while promoting upregulation of heme oxygenase (an important antioxidant defense enzyme). Statins appear to inhibit vascular disease through pleiotropic mechanisms, including decreased synthesis of LDL, increased removal of LDL (through hepatic LDL receptors), upregulation of eNOS, increased tissue-type plasminogen activator, and also inhibited endothelin 1, a potent vasoconstrictor and mitogen. All of these promote improved endothelial function. Statins also reduce free radical release, thus inhibiting LDL-C oxidation (Liao and Laufs, 2005), while increasing endothelial progenitor cells and reducing both the number and activity of inflammatory cells and cytokines. They also may help stabilize atherosclerotic plaques, reduce production of

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metalloproteinases, and inhibit platelet adhesion/aggregation (Liao and Laufs, 2005). Although it is extremely common in Western societies (at least in some stage, even if clinically silent), extensive vascular disease is virtually nonexistent in HG groups (Eaton and Eaton, 2002). This suggests a primary role for etiology in the Western lifestyle and diet (see later sections on diet and lifestyle variables), in which multiple, if not virtually all, components of the Western diet and lifestyle appear proinflammatory relative to HG lifestyles (sedentary vs highly aerobically active, altered omega-6/ omega-3 ratios, poorer sleep, greater social isolation, lower consumption of fiber, lower consumption of protective polyphenol phytochemicals, and high BMI vs low BMI in HG groups). In addition to atherosclerosis (which is clearly the largest problem in pathological vascular aging in Western cultures), there is also vascular aging independent of atherogenesis. Increasing evidence implicates angiotensin II (Ang II) signaling as central to this process (Wang, Khazan, and Lakatta 2010). Arterial remodeling and decline in aging (even without atherosclerosis) is increasingly thought to be linked to Ang II signaling (Wang, Khazan, and Lakatta, 2010a). Components of Ang II signaling (including several reactive oxygen species, multiple growth factors, matrix metalloproteinases, chemokines, and nicotinamide adenine dinucleotide phosphate-oxidase) are upregulated within arterial walls in many species including humans, during aging. In vivo studies suggest that elevation of Ang II signaling drives accumulation of AGE (advanced glycated end products, which are themselves proinflammatory), increased collagen, disruption of elastin, and invasive hypertrophy of both smooth muscle and endothelial cells (Wang, Khazan, and Lakatta 2010a). Obvious clinical implications are that attenuating Ang II signaling may significantly retard this age-associated arterial remodeling, suggesting important protective effects for ACE inhibitors and ARB compounds. Intriguingly, multiple polyphenols, including those in pomegranate juice (rich in tannins and anthocyanins), appear to inhibit angiotensin signaling (perhaps in part from nonspecific antioxidant effects, but also from inhibition of angiotensin-converting enzyme activity) and may also reduce blood pressure (Stowe, 2011). Ang II also enhances ROS production by activating NAD(P)H oxidase and uncoupling eNOS. Systemic inhibition of Ang II thus may potentially have CR mimetic (antiaging) effects, due to its central role in coordination of vascular aging, OS, and impact on the mitochondria (de Cavanagh, et al., 2011). These processes driving vascular aging and disease are of obvious primary relevance to vascular dementias, as well as to common findings of white matter erosion (typically referred to as white matter hyperintensities or white matter ischemic change on MRI and CT scans), sometimes appearing as a highly comorbid pathology with AD (Brickman et al., 2009). Indeed, separating amyloid

angiopathy (a frequent vascular concomitant to AD) from other forms of atherosclerosis is almost impossible within clinical settings.

Alzheimer’s disease As the disease of aging with perhaps the greatest relevance to this textbook, there has been a paradigm shift over the last 20 years away from the original assumption that AD has nothing to do with aging. Of course, this could not possibly have been true, given the simple fact that AD roughly doubles in incidence every 5 years after the age of 60–65 and that aging remains the greatest risk factor for nonfamilial sporadic AD. Recent research suggests that markers for OS and mitochondrial decline (Pratico, 2010; Aliev et al., 2010; Mancuso et al., 2007) are elevated even prior to the appearance of extracellular amyloid deposition, which takes place in the preclinical stages of the disease. Indeed, multiple lines of evidence link AD to many, if not virtually all, of the phenotypes of aging, including inflammation (Masters and O’Neill, 2011), OS, accumulation and/or clearance failure of characteristic pathogenic proteins (Barnett and Brewer, 2011), and increasing deleterious synaptic effects from those proteins and from associated inflammation (De Strooper, 2010; Mondragon-Rodriguez et al., 2010; Palop and Mucke, 2010). Recent work has suggested that pathogenic proteins (such as oligomeric amyloid) are not being cleared out (Mawuenyega et al., 2010), underlining an important role for declining autophagy in the etiology. These considerations suggest that AD is indeed a highly pleiotropic and complex disease with several stages in which we may still not understand fully all the critical factors, or exactly how they interact to create a cascade with distinct stages, and with different processes and interactions presumably critical at different stages. What were originally adaptive mechanisms (such as inflammation, recruitment of amyloid pathways by various stresses and neuroplasticity challenge, phosphorylation, apoptosis, cell cycling, and so on) may become pathogenic in the context of chronic synergistic recruitment, biological stress, and neuroplasticity challenge. This suggests an image of AD in which a host of individually adaptive and compensatory mechanisms jointly “conspire” to drive the brain into a neurodegenerative process (MondragonRodriguez et al., 2010). Given that these interactions among a host of individually adaptive processes occur well past a reproductive period, they would escape virtually any conceivable selection pressure or modification. In this sense, the vulnerability to AD may reflect a “fault line” in the human genome consistent with the evolutionary perspectives outlined earlier. Thus, AD itself may be an expression of antagonistic pleiotropy in which genes and molecular pathways that were adaptive during periods of youth and fecundity potentially backfire in aging, particularly when synergistically recruited. Table 1.1 summarizes some, but not all, of the complex interactions

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

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Table 1.1 Factors contributing to a neurodegenerative mratrix in AD Biomarker

Produced by

Producing

Clinical/Other correlates

Beta amyloid plaque (extracellular Aβ)

Inflammation (glial activation), oxidative stress, more oligomers?

Subtle regional atrophic changes. Second biomarker appearing after OS/MITO decline

Synaptic loss and dysfunction, OS, inflammation

Synaptic loss (NMDA, AMPA), loss of LTP, increased LTD

Inflammation (INFLAM) (↑ innate immunity)

Aging, ↓ clearance, oxidative stress/ inflammation APOE4, altered BBB function? ↑ gonadotropins (LH/FSH) and declining sex steroids? β/γ secretases, inflammation, oxidative stress, ↓ clearance, endocrine dyscrasia? Plaque? Amyloid fibrils and oligomers, ↓ ACh, ↑ rAGE signaling, aging, OS, endocrine dyscrasia?

Contributes directly to cognitive dysfunction via multiple effects

Central insulin resistance (in CNS)

Inflammation (↑ NFk-b, AP-1, TNF-α, other proinflammatory cytokines), chronic stress?

Oxidative stress (OS), MITO decline

Declining control over OS in aging, Aβ oligomers in MITO, metal ions, INFLAM, advanced glycation end products, junk protein

Synaptic dysfunction, apoptosis, declining neurotrophins, OS, ↑Aβ? ↓ Energy, HC damage, ↑ kinases (→ neurofibrillary tangles?), declining autophagy? Synaptic and neural loss, INFLAM, Aβ, increased tangling? aberrant cell cycling → apoptosis

Excitotoxicity and Ca++ dysfunction

Oligomers (Aβ) in MITO, and at Ca++ channels, ↑ kynurenine (from increased cytokines) Oligomers (Aβ) → receptor internalization, tau pathology → microtubule dysfunction, inflammation Oxidative stress (OS) → ↑ kinases (w/ ↓ phosphatases), insulin resistance? Downstream effect of Aβ oligomers? Aberrant cell cycling? Multifactorial, with many factors listed contributing to synaptic loss and apoptosis

Proceeds functional declines (slightly)

Tracks atrophic change (SL/NL) and declining cognitive function closely. Precursors (PHF) appear long before beta amyloid deposition Major biomarker for degenerative changes in clinical stages of AD

Synaptic loss early, SL plus NL later (apoptosis)

Declining fxn, compensatory neuroplasticity effort?

Primary functional measure, necessary for diagnosis

Small aggregate amyloid (oligomeric Aβ)

Neurotrophin and neurotransmitter depletion Neurofibrillary tangling and tau aggregates

Atrophy HC/EC → lateral temporal → frontal/ parietal Cognitive loss, especially STM, then language and executive function

Synaptic dysfunction, apoptosis, esp. in HC/EC regions ACh loss → ↑ Aβ, BDNF/ NGF declines, aberrant cell cycling and apoptosis Basal forebrain (ACh) loss, SL, apoptosis

Promotes synaptic dysfunction and loss; promotes amyloidosis Appears before plaques/tangling; membrane OS increases with disease, but DNA OS markers do not Synaptic dysfunction, eventually SL/NL Synaptic dysfunction, promotion of both SL and apoptosis

Source: Adapted from Watt et al. (2012) with permission from Springer. SL: synaptic loss, NL: neural loss (neuronal cell death), Aβ: beta-amyloid, BBB fx: Blood Brain Barrier Function, MITO: mitochondria, ACh: acetylcholine, NGF: nerve growth factor, BDNF: Brain Derived Neurotrophic Factor, rAGE: receptors for advanced glycation end products (which promote inflammation), HC: hippocampus, EC: entorhinal cortex, apoptosis: programmed cell death, NFk-b: Nuclear Factor Kappa B (transcription factor involved in inflammatory signaling), AP-1: activator protein 1 (transcription factor involved in inflammatory signaling), Oligomers: several molecules of beta amyloid stuck together, Kinases: enzymes promoting phosphorylation and tangling, NMDA/AMPA: subtypes of glutamate receptor, LTP: long-term potentiation, LTD: long-term depression, lateral temporal: lateral temporal lobe, frontal/parietal: frontal and parietal convexity.

between putative etiological factors in AD, emphasizing an image of the disease as highly multifactorial, but one in which many primary phenotypes of aging (OS, disordered cell cycling, inflammation, glycation, apoptosis, mitochondrial decline, accumulation of junk proteins, and declining autophagy) appear not only contributory, but also highly interactive, arguing against any version of a single factor etiology.

Parkinson’s disease PD and its more aggressive and malignant close relative, diffuse Lewy body disease (DLBD), are idiopathic neurodegenerative diseases characterized by intraneuronal accumulation of Lewy bodies (aggregates of alpha-synuclein), particularly in substantia nigra (midbrain dopamine-producing

regions) in classical PD (and much more widely in DLBD). It is marked by progressive loss of DA cell bodies, deafferentation of basal ganglia, and dysfunction in direct and indirect corticostriatal pathways. Subsequent primary symptoms include resting tremor, slowing of movement, rigidity and gait difficulties, and eventual postural instability. There is evidence of differential vulnerability to degeneration in nigral regions, with “ventral tier” neurons more vulnerable than “dorsal tier,” and with VTA neurons least effected (Collier et al., 2011), despite the fact that these fields form a continuous sheet of DA neurons. This differential vulnerability is viewed in recent work as multifactorial. In animal models, it appears linked to several markers, including the appearance of alpha-synuclein, ubiquitin (as a marker of proteasome activation), lipofuscin (as a marker of lysosome

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activation), 3-nitrotyrosine (as a marker for nitroxidative stress), dopamine transporter activation, and markers of astrocyte and microglial activation (inflammation markers). Dysfunctional mitochondria and activated microglial cells are thought to be the primary intracellular source of reactive oxygen species, and lysosome-mediated autophagy is the primary cellular mechanism for removing defective mitochondria. The progressive accumulation of lipofuscin (conventionally regarded as “age pigment”) is thought to reflect an index of mitochondrial damage and subsequent lysosomal degradation of defective mitochondria (Terman et al., 2006). Collier et al. (2011) argue that the etiology of PD, while still uncertain, may reflect stochastic interactions among inflammation, OS, declining autophagy, and accumulations of pathogenic junk proteins, producing a “stochastic acceleration hypothesis”. These kinds of basic models (although omitting inclusion of many other aging phenotypes such as glycation, endocrine change, and telomere loss) (Figure 1.1) may provide a template for unraveling the etiology of other neurodegenerative disorders, particularly AD, but also the FTD family and some types of cancer, where the connections to aging and aging phenotypes are less clearly established. The high percentage of AD pathology in patients with DLBD argues also for a fundamental relationship between AD and PD that is still incompletely mapped.

Aging processes and the brain: cognitive changes in aging Although enormous evidence suggests that aging in the brain cannot be neatly separated from aging of the whole organism, at the same time, one has to consider that aging may be differentially expressed across different organ systems, and that the brain might be exposed differentially to aging processes (and perhaps differentially protected as well), including effects on the brain of pathological forms of aging, as described in the discussions of AD and PD. Much work suggests that a variety of neurocognitive functions decline with aging, even in those without demonstrable neurological disease (although the enormous difficulty in removing preclinical AD completely from one’s aging cohort/control group, plus the ubiquitous penetration of vascular disease in Western societies raises serious questions about how many studies purporting to show age-related cognitive change may be measuring at least in part prodromal stages of neurological decline from a major disease of aging). In any case, robust evidence suggests that a host of neurocognitive processes decline in aging, including episodic memory, working memory, spatial memory, processing speed, and even implicit (skill) learning, along with various motor functions, particularly motor speed and fine motor control (see Yeoman et al., 2012 for overview). The precise neural bases for these declines are still open to debate, and although initial

assumptions heavily emphasized age-related neuronal loss, increasing evidence argues that these neurocognitive declines are probably pleiotropic in origin, with synaptic loss possibly more important than actual neuronal loss. This itself also appears multifactorial, with roles for aminergic and neurotrophin decline, and where increased CNS inflammation might also play a role, but this has until recently been minimally probed, both in clinical and preclinical approaches (Cribbs et al., 2012). Loss of the smaller and highly plastic thin dendritic spines (more than the “fat” mushroom spines which appear more resistant to aging) appears to be one of the best candidates for an ultrastructural basis to age-related cognitive change, at least in relevant animal models (and thin spines which are more NMDA receptor-dense also appear more sensitive to deprivation of classic sex steroid hormones) (Dumitriu et al., 2010). A physiological correlate to cognitive declines in aging related to declarative (episodic) memory appears to be the phenomenon of prolonged hyperpolarization in aged hippocampal neurons, associated with changes in NMDA, AMPA, calcium channels, and other ion channels (Yeoman et al., 2012).

Departure from ancient evolutionary environment: impact on aging processes and promotion of diseases of aging Enormous evidence indicates that Western societies involve diets and lifestyles that are radically different from HG lifestyles and diets and, indeed, radically different from the original evolutionary environment in which the entire hominid line evolved. This may produce an “evolutionary discordance” (Konner, 2001) that may have profound effects on human health and a major influence on the biological trajectories of human aging. This notion of a radical departure from an evolutionary environment and a subsequent mismatch between our genes and our environment may provide a unifying context for connecting all increased risk factors for all the diseases of aging: Humans in modern technological societies are now living much longer (primarily due to our successful control over predation, starvation, and infection as primary causes of early mortality for children and younger adults). Put differently, all of the so-called healthy lifestyle practices that have been discovered piecemeal through many empirical studies (such as a diet high in fruits and vegetables, healthy omega-3/omega-6 ratios, high intake of fiber, and regular exercise) all have as a unifying context that they are components of our original long-term biological environment as HGs (Eaton and Eaton, 2002). This suggests that healthy lifestyle practices reduce or perhaps even virtually eliminate chronic mismatches between a genome carved in a more ancient HG environment and our current technological environment. Unfortunately, adoption of these healthy lifestyle practices is far from widespread in the United States or in other Western societies, and it may be relatively restricted

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

to those better educated and those belonging to more fortunate socioeconomic groups (Johannson et al., 1999). The fundamental hominid diet for probably more than two million years (preagriculture) was lean protein sources (game and fish), supplemented by significant quantities of fruits and vegetables (Cordain et al., 2005). Modern technological diets are higher in fat (particularly omega-6 fats) and carbohydrates (largely from grains and other agricultural products) and now contain significant transfats (which did not exist in our original biological environment); they also are frequently deficient in fiber and multiple protective phytochemicals (polyphenols) and possibly low in other several critical micronutrients, including choline and phospolipids, multiple B vitamins, and several minerals (Eaton et al., 2007). In addition, vitamin D deficiency is now quite common (Holick, 2007), while this was probably very rare, if not nonexistent, in ancient HG societies, in which skin color seems to have evolved to match latitudes and to balance vitamin D production with skin protection, given that both modern sunscreens and indoor living were nonexistent. The following tables summarize some of these fundamental differences between an ancient biological environment for humans and the current environment, including

Original Evolutionary Environment 1 2 3 4 5 6 7 8 9 10 11 12

Regular aerobic exercise (2-3+ hours per day) 9+ hours sleep (see #1) Calorie limitations (intermittent CR) High-phytochemical/polyphenol diets Omega-6/omega-3 ratio 1:1 to 3:1 with modest intake of overall fats High intake of fiber (about 50-100 g per day) Low sugar/carbs, except fruits/veggies Intake of K+ > Na+ (K+ > 4 gm/d) Pro-alkaline diet Minimal to no glycated proteins Intimate social groups/tribes Early mortality: infection, starvation, predation, and intraspecies violence: life expectancy 35-45 years

work on biomarkers from studies of HG societies (Eaton and Eaton, 1999; Eaton et al., 2007; Eaton et al., 1998a,b; Cordain et al., 2005). This evidence for huge biological environment shifts during a period of minimal genetic change for humans (the last 10,000 years) suggests a potential “unified field theory” for the diseases of aging (and that diseases of aging are largely “diseases of civilization”; Melnik et al., 2011). Ironically, humans have never lived longer than they are living in modern technological societies: The average life expectancy at birth within preindustrial HG societies was probably roughly 30–35 years (Konner and Eaton, 2010). However, this significantly extended lifespan in technological cultures is one in which penetration by a major disease of aging (excepting osteoarthritis, which is common in HG groups) appears more likely, relative to the few elders who existed in HG societies (Dunn, 1968; Konner and Eaton, 2010). Conclusive data on this question is lacking, however, and reconstruction of more ancient (Paleolithic) HG lifestyles and biological state involves extrapolating from the relatively few HG societies that survived into the twentieth century (columns adapted from Eaton and Eaton, 1999; Eaton et al., 2007; Eaton et al., 1998a,b; Cordain et al., 2005).

Modern Technological Environment 1 2 3 4 5 6 7 8 9 10 11 12

Minimal to no aerobic exercise (< 15 min/d) 7 hours or less of sleep (see #1) Unlimited calories Low phytochemical/polyphenol diets Omega-6/Omega-3 ratio 10:1 to 20:1 with typically higher intake of fats Low intake of fiber (≤ 15 gm/d) High sugar/carbs, not from fruits/veggies Intake of Na+ > K+ (Na+ > 4 gm/d) Pro-acidic diet Common glycated protein (especially milk products) Social isolation common Death from an advanced disease of aging: life expectancy 75-85 years

Biomarkers Hunter Gatherers 1 2 3 4 5 6 7 8 9 10 11

BMI 21–24 Total cholesterol under 125 Blood pressure 100–110/70–75 VO2 max good to superior Homocysteine low Vitamin D about 50–100 ng/mL Higher B vitamin/folate levels High insulin sensitivity Fasting plasma leptin 2–4ng/mL Waist/height ratio <45 Physical activity >1000 kcal/d

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Current Technological Societies 1 2 3 4 5 6 7 8 9 10 11

About 30% BMI >30, about 30% BMI 25–30 Total cholesterol about 200 or higher 120/80 (normative), with hypertension common VO2 max fair to poor (sedentary lifestyles) Homocysteine significantly higher Vitamin D deficiency common (10–30 ng/mL) Common B12 and folate deficiencies Variable degrees of insulin resistance Fasting plasma leptin 4–8ng/mL Waist/height ratio 52–56 Physical activity about 150–490 kcal/d for most

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Although conclusive data is still lacking, preliminary evidence suggests that HG societies did not appear to have nearly the incidence of cancer and heart disease (Eaton and Eaton, 2002), diabetes (Eaton et al., 2002), or AD (Eaton and Eaton, 1999) suffered by modern societies, even when the relative rarity of elder members is taken into account (Konner and Eaton, 2010). Consistent with these findings and hypotheses, a paleolithic diet improved diabetic biomarkers more than the highly touted Mediterranean diet (Lindeberg et al., 2007) and improved BP and glucose tolerance, decreased insulin secretion, increased insulin sensitivity, and improved lipid profiles, all without weight loss in healthy sedentary humans (Frassetto et al., 2009). Additional evidence (summarized in Spreadbury, 2012) suggests the provocative hypothesis that virtually all processed or “acellular” carbohydrates—which tend to be high-density carbohydrate foods—(ancient sources of carbohydrates in fruits and vegetables were low density) contribute directly to an inflammatory gastrointestinal microbiota which leads directly to leptin resistance, disordering of fundamental energy homeostasis through effects on multiple satiety peptides, and promotion of obesity. Spreadbury further argues that modern diets are truly distinct from ancient diets not in relationship to either nutrient density or glycemic index but only around carbohydrate density (Spreadbury, 2012) due to acellular grain-based foods. It is difficult to know precisely what the sum total or composite effect of such global and pervasive shifts in our basic biological environment might be, or what each factor may contribute to the overall increasing burden of diseases of aging in Western societies. However, the evidence favors the hypothesis that these shifts are first of all individually deleterious. Therefore, collectively, they are likely to be highly undesirable and potentially profound. Indeed, there may be poorly mapped synergisms among these various factors in promoting diseases of aging, as virtually every one of these factors—the complex multifactorial dietary shifts, sedentary versus aerobic lifestyles, common obesity generated by these two factors, vitamin D deficiency, low-grade sleep deprivation, and increased social isolation and stress (vs the intimate social groups of our ancestors)—all impact the regulation and management of inflammation (as even psychosocial isolation and social stress is a proinflammatory event). This suggests that, collectively, Western lifestyles (when compared to the lifestyles of our HG ancestors) may be hugely proinflammatory. There is evidence that autoinflammation involves increased OS (Finch, 2011), drives insulin resistance, and is potentiated by glycation (Semba et al., 2010), and increases cellular senescence. Such a global view of the biological environment also suggests strongly that singlecomponent “fad diet” approaches, such as the elimination of all fructose, sugar, or carbohydrates, are not likely to be successful unless combined with a larger group of dietary and lifestyle changes (although refined carbohydrate reduction as noted may help with reducing obesity, inflammation,

and pulsatile insulin over-production all of which may be critical in the Western society burden of diseases of aging). In any case, this analysis, which suggests a complex and highly interactive composite of environmental shifts relative to ancient HG environments that collectively are probably biologically profound. Many, if not most, of these lifestyle and dietary factors may also deteriorate the endogenous management of OS (Kaliman et al., 2011). Given that autoinflammation creates OS for “bystander” tissues (Finch, 2011), these lifestyle variables may impose a double burden: increasing OS while depriving us of several protective factors (found in our ancient evolutionary diet and lifestyle) that might ameliorate or protect against OS. OS, modulated by both diet and exercise, is also believed to be a primary factor in genetic damage and genomic instability (Prado et al., 2010), leading potentially into cancers and the acceleration of cellular senescence, as a primary defense against cancer (Ogrunc and Fagagna 2011). Cellular senescence in turn appears to be proinflammatory, creating a so-called “senescence-associated secretory phenotype” (SASP) (Blagosklonny, 2011). Many of these dietary and lifestyle factors also modulate the glycation of proteins and the formation of AGEs (particularly diets low in fiber and polyphenols and high in refined sugars/carbs), with AGE products a primary regulator and inducer of inflammation. Inflammation itself may promote insulin resistance and, thus, glycation, suggesting many positive feedback loops between these classic metabolic and age-related processes. Common vitamin D, B12 and folate deficiencies may contribute to declining autophagy, and also increasing inflammation (Holick, 2007), promoting cognitive decline in aging, increased homocysteine (as a marker and proxy for OS and inflammation), and possibly increased AD (Tangney et al., 2011). Many lifestyle factors also impinge on the cell signaling related to endogenous defenses against OS, particularly exercise, polyphenol intake, inflammatory state, obesity and excessive energy, and insulin resistance. Indeed, the typical alterations in energy homeostasis in Western diets and lifestyles, leading to an excess of energy (in turn, leading to obesity), are a primary activator of mTOR (mTOR, as a pathway that integrates nutrient signaling and growth factors), increasingly implicated as a central factor in the regulation and induction of aging (Blagosklonny, 2009, 2010a). In addition, multiple polyphenols (modestly) and DR, particularly protein restriction, inhibit mTOR. Collectively, these considerations suggest that Western lifestyles may directly impact the biology of the diseases of aging (and aging itself) directly and powerfully in a multitude of undesirable ways. Thus, although the central prolongevity triumph of Western civilization and medicine, the prevention and treatment of bacterial infection, has had a very positive impact on median survival to old age, Western lifestyles may accelerate aging and the diseases of aging in a multitude of other ways. Preventing the diseases of aging therefore has to begin with an appreciation for the central importance of lifestyle change,

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

back toward at least some approximation of our evolutionary environment.

What constitutes optimal prevention of the diseases of aging? In sum, this large constellation of globally altered lifestyle variables impacts the fundamental biology of aging and also modulates the underlying mechanisms directly driving all the diseases of aging. Jointly, these lifestyle factors, interacting with our genome (containing many currently unmapped polymorphisms that presumably directly modulate aging processes and the vulnerability to diseases of aging variably across individuals), in concert with multiple lifestyle behaviors, determine what aging trajectories our systems enter as we get older. These basic interactions between lifestyle (which we can map out) and many polymorphisms in our genetic endowment (which we can now map only minimally) determine how much our fundamental cellular repair mechanisms and defenses against cellular damage and aging are supported and enhanced as much as possible, versus overtaxed and overwhelmed. The primary and multifactorial mechanisms of aging reviewed in this chapter appear to lead invariably into the diseases of aging, if given enough time and enough room to work. Indeed, the sum total of presence or absence of all the diseases of aging in an individual may be one of the best ways to globally index aging itself (Blagosklonny, 2009). Challenges remain in operationalizing such a definition, of course, given that practical, cost-effective (and nonintrusive) metrics in relation to many of the diseases of aging are not yet clinically available. Unfortunately, the conventional medical perspective on diseases of aging in this country is still largely unaware of evidence that they may reflect common mechanisms operating in different tissues and systems; instead, conventional medicine mostly approaches each major disease of aging in a piecemeal and fragmented fashion. This chapter argues strongly against that traditional approach. Western lifestyles (consisting of a typical Western diet pattern and a sedentary lifestyle with poor sleep and increased social isolation) appear quite undesirable in terms of aging of the brain and body, deteriorate capacities to deal with various biological and social stresses, and remove us from our proper and ancient evolutionary environment. We have changed remarkably little genetically since our days as HGs, but our lifestyles have changed dramatically. This suggests that much of our current difficulties with health are not due to some exotic collection of esoteric biological derailments that can only be interpreted and treated by a “medical–industrial complex” and understood by someone with a doctoral degree; instead, they are due to a fundamental, if not profound, mismatch between our genes and our environment (Stipp, 2011). This suggests that basic health considerations should focus on approximating that ancient

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biological environment as much as possible: regular aerobic exercise, large amounts of fruits and vegetables, not too many calories, minimal processed food and other products of “food technology” (particularly our highly addicting fast food), a better omega-6/omega-3 ratio (typically very high in most Western diets with significant omega-3 deficiency), reduced social isolation, and improved sleep quality and quantity. As noted earlier, all these common recommendations place us closer to our ancient evolutionary environment and reduce this fundamental and destructive discordance between genes and environment in Western lifestyles. At this point, there is no cure for virtually any disease of aging (perhaps excepting some cancers), so meaningful prevention needs to a genuine priority instead of an afterthought in our health-care system. We must be willing to spend money on prevention and to make lifestyle changes a genuine cultural priority. It is also quite sobering to realize that, even in the context of the best possible preventative efforts, all one can do is delay the onset of a major disease of aging: Eventually, we will all succumb to one of these manifestations of aging. However, such delay in onset of a major disease of aging can potentially increase healthspan (even if major lifespan extension remains elusive) and substantially decrease the burden of diseases of aging in old age, along with their often punitive impact on quality of life and personal and societal economics (see Chapter 21). Prevention, in this context of the many considerations reviewed in this chapter, thus has to mean much more than “statins and beta-blockers” (controlling multiple conventional risk biomarkers that clearly have some prognostic value but may only minimally index our deceptive yet radical physiological departure from our ancestors). Instead, real prevention must mean, for the large majority of individuals in a culture and not simply for a fortunate few, reapproaching our original evolutionary environment. In simplest terms, as a culture, these major lifestyle changes must mean that we exercise and sleep significantly more, eat significantly less, and eat more wisely (consuming more of the “paleolithic” foods of our ancestors and less the questionable and addictive products of food technology). In addition, we need to aim more for quality of social connection than quantity of material consumption, as quality and depth of social attachment is emerging as one of the better predictors of long-term health (Seeman and Crimmins, 2001; see Chapter 10). Making these critical changes in priorities and approach, both individually and in terms of the embedded high-tech priorities of our health-care systems, is likely to be painful in many ways, as well as profoundly politically contentious. However, one cannot envision any viable long-term prescription or big-picture view of biological health that does not place these simple principles first. Additionally, this view of health (that it emerges from the basic fit between genes and environment) places health back into a proper evolutionary perspective that is badly lacking in many treatments of diseases of aging. There seems to be little

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sense in the current health-care environment that Darwin’s central insights (about the match between genetic endowment and environment determining adaptive success) has any relevance to discussions of basic health or illness. Has modern medicine abandoned Darwin? A central implicit myth of the “medical–industrial complex” (implicit in the sense that it is largely embedded in relentless advertising and is never explicitly stated) may be that high-tech medicine and first-line drugs are our best defense against the chronic diseases of aging, a supposition for which there is very little substantive evidence, and much counterevidence. An additional option for the future may be the possibility of a highly effective CR mimetic: perhaps a future version of resveratrol or rapamycin, some combination of our current (partial) CR mimetics, or perhaps even a completely new and different compound yet to be discovered. It seems an easy prediction that a truly safe and effective CR mimetic (which, by definition, would give the physiology of CR without the pain of chronic hunger) that could both slow aging and substantively delay onset of all the diseases of aging would be a compound that almost everyone would readily consider taking and many if not virtually everyone would find highly attractive. Indeed, if a patentable agent were proven highly effective and safe, one could easily predict that it would eventually become the best-selling prescription medicine of all time. However, such considerations (potential widespread use of CR mimetics) embed a major conundrum, similar to that posed by the potential creation of an “exercise pill.” Would individuals with the option to take a safe and effective CR mimetic still be adequately motivated to modify problematic lifestyle habits and move closer toward the original evolutionary environment of humans, which we believe promotes long-term health and healthy (or at least healthier) aging? One can readily appreciate the temptation to continue eating problematic but tasty foods and remaining overweight and sedentary, if one’s anxiety about any potential disease of aging could be significantly ameliorated by simply taking a pill. Such a dilemma in many ways goes to the heart of difficult choices confronting modern technological Homo sapiens in relation to both health care and, more fundamentally, long-term health. Do we trust in our high technology first and foremost? Do we place exclusive faith in our technological competencies, to the exclusion of trusting in biological relationships that are (at least, in some sense) pretechnological? Or must we place equal or even greater trust in our basic evolutionary heritage and our embeddedness in a complex biological matrix and ecology, the environment that carved our genome? Put in simplest terms, do we think that health promotion is primarily a technological or a lifestyle matter? Answers to these questions may determine a great many things about our long-term health in the coming century and our health-care system. Additionally, these choices mirror much larger and even more difficult choices about our basic relationship to a complex biological matrix (the extended environment), which is clearly showing

the negative impact of human technologies. A tempting hypothesis is that our disregard of the environment may be intrinsically hinged to the overvaluation of technology and the undervaluation of our biological “embeddedness” and our fundamental evolutionary context; these considerations were summarized in the previous sections regarding the basic notion of an evolutionary discordance between our genes and our current technological environment, diet, and lifestyles. In simplest terms, overvaluing high-tech medicine over “low-tech” lifestyle change may be a mistake we are culturally primed to make in how we view health and how we construct and finance our health-care systems. Whatever answers we might construct to such questions, there seems little question that Western societies face enormous challenges in a tsunami of age-related disease, in an aging population, at a time when fundamentally unhealthy lifestyles promoting those very same diseases of aging are widespread within the United States and in other Western societies. Health-care professionals of virtually all disciplinary persuasions need to take responsibility for educating both patients and the general public about these issues, as a critical part of reprioritizing genuinely proactive and early prevention efforts and health maintenance via lifestyle change over much later high-technology interventions that are proving to be prohibitively costly while at the same time yielding very uncertain if not minimal benefits in relation to quality of life.

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Chapter 2 Functional Changes Associated with the Aging Nervous System Julie A. Schneider1,2,3 and Chunhui Yang1,2 1

Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA Department of Pathology, Rush University Medical Center, Chicago, IL, USA 3 Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA 2

Summary • The aging brain undergoes complex changes with an increased vulnerability to distinct pathologies, particularly degenerative and vascular. • Age-related brain changes may include changes in volume, neuron size and number, white matter integrity, and synapse/dendrites; however, may be difficult to distinguish effects of normal aging vs. disease. • Amyloid plaques one of the hallmarks of Alzheimer’s disease (AD) are common in aging and may represent early AD. • Neurofibrillary tangles (NFT) another hallmark of AD are seen in other conditions, and in the hippocampus in the aging brain, where they may be related to memory loss separate from AD. • Vascular diseases including atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, and infarcts are exceedingly common in the brains of older persons. • The most common causes of dementia in aging are AD, vascular, and Lewy body pathology. These pathologies are often mixed in the brains of older persons. • AD is characterized by the wide-spread accumulation of amyloid, neocortical neuritic plaques and extensive limbic NFT (often extending to neocortex). A pathologic diagnosis of AD is found in some “normal” elders suggesting subclinical disease. • Dementia with Lewy bodies (DLB) is characterized by Lewy bodies in the substantia nigra, limbic structures and neocortex. AD changes often coexist • Vascular dementia is characterized by diffuse or strategically located infarcts or other vascular lesions (eg. hemorrhages). Microinfarcts are also related to dementia. • Frontotemporal Lobar degeneration (FTLD) with tau or ubiquitin (TDP) inclusions is increasingly recognized; FTLD is the underlying pathology of Frontotemporal dementia but may also underlie dementias with more typical presentations. • Less common causes of dementia include Corticobasal degeneration (CBD), Progressive Supranuclear Palsy (PSP), Creutzfeld-Jacob disease, Wernicke-Korsakoff syndrome (WKS) and other structural, metabolic, or infectious conditions. • Mild cognitive impairment (MCI) is characterized by the same common age-related pathologies, but often the pathology is intermediate in severity. In some cases there is sufficient pathology for a pathologic diagnosis of AD. • The presence of significant brain pathology in persons with MCI and dementia suggests that there are structural and cognitive reserve mechanisms in aging. • Movement disorders, particularly parkinsonism are very common in aging. Mild changes often don’t fit into a specific disease category. • Idiopathic Parkinson’s disease (bradykinesia, rigidity, tremor, and gait impairment) is characterized by loss of dopaminergic neurons in the substantia nigra and Lewy bodies. Co-existing dementia is common and may be related to concomitant AD changes or neocortical Lewy bodies (DLB) • Multisystem atrophy, CBD and PSP are less common causes of parkinsonism. • Amyotrophic Lateral Sclerosis is characterized by loss of upper and lower motor neurons and leads to progressive weakness and may have accompanying dementia. • Brain tumors, notably metastases, glioblastomas (malignant glial tumor), and meningiomas (benign growths attached to the dura) are common in aging. • Toxic metabolic encephalopathies may include changes related to systemic diseases such as liver or kidney disease, in which astrocytes undergo Alzheimer type II changes. Excessive alcohol use may lead to thiamine deficiency and WKS.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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• Older persons are more susceptible to infectious diseases including bacterial, viral and fungal meningitis, cerebritis and encephalitis. • Recent and past head trauma may cause problems in aging. • Subdural hematomas are most commonly related to tearing of bridging veins from relatively minor head trauma and falls. • Chronic traumatic encephalopathy is related to repeated clinical or subclinical concussions and may be associated with a degenerative dementia characterized by changes in memory, personality and behavior.

Introduction It is widely recognized that the brain and other parts of the nervous system undergo complex changes with age. For example, loss of brain weight and volume, changes in neurons and synapses, and oxidative, inflammatory, and biochemical changes have all been described in the aging brain. Moreover, the aging brain and nervous system show an increased vulnerability to a variety of distinct pathologies, particularly degenerative and vascular. The relationship between what may be considered “normal” age-related brain changes and disease has been debated. This chapter provides an overview of the neuropathology of the aging brain, including “normal” aging, the pathology of cognitive impairment and dementia, vascular disease, motor impairments, and other common geriatric brain conditions, such as toxic metabolic conditions, neoplasms, infections, and traumatic injury that may affect the elderly.

The aging brain The differentiation between “normal” aging and disease in the brain is complicated by multiple factors, including changing historical perspectives on what constitutes normal cognition and motor function in aging, the presence of slowly accumulating pathologies, and the concept of neural reserve (that is, normal cognitive or motor function in spite of significant amounts of pathology). This is to be considered on a background of changing techniques, more sophisticated studies, and semantic arguments about common changes versus disease. Although concepts regarding normal versus disease will likely continue to change, it remains valuable to discuss some of the currently considered age-related neuropathologic changes.

Brain size and neuronal loss Numerous studies have investigated age-related changes in brain weight, size, and neuron number. Although studies have been conflicting, it remains widely accepted that most of these brain parameters

decrease with advancing age. Most of the data from the early part of the twentieth century were based on studies with variable clinical information, making conclusions uncertain (Duckett, 2001). In general, studies of normal aging have been hindered by the intrusion of early disease states and the absence of detailed cognitive testing proximate to death (Peters et al., 1998). Recent pathologic studies using carefully selected controls and/or sophisticated stereologic techniques have shown that, on average, normal older subjects show only slight changes in the overall weight (Tomlinson and Blessed, 1968), cortical thickness (Mouton et al., 1998), and neuronal number in the absence of diseases (Tomlinson and Blessed, 1968; Terry and DeTeresa, 1987; Hof and Glannakopoulos, 1996; Mouton et al., 1998; Peters et al., 1998; Duckett, 2001). Inherent intersubject premorbid variability, especially for neuron number, remains a concern in evaluating the results of pathologic studies. Neuroimaging studies can provide expanded data on size and also evaluate longitudinal change. These studies suggest that ventricular rather than cortical volume shows the largest annual change (Resenick et al., 2000). Effects may also be regional; neuroimaging studies show agerelated thinning of the prefrontal cortex (Fjell et al., 2009), with lesser (Sullivan et al., 1995) or more variable (Fjell et al., 2009) involvement of the entorhinal and hippocampus in normal aging. Overall, neuronal loss is probably small, estimated at likely no more than 10% (Peters et al., 1998). Importantly, although morphologic changes may be slight, animal (Stemmelin and Cassel, 2003) and neuroimaging (Resenick et al., 2000) studies suggest that even small changes in the structure may have functional consequences. Studies on aging are now increasingly focused on cell-specific and lamina-specific vulnerabilities (Peters et al., 1998), regional modifications in synaptic remodeling (Terry et al., 1991; Masliah et al., 2006) and dendritic complexity (Scheibel, 1988; Richard and Taylor, 2010), white matter changes (Moody et al., 1995; Fernando et al., 2006; Gunning-Dixon et al., 2009; Simpson et al., 2009; Murray et al., 2010), and other downstream or compensatory changes, such as neurogenesis (Willott, 1999; Lowe et al., 2008; Pannese, 2011).

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White matter changes Neuroimaging studies have shown that there is a greater loss of volume in the cerebrum from white matter compared to gray matter in aging (Resenick et al., 2000). Moreover, these changes appear to preferentially affect the prefrontal white matter (Gunning-Dixon et al., 2009). This partly explains the increase in ventricular size often seen in aging (Tomlinson and Blessed, 1968; Duckett, 2001). Neuropathologic studies also show age-related white matter changes (Moody et al., 1995; Fernando et al., 2006; Simpson et al., 2009), with changes in multiple functional pathways (Simpson et al., 2009) and a possible relationship with chronic hypoperfusion (Fernando et al., 2006). White matter changes may result in cortical “disconnection” (Gunning-Dixon et al., 2009), and executive function appears to be specifically vulnerable to these age-related white matter changes (Murray et al., 2010). Synaptic and dendritic changes in aging Synapses are among the most important structures for neuronal communication. Synaptic loss during normal aging has been studied extensively in the last couple of decades. Quantitative studies using electron microscopy have revealed significant losses of synapses with age in laboratory animals and humans and have been estimated at about 10% (Terry et al., 1991; Duckett, 2001; Masliah et al., 2006; Pannese, 2011). However, neurons in older brains appear to retain some capacity for synaptic and dendritic plasticity and ability to form new synapses in response to injury or environmental manipulations (Pannese, 2011). These data are supported by studies suggesting that cognitive activities and training may improve function (Wilson and Mendes de Leon, 2002; Treiber et al., 2011). Dendrites (see Figure 2.1) account for 90% of the total surface area of a neuron’s receptive area, with more than 90% of excitatory synapses connected by dendritic spines (see Figure 2.2) and complexity that may vary by region (Scheibel, 1988). Studies have reported a significant

Figure 2.1 Apical dendrite (arrow head) and cell body (arrow) of pyramidal neuron, hippocampus CA1, mouse brain (Golgi stain). (For a color version, see the color plate section.)

Figure 2.2 Dendritic spines, mouse brain, hippocampus CA1 (Golgi stain). (For a color version, see the color plate section.)

age-related loss of dendrites, both shortening and fewer dendritic branches, in the cerebral cortex (Masliah et al., 2006). Large projection neurons have been shown to have simplification (pruning) of the neuronal dendritic tree; because these dendrites are located in layer I of the cerebral cortex, this loss may result in layer I cortical atrophy (Lowe et al., 2008).

Alzheimer’s disease changes in “normal aging” Neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques are the pathologic hallmarks of Alzheimer’s disease (AD; Section “Alzheimer’s disease”) and accumulate in large number in persons with AD dementia. Yet it is not uncommon to see NFT and plaques in small numbers in the aging brain of persons without cognitive impairment (Bennett et al., 2006). In some instances, this may represent the earliest pathologic stage of AD. Indeed, with notable exceptions such as chronic traumatic encephalopathy, Aβ plaques appear to be relatively specific to the AD pathophysiologic process. In contrast, NFTs are observed in a variety of other diseases and are extremely common in the limbic regions of almost all older persons. It has been suggested that NFT in the mesial temporal lobe may be related to the memory loss in AD and separately underlie age-related memory loss (Jack et al., 2010). Microscopic vascular pathology in the aged brain Vascular changes are extraordinarily common, with the majority of older persons having some degree of atherosclerosis, arteriosclerosis, or cerebral amyloid angiopathy (CAA) (Section “Cerebrovascular disease in the elderly”). Atherosclerotic plaques commonly occur in the intra and extracranial vessels of the Circle of Willis. Arteriolosclerosis (hyaline thickening of small vessels) is particularly common in the white matter, basal

Functional Changes Associated with the Aging Nervous System

ganglia, and thalamus. More severe forms are associated with hypertension and diabetes and are thought to underlie the development of infarcts. Mild dilation of perivascular Virchow–Robin spaces may occur with or without small vessel disease. Small venules in the periventricular white matter tend to show increased deposition of collagen in the adventitia (Moody et al., 1995), referred to as periventricular venous collagenosis. Mild forms of amyloid angiopathy are also common even in the absence of AD (Arvanitakis et al., 2011a). The role of each of these vascular changes, particularly when mild or in the absence of infarction, is not clear, although data suggest that severe vessel disease in the absence of frank infarction is related to damage to the brain and functional impairment (Arvanitakis et al., 2011a; Buchman et al., 2011). Vascular disease is discussed in detail in Section “Cerebrovascular disease in the elderly.”

Other changes Age-associated macroscopic changes also include thickening of the arachnoid and prominence of arachnoid granulations. Microscopically, aged brains often show an accumulation of lipofuscin in specific neuronal populations and regional prominence of corpora amylacea. Although not related to a specific disease state, and often considered benign, the significance of these changes has been debated. In addition, although more numerous in disease, older brains may show granulovacuolar degeneration and Hirano bodies primarily in the hippocampal region. Other biochemical and cellular changes, such as inflammatory shifts, oxidative stresses, and glial pathology, may also be important in normal aging and/or disease. For instance, microglia are normally inconspicuous in the young brain, but with aging, microglia may show signs of activation (Jurgens and Johnson, 2012), even in older persons with normal cognition. This is particularly the case with expression of class II major histocompatibility antigen (MHCII; see Figure 2.3).

Neuropathology of mild cognitive impairment and dementia Mild cognitive impairment (MCI) and dementia are clinical diagnoses based on history, cognitive testing, neurologic examination, and supportive studies. It is currently believed that there is a continuum of normal cognitive aging, MCI, and dementia, and although each has a characteristic clinical phenotype, it can be difficult to distinguish normal aging from MCI and to distinguish MCI from dementia, especially at their intersections. The brain pathologies underlying normal cognitive aging, MCI, and dementia also lie on a continuum

41

Figure 2.3 Activated cortical microglia in older person without cognitive impairment; antibody to class II major histocompatibility antigen (MHCII). (For a color version, see the color plate section.)

from no pathology to mild pathology and from mild pathology to abundant pathology. The most common pathologies associated with MCI and dementia are AD, infarcts (with or without associated clinical stroke), and Lewy body (LB) pathology. Although it has long been recognized that AD pathology is the most common pathology underlying dementia, we now know that older persons with dementia most often have mixed brain pathologies, most commonly AD pathology and infarcts, followed by AD and LBs (MRC CFAS, 2001; White et al., 2005; Schneider et al., 2007a; Sonnen et al., 2007; O’Brien et al., 2009; Nelson and Abner, 2010). Furthermore, it is recognized that older persons without cognitive impairment may have many of the same types and burdens of pathologies as in persons with dementia, suggesting neural or cognitive reserve and subclinical disease (Elkins et al., 2006; Rentz et al., 2010; Tucker and Stern, 2011). This section focuses on the neuropathology of AD, MCI, mixed dementias, vascular dementia (also known as vascular cognitive impairment), and dementia with Lewy bodies (DLB). This section also covers the expanding spectrum of the less common frontotemporal lobar degenerations (FTLD) and briefly reviews less common conditions associated with age-related cognitive impairment, such as Wernicke–Korsakoff syndrome (WKS) and Creutzfeldt– Jakob disease (CJD). Cognitive impairment may also occur as a result of other changes in the brain, including infections, trauma, and neoplasms, which other sections discuss.

Alzheimer’s disease There are both macroscopic and microscopic changes that occur in AD. These changes are evident prior to the clinical diagnosis in majority of the patients.

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The Aging Brain in Neurology

(a)

(b)

Figure 2.4 Alzheimer’s disease brain showing

(a) narrowing of gyri and widened sulci, and hippocampal atrophy with enlargement of lateral ventricles, especially temporal horn (b). (For a color version, see the color plate section.)

Macroscopic appearance of AD A decrease in brain weight is a usual but inconstant finding. Cortical atrophy is typical but also variable and has been shown to correlate with the level of cognition (Mouton et al., 1998). The mesial temporal lobe structures, including the temporal cortex, amygdala, entorhinal cortex, and hippocampus, are most affected, with the temporal horns of the lateral ventricles often being enlarged (see Figure 2.4); frontal and parietal regions are also commonly affected. The occipital lobe and the motor cortex are relatively spared (see Figure  2.4). The gross appearance of the basal ganglia, thalamus, and hypothalamus is usually unremarkable. The midbrain exhibits pallor of the substantia nigra (SN) in about one-quarter to one-third of AD cases. Pallor of the locus coeruleus in the rostral pons is common in AD.

(a)

Microscopic findings of Alzheimer’s disease: neurofibrillary tangles and amyloid beta plaques The two histologic hallmarks defining the pathology of AD since the original description by Alois Alzheimer in 1906 are NFTs and the extracellular amyloid beta (Aβ) deposits of senile plaques. NFTs are intraneuronal inclusions that consist of abnormally phosphorylated tau protein aggregate as paired helical filaments. NFTs occupy the cell body and extend into the apical dendrite. They are not easily discerned on hematoxylin–eosin (H&E) staining but are agyrophilic (that is, visualized by silver impregnation methods, such as modified Bielschowsky (see Figure  2.5), Gallyas, Campbell–Switzer, and Bodian stains. In addition, specific immunohistochemical staining with antibodies to the abnormal tau protein sensitively demonstrates NFT (see Figure 2.5). The morphology

(b)

Figure 2.5 Neurofibrillary tangles:

(a) hippocampus CA1 (modified Bielschowsky stain); (b) frontal cortex (immunohistochemistry with antibodies to paired helical filament). (For a color version, see the color plate section.)

Functional Changes Associated with the Aging Nervous System

Figure 2.6 Ghost tangles, hippocampus CA1 (modified

Bielschowsky silver stain). (For a color version, see the color plate section.)

of NFTs varies with the nature of the neurons in which they reside. Those in the cortex are usually flame shaped or triangular, and those in the subcortical or brainstem nuclei are typically globose. NFTs that survive after the neurons have died are visualized as “extracellular ghost tangles” and tend to be slightly larger and less densely stained than typical NFT (see Figure 2.6). Braak and Braak observed that the progression of NFT changes in older persons follow a predictable pattern (Braak and Braak, 1991). They found a characteristic distribution and progression of NFTs in older persons, which comprised of six stages, starting in the transentorhinal and entorhinal layers and progressing to the neocortex. The first two stages involve NFTs in the entorhinal, transentorhinal, CA1, and subiculum. In stages III and IV, increasing numbers of NFTs accumulate in the limbic system, and in stages V and VI, NFTs become abundant in neocortical areas. NFTs generally occur in a predictable laminar distribution; in the entorhinal cortex, NFTs are almost always present in large projection neurons of layers II and IV, whereas layers III, V, and VI have relatively few tangles.

(a)

Figure 2.7 Neuritic plaque

pathology in AD. (a) Three NPs in the neocortex on H&E stain are difficult to see. (b) The same NPs are easily visualized on modified Bielschowsky silver stain. (For a color version, see the color plate section.)

43

Senile plaques are the other hallmark of AD pathology and consist of fibrillar amyloid material, composed of Aβ, which shows a characteristic red–green birefringence in Congo red-stained sections. Aβ is produced by the abnormal proteolytic cleavage of amyloid precursor protein (APP), a membrane protein that, when normally cleaved by alpha secretase, secretes nonamyloidogenic fragments. Abnormal cleavage with beta secretase and gamma secretase results in the production of Aβ peptide that is 39–43 amino acids in length; the insoluble form is deposited as Aβ40 or Aβ42. Other proteins, such as interleukins, apoE, and components of the complement system, also deposit in plaques (Thal et al., 2006). AD is pathologically characterized by at least two plaque types, neuritic plaques (NP) and diffuse plaques (DP). NP is the type of plaque critical for neuropathologic diagnosis of AD (Mirra et al., 1991) and is characterized by thickened neurites; these plaques often have a dense central core of amyloid surrounded by a less compact peripheral halo of amyloid. Plaques may be difficult to visualize on routine H&E stains but are easily seen on silver stain (see Figure 2.7) or with antibodies to the Aβ protein (see Figure 2.8). The dense core and peripheral halo are often separated by a clear zone that contains glial cells and dystrophic neuronal processes that often show abnormally phosphorylated tau protein (Thal et al., 2000). NP may be associated with reactive astrocytes, and microglial cells may be seen within the dense central core (Thal et al., 2000). Immunostaining with antibodies to specific forms of Aβ typically shows that the dense center core is enriched in Aβ40, while the periphery has predominantly Aβ42 (Thal et al., 2000). NPs are prominent in the amygdala and hippocampal subicular complex and are present in association cortices in AD; similar to NFTs; however, they are less common in primary motor and visual cortices. DPs are also common in AD and consist of deposits of amyloid without thickened or PHF-containing neurites. Some plaques, especially DPs, have a perivascular orientation, usually in association with amyloid angiopathy (see Figure 2.8). Morphologic characteristics and protein and cellular components of senile plaques permit differentiation of plaque types (Thal et al., 2000).

(b)

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The Aging Brain in Neurology

(a)

(b)

(c)

(d)

Figure 2.8 Amyloid pathology

in AD. (a) Numerous amyloid immunostained plaques in the cortex at low power. (b) Leptomeningeal arterioles also may show amyloid deposition. (c, d) Higher power of plaque pathology using amyloid immunostain. (For a color version, see the color plate section.)

Similar to the stages of NFT as described by Braak, the progression of senile plaque pathology has also been described (Thal et al., 2000; Thal et al., 2006). In the first phase, DPs deposit in the neocortex. In the second phase, Aβ plaques deposit in allocortical areas, such as the entorhinal region, and in the subiculum/CA1 region of hippocampus. In the third phase, the basal ganglia, the thalamus, and the hypothalamus become involved, followed in the fourth phase with the involvement of the midbrain and the medulla oblongata. Finally, in the fifth phase, senile plaques develop in the pons and the cerebellum. Deposition of Aβ amyloid in the leptomeningeal and cortical small arteries and arterioles occurs in most individuals with AD, but it also occurs in “normal” aging (Arvanitakis et al., 2011a). When severe, CAA is associated with lobar hemorrhages, perivascular scarring, and less commonly infarcts. CAA is preferentially deposited in the small vessels of the occipital cortex and meninges; thus, CAA should be considered in the presence of posterior lobar hemorrhages (see Figure 2.8).

Criteria for the pathologic diagnosis of AD Significant progress has been made in identifying clinical biomarkers for the diagnosis of AD, yet a definitive diagnosis of AD still requires pathologic examination of the brain. Pathologic criteria for the diagnosis of AD were initially established to confirm the clinical diagnosis in persons with dementia. These criteria have changed three times over the past four decades and have been strongly influenced by the contemporaneous views of dementia and the normal aging brain. The

first set of criteria developed in 1985, termed Khachaturian criteria, used an age-dependent specific density of senile plaques (Zhachaturian, 1985). More plaques were required in older persons than younger patients to confirm a diagnosis of AD, apparently to allow for sparse plaques in older individuals without dementia. Plaque type was not specified. The Consortium to Establish a Registry for Alzheimer’s disease (CERAD) criteria for a pathologic diagnosis of AD, developed in 1991, proposed semiquantitative measures of neocortical NP to establish a probability statement on the diagnosis of AD (possible, probably, definite) after considering age and clinical diagnosis (Mirra et al., 1991). Probable or definite AD required a larger number of plaques in older persons and a premorbid diagnosis of dementia. NIA–Reagan criteria (The National Institute on Aging, 1997), proposed in 1997, made a couple of important changes, including incorporation of NFT—using Braak score (Braak and Braak, 1991), and included plaque estimates without regard to age, to allow for probability statements of the likelihood that dementia occurs as a result of AD (high, intermediate, low). These criteria were formulated for pathologic examination of brains with dementia but do not take into account AD neuropathologic changes in MCI (Section “Mild cognitive impairment”) and in persons with no cognitive impairment. Criteria are currently being revised to allow for the description of AD neuropathologic changes in persons with MCI and no cognitive impairment. The presence of significant AD pathology in normal older persons suggests the presence of preclinical disease and neural reserve.

Functional Changes Associated with the Aging Nervous System

Mild cognitive impairment MCI is a clinical diagnosis and represents an intermediate stage between normal aging and dementia (Bennett et al., 2002). Persons with MCI have cognitive impairment, memory, or nonmemory, but do not fulfill the criteria for dementia. In the past decade, there has been expanding data on the pathologic basis of MCI (Morris et al., 2001; Markesbery et al., 2006; Petersen et al., 2006). As with dementia (Section “Mixed pathology (AD, infarct, and LB Pathology) in dementia”), the underlying pathology is heterogeneous, with AD being the most common underlying pathology, followed by infarcts and then LBs, supporting that MCI represents a transition between normal aging and dementia (Bennett et al., 2006). While the pathology is often intermediate, it is interesting to note that more than half of persons with MCI have sufficient pathology to render a pathologic diagnosis of AD (Schneider et al., 2009). This has implications for preventions and treatments targeting early disease. Infarcts are also common, especially in persons with nonamnestic MCI and mixed with AD pathology in persons with amnestic MCI. LB disease is the third most common pathology in MCI and is most commonly mixed with AD pathology. FTLD and related dementias also likely pass through an intermediate clinical stage, but a little is known regarding the pathologic phenotype. Vascular cognitive impairment and dementia Early in the twentieth century, vascular disease was believed to be the primary pathologic cause of cognitive decline in older persons, often called senility. Recognition that AD pathology was the most common pathology underlying late-life dementia and the lack of definitive criteria for a pathologic diagnosis of vascular dementia resulted in a lesser emphasis on vascular dementia as a pathologic substrate for age-related dementia. More recently, there has been a resurgence of interest in vascular disease as a pathologic substrate for age-related dementia, especially as a mixed disorder (Schneider and Bennett, 2010). Community-based and population-based prospective epidemiologic studies have shown that infarcts and other vascular pathologies are very common in the brains of older persons, from one-third to one-quarter of older persons with some vascular brain pathology (MRC CFAS, 2001; White et al., 2005; Schneider et al., 2007a; Sonnen et al., 2007). Initial studies suggested that infarcts must be in a certain volume, such as 100 mL (Lowe et al., 2008) order to result in dementia, but it was later recognized that multiple infarcts were also an important factor, so the term multi-infarct dementia (MID) was coined (Hachinski et al., 1974). Because myriad vascular lesions, including smaller strategically located infarcts, can also result in dementia, the terminology was subsequently changed to vascular dementia. The alternative nomenclature vascular cognitive impairment is based on the recognition that

45

vascular lesions may not result in the pattern of cognitive impairment required for the clinical diagnosis of dementia, which is typically geared toward the diagnosis of AD, emphasizing episodic memory impairment (Hachinski et al., 2006). Indeed, though vascular and AD pathology may have overlapping phenotypes, studies show that cerebral infarcts do not affect all cognitive systems equally, showing the strongest association with perceptual speed and the weakest with episodic memory (Schneider et al., 2003). While AD is still considered the most common pathology underlying dementia, vascular disease is considered the second leading cause of dementia, representing about 10% of the cases (Roman, 2003). This number is most certainly greater if one considers microscopic infarcts, mixed pathologies, and the role of additional vascular lesions, such as amyloid angiopathy. No generally accepted pathologic criteria apply for a diagnosis of VCI or vascular dementia. Vascular substrates for dementia are heterogeneous and include single strategic infarcts, multiple infarcts, cortical infarcts, subcortical infarcts, and microscopic infarcts. Other vascular pathology, including global ischemia, white matter degeneration, and small vessel disease (arteriolosclerosis and amyloid angiopathy) may also play a role. Finally, there has been increasing interest in the hippocampal sclerosis, which is at least partly related to global ischemia and selective vulnerability. There are numerous classification schemes used to differentiate vascular lesions that may contribute to vascular dementia, including divisions into large and small vessel diseases, ischemic and hemorrhagic infarcts, and focal versus multifocal disease (Hachinski et al., 1974; Romàn et al., 2002; Roman, 2003; Hachinski et al., 2006; Chui, 2007; Jellinger, 2008; Schneider and Bennett, 2010). Focal disease includes single infarcts and hippocampal sclerosis, whereas multifocal disease includes multiple infarcts, as well as global ischemia and ischemic white matter disease.

Infarct size, number, and location It has long been recognized that large infarcts can be related to dementia, especially in the form of post-stroke dementia. Data from longitudinal clinical pathologic studies of aging and AD (Schneider et al., 2003) have also shown that the odds of dementia are higher in persons with large or clinically evident infarctions. With large infarcts, the underlying disorder is atherosclerosis affecting large intracranial or extracranial blood vessels, giving rise to local thromboses or emboli. In addition, cardiac disorders, such as atrial fibrillation and myocardial infarction, can be the source of cerebral emboli. The number of lesions also contributes to the development of dementia (Hachinski et al., 1974). Dementia associated with MID has been reported to account for a substantial proportion of vascular dementia and to more frequently involve the dominant hemisphere (Jellinger, 2008). Indeed, location of lesions may be more

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(a)

The Aging Brain in Neurology

(b)

Figure 2.9 An old lacunar infarct in the

anterior thalamic nucleus: (a) gross coronal brain slab; (b) histologic appearance of old infarct with few macrophages and cavitation. (For a color version, see the color plate section.)

critical than total volume. In some cases, a single relatively small infarct (strategic infarct) can damage the brain enough to cause dementia (Chui, 2007). Infarcts in the left hemisphere disproportionately increase the risk of dementia (Roman, 2003; Kuller et al., 2005) as do infarcts in the hippocampus, anterior thalamus, genu of internal capsule, and anterior caudate (Chui, 2007; see Figure 2.9).

Subcortical ischemic vascular dementia Subcortical ischemic vascular dementia (SIVD) is a subtype of vascular dementia defined by the presence of lacunar infarcts and deep white matter changes (Romàn et al., 2002; Chui, 2007). The syndrome conceptually includes at least two previously defined pathologies: lacunar states (état lacunaire), with multiple lacunes in the subcortical nuclei and softening of the white matter; and Binswanger’s disease, with white matter degeneration and secondary dilatation of ventricles (subcortical arteriosclerotic/ leukoencephalopathy (SAE) and leukoaraiosis (Romàn et al., 2002; Roman, 2003; Chui, 2007). État crible, which describes the appearance of multiple enlarged perivascular spaces in deep gray and white structures, may also be present (see Figure 2.10). The microangiopathy underlying these changes is thought to be the result of arteriolosclerosis (often erroneously referred to has lipohyalinosis (LH)) and is related to aging, hypertension, diabetes mellitus, and possibly other conditions, such as hyperhomocysteinemia (Esiri et al., 1997; Chui, 2007; Jellinger, 2008; Schwartz et al., 2010). Lacunar infarcts, generally about 1 cm or less in diameter, are cavitating lesions in the gray and white matter (see Figure 2.9). Lacunar infarcts occur predominantly in subcortical gray matter, predominantly basal ganglia and thalamus, internal capsule, and brainstem. Subcortical infarcts may not be clinically recognized and may be

discovered incidentally on neuroimaging (Chui, 2007) or at autopsy (Schneider et al., 2007b). Lacunar infarcts are frequently multiple and bilateral and often coexist with other vascular lesions. These lesions appear as foci of ischemic necrosis and result from narrowing or occlusion (arteriolosclerosis) of penetrating (striate) arteries branching directly from larger cerebral arteries. White matter degeneration (subcortical arteriolar encephalopathy and leukoaraiosis) is associated with small vessel disease with vascular hyalinization (arteriolosclerosis), expansion of the perivascular space, pallor of perivascular myelin, and astrocytic gliosis (see Figure 2.10). Pathologically, ischemic white matter lesions appear as foci of confluent white matter softening, with pale staining of myelin, often sparing subcortical U-fibers. Radiographic studies have proposed that 25–38% of the cerebral white matter needs to be affected to allow for a diagnosis of subcortical vascular dementia (Price et al., 2005). Clinical signs may be the result of disruption of pathways from the prefrontal cortex to the basal ganglia and of thalamocortical pathways. Although executive function is often considered the most commonly affected cognitive system, subcortical infarcts can also be related to memory loss (Schneider et al., 2007b) and parkinsonism (Buchman et al., 2011) (see Figure 2.10).

Microscopic infarcts Microscopic infarcts are most commonly defined as the infarcts visualized by light microscopy in the absence of the infarcts seen on gross examination. Microscopic infarcts are found in about 50% of older persons with macroscopic infarcts but also may be seen in the absence of macroscopic infarcts (Arvanitakis et al., 2011b ). When cortical and multiple, these tiny infarcts have been shown to be a strong correlate and add to the

Functional Changes Associated with the Aging Nervous System

(a)

47

(b)

Figure 2.10 Subcortical ischemic vascular

disease. Both (a) gross and (b) histologic brain sections show lacunar infarcts and enlarged perivascular spaces predominantly in the caudate in a person with vascular parkinsonism. (For a color version, see the color plate section.)

likelihood of dementia even after controlling for macroscopic infarcts and AD (White et al., 2005; Sonnen et al., 2007; Arvanitakis et al., 2011b). These infarcts are not yet identifiable on neuroimaging, although they have been found to correlate with measures of white matter pathology, including macroinfarcts, hemorrhages, and leukoencephalopathy (Longstreth and Sonnen, 2009). The mechanism by which these tiny infarcts result in dementia is not known. Because only a very small amount of tissue is sampled in most brains, several microinfarcts may represent a far greater number of occult infarctions and a large loss of tissue. Alternatively or in addition, microinfarcts may be a surrogate for the presence of other vascular damage.

Dementia with Lewy body disease Lewy bodies are the pathognomonic inclusion found in the SN in Parkinson’s disease (PD). Almost five decades ago, cortical LBs were found in an atypical dementia syndrome (Kosaka et al., 1984), variably called diffuse LB disease (Dickson et al., 1987), DLB (Sima et al., 1986), and LB variant of AD (Samuel and Galasko, 1996). Most recent criteria use the term dementia with LBs (DLB; McKeith et al., 1996). DLB manifests with a decline in cognition with associated fluctuations, hallucinations, and parkinsonism. While pure DLB (without concomitant AD pathology) is a relatively uncommon cause of dementia (Schneider et al., 2007a), probably representing only about 5% of all dementia cases, DLB with concomitant AD pathology is more common, including about 10–20% of dementia cases, depending on the cohort. Because of associated neurobehavioral difficulties, DLB may be more common in clinic cohorts, compared to the community (Wakisaka et al., 2003). Overall, DLB is currently considered as the second most common neurodegenerative cause of dementia. Similar to AD, diagnosis requires pathologic confirmation.

Macroscopic and microscopic appearances of DLB The macroscopic appearance of the brain in DLB is usually similar to that in PD, including mild cortical atrophy of the frontal lobe, with variable pallor of the SN and locus coeruleus. Pallor of the locus coeruleus also occurs in AD without LB. In DLB with significant AD changes, there may be more severe atrophy of the hippocampus and temporal and parietal lobes. LBs and Lewy neurites (LN) are present in multiple selective brain regions, including the brainstem, limbic, and neocortical regions. The olfactory bulb and spinal cord are also commonly involved in LB disease and may be related to olfactory and autonomic disturbances. LBs are believed to progress in a caudal to rostral distribution; however, amygdala LBs may occur in the absence of brainstem involvement and may represent a distinct form of LB disease (Uchikado et al., 2006). The pathology of DLB overlaps with the pathology of idiopathic PD and PD dementia. The neuronal loss from the SN and locus coeruleus is more variable than in typical PD but may also be severe. Nigral and other brainstem neurons often contain classic LBs (see Figure 2.11), and LBs may also lie free in the neuropil. The cortical LBs (see Figure 2.12) that are predominant in the lower layers of cortex, particularly in the small-size to medium-size pyramidal neurons, are smaller and less well-defined and lack halos (see Figure  2.12). LB can be seen in the sections stained with H&E and ubiquitin immunohistochemistry, but α-synuclein is the most sensitive and most specific stain. LN can be seen in all regions with LBs but can also be seen separately in CA2-3 region of the hippocampus. In DLB, cortical LB density has been associated with severity of cognitive impairment (Samuel and Galasko, 1996). In addition to LB and LN, DLB cases commonly have transmural spongiform change in the entorhinal cortex and other temporal regions. Coexisting AD pathology is very common in DLB; conversely, LBs

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The Aging Brain in Neurology

(a)

(b)

Figure 2.11 Substantia nigra

neurons with multiple LBs: (a) classic dense concentric appearance with peripheral halo on H&E; (b) LB halo stains darker using antibodies to α-synuclein. (For a color version, see the color plate section.)

are common in AD, described in more than 50% of cases (Hamilton, 2000), depending on the cohort and regions (for example, the amygdala). The presence of significant AD pathology may modify and obscure the typical DLB clinical presentation (McKeith et al., 2005).

pathologic diagnosis of AD or mixed with sufficient AD pathology to render an additional pathologic diagnosis of AD. It has been suggested that there is an interaction of β-amyloid and α-synuclein, accounting for the common co-occurrence of these two types of pathologies (Pletnikova et al., 2005).

Diagnostic criteria for DLB Current criteria for the neuropathologic diagnosis of DLB require the histologic observation of LB and divide the disease into three types: brainstem-predominant, limbic type, and neocortical type (McKeith et al., 1996; McKeith et al., 2005). Evaluation of LBs in the brainstem is recommended and includes SN, locus coeruleus, and dorsal nucleus of the vagus. Basal forebrain/limbic system evaluation includes the basal nucleus of meynert, amygdala, anterior cingulate cortex, and entorhinal cortex. Neocortical regions include the middle temporal gyrus, middle frontal gyrus, and inferior parietal lobule. DLB may be “pure” without sufficient AD to render an additional (a)

Mixed pathology (AD, infarct, and Lewy bodies pathology) in dementia Both infarcts and LBs more commonly coexist with AD pathology than as an isolated pathology in older persons with dementia (MRC CFAS, 2001; White et al., 2005; Schneider et al., 2007a; Sonnen et al., 2007; O’Brien et al., 2009; Nelson and Abner, 2010). Indeed, mixed brain pathologies are very common in the brains of community-dwelling older persons and are more common than any single pathology in older persons with dementia (Schneider et al., 2007a). AD pathology mixed with infarcts is the most common mixed pathology, followed by AD mixed with LBs.

(b)

(c)

Figure 2.12 Cortical LBs in the superior

temporal cortex. (a) H&E stain shows an eosinophilic cytoplasmic inclusion without a clearly defined halo. (b) Low-magnification view showing numerous α-synucleinimmunostained cortical LBs. (c) Cortical LBs may stain uniformly or show a peripheral halo with α-synuclein immunostain. (For a color version, see the color plate section.)

Functional Changes Associated with the Aging Nervous System

The addition of each pathology is not benign but rather further adds to the likelihood of dementia and the severity of cognitive impairment (Schneider et al., 2003; Schneider et al., 2007b; Schneider et al., 2009). Mixed pathologies are also common in clinically diagnosed probable AD and may be seen in MCI, particularly amnestic MCI (Schneider et al., 2009). Clinicians should recognize mixed pathologies (particularly AD mixed with infarcts and/or LBs) as an important etiology of dementia in older persons.

Frontotemporal lobar degeneration FTLD is the designation for a heterogeneous group of non-AD neurodegenerative disorders typically associated with frontotemporal dementias (FTD). In contrast to AD, FTD typically presents with behavioral (behavioral variant) or language (including primary progressive aphasia or semantic dementia) disturbances rather than episodic memory, which is preserved until later in the disease. As its name implies, FTLD is associated with selective degeneration of the frontal and/or temporal lobes and also variable involvement of subcortical gray matter. Atrophy may be asymmetric, with corresponding underlying neuronal loss and gliosis. Layer 2 spongy change of the cortical regions is often noteworthy. Clinical phenotypes in FTLD may reflect the abnormalities associated with these anatomic regions. The increased application of immunohistochemistry for tau, ubiquitin, and the recent recognition of TAR DNAbinding protein 43 (TDP-43) and FUS protein inclusions has led to increased recognition of FTLD and has enhanced the two main classification groups: FTLD-tau (tau-associated disorder) and FTLD-ubiquitin (FTLD-TDP-43 and FTLDFUS; Mackenzie et al., 2009). These pathologies (especially FTLD-TDP-43) are now more easily and commonly recognized, which will allow for increased detection and a recalculation of the frequency of the different subgroups of disease (Cairns et al., 2007; Mackenzie et al., 2009). When no inclusions are identified (FTLD-NI), this is often referred to as dementia lacking distinctive histology (DLDH). Clinical phenotypes of dementias are currently being investigated in relation to the broadening spectrum of inclusions that are now recognized in the FTLD spectrum.

FTLD-tau and other tauopathies The non-Alzheimer tauopathies are characterized by the accumulation of abnormal tau protein in neurons or glial cells or both. The major tauopathies associated with dementia under the rubric of FTLD-tau include Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and multisystem tauopathy with dementia. Most of these disorders can be distinguished by characteristic patterns of pathologies, inclusions, and predominant tau isoforms. FTD with parkinsonism linked to chromosome 17 (FTLD17) is also a FTLD-tau that is linked to MAPT mutations and typically has three and four repeat isoforms of tau-tangles, but it does not

49

have a characteristic pattern of pathology (Mackenzie et al., 2009). Other disorders more variably linked to the typical FTD syndrome that have characteristic tau pathology include agyrophilic grain disease, chronic traumatic encephalopathy, and tangle-predominant dementia.

Pick’s disease Pick’s disease was first described in 1892 by Albert Pick. The histopathology was detailed by Alzheimer and Altman two decades later (Lowe et al., 2008). In the past, the designation of Pick’s disease was synonymous with FTLD; we now recognize that Pick’s disease is one of the multiple pathologic subtypes of FTLD, specifically one of the subtypes of FTLD-tau (Mackenzie et al., 2009). Gross pathology includes frontotemporal atrophy, usually superior temporal gyrus, with relative sparing of the posterior twothirds of cortex. With severe atrophy, the involved cortical gyri have a so-called knife blade appearance. There is variable atrophy of the caudate and SN. Microscopically, in addition to severe neuronal loss and gliosis in the described regions, the pathognomonic finding is the Pick body, which is the cytoplasmic inclusion found in neurons in the frontal and temporal cortices, as well as in the limbic and paralimbic cortices and temporal lobe, especially the granule cell layer of the hippocampus. Pick bodies are commonly found in layers II and IV, are argyrophilic, and stain with antibodies to abnormally phosphorylated tau protein. Pick bodies consist of mostly straight but also twisted filaments, compared to the paired helical filaments of AD (Lowe et al., 2008). Biochemically, Pick bodies consist primarily of the three repeat-tau isoform. In addition to Pick bodies, cases often show ballooned neurons, called Pick cells, in the involved regions of cortex. These can be highlighted using antibodies to neurofilament.

Corticobasal degeneration CBD was first described in 1967 as “corticodentatonigral degeneration with neuronal achromasia” (Gibb et al., 1988). The patients with classic CBD develop an atypical parkinsonian disorder, asymmetrical clumsiness, and stiffness or jerking of a limb, commonly an arm. Dystonic rigidity, akinesia, and myoclonus develop after 2–3 years. Many patients develop the “alien limb” phenomenon (Gibb et al., 1988; Paulus and Selim, 2005; Lowe et al., 2008). It has been increasingly recognized that CBD may also be associated with focal cortical syndromes, such as frontal lobe dementia or progressive aphasia, with the clinical phenotype of CBD corresponding to the specifically affected cortical regions of damage (Dickson, 1999). For example, in cases with language abnormalities, the brunt of the pathology may be in the peri-Sylvian region. Macroscopically, typically there is asymmetrical cortical atrophy of the posterior frontal, parietal, and perirolandic cortex. The superior frontal and parietal gyri are usually more involved than the middle and inferior frontal gyri

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The Aging Brain in Neurology

and the temporal or occipital lobes. There is usually pallor of the SN. Histologically, there is neuronal loss with astrocytosis, which is often most severe in the superficial cortical laminae and associated with superficial spongiosis similar to that seen in FTLD. Ballooned neurons (see Figure 2.13) are seen usually in layers III, V, and VI (Lowe et al., 2008). The ballooned neurons are enlarged eosinophilic and are weakly argyrophilic, lack Nissl substance, and are occasionally vacuolated; and this is referred to as neuronal achromasia (Dickson, 1999). The presence of these ballooned neurons in the cortical areas of the cerebral convexities is important for the diagnosis of CBD. These ballooned neurons are immunoreactive for phosphorylated neurofilaments and αβ-crystallin and are variably reactive for tau protein and ubiquitin (Dickson, 1999). The SN typically usually shows moderate-tosevere neuronal loss with gliosis. The remaining neurons may contain ill-defined neurofibrillary inclusions or corticobasal bodies (Riley et al., 1990; Schneider et al., 1997). Immunohistochemistry shows widespread tau-positive inclusions within glial processes in the involved regions and abundantly in white matter. These can be a helpful diagnostic feature. Tau-positive, argyrophilic granular, and coiled bodies (oligodendroglial filamentous inclusions) are also widespread in the cortex and white matter. Another helpful diagnostic feature is astrocytic plaques (see Figure  2.14), which consist of a collection of tauimmunoreactive processes of astrocytes that surround unstained neuropil and are frequent in premotor, prefrontal, and orbital regions, as well as the striatum, caudate, and putamen. There is regional and immunohistochemical heterogeneity of CBD pathology; and the distinction between CBD and PSP can be difficult in some cases (Bergeron et al., 1997; Schneider et al., 1997). Extensive neuropil tau-positive threads, ballooned neurons, and astrocytic plaques are of significant value in the diagnosis of CBD (Bergeron et al., 1997; Dickson, 1999).

Figure 2.13 Corticobasal degeneration: ballooned neuron (neuronal achromasia) on H&E stain. (For a color version, see the color plate section.)

Figure 2.14 Tau-immunopositive astrocytic plaques are characteristic of CBD (AT8 immunohistochemistry). (For a color version, see the color plate section.)

Progressive supranuclear palsy PSP is typically described as sporadic movement disorder; but as with CBD, it can also be associated with dementia. While the initial clinical description of PSP by Steele et al. (1964) (Lowe et al., 2008) emphasized a unique constellation of clinical findings (parkinsonism, supranuclear gaze palsy, and falls), other presentations may suggest typical PD, multiple system atrophy (MSA), CBD, or another degenerative disease (Collins et al., 1995; Bergeron et al., 1997; Schneider et al., 1997; Dickson, 1999). Macroscopically, in PSP, the cerebral cortex is usually unremarkable, but there may be atrophy and discoloration, especially of the subthalamic nucleus, but also involving globus pallidus, dentate nucleus of cerebellum, midbrain, and pontine tegmentum; there may also be tectal and tegmental atrophy with dilatation of the cerebral aqueduct. Decreased pigmentation of the SN and locus coeruleus is also typical but variable (Gibb et al., 1988; Schneider et al., 1997). Histologically, there is neuronal loss and gliosis predominant in the subcortical nuclei, particularly in the globus pallidus, subthalamic nucleus, red nucleus, and SN. The subthalamic nucleus is typically severely involved; the SN shows diffuse involvement but is most severe in the ventrolateral tier, as in PD and CBD (Dickson, 1999). Cortical pathology is less severe and may be noted in the precentral cortex (Dickson, 1999); specific pathology is also typical in the dentate granule cells (Gibb et al., 1988; Dickson, 1999). The hallmark of PSP is the presence of NFTs and tau-positive threads in subcortical gray matter, including subthalamic nucleus, globus pallidus, and striatum (see  Figure 2.15). Tau pathology including tangles and threads is detected using antibodies specific for 4-repeat forms of tau, but it is negative for 3-repeat forms of tau, consistent with a

Functional Changes Associated with the Aging Nervous System

51

(a)

(b)

(c)

Figure 2.15 Progressive supranuclear

palsy: neurofibrillary tangle (NFT) pathology. (a) Globose NFT with basophilic filamentous appearance (H&E). (b) NFT in SN highlighted with tau immunohistochemistry. (c) Antibody to 4-repeat tau isoforms labels two NFT. (For a color version, see the color plate section.)

4-repeat tauopathy (Collins et al., 1995; Katsuse et al., 2003). A distinctive form of astrocytic pathology in gray matter is designated tufted astrocytes (see Figure 2.16), which are stellate with fine radiating processes surrounding the nucleus and contrast with the “astrocytic plaques” of CBD (Matsusaka et al., 1998; Dickson, 1999). Another distinctive form of inclusions is coiled bodies (see Figure 2.16), which are tau-immunopositive and silver-positive oligodendroglial inclusions presenting in the white and gray matter; however, these are identical to those seen in CBD (Collins et al., 1995; Bergeron et al., 1997; Dickson, 1999). PSP pathology may also be found in the superior colliculus, tegmentum, periaqueductal gray matter, red nucleus, oculomotor complex, trochlear nucleus, pontine nuclei, inferior olives, and cerebellar dentate (Gibb et al., 1988; Riley et al., 1990; Daniel et al., 1995; Schneider et al., 1997; Dickson, 1999; Paulus and Selim, 2005). (a)

Figure 2.16 PSP: astrocytic pathology. (a)

Tau-immunoreactive tufted astrocyte in the subthalamic nucleus (AT8 antibody). (b) Coiled bodies that immunolabel with antibodies specific to 4-repeat tau. (For a color version, see the color plate section.)

FTLD-ubiquitin FTLD-U was originally named for cases in which the characteristic inclusions were visible only with ubiquitin immunohistochemistry. TDP-43, a nuclear protein implicated in exon skipping and transcription regulation, was recently identified as the major ubiquinated component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease, and sporadic amyotrophic lateral sclerosis (ALS) (Mackenzie et al., 2009). Thus, most, but not all, cases that were previously designated as FTLD-U have been renamed as FTLDTDP (Cairns et al., 2007; Mackenzie et al., 2009). This pathology is associated with several genes, including progranulin, and, much less commonly, mutations associated with valosin-containing protein (VCP), TDP, and cases linked to chromosome 9. About 10% of cases that were (b)

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ubiquitin-positive but not related to TDP-43 have been subsequently found to consist of FUS (fused in sarcoma), a protein previously implicated in ALS. The designation of FTLD-UPS (ubiquitin–proteasome syndrome) now refers to cases with ubiquitin positivity that have not been linked to a specific protein (such as familial syndrome of FTD3 as a result of CHMP2B mutations; Mackenzie et al., 2009). In FTLD-TDP, brain atrophy is variable but may be severe, especially in frontotemporal distribution and the hippocampus, and there is associated dilation of the lateral ventricles. There may also be pallor of the SN, atrophy, and discoloration of the head of the caudate nucleus and cerebral white matter. Histologically, there is variable neuronal loss in the affected regions, and there may be hippocampal sclerosis. Cases may be screened using ubiquitin immunohistochemistry but must be confirmed by immunohistochemical assessment for TDP-43 protein, which is translocated from the nucleus to the cytoplasm, ubiquinated, and phosphorylated (see Figure 2.17). Ubiquitin and TDP-43-positive neuronal cytoplasmic inclusions (NCIs), neuronal intranuclear (NIIs), dystrophic neuritis (DNs), and glial cytoplasmic inclusions (GCIs) are most often seen in neurons in outer cortical layers of the frontal and temporal lobes, in the dentate layer of the hippocampus, and in the basal ganglia (Cairns et al., 2007).

ALS-dementia Dementia is now recognized as a common co-occurrence in ALS, and the neuropathology associated with ALS-dementia shares many of the characteristics of FTLD-TDP, which is also the major disease protein implicated in the anterior horn neurons in ALS. TDP-43 pathology is found in multiple brain areas and in a spectrum of diseases as both a primary and a secondary pathology, suggesting that ALS is a disease that not only affects the pyramidal motor system, but instead it is a multisystem neurodegenerative TDP-43 proteinopathy (Geser et al., 2008). In ALS-dementia cases, TDP-43 positive inclusions are most predominantly found in neurons in outer cortical layers of the frontal and temporal cortices and in the dentate layer of the hippocampus, as well as in the basal ganglia (Geser et al., 2008).

Creutzfeldt–Jakob disease CJD is a spongiform encephalopathy associated with a rare form of dementia that may be sporadic (sCJD), iatrogenic, or familial (Mahadevan et al., 2002; Gambetti et al., 2003). sCJD is the most frequently occurring human prion disease. Prions are infectious proteineous agents that lack DNA or RNA structure and are normally produced by cells in a nonpathogenic form. Brains of CJD patients may be grossly normal or exhibit mild, diffuse atrophy and are distinguished from other causes of dementia by histologic examination characterized by variable distribution and severity of spongiform change, neuronal loss, and reactive astrocytosis in the frontal, temporal, and occipital lobes; basal ganglia; and cerebellum. Ten percent of cases of sCJD show amyloid plaques composed of prion protein (kuru plaques; Mahadevan et al., 2002; Gambetti et al., 2003). Prion protein (PrP) immunohistochemistry is used routinely to aid diagnosis (Mahadevan et al., 2002; Gambetti et al., 2003). Variant CJD (vCJD), first reported in the United Kingdom, is believed to occur as a result of the transmission of an animal prion disease, bovine spongiform encephalopathy, to humans. vCJD is characterized by severe neuronal loss and severe astrocytosis in the posterior thalamic nuclei, particularly the pulvinar, with spongiform change most severe in the basal ganglia, particularly the putamen and caudate nucleus (Ironside et al., 2002). Florid plaques encircled by a rim of microvacuolar spongiform change are immunopositive for PrP and are especially prominent in the occipital and cerebellar cortices (Ironside et al., 2002). Wernicke–Korsakoff syndrome Two overlapping clinical pathologic entities exist within the WKS spectrum: Wernicke’s encephalopathy (WE) and Korsakoff’s psychosis (KP). Wernicke’s and Korsakoff’s are generally considered to be different stages of the same disorder, WKS, caused by the deficiency of thiamine (Vitamin B1). It is most commonly seen in persons with alcohol abuse, dietary deficiencies, prolonged vomiting, eating disorders, or the effects of chemotherapy. Clinical

(a)

Figure 2.17 FTLD-TDP: TDP-43 immunoreactive

(b)

inclusions in the neurons of the dentate layer of hippocampus. (a) Low magnification shows diffuse nuclear staining and numerous TDP-43 positive inclusions (arrows). (b) High magnification shows cytoplasm inclusions with nuclear clearing in affected neurons. (For a color version, see the color plate section.)

Functional Changes Associated with the Aging Nervous System

features of WE include mental confusion, visual impairment, and ataxia and hypotension/hypothermia. Patients with KP have a memory disorder with amnesia, confabulation, attentional deficits, disorientation, and vision impairment. KP may be the end result of the repeated episodes of WE, but it has also been described without a known episode of WE. The characteristic lesions of WKS, particularly WE, are surrounding the third and fourth ventricles and include the mamillary bodies, which show atrophy and brown discoloration from old hemorrhage. Other regions of similar involvement include the hypothalamus, thalamus, periaqueductal gray matter, colliculi, and floor of the fourth ventricle (oculomotor nuclei, dorsal motor nuclei of vagus, vestibular nuclei). Lesions of the medial dorsal nuclei or, alternatively, the anterior nucleus of thalamus (Harper, 2009) showing neuronal loss and gliosis, with or without hemorrhages, have been postulated to be responsible for the memory defect of KP. More recently, it has been postulated that an interruption of complex diencephalic-hippocampal circuitry including thalamic nuclei and mamillary bodies rather than a single lesion in the thalamus is responsible for KS (Harper, 2009). In about 27% of cases, there is degeneration of the anterior superior aspect of the cerebellar vermis (Harper, 2009). Other changes may be seen specifically as a toxic effect of alcohol, including neuronal loss and white matter degeneration; some changes may be temporary, with others permanent (Harper, 2009).

53

pathology in dementia, some of these conditions have already been reviewed in Section “Neuropathology of other dementias.”

Atherosclerosis Atherosclerosis of the cerebral vasculature is common in older persons and represents the most common underlying pathology for large territory and embolic cortical infarcts. As might be expected, the risk factors for atherosclerosis are similar as those for stroke and include hypertension, diabetes, dyslipidemia, and cigarette smoking. White people have been described to more often harbor atherosclerotic lesions in extracranial vessels, whereas Afro-Caribbean populations are more likely to have intracranial atherosclerosis (Moossy, 1993). Atherosclerosis affects medium and large arteries, particularly in the major branches of the Circle of Willis and occurs when fat, cholesterol, and other substances build up in the walls and form plaques (see Figure 2.18). Sufficient blood flow is often maintained in spite of significant narrowing and rigidity from plaques. Complicated plaques with damage to the endothelium are the key triggers for the development of thrombus, occlusion, and emboli (Ferrer et al., 2008). Emboli cause abrupt occlusion of distal downstream arteries, whereas local thrombotic processes are typically slower, allowing time for collateral channels to develop. Clots can also form around tears (fissures) in the plaques. In some cases, the atherosclerotic plaque is associated with a weak-

Neuropathology of other dementias Numerous other rare forms of dementia exist, including neurodegeneration with brain iron accumulation, adultonset polyglucosan disease, adult-onset leukodystrophy, adult neuronal ceroid lipofuscinosis, and some of the spinocerebellar atrophies. In addition, nondegenerative dementias may result from inflammatory, neoplastic, and demyelinating conditions. The following sections discuss some of these more common conditions.

Cerebrovascular disease in the elderly Vascular disease is common with aging, and the pathologic classification of cerebrovascular disease is similar to other age groups; it includes large vessel disease, small vessel disease, ischemic parenchymal injury, and hemorrhagic parenchymal injury. Older persons are particularly prone to large vessel disease in the form of atherosclerosis, small vessel diseases including arteriolosclerosis and CAA, and ischemic and hemorrhagic parenchymal injury. In addition, older persons are more likely to experience global hypoxic events from cardiac disease resulting in global/hypoxic ischemic encephalopathy and are more prone to subdural hematomas (SDH) from falls. Because cerebrovascular disease is a common underlying

Figure 2.18 Atherosclerosis, the Circle of Willis. Note the asymmetric involvement of vertebral arteries, extension into basilar artery, and posterior cerebral arteries. (For a color version, see the color plate section.)

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The Aging Brain in Neurology

ening of the wall of an artery, leading to an aneurysm. Severe atheroma, especially in the basilar artery, may cause fusiform enlargement (see Figure 2.19), or fusiform aneurysm, and result in mechanical compression, clinical cranial nerve palsies, excitation, and hydrocephalus. While hemorrhage is rare, ischemia and infarction may result from thrombi or fragments of plaques that embolize (Ferrer et al., 2008).

Small vessel disease Small cerebral vessels include perforating arteries with diameters of 40—900  μm (Ferrer et al., 2008). Diseases of small vessels have been associated with lacunar infarcts (Sections “Vascular cognitive impairment and dementia” and “Infarction”), subacute ischemic vascular dementia, and primary intraparenchymal hemorrhages (Section “Intraparenchymal hemorrhages”). The most common small vessel disease in aging is arteriosclerosis/ arteriolosclerosis (AS; see Figure 2.20). Arteriolosclerosis affects arteries 40–150 μm in diameter (Ferrer et al., 2008). Microscopic features of AS include hyaline thickening, intimal fibromuscular hyperplasia, luminal narrowing, thinning of the media, and concentric onion-skintype smooth muscle cell proliferation, with or without the presence of foamy macrophages in the arterial wall (Vinters, 2001; Yahnis, 2005; Ferrer et al., 2008). Although the term lipohyalinosis (LH) is often used synonymously with AS, LH was initially used to describe small blood vessels that first underwent fibrinoid change and then subsequent hyalinization, especially in association with

Figure 2.19 Fusiform aneurysm of the basilar artery. Artery is

dilated and tortuous and may compress and distort the brain stem. (For a color version, see the color plate section.)

Figure 2.20 Arteriolosclerosis: hyaline thickening of two small vessels in the deep white matter. Note that the upper vessel appears occluded. (For a color version, see the color plate section.)

hypertension. The uniform eosinophilia on H&E-stained sections may result from either fibrinoid change (necrosis) or collagenous fibrosis (hyalinosis). Special stains may be needed to distinguish the two changes. Traditionally, hypertension, age, and diabetes mellitus are the main risk factors for small vessel disease (Yahnis, 2005).

Cerebral amyloid angiopathy Cerebral amyloid angiopathy affects capillaries, arterioles, and small-size and medium-size arteries of the cerebral and cerebellar cortex and leptomeninges (see Figures 2.8 and 2.21), with the subcortical regions and brain stem relatively spared (Mandybur, 1986; Vonsattel et al., 1991; Ellis et al., 1996; Vinters, 1998). The distribution is very patchy, and heavily involved vessel segments alternate with amyloid-free regions (Mandybur, 1986). The most common form of CAA is sporadic and associated with deposition of Aβ, the same protein implicated in AD (Vinters, 1998). Indeed, most AD cases have concomitant CAA (Ellis et al., 1996; Arvanitakis et al., 2011a), but CAA also increases in extent and severity with age and is common in older persons without a pathologic diagnosis of AD. When CAA appears to be “leaking” from the capillary wall into the adjacent brain, the latter is described as dysphoric angiopathy (Attems and Jellinger, 2004). The affected blood vessels in Aβ-CAA may show segmental dilations, micro-aneurysms, fibrinoid necrosis (Ellis et al., 1996), and inflammation (Vonsattel et al., 1991). In general, the extent of amyloid deposition within vessel walls correlates with the increasing risk of cerebral lobar hemorrhage (Ellis et al., 1996). CAA has also been associated with microbleeds and cognitive impairment (Arvanitakis et al., 2011a). Hereditary forms of CAA may be associated with Aβ or other amyloid-forming proteins (Yahnis, 2005).

Functional Changes Associated with the Aging Nervous System

(a)

(b)

(c)

(d)

55

Figure 2.21 Cerebral amyloid

angiopathy. (a) Cortex involves small-size and medium-size arteries, arterioles, and capillaries (arrows; small arrow also shows dysphoric change). (b) Leptomeninges vessels. (c) Amyloid alternating with amyloid-free regions. (d) “Double-barrel” appearance from separation of endothelium from the affected muscularis. (a–c, Aβ immunostain.) (For a color version, see the color plate section.)

Vasculitis Vasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Vasculitis is classified according to vessel size, systemic versus primary CNS localization, and the presence or absence of giant cells. Vasculitis may also be secondary to infections such as syphilis, tuberculosis, or fungal infections. Giant cell arteritis (GCA, temporal arteritis) is particularly important in the aging brain. Giant cell arteritis occurs in adults older than 50 years and has a peak incidence between 75 and 85 years of age. Women are affected twice as often as men. The classic symptoms are headache, scalp tenderness, jaw claudication, and blindness. The blindness occurs usually as a result of the extension of the disease into the ocular (most commonly, the ophthalmic) arteries and/or their branches (Weyand et al., 2004; Yahnis, 2005; Ferrer et al., 2008). Extracranial branches of the aorta are also typically involved, especially the external and internal carotid arteries and vertebral arteries, which may lead to brain infarct in a small percentage of cases (Yahnis, 2005). The affected vessel becomes tortuously thickened and tender, with diminished pulsations. Microscopically, there is intimal proliferation with a transmural infiltration by lymphocytes, including CD4+ T-lymphocytes, and lesser numbers of CD8+ T-lymphocytes, monocytes/macrophages, and giant cells. A definitive diagnosis can be made only by temporal artery biopsy. The changes are most often focal and patchy rather than generalized, thus a negative biopsy cannot completely rule out GCA (Yahnis, 2005). Multiple other pathologies can affect large and small cerebral vessels, including other types of emboli (septic,

fat, tumor), vasculitis (infectious, systemic), hereditary angiopathies (CADASIL), arterial dissection, and vascular malformations. Saccular aneurysms are discussed later in this section. In spite of a multitude of vessel pathologies, the final common pathway of most, if not all, of the vessel pathologies is cerebral ischemia, infarction, and/or hemorrhage.

Infarction Brain infarction accounts for the majority of strokes and has been related to both cognitive and motor changes in aging (Schneider et al., 2003; Buchman et al., 2011). However, it is very common to find brain infarcts in older persons without a history of clinical stroke (Schneider et al., 2003). Pathologically, gross (macroscopic) infarcts are the infarcts that can be visualized by the naked eye. Similar to neuroimaging studies, about one-third of the older persons have evidence of chronic gross infarcts at the time of autopsy (Schneider et al., 2003). Gross infarcts can be described as acute, subacute, or chronic. At around 8–12 hours, there is blurring of the cortical white matter junction and, microscopically, red or ischemic neurons appear. Cytotoxic edema reaches a maximum at 48–96 hours, during which time there is a higher risk of herniation. If reperfusion occurs, as is typical for most embolic infarcts, the area of ischemia may become hemorrhagic. At the same time, macrophages infiltrate, and by 10 days, there is a reactive gliosis. At 3 weeks, the infarct begins to cavitate (liquefaction necrosis) and there are abundant macrophages by microscopy. Eventually, the infarct is filled with fluid and traversed by a network of small vessels. The subpial cortex, which has a separate

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blood supply, is typically preserved in cortical infarcts. Lacunar infarcts refer to small (10 or 15  mm maximal dimension) regions of cystic cavitation most often seen within basal ganglia, thalamus, pons, internal capsule, and deep subcortical white matter. Microscopic infarcts are lesions that are not visible on macroscopic inspection but are observed during the examination of the histologic sections (Arvanitakis et al., 2011b).

Anoxic/hypoxic encephalopathy In older persons, this is most often the result of cardiac arrest with low blood flow and oxygenation and tissue anoxia. The brain shows selective regional and cell type vulnerability, with the neurons of the CA1 sector of the hippocampus, Purkinje cells of the cerebellum, and layers III and V of the cortex preferentially damaged. There is variable damage of the basal ganglia. If the person survives, these regions acutely show red neurons, followed by infiltration of macrophages and liquefaction necrosis, typically in a linear pattern called laminar necrosis. Carbon monoxide results in an acute pink discoloration of the brain, followed by bilateral necrosis of the globus pallidus. Intraparenchymal hemorrhages Intraparenchymal hemorrhage most often occurs from the rupture of small blood vessels, such as lenticulostriate or pial perforating artery, in association with hypertension, CAA, or other predisposing factors. Hypertensive hemorrhage typically occurs from rupture of the lenticulostriate branches of the middle cerebral artery or pontine perforators of the basilar artery, accounting for the common subcortical distribution of hypertensive hemorrhage in the deep cerebral nuclei (putamen, thalamus) and pons/

cerebellum (Ferrer et al., 2008). Massive hemorrhages are manifested as foci of acutely clotted blood that displace and disrupt, resulting in mass effect and possible herniation. Although Charcot–Bouchard microaneurysms (see Figure 2.22) formed by focal weakening and aneurysmal dilatation of small vessels are often reported as the classic underlying pathology of hypertensive hemorrhage, these are rarely found on pathologic examination and rupture of nonaneurysmal, but damaged vessel walls have been argued as the more common pathophysiology (Yahnis, 2005; Ferrer et al., 2008). Sporadic CAA accounts for about 10% of primary nontraumatic intraparenchymal hemorrhage and is the most common cause of lobar intracerebral hemorrhage in normotensive older persons (Vonsattel et al., 1991; Ferrer et al., 2008). CAA hemorrhages tend to superficial and may also cause subarachnoid hemorrhage (SAH). Microhemorrhages from arteriolosclerosis and CAA are probably even more frequent (see Figure 2.22) and can be detected using special neuroimaging techniques.

Subarachnoid hemorrhage By definition, a SAH is located between the meninges and the pial surface of the brain. SAH is most commonly caused by the rupture of a cerebral artery aneurysm or trauma. The annual incidence of aneurysmal SAH increases with age, with a median age of onset in the fifth or sixth decade (Fogelholm et al., 1993; Yahnis, 2005). Saccular aneurysms (berry aneurysms) typically arise at the points of bifurcation of intracranial arteries, within the Circle of Willis. Aneurysms increase in size with time, and size is closely associated with rupture (Yahnis, 2005). Pathologically, aneurysms have a narrow neck and thin walls and show attenuation and disruption of

Figure 2.22 Charcot–Bouchard aneurysm; note the markedly thinned region of the vessel wall. (For a color version, see the color plate section.)

Functional Changes Associated with the Aging Nervous System

the internal elastic lamina and fibrosis of the vessel wall. Although rupture typically causes SAH, blood may also penetrate into brain tissue (intracerebral hemorrhage). Rebleeding may rise during the first 24 hours and at 1–4 weeks after the initial hemorrhage (Inagawa et al., 1987). One of the complications of SAH is arterial vasospasm and associated delayed cerebral ischemia and infarction about 4–7 days post-hemorrhage. SAH is also a common consequence of trauma. Older persons at risk of falling are particularly prone to focal SAH, along with contusions of the frontal orbital and anterior temporal superficial cortex.

Movements disorders The most commonly diagnosed movement disorder associated with aging is PD. Parkinsonism also occurs with other neurodegenerative diseases, including CBD, PSP, and MSA. In addition, older persons often show mild motor problems, including problems with gait and slowing that does not easily fit into a specific disease category. Other subclinical degenerative and vascular diseases (Buchman et al., 2011) in the aging brain likely can disturb the nigrostriatal and frontostriatal pathways.

Parkinson’s disease Idiopathic PD describes the common idiopathic disorder that shows a slowly progressive course and is characterized by bradykinesia, rigidity, gait disorder, and tremor. Gross pathologic features include pallor of the SN and locus coeruleus, with severe loss of the melanin-containing dopaminergic neurons with melanin-containing macrophages and free melanin pigment in the SN pars compacta, most prominently in the ventrolateral portion of SN. It has been estimated that symptoms of PD occur when more than 50% of nigra neurons have been lost, but recent data challenge this notion (Ince et al., 2008). LBs, the pathologic hallmark of PD (see Figures 2.11 and 2.12), not only occur in the SN in PD but also are found in the dorsal motor nucleus of the vagus, substantia innominata, other brainstem nuclei, the intermedolateral cell columns of the spinal cord, and sympathetic ganglia (Braak et al., 2003). More caudal structures, including brainstem, olfactory bulbs, spinal cord, and peripheral nervous system, are believed to be involved prior to the SN (Braak et al., 2003; Beach et al., 2009), and the development of LB probably follows a caudal-to-rostral progression in most cases of PD. Extension into cortical regions is common and associated with DLB as well as PD dementia. PD dementia is clinically separated from DLB by the temporal sequence of motor signs being established before the onset of dementia (McKeith et al., 2005). LBs and LN are the central pathology of DLB and PD, and there is significant overlap between the pathologic features. Synuclein

57

has been reported in the olfactory bulbs of subjects with PD and DLB, suggesting that olfactory bulb involvement is common to all LB disorders and occurs at an early stage of the disease (Beach et al., 2009). Pathologic staging of PD has been suggested based on anatomic distribution and severity of LB and LN (Braak et al., 2003). In stages 1 and 2, the pathology is restricted to the brainstem and olfactory bulb. Involvement of the pars compacta of the substantia nigra (SNc) occurs in stage 3, without degeneration until stage 4. In stages 5 and 6, the α-synuclein pathology involves the neocortex (Braak et al., 2003; Ince et al., 2008; Beach et al., 2009; Jellinger, 2009). Motor and cognitive manifestations have been proposed to depend on the anatomic distribution and load of α-synuclein pathology (Braak et al., 2005; Beach et al., 2009). Dementia is seen in a large number of PD patients (Braak et al., 2005; Ince et al., 2008; Beach et al., 2009), and although the pathologic correlates of dementia have been debated, cortical LBs are believed to play a role (Braak et al., 2005; Beach et al., 2009). In PD dementia, the amount of concomitant AD pathology is typically less than that in classic DLB (Cummings, 2004), but cortical LBs are said to be present in small numbers in virtually all cases of idiopathic PD, with or without a history of dementia (Ince et al., 2008). Incidental LB disease is the term used when LBs are pathologically found in the nervous system in subjects without clinically documented parkinsonism or cognitive impairment. Epidemiologic studies indicate that autonomic symptoms, REM sleep behavioral disorder, and olfactory dysfunction may precede the presentation of parkinsonian motor signs and symptoms by years and may be related to LBs and LNs in these more caudal structures (Jellinger, 2009).

Multiple System atrophy MSA is a sporadic neurodegenerative disease that presents with the cardinal features of orthostatic hypotension, parkinsonism, and cerebellar signs and symptoms (Gilman et al., 1998; Gilman et al., 2008); it encompasses the previous nomenclature of olivopontocerebellar atrophy, Shy–Drager syndrome, and striatonigral degeneration. Diagnostic criteria for MSA proposed by a Consensus Conference in 1998 (Gilman et al., 1998) recommended MSA to encompass two groups, including MSA-P (parkinsonian-predominant) and MSA-C (cerebellar-predominant). α-synuclein immunoreactive glial cytoplasmic oligodendroglial inclusions in areas of degeneration are a required feature for a definite diagnosis of both MSA-P and MSA-C (Gilman et al., 1998; Gilman et al., 2008). MSA-P accounts for the majority of the cases of MSA. Pathologically, there is atrophy and grayish discoloration of the putamen, pallor of the SN, and slight cortical

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atrophy. Neuronal loss and gliosis are most severe in the dorsolateral zone of the caudal putamen and lateral portion of the SN. MSA-C shows grayish discoloration of the cerebellum, middle cerebellar peduncle, and the pons. There is Purkinje cell loss and proliferation of Bergmann glia, especially in the vermis. In addition, neuronal loss and gliosis are prominent in the basis pontis and accessory and inferior olivary nuclei, and the cerebellopontine fibers are degenerated. Both MSA-P and MSA-C may have degeneration of the SN, intermediolateral cell column, and locus coeruleus (Watanabe et al., 2002).

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of upper (UMN) and lower motor neurons (LMN). There is progressive and often asymmetric weakness and wasting, with involvement of the bulbar/respirator muscles, but sparing of ocular, urinary, and anal sphincter muscles. Fasiculations are a prominent feature, reflecting LMN involvement. Pseudo-bulbar palsy, progressive atrophy, and corticospinal signs may be present. Sensory nerves and the autonomic nervous system are generally unaffected but may be involved for some patients. Patients with familial ALS associated with an SOD1 mutation frequently have degeneration of the posterior columns, Clarke’s column, and spinocerebellar tracts (Ince et al., 2008). At autopsy the cervical and lumbosacral enlargements of the spinal cord may be atrophic, and anterior motor roots shrunken and gray. The brain may show frontal or temporal lobe when there is coexisting dementia. The key histology is loss of motor neurons, with associated astrocytosis, in anterior horns of the spinal cord. In the medulla, the hypoglossal nucleus is most obviously degenerated, and the nucleus ambiguous, motor nuclei of the trigeminal and facial nerves, and motor cortex may be affected. The nuclei of cranial nerves III, IV, and VI and Onufrowicz nuclei are preserved, consistent with the preservation of (a)

(b)

eye movements and sphincter control. Axonal spheroids are frequently seen in the anterior horns but are not specific for ALS. The spinal cord typically shows myelin pallor in the anterior and lateral corticospinal tracts, which can be demonstrated using immunohistochemistry for microglial markers (see Figure 2.23). Myelin loss is most evident in lower cord segments. Muscle morphology at biopsy or autopsy shows neurogenic atrophy, including grouped atrophy and fiber-type grouping affecting type 1 and type 2 fibers. A variety of inclusion bodies are seen in surviving motor neurons (Ince et al., 2008). Bunina bodies (see Figure 2.24) are thought to be a specific feature of ALS and are small intracellular eosinophilic inclusions, often arranged in small beaded chains. Ubiquitin-immunostained inclusions (see Figure 2.25) are typically seen in both UMN and LMN and include skein inclusions or threadlike structures, and hyaline-like or Lewy-like inclusions. It is now recognized that the underlying ubiquinated protein in these inclusions is TDP-43 (see Figure 2.24), the same protein of FTLD. Indeed, in some cases of ALS, TDP-43 positive inclusions are also seen in the neurons of dentate nucleus of hippocampus, basal ganglia, and cortex. Accordingly, ALS may affect cognition and is associated with FTLD. Patients with ALS may have subtle executive deficits, and a small number will have a clinical subtype of FTLD (Geser et al., 2008). Indeed, cognitive and behavioral symptoms in association with ALS and an association between ALS and FTD were considered in the earlier part of the twentieth century. Indeed, it now appears that ALS and FTLD may represent a multiple-system TDP-43 proteinopathy, with ALS and FTLD at two ends of the disease spectrum (Geser et al., 2008; Traub et al., 2011).

Huntington’s disease Huntington’s disease (HD) is an autosomal dominant disorder caused by a mutation in the HD gene on (c)

Figure 2.23 Amyotrophic

lateral sclerosis. (a) Pallor of the lateral corticospinal tracts of spinal cord on myelin stain. (b) Low and (c) high magnification show CD8 immunostained macrophages indicative of degeneration. (For a color version, see the color plate section.)

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Brain tumors The overall incidence of brain tumors appears to be increasing, with the highest increase noted in patients older than 60 years of age (Flowers, 2000). The average annual percentage increases in primary brain tumor incidence for ages 75–79, 80–84, and 85 and older are 7, 20.4, and 23.4%, respectively (Flowers, 2000). These tumors include astrocytoma, glioblastoma multiforme (GBM), meningioma, schwannomas, primary malignant lymphomas of the brain, and metastatic brain tumors. Figure 2.24 Amyotrophic lateral sclerosis anterior horn cell with a

Bunina body. (For a color version, see the color plate section.)

chromosome 4p16.3 that typically manifests as chorea and psychiatric symptoms and progresses to dementia (Yahnis,  2005; Ince et al., 2008). HD results from an expansion of the trinucleotide repeat CAG to over 36 repeats, compared to normal repeats of 26. Onset is usually in midlife, with a mean survival of 17 years. The first clinical manifestation of the hyperkinetic form is chorea, but neuropsychological problems such as personality change, depression, and psychosis can antedate the onset of the movement disorder (Yahnis, 2005). Neuropathologically, the brain is atrophic, with specific atrophy of the caudate and putamen and compensatory enlargement of the lateral ventricles. Histologically, there is neuronal loss, especially of the GABAergic medium spiny neurons (Joel, 2001) of the striatum. Ubiquitin-positive intranuclear inclusions and abnormal neurites are present in degenerated regions (Yahnis, 2005; Ince et al., 2008; Cochran, 2005).

(a)

(c)

Figure 2.25 Amyotrophic lateral sclerosis.

Hyaline inclusions in an anterior horn motor neuron on H&E (a) and ubiquitin (b). (c) Skein-like inclusions in the anterior horn cells in ALS also stain with antibodies to ubiquitin. (For a color version, see the color plate section.)

Glial neoplasms Glial neoplasms include astrocytomas, GBMs, oligodendrogliomas, and other glial neoplasms. These tumors develop in all ages but are particularly challenging in geriatric patients.

Astrocytomas Diffuse astrocytomas (WHO grade II) including fibroblastic, protoplasmic, and gemistocytic variants, occur at any age but most frequently in the sixth decade of life (Perry, 2005). Like most tumors, they may present with headache, seizures, or focal signs, depending on the location. Astrocytomas are most frequent in the cerebral white matter, where they appear as ill-defined, slightly firm, yellow-white, homogeneous tumors that enlarge and distort the hemisphere. Tumor cells individually and diffusely infiltrate surrounding normal tissue without obvious borders between normal and diseased tissue (Louis et al., 2008). There is increased cellularity with mild pleomorphism; mitoses, vascular proliferation, and necrosis are absent, and the proliferative index (MIB1/Ki67) tends

(b)

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to be low (less than 5%). Tumor cells are confirmed as astrocytes using antibodies against glial fibrillary acidic protein (GFAP). Diffuse astrocytomas frequently undergo malignant transition to anaplastic astrocytoma and GBM multiforme.

Anaplastic astrocytoma Anaplastic astrocytomas (WHO grade III) may arise from diffuse astrocytoma, WHO grade II or de novo, without the evidence of a less malignant precursor. They tend to occur in slightly older individuals, compared to diffuse astrocytomas, and are located in the hemispheres, leading to enlargement of invaded structures and a more discernible mass, compared to diffuse astrocytomas (Louis et al., 2008). There may be edema, mass effect, and increased intracranial pressure. Anaplastic astrocytomas show histologic features of malignancy, including cellular and nuclear pleomorphism, increased cellularity and mitotic activity, and Ki-67/MIB-1, usually in the range of 5–10%.

Glioblastoma Glioblastomas are malignant (WHO grade IV) glial neoplasms that manifest at any age but preferentially affect older adults (Ohgaki et al., 2004; Louis et al., 2007). Primary GBMs develop in older patients (mean age about 62 years), whereas secondary GBMs derived from lowergrade astrocytomas usually occur in younger patients (mean age about 45 years). Clinical presentations depend on the region involved; with frontal lobe tumors, extensive growth may already be evident at the time of presentation. GBMs occur most often in the subcortical white matter and may spread along myelinated tracks across corpus callosum, giving rise to a characteristic butterfly pattern. Although they may appear discrete, distant cellular spread is extensive, making complete surgical resection impossible in most cases (Louis et al., 2008). Pathologically, GBM shows variable colors with grayish tumor masses and central areas of yellowish necrosis and hemorrhages (see Figure 2.26). Histologically, there is high cellularity, pleomorphism, mitoses, and microvascular proliferation and/or necrosis. Necrosis characteristically has a pseudopalisading pattern (see Figure 2.27) of large necrotic areas surrounded by viable tumor cells at the periphery. Recent data show that the cellular pseudopalisades are hypoxic, thereby overexpressing hypoxiainducible factor (HIF-1), and secrete proangiogenic factors such as VEGF and IL-8 (Rong et al., 2006). Proliferative activity is usually prominent, and the proliferative index determined using Ki-67/MIB-1 may reach very high percentages. GFAP immunopositivity is variable but, if positive, may be helpful in the diagnosis.

Other glial neoplasms Oligodendrogliomas can develop at any age, but the majority of tumors arise in adults with an incidence peak

Figure 2.26 Glioblastoma multiforme: gross appearance with

variegated necrotic-appearing mass without definite borders. (For a color version, see the color plate section.)

between 40 and 45 years of age (Ohgaki and Kleihues, 2005). Oligodendrogliomas are diffusely infiltrating lowgrade (WHO grade II) gliomas and often harbor deletions of chromosomal arms 1p and 19q (Louis et al., 2007; Louis et al., 2008). These tumors account for approximately 2.5% of all primary brain tumor and 5–6% of all gliomas (Louis et al., 2007; Louis et al., 2008). They develop in the cortex and white matter of the cerebral hemispheres, and calcifications are frequent. Histologically, they are diffusely infiltrating gliomas composed of uniform round nuclei with perinuclear halos, resulting in the characteristic

Figure 2.27 Glioblastoma: histologic appearance of pseudopalisading necrosis. (For a color version, see the color plate section.)

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“fried-egg” appearance on paraffin sections. Extracellular mucin and microcysts are frequent, and a dense network of branching capillaries resembles the pattern of chicken wire (Herpers and Budka, 1984; Louis et al., 2007; Louis et al., 2008). Ependymomas are slowly growing gliomas, originating from the cells of the ventricular walls or spinal canal, and are composed of neoplastic ependymal cells. Ependymomas correspond histologically to WHO grade II. These tumors develop in all age groups ranging from 1 month to 81 years (Louis et al., 2007), but most commonly in the fourth ventricle in children and in the spinal cord in adults. A specific variant, called myxopapillary ependymoma, is found at the filum terminale in adults. The key histologic features are perivascular pseudorosettes and ependymal rosettes. Subependymomas of the fourth ventricle are typically an incidental finding in older adults and uncommonly are symptomatic.

Metastatic lesions Metastatic tumors originate outside the CNS and spread secondarily to the CNS via blood or by direct invasion. Metastatic tumors to the brain are approximately 10 times more common than primary intracranial neoplasms (Ellison et al., 2008) and are arguably the most common CNS neoplasm in older persons. About 25% of patients who die from cancer have CNS metastases detected at autopsy (Gavrilovic and Posner, 2005). Lung (especially small cell and adenocarcinoma), breast, and skin (melanoma) are the most common sources (Soffietti et al., 2002). More than 80% of brain metastases are located in the cerebral hemispheres, 10–15% in the cerebellum, and 2–3% in the brain stem. Because they are typically of hematogenous origin, their distribution is generally in arterial border zones and at the junction of cerebral cortex and white matter (Louis et al., 2007; Ellison et al., 2008). Melanoma and lung carcinoma more often cause multiple lesions, whereas breast carcinoma frequently is single (Delattre et al., 1988; Ellison et al., 2008). Pathologically, they are usually well-demarcated, rounded masses that displace the surrounding brain parenchyma (see Figure 2.28). Malignant melanoma, lung carcinoma, renal cell carcinoma, and choriocarcinoma tend to be hemorrhagic and may present as intracranial hemorrhages (Nutt and Patchell, 1992; Louis et al., 2007). Histopathologic features of metastatic tumors are usually similar to those of their primary lesions, but there may be less differentiation. For example, metastatic melanomas may be amelanotic. Primary CNS lymphoma Primary CNS lymphomas (PCNSL) are malignant lymphomas that occur in the CNS without evidence of a coexisting systemic lymphoma. The incidence of PCNSL has markedly increased, at least partly because HIV-positive patients develop CNS lymphomas. PCNSL affect all ages,

Figure 2.28 Metastatic adenocarcinoma: cortical lesion appears well demarcated and necrotic. (For a color version, see the color plate section.)

with a peak incidence in immunocompetent subjects during the sixth and seventh decades of life (Koeller et al., 1997; Louis et al., 2007). More than half of PCNSLs involve the supratentorial space, most commonly frontal, temporal, or parietal cortex, and they are occasionally multiple (Louis et al., 2007). PCNSLs also have a propensity to involve periventricular regions. The tumors are often centrally necrotic or focally hemorrhagic, and visible demarcation from surrounding parenchyma is variable (Koeller et al., 1997). Tumor cells typically form concentric collars of perivascular cuffs, packing the perivascular spaces and creating a concentric pattern of reticulin-positive material around vessels. Tumor cells also invade the surrounding parenchyma and may form tumor masses. The vast majority of CNS lymphomas are classified as diffuse large B-cell lymphoma (Koeller et al., 1997; Louis et al., 2007; Ellison et al., 2008). Reactive small T-lymphocytes are identified among the tumor cells, usually in moderate numbers. Most B-cell PCNSLs have a very high Ki-67 labeling index (Koeller et al., 1997; Louis et al., 2007; Ellison et al., 2008). Because individual tumor cells extensively invade the surrounding parenchyma, similar to most glial tumors and unlike metastases, complete resections are typically not feasible. PCNL are, at least initially, steroid responsive and also responsive to radiation and chemotherapy; however, long-term prognosis remains poor.

Meningiomas Meningiomas are derived from meningothelial (arachnoid) cells and are typically attached to the dural inner

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surface. Most meningiomas are benign and correspond to WHO grade I. Meningiomas account for about 24–30% of primary intracranial tumors occurring in the United States (Louis et al., 2007) and can occur at any age but most commonly are seen in middle-aged and elderly patients, with a peak during the sixth and seventh decades (Louis et al., 2007; Ellison et al., 2008). They are significantly more common in women than in men, with a female:male ratio of nearly 2:1 (Louis et al., 2007). Meningiomas are wellcircumscribed spherical growths that are firmly attached to the dura. Dural and bone invasion are common and do not indicate malignancy; brain invasion is relatively rare. Meningiomas present a wide range of histologic patterns, and mixed patterns are frequent. Characteristic histologic features include whorls and psammoma bodies. The atypical designation is largely based on histologic features, especially mitoses, and specific morphologic patterns rather than brain invasion, although the latter is also associated with higher recurrence (Louis et al., 2007). Anaplasia (malignancy) is also based on histology/morphology and is associated with aggressive behavior, but metastases are rare.

Schwannomas Schwannomas are benign nerve sheath tumors (WHO grade I) and represent about 8% of intracranial tumors, 85% of cerebellopontine angle tumors (acoustic neuromas), and 29% of spinal nerve root tumors (Louis et al., 2007). Approximately 90% of the cases are solitary and sporadic. All ages are affected, with the peak incidence from the fourth to sixth decade. Schwannomas are generally well-encapsulated globoid tumors and may have cysts, lipid accumulation, and hemorrhage. The histology shows a spindle cell neoplasm with dense (Antoni A) and loose (Antoni B) areas and characteristic nuclear palisades (Verocay bodies). Schwannomas are adjacent to the involved nerve and, therefore, can be surgically removed with preservation of some, if not all, nerve function in many cases (Ellison et al., 2008). Neurofibromas Neurofibromas consist of a mixture of cell types, including Schwann cells, perineurial-like cells, and fibroblasts. Solitary neurofibromas are the most common tumor of peripheral nerves. They may be well-demarcated intraneural lesions or diffusely infiltrative extraneural tumors. Multiple and particularly plexiform neurofibromas are associated with neurofibromatosis type I (Louis et al., 2007; Ellison et al., 2008). Unlike schwannomas, neurofibromas are extremely rare within the cranium; in addition, they show a tendency to undergo malignant transformation, which occurs in about 5–10% of plexiform neurofibromas (Ellison et al., 2008). Complete resection of neurofibromas is difficult, because tumor cells are intermixed within the nerve.

Toxic metabolic encephalopathy Primary metabolic encephalopathies are those resulting from inherited metabolic abnormalities. Secondary or acquired metabolic encephalopathies describe the abnormalities of the water, electrolytes, malnutrition, alcohol, blood sugar, and other chemicals that adversely affect brain function.

Hepatic encephalopathy Hepatic encephalopathy occurs in patients with significant liver disease and conditions in which blood circulation bypasses the liver. Neuropathologically, astrocytes, particularly in the basal ganglia, undergo Alzheimer type II change, which includes enlarged, pale nuclei, with a rim of chromatin and prominent nucleoli. These astrocytes lose GFAP immunoreactivity and contain increased numbers of mitochondria; in severe cases, the nuclei may be lobulated and contain glycogen granules (Norenberg, 1994). It is hypothesized that elevated ammonia levels impair postsynaptic inhibitory neurotransmission, eventually resulting in impaired uptake of synaptic glutamate, increased extracellular glutamate, and the downregulation of glutamate receptors (Norenberg, 1994; Harris et al., 2008). Alcohol Alcohol may be related to a host of acute and chronic brain impairments. WKS, related to thiamine deficiency, was described with pathologies of cognitive impairment (Section “Wernicke-Korsakoff syndrome”). Atrophy of the cerebellum may occur separate from WKS and is less clearly linked to thiamine deficiency. In addition, long-term alcohol use has been related to atrophy involving both gray and white matter, which may be reversible with cessation of drinking. Neuronal loss appears to be specific to the superior frontal cortex (Smith et al., 1992). Central pontine myelinolysis Central pontine myelinolysis (CPM) is a relatively uncommon disorder with a very high mortality, usually occurring in alcoholics with WKS, severe liver disease, severe burns, malnutrition, anorexia, and severe electrolyte disorders (Harris et al., 2008). Too-rapid correction of a profound hyponatremia gives rise to the absolute change in serum sodium and appears to be an important contributing factor. Macroscopically, the area of demyelination is often triangular- or butterfly-shaped and symmetrical in transverse sections. Histopathologically, myelin-stained sections show a relatively sharply demarcated area of pallor within the basis pontis, with a relative preservation of axons. Extrapontine regions of demyelination have been reported to occur in over half the cases (Harris et al., 2008).

Functional Changes Associated with the Aging Nervous System

Infections and inflammation of the CNS Older persons are more susceptible to specific infections, probably reflecting an age-associated decline in cell-mediated immunity and antibody responses (Smith et al., 1992; Kipnis et al., 2008). In aging, immune competence declines with an alteration of T-cell populations and monocytes/macrophage cell efficiency. This may also make older persons more susceptible to certain inflammatory conditions.

Bacterial meningitis More than half of deaths from meningitis occur in persons over the age of 60 and are most commonly the result of Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, Haemophilus influenzae, and Staphylococcus aureus (Chimella, 2001). Bacterial meningitis may result from hematogenous spread or from local extension. Signs and symptoms may progress rapidly and include headache, fever, lethargy, and confusion. The brain is swollen and congested and is surrounded by creamy yellow or green pus. On microscopic exam, neutrophils fill the subarachnoid space and the perivascular spaces within the brain parenchyma. Unless there was treatment prior to death, Gram stain often demonstrates bacteria. Complications include cerebral ischemia, infarction, hydrocephalus, subdural effusion, sagittal sinus, or cortical vein thrombosis (Chimella, 2001; Gyure, 2005). Viral infections Viral infections of the CNS may result in aseptic meningitis or meningoencephalitis. Viral meningitis is typically less severe than bacterial, and most patients recover without complications. This disorder is usually caused by enterovirus and is uncommon in older adults (Chimella, 2001). The meninges may be slightly opaque, and inflammatory infiltrate is composed almost exclusively of lymphocytes.

Herpes simplex encephalitis Herpes simplex virus (HSV) encephalitis, the most common sporadic, nonseasonal encephalitis, occurs at all ages, and about half are in patients older than 50. Indeed, in older age groups, HSV (typically, HSV-1) is the most prevalent cause of encephalitis (Chimella, 2001). Clinically, patients present with a subacute onset of fever, headache, and confusion. Grossly, HSV encephalitis typically shows bilateral, asymmetric, hemorrhagic necrosis affecting the temporal lobes, the insula, the cingulate gyri, and the posterior orbitofrontal cortices (Chimella, 2001; Gyure, 2005). Histology shows hemorrhagic necrosis with perivascular and parenchymal chronic inflammation, macrophages, and microglial nodules. Cowdry A intranuclear inclusions are a characteristic feature of HSV encephalitis. Immunohistochemistry and electron microscopy may be helpful in identifying the organisms.

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Progressive multifocal leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an infectious demyelinating disease of the CNS that results from the infection of oligodendroglial cells by JC virus, a papovavirus. It occurs most commonly in immunocompromised patients and has been described as a complication of specific drugs, cancers, and aging; it is commonly associated with HIV infection (Gyure, 2005). Clinical presentations include focal signs/symptoms and cognitive impairment. Grossly, the white matter shows small foci of gray discoloration, often forming large confluent areas of abnormal parenchyma. Lesions are typically subcortical in the cerebral hemispheres and have a predilection for the parieto-occipital regions (Chimella, 2001; Gyure, 2005). Microscopic examination shows foci of demyelination with surrounding infected enlarged and hyperchromatic oligodendroglial nuclei. Astrocytes in PML often appear “neoplastic” and show lobulated, hyperchromatic nuclei (Gyure, 2005).

Cryptococcosis Cryptococcosis infections are caused by the fungus Cryptococcus neoformans, a common environmental fungus that infects mostly immunocompromised humans via the lungs. It is associated with lymphoproliferative disorders, alcoholism, advanced age, generalized malnutrition, corticosteroid therapy, organ transplantation, and HIV (Chimella, 2001). It signifies transition into AIDS in patients with HIV who present as subacute meningitis. In patients without HIV, it is usually diagnosed postmortem, as these patients rarely present with the clinical signs and symptoms of subacute or chronic meningitis. Grossly, the leptomeninges are thickened and opaque, and there might be associated hydrocephalus. There might be a Swiss cheese-like appearance, especially in the basal ganglia. The fungi are budding oval yeasts and typically have an empty-looking appearance. They can be highlighted with PAS stain and may be found around blood vessels. Toxoplasmosis Toxoplasmosis is caused by the intracellular protozoan toxoplasma gondii. The definitive hosts for this parasite are domestic cats and other feline species. It is most commonly associated with HIV, but other causes of immunosuppression can also underlie reactivation (Chimelli et al., 1992; Chimella, 2001). Brain lesions may produce focal signs and symptoms. The brain lesions are typically necrotic, with focal hemorrhage, acute and chronic inflammation with neutrophils, mononuclear cells, newly formed capillaries, astrocytes, and microglial cells. The organisms are characteristically located at the periphery of the necrotic areas, either free in the parenchyma or within cysts.

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Other infectious and inflammatory diseases of the brain Over the past decades, there has been a growing list of inflammatory conditions of the nervous system (Rosenbloom and Smith, 2009). These diseases typically have a subacute presentation with the evidence of pathologic antibodies and/or extensive inflammation. Signs and symptoms vary but, in older age groups, commonly include a subacute onset of cognitive and behavioral changes, as seen in limbic encephalitis. These conditions may or may not be associated with specific antibodies, and those associated with antibodies may or may not be paraneoplastic. Small-cell lung carcinomas are one of the more common underlying tumors of the paraneoplastic syndromes, so determining whether there is a history of smoking is important. Some diseases have been associated with specific pathologies, such as limbic encephalitis and systemic lupus erythematosus, whereas the underlying pathology of some of the other conditions (such as Hashimoto’s encephalitis) is less clear. There is also a group of inflammatory diseases without specific antigen or antibodies, such as sarcoidosis and primary CNS vasculitis. Overall, these diseases are uncommon, and late presentations in the geriatric population are relatively rare. Pathology may show a fulminant encephalitis, with inflammation, neuronophagia, and microglial nodules (as seen in limbic encephalitis), or inflammation and necrosis focused primarily at the blood vessels (vasculitis). Some of these pathologies have been described in the previous sections, and a complete review of these neuropathologies is out of the scope of this chapter. Finally, markedly improved treatments have significantly increased longevity in persons with HIV, and some studies suggest that aging HIV patients may be at higher risk for specific age-related conditions, such as AD; interestingly, IV drug abusers without HIV may also be at higher risk (Anthony et al., 2010).

Trauma Acute hemorrhages and chronic traumatic encephalopathy are significant in the geriatric population. Both conditions can significantly increase the morbidity and decrease the functional ability.

Subdural hematomas Subdural hematomas (SDHs) may be acute or chronic. Acute traumatic SDHs may be associated with diffuse cerebral contusions and lacerations and adjacent intracerebral hematoma. These patients are typically unconscious from the time of injury (Blumbergs et al., 2008). More commonly, there is a less severe type of acute SDHs that may not be associated with obvious trauma and that is the result of rupture of bridging veins, with little or no associated brain damage (Blumbergs et al., 2008).

Pathologically, SDHs are considered chronic when at approximately 3 weeks of age or status post injury. Chronic SDHs may or may not be associated with recognized trauma and are usually the result of rupture of bridging dural arachnoid veins. Chronic SDHs occur most commonly in patients over the age of 50 years and are most common in those from 70 to 80 years old (Blumbergs et al., 2008). Cerebral atrophy seems to be an important predisposing factor, supposedly secondary to tension on bridging veins. This atrophy may allow hemorrhage without a significant mass effect. The age of the SDH may be approximated by the microscopic examination of the clot and subdural membranes. In the first few days, the outer dural membrane shows a few layers of fibroblastic membrane; this progresses to equal the dura thickness after 4–6 weeks (Blumbergs et al., 2008). The membrane is highly vascular, which predisposes to rebleeding; thus, an SDH may show hemorrhage and membranes of varying age.

Chronic traumatic encephalopathy It has long been recognized that boxers with repeated head injury and concussions are predisposed to an earlyonset dementia syndrome often referred to as dementia pugilistica. The pathology underlying this syndrome has been shown to have similarities but also distinctions compared to AD. This relationship is intriguing, given that repeated head trauma has been shown to be a risk factor for sporadic late-onset clinical AD. More recent studies have provided a more in-depth description of this disorder. Clinical symptoms include changes in memory, personality, and behavior with parkinsonism. The syndrome is not only in boxers, but also in those involved in other competitive sports, such as football (McKee et al., 2009). The pathology shows what appears to be a separate degenerative tauopathy with tangles and threads in a patchy but unique distribution, with a predilection for superficial cortex, sulcal depths, and perivascular regions in the frontal and temporal cortices. Diffuse amyloid is a common but variable feature (McKee et al., 2009). Further work is needed to determine the relationship between chronic traumatic encephalopathy and AD.

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Functional Changes Associated with the Aging Nervous System

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Part 2 Assessment of the Geriatric Neurology Patient

Chapter 3 Approach to the Geriatric Neurology Patient: The Neurologic Examination Marwan N. Sabbagh1 and Anil K. Nair2 1 2

Banner Sun Health Research Institute, Sun City, AZ, USA Clinic for Cognitive Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA

Summary • Neurologic examinations of geriatric patients must focus on the patient’s overall functional ability according to his or her physical, neurologic, behavioral, and cognitive changes that occur with aging. • A review of medications and physical, head and neck, and cardiovascular examinations are essential. • Neurologic examinations include/assess: • Mental status testing using a cognitive screen such as the MOCA. • Speech articulation, loudness, and phonation. • Language comprehension, repetition, naming, ability to follow commands, fluency, and prosody. • Cranial nerves. • Muscle bulk, tone, and strength as well as pronator drift and other abnormal movements. • Sensory perception, loss, neglect, pain, and proprioception. • Deep tendon and primitive reflexes, as well as clonus. • Coordination/Cerebellar function. • Gait and posture. • Careful investigation of the nervous system can reveal underlying causes of various symptoms and prompt further investigation and treatment. Examinations can also provide information that helps to improve care.

Introduction As the population ages, the number of patients over age 65 is expected to grow almost exponentially. In fact, the geriatric population is the fastest-growing segment of the population. The geriatric population has unique medical challenges. Their physical and neurologic findings have different root etiologies from their younger counterparts. Thus, there is a consideration for reviewing the neurologic examination for the geriatric patient. Like geriatrics and geriatric psychiatry, which are wellestablished subspecialties of primary care and psychiatry, respectively, geriatric neurology is emerging as a subspecialty of neurology. This emergence reflects the growing understanding that geriatric patients have different neurologic conditions that require different diagnostic evaluations and, ultimately, different features. As such, clinical syndromes can have features common to younger patients, but the etiologies are frequently different. Careful attention to features of the physical and neurologic examination as findings, as with the younger patient, frequently points to root causes, prompting

further investigation. In this chapter, we review the neurologic examination of the geriatric patient and briefly review key elements of the physical examination. Physical and neurologic findings are also detailed throughout the textbook and are cross-referenced accordingly.

The geriatric neurologic examination with a focus on function The focus of the geriatric neurologic examination is different from an examination for a typical patient seen at a neurology service or in an office setting. For the latter, the primary purpose of the examination is to localize the site of the lesion and guide the appropriate workup to determine the diagnosis and most appropriate treatment for the condition (Bickley, Szilagyi, and Bates, 2007). In contrast, the focus of the geriatric neurology examination is determining the physical, neurologic, cognitive, and behavioral deficits that will impair a patient’s functional ability, as well as identifying his or her ability to carry out specific tasks. The geriatric neurologist must go beyond

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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neurologic impairment and assess the impact that other diseases, such as arthritis, chronic obstructive pulmonary disease, and cardiovascular disease, may have on the patient’s function, in a way a primary care physician would not be able to do. For example, muscle rigidity may affect a person’s ability to transfer, dress, or walk independently. Spasticity might impede nursing care by causing difficulty in catheterization or by causing problems with positioning in a wheelchair or bed. Identifying these deficits and determining their effect on function allows the care team to set appropriate goals and develop specific treatment strategies to address a patient’s needs. This also allows the team to plan for a patient’s continued functioning at home and within the community. Serial examinations in a patient may also provide useful information regarding prognosis for functional recovery. The initial evaluation of a patient in the geriatric setting should include a detailed history, including the history of psychiatric disorders. Because many patients with cognitive and language impairments have difficulty communicating, obtaining the history from family and medical records may be necessary. Additional information about the inciting event should be sought. In patients with mild cognitive impairment (MCI), the presence and duration of amnesia is important. Concurrent medical problems, such as strokes, brain hemorrhage, hypoxia, hypotension, and seizures; systemic injuries, including skeletal fractures and peripheral nerve injuries; and the presence of intoxicant drugs and alcohol may help in establishing a cognitive prognosis. Knowledge of premorbid cognitive and functional status is important. An education and employment history is essential. A general physical examination is to be performed on all patients. This examination should include the assessment of the level of consciousness, as detailed in Chapter 4.1, “Mental Status Examination in the Geriatric Neurology Patient.” The skin should be examined for evidence of skin breakdown (decubitus ulcers). A thorough musculoskeletal examination should be performed, focusing on joint range of motion, skeletal deformities, and abnormal postures of limbs. Finally, a detailed neurologic examination should be performed, including an assessment of mental status, cranial nerves, motor and sensory systems, reflexes, coordination, and gait.

Physical examination The physical examination of the geriatric patient is quite important and might be considered part of the neurologic examination.

Biometrics Gathering vital signs and body weight is seemingly obvious and is routine. Nevertheless, complaints of

syncope and dizziness might prompt checking orthostatic blood pressures, as orthostatic hypotension is common in the elderly (see Chapter 14, “Autonomic Dysfunction and Syncope,” and Chapter 16, “Vertigo and Dizziness in the Elderly”). Additionally, hypotension can be caused by neurologic conditions (see Chapter 12.1, “Parkinson’s Disease”). Similarly, checking pulse is important, as bradycardia can be symptomatic as syncope and dizziness. Tachyarrhythmias can also present as dizziness and syncope. Serial weight measurements over time might be important. For example, weight loss is common in the elderly. It is particularly common in degenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) and can portend a negative prognosis. Alternately, weight loss might be related to medication consumption, as many medications can cause anorexia. Taking the temperature of the geriatric patient is also important. Geriatric patients do mount fever, but in many cases, the hyperthermia can be mild, even in the setting of significant infections. Conversely, hypothermia could indicate sepsis.

Medications The assessment of the geriatric patient, including the neurologic patient, should start with a review of the medications. Patients are unaware of their medications, in many cases. Redundancy is common, and medication errors are frequent. Another confounding feature in the elderly is polypharmacy. The elderly tend to consume more medications and more classes of medications than other groups of patients. Thus, drug–drug interactions emerge, which can contribute to symptoms. Medications frequently have neurologic side effects (dizziness, lightheadedness, confusion, tremor, somnolence). Thus, a common therapeutic approach might be to reduce medication or reduce the doses of medication rather than add medication to treat specific symptoms. Head and neck examination The assessment of the head and neck is important as well, primarily with vision and hearing. Vision and hearing loss are ubiquitous among the elderly and can cause significant challenges in assessing the patient in other areas, such as mentation, and so should be accounted for. Patients with severe hearing loss can present as cognitively impaired. Examination of the neck for bruit, carotid hypersensitivity, and thyromegaly should be routine. The presence of a unilateral bruit can be an indication of vascular stenosis in the carotids but is unreliable as a marker of vascular disease (see Chapter 11, “Cerebrovascular Diseases in Geriatrics”), whereas bilateral bruit can be referred from the chest from aortic stenosis.

Approach to the Geriatric Neurology Patient: The Neurologic Examination

Cardiovascular Though neurologists are unlikely to suddenly become cardiologists, they should have a solid grasp of common cardiac findings, as these findings can manifest as neurologic conditions. For example, bradycardia can be symptomatic as syncope and dizziness. Tachyarrhythmias can also present as dizziness and syncope. Atrial fibrillation is very common in the elderly and can manifest as tachy- or bradyarrhythmias. A right apical crescendo decrescendo murmur might indicate aortic stenosis, which is often referred to the neck as bilateral bruit.

Neurologic examination Changes in the nervous system that occur with aging (see Table 3.1) are to be considered when a geriatric patient is examined (Rathe, 1996).

Mental status testing Mental status testing, including the assessment of cognition, alertness, concentration, praxis, speech, and language, is covered in detail in Chapter 4.1, “Mental Status Examination in the Geriatric Neurology Patient.” A cognitive screen such as www.mocatest.org is typically used (Figure 3.1). As mentioned earlier, this can be confounded by hearing and vision loss, so patients should be screened for impairments of vision and acusis in the context of the mental status examination. In many cases, their cognitive assessment might appear artificially worse because of visual or auditory impairment. Speech Several elements of speech need to be evaluated, including articulation, loudness, and phonation. When listening to your patient, pay attention to the articulation. Are the words spoken clearly? Disturbances in articulation of speech are called dysarthria. Dysarthria refers to defective Table 3.1 Changes in the neurologic examination with age Localization

Diminished modality

CN I

Diminished smell

CN 2

Diminished pupil size Abnormal pupillary reaction time Diminished accommodation Abnormal upward gaze

CN 8

High-tone hearing loss

Motor system

Diminished bulk and power Prolonged reaction time Diminished coordination

Sensory

Diminished vibration

Reflexes

Diminished ankle jerk

Gait

Diminished fluidity of movement Diminished coordination

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articulation without ascribing etiology. It could be from mechanical issues (such as dentures) but also can reflect neurologic conditions, such as cerebrovascular accidents (CVAs), amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and progressive supranuclear palsy. Loudness also needs to be assessed. Loudness is compromised in PD and progressive supranuclear palsy (PSP) but can be seen in depression. Phonation refers to the utterance of vocal sounds. It also refers to the production of voiced sound by means of vocal cord vibrations. Phonation can be impaired in cranial neuropathies and in bulbar conditions such as ALS.

Language Language evaluation includes the assessment of comprehension, repetition, naming, ability to follow commands, fluency, and prosody. Prosody is the rhythm, stress, and intonation of speech. Aprosodia is the impairment in comprehending or generating the emotion conveyed in spoken language. Producing these nonverbal elements requires intact motor areas of the face, mouth, tongue, and throat. Damage to areas 44/45 produces motor aprosodia, with the nonverbal elements of speech being disturbed (facial expression, tone, rhythm of voice). Right-hemispheric area 22 aids in the interpretation of prosody, and damage causes sensory aprosodia, with the patient unable to comprehend changes in voice and body language. Prosody is dealt with by a right-hemisphere network that is largely a mirror image of the left perisylvian zone. Damage to the right inferior frontal gyrus causes a diminished ability to convey emotion or emphasis by voice or gesture, and damage to right superior temporal gyrus causes problems comprehending emotion or emphasis in the voice or gestures of others. Disorders of comprehension, repetition, naming, and fluency are broadly subsumed under the category of the aphasias. Aphasia refers to impairment of language ability (Aphasia Symptoms, Causes, Treatment–-How Is Aphasia Diagnosed? 2011). Aphasia disorders have multiple etiologies in the elderly. Among the more common considerations in the geriatric population are head injury, stroke, brain tumor, infection, and dementia. Degenerative forms of aphasias are referred to as the progressive aphasias. (See Chapter 9.6, “Primary Progressive Aphasias,” for more details.) The area and extent of brain damage determine the type of aphasia and its symptoms. Aphasia types include Broca’s aphasia, nonfluent aphasia, motor aphasia, receptive aphasia, global aphasia, and many others. Broca’s aphasia (also termed expressive aphasia) is caused by lesions to the medial insular cortex. In contrast to Broca’s aphasia, damage to the temporal lobe may result in a fluent aphasia that is called Wernicke’s aphasia (also termed sensory aphasia). The other types of aphasia in the localizationist model include pure word deafness, conduction aphasia,

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Assessment of the Geriatric Neurology Patient

Image not available in this digital edition.

Figure 3.1 Montreal cognitive assessment (MOCA)—http://www.mocatest.org (accessed on April 8, 2013).

global aphasia, transcortical motor aphasia, transcortical sensory aphasia, and anomic aphasia. In most cases in the geriatric population, cerebrovascular disease is the leading cause, followed by progressive aphasias. However, anomic aphasia is commonly seen in AD.

Cranial nerves The cranial nerve examination is routinely performed, but findings from the examination may have different etiologies than similar findings from younger individuals. Start with observation of the individual. Consider these

Approach to the Geriatric Neurology Patient: The Neurologic Examination

possibilities when examining a patient for ptosis (III), facial droop or asymmetry (VII), hoarse voice (X), articulation of words (V, VII, X, XII), abnormal eye position (III, IV, VI), and abnormal or asymmetrical pupils (II, III).

Cranial nerve I Olfaction is frequently impaired in the elderly. It is not routinely assessed. This is manifested as anosmia, ageusia, or dysgeusia. Etiologies of olfactory dysfunction include sinus disease, medication, and degenerative neurologic disorders such as AD and PD. Though olfaction is not routinely assessed in neurologic practice, smell testing is available and can be a sensitive detection method for neurodegenerative disease; however, the specificity is somewhat lacking. Although uncommon except following stroke, anosmia (olfactory dysfunction) occurs in 13–50% of patients with AD, most commonly because of malfunction to olfactory pathways. Anosmia also develops in 18% of patients following ruptured cerebral aneurysms, correlating to the presence of intraventricular hemorrhage. Anosmia can cause decreased life satisfaction and lead to safety concerns, as with, for example, the inability to smell smoke, gas, or spoiled food. Standardized, commercially available “scratch-and-sniff” tests may be used for formal testing.

Cranial nerve II The optic nerve and anterior visual pathways are affected in many patients with dementia and other geriatric illnesses, resulting in impaired visual acuity, visual field defects, or blindness. Stroke can affect the visual pathways anywhere along their course, with monocular blindness from optic nerve injury or retinal lesions, bitemporal hemianopsia from the optic chiasm, homonymous hemianopsia from injury to the optic radiations, and cortical blindness from an insult to the calcarine cortex in the occipital lobes. Visual acuity may be affected by direct injury to the optic nerve or by diffuse occipital lobe injury. Loss of vision can significantly impair function by affecting the ability to read, navigate safely, and perform activities of daily living (ADLs), and is important to document at each visit. Vision and fundoscopy are very important. Presbyopia is expected. Diminished vision comes from many causes, including cataracts, glaucoma, and macular degeneration. Age-related macular degeneration is a medical condition that usually affects older adults, resulting in a loss of vision in the macular (central) region of the retina. It occurs in “dry” and “wet” forms. It is a major cause of visual impairment in adults older than 50 years (de Jong, 2006). Macular degeneration can make it difficult or impossible to read or recognize faces, although enough peripheral vision remains to allow other activities of daily life. Other forms of macular degeneration include dry central geographic atrophy, the “dry” form

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of advanced age-related macular degeneration (AMD). It results from atrophy to the retinal pigment epithelial layer below the retina, which causes vision loss through loss of photoreceptors (rods and cones) in the central part of the eye. Neovascular or exudative AMD, the “wet” form of advanced AMD, causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) in the choriocapillaris, ultimately leading to blood and protein leakage below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated (Horton, 2005). Glaucoma is an ocular disorder that is common in the elderly. With glaucoma, the optic nerve is damaged, permanently damaging vision in the affected eye(s) and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the aqueous humor (Rhee, 2008). The two subtypes of glaucoma are termed open-angle and closed-angle glaucoma. Closed-angle glaucoma can appear suddenly and is often painful; visual loss can progress quickly, but the discomfort often leads patients to seek medical attention before permanent damage occurs. Open-angle, chronic glaucoma tends to progress at a slower rate, and patients may not notice that they have lost vision until the disease has progressed significantly. Cataracts are among the most common age-related ocular changes. Cataracts affect the anterior chamber of the eye, where clouding develops in the crystalline lens. Cataracts vary in degree from slight to complete opacity and obstruct the passage of light. Cataracts typically progress slowly to cause vision loss and are potentially blinding if untreated. The condition usually affects both eyes, but almost always one eye is affected earlier than the other (Pavan-Langston, 2007). The senile cataract is characterized by an initial opacity in the lens, subsequent swelling of the lens, and final shrinkage with complete loss of transparency (Quillen, 1999).

Testing cranial nerve II • Test visual acuity: 1 Allow the patient to use his or her glasses or contact lens, if available. You are interested in the patient’s best corrected vision. 2 Position the patient 20 feet in front of the Snellen eye chart (or hold a Rosenbaum pocket card at a 14 in “reading” distance). 3 Have the patient cover one eye at a time with a card. 4 Ask the patient to read progressively smaller letters until he or she can go no further. 5 Record the smallest line the patient can read successfully (such as 20/20 or 20/30). Visual acuity is reported as a pair of numbers (20/20); the first number is how far the patient is from the chart, and the second number is the distance from which the “normal” eye can read a

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Assessment of the Geriatric Neurology Patient

line of letters. For example, 20/40 means that, at 20 feet, the patient can read only letters a “normal” person can read from twice that distance. 6 Repeat with the other eye. • Screen visual fields by confrontation: 1 Stand 2 feet in front of the patient and have him or her look into your eyes. 2 Hold your hands about 1 foot away from the patient’s ears, and wiggle a finger on one hand. 3 Ask the patient to indicate on which side he or she sees the finger move. 4 Repeat two or three times, to test both temporal fields. 5 If an abnormality is suspected, test the four quadrants of each eye while asking the patient to cover the opposite eye with a card (optional). • Test pupillary reactions to light: 1 Dim the room lights as necessary. 2 Ask the patient to look into the distance. 3 Shine a bright light obliquely into each pupil, in turn. 4 Look for both the direct (same eye) and consensual (other eye) reactions. 5 Record pupil size in millimeters and any asymmetry or irregularity. 6 If abnormal, proceed with the test for accommodation. • Test pupillary reactions to accommodation (optional): 1 Hold your finger about 10 cm from the patient’s nose. 2 Ask the patient to alternate looking into the distance and at your finger. 3 Observe the pupillary response in each eye. Pupillary abnormalities need to be assessed in the elderly but are confounded by the frequent use of ophthalmic treatments for glaucoma and macular degeneration. Considerations include anisocoria, posterior communicating artery aneurysm, diabetes, Adie’s tonic pupil, and surgical coloboma following cataract surgery. Evaluation of papillary abnormalities is done in conjunction with the ophthalmologist.

Cranial nerves III, IV, and VI Injury to the oculomotor, trochlear, or abducens nerves can occur following a brainstem stroke or contusion, orbital wall fracture, or basilar skull fracture resulting in cavernous sinus injury. Patients may complain of double vision and dizziness, and findings on examination may include eye deviation, dysconjugate gaze, abnormal head postures, and problems with balance and coordination. Alternate eye patching may be beneficial, especially during therapy sessions. Evaluation of the extraocular movements can be revealing of specific pathologies. Eye movement abnormalities are referable to nuclear lesions in the form of cranial neuropathies (III, IV, and VI) or in the form of supranuclear impairment. Cranial neuropathies affecting eye

movement most commonly present as diplopia. Cranial neuropathies affecting ocular movements have many causes, including sarcoid, DM, cavernous sinus thrombosis, aneurysms, and CVAs. Supranuclear oculomotor impairments are common in the elderly also. These types of impairments affect vertical gaze, smooth pursuit, and saccades. Saccades are the very quick, simultaneous movements made by the eye to receive visual information and shift the line of vision from one position to another (Iwamoto and Yoshida, 2002). The area of the brain that controls saccades is the superior colliculus, specifically the fastigial oculomotor region (FOR) (Iwamoto et al., 2002). The information is received from the retina, translated into spatial information, and then transferred to motor centers for motor response. A person with saccadic dysmetria constantly produces abnormal eye movements, including microsaccades, ocular flutter, and square wave jerks, even when the eye is at rest (Schmahmann, 2004). During eye movements, hypometric and hypermetric saccades occur, and interruption and slowing of normal saccadic movement is common (Schmahmann, 2004). Ocular dysmetria makes it difficult to focus vision on one object. Impairments in vertical gaze are typical of progressive supranuclear palsy. Impairments of smooth pursuit gaze reflect abnormal function of the frontal eye fields and can be seen in neurodegenerative diseases such as PD and AD.

Testing cranial nerves III, IV, and VI • Observe for ptosis. • Test extraocular movements: 1 Stand or sit 3–6 feet in front of the patient. 2 Ask the patient to follow your finger with the eyes without moving the head. 3 Check gaze in the six cardinal directions using a cross or “H” pattern. 4 Pause during upward and lateral gaze to check for nystagmus. 5 Check convergence by moving your finger toward the bridge of the patient’s nose. • Test pupillary reactions to light.

Cranial nerve V Trigeminal nerve injuries occur in patients with head injuries, most commonly because of facial bone fractures. These injuries can also occur following brainstem stroke or contusion. Complete trigeminal nerve injury causes hemianesthesia of the face, whereas partial injuries generally result in facial pain. Motor branch involvement can lead to chewing problems, and loss of sensation inside the mouth may cause pocketing of food and increase the risk of aspiration. Facial sensation reflects the trigeminal nerve dermatomes (cranial nerve V). The three divisions of the trigeminal nerve include ophthalmic, maxillary, and mandibular.

Approach to the Geriatric Neurology Patient: The Neurologic Examination

The ophthalmic region includes the forehead, eyebrow, eyelid, and cornea. The maxillary region includes the zygomatic arch to the mouth. The mandibular region covers the mouth to the jaw. The subdivisions overlap. Hypoesthesia involving the trigeminal nerve dermatomes can be caused by either a cranial neuropathy or a CVA in the elderly. Hyperesthesia/dysesthesia involving the trigeminal nerve is referred to as trigeminal neuralgia. The pain of trigeminal neuralgia originates on the trigeminal nerve. This nerve carries pain, feeling, and other sensations from the brain to the skin of the face. It can involve all divisions. The condition usually affects older adults, but it may affect anyone at any age. Trigeminal neuralgia may be part of the normal aging process. Alternatively, trigeminal neuralgia may be caused by pressure on the trigeminal nerve from a swollen blood vessel or tumor. Often no specific cause is found. Symptoms are unilateral and intermittent and can be triggered by touch or sounds (such as brushing teeth, chewing, drinking, eating, light touching, or shaving). The neurologic examination is usually normal. For additional details, see Chapter 17, “Disorders of the Special Senses in the Elderly.”

Testing cranial nerve V • Test temporal and masseter muscle strength: 1 Ask the patient to both open the mouth and clench the teeth. 2 Palpate the temporal and masseter muscles as the patient does this. • Test the three divisions for pain sensation: 1 Explain what you intend to do. 2 Use a suitable sharp object to test the forehead, cheeks, and jaw on both sides. 3 Substitute a blunt object occasionally and ask the patient to report “sharp” or “dull.” • If you find an abnormality: 1 Test the three divisions for temperature sensation with a tuning fork heated or cooled by water (optional). 2 Test the three divisions for sensation to light touch using a wisp of cotton (optional). • Test the corneal reflex (optional): 1 Ask the patient to look up and away. 2 From the other side, touch the cornea lightly with a fine wisp of cotton. 3 Look for the normal blink reaction of both eyes. 4 Repeat on the other side.

Cranial nerve VII Facial movement (Bell’s, CVA, hypomimia) involves the facial nerve (cranial nerve VII). The examination involves having the patient show the teeth or raise eyebrows. When the frontalis muscle is spared in an asymmetric presentation of facial droop, consider a central nervous system (CNS) event such as a CVA. If the frontalis muscle is involved, consider Bell’s palsy.

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Facial muscle weakness is common in patients who have experienced a stroke or traumatic brain injury (TBI) and can affect articulation and swallowing. Injury to the upper motor (corticobulbar) pathways in the frontal lobe, internal capsule, and upper brainstem causes contralateral facial weakness, usually sparing the forehead. Lower motor neuron injury in the pons (brainstem stroke or trauma) results in ipsilateral facial weakness, including the forehead.

Testing cranial nerve VII • Observe for any facial droop or asymmetry. • Ask the patient to do the following, and note any lag, weakness, or asymmetry: 1 Raise the eyebrows. 2 Close both eyes to resistance. 3 Smile. 4 Frown. 5 Show the teeth. 6 Puff out the cheeks.

Cranial nerve VIII Hearing loss occurs in the majority of patients with geriatric neurologic conditions. High-frequency hearing loss from cochlear insensitivity and dislocation and disruption of the ossicles may be associated with vertigo and disequilibrium due to injury to the acoustic nerve, cochlea, and/or labyrinths. Brainstem contusion or stroke, damaging the acoustic or cochlear nuclei, can result in similar symptoms. Vestibular dysfunction can lead to problems with balance and coordination. The presence of horizontal nystagmus is suggestive of unilateral vestibular nerve injury. Vertical nystagmus may be seen following brainstem or cerebellar injuries. Certain medications, including anticonvulsants, can also cause nystagmus.

Testing cranial nerve VIII • Screen for hearing loss: 1 Face the patient and hold out your arms, with your fingers near each ear. 2 Rub your fingers together on one side while moving the fingers noiselessly on the other. 3 Ask the patient to tell you when and on which side he or she hears the rubbing. 4 Increase intensity as needed and note any asymmetry. 5 If abnormal, proceed with the Weber and Rinne tests. • Test for lateralization (Weber) (optional): 1 Use a 512 Hz or 1024 Hz tuning fork. 2 Start vibrating the fork by tapping it on your opposite hand. 3 Place the base of the tuning fork firmly on top of the patient’s head. 4 Ask the patient from where the sound appears to be coming from (normally in the midline).

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Assessment of the Geriatric Neurology Patient

• Compare air and bone conduction (Rinne) (optional): 1 Use a 512 Hz or 1024 Hz tuning fork. 2 Start vibrating the fork by tapping it on your opposite hand. 3 Place the base of the tuning fork against the mastoid bone behind the ear. 4 When the patient no longer hears the sound, hold the end of the fork near the patient’s ear (air conduction is normally greater than bone conduction). • Vestibular function is not normally tested routinely.

Cranial nerves IX and X The glossopharyngeal and vagus nerves are often affected in patients with medullary strokes. Injury results in impaired phonation and swallowing. The gag reflex is diminished or absent on the side of nerve injury. The palate and uvula may also be deviated to the opposite side. The gag reflex may be hyperactive in patients with injuries to the corticobulbar tracts bilaterally, bilateral strokes, or injuries to the deep white matter. This is often accompanied by spastic quadriparesis and emotional lability. The oropharynx, soft and hard palates, and tongue need to be assessed for asymmetry. These are innervated by cranial nerves IX–XII. Asymmetry of responsiveness to gag or palatal elevation might represent cranial neuropathies, which, in turn, could reflect brainstem lesions. These abnormalities would manifest as dysphonia, dysarthria, or hypophonia. Ungual paresis could reflect a brainstem abnormality as well, but fasciculation or atrophy of the tongue might represent denervation, which is seen in ALS. This would also manifest as dysarthria.

• Ask the patient to shrug the shoulders against resistance. • Ask the patient to turn the head against resistance. Watch and palpate the sternomastoid muscle on the opposite side.

Cranial nerve XII The hypoglossal nerve, which provides motor function to the ipsilateral tongue, is rarely affected as a consequence of geriatric neurologic diseases but can be involved in fracture or medullary stroke. Swallowing difficulties in dementia and parkinsonism can arise because patients may have difficulty manipulating a food bolus in the mouth.

Testing cranial nerve XII • Listen to the articulation of the patient’s words. • Observe the tongue as it lies in the mouth. • Ask patient to: 1 Protrude tongue. 2 Move tongue from side to side.

Motor examination As with the neurologic examination of the younger patient, the neurologic examination of the geriatric patient includes the motor exam. Elements of the motor examination include tone, bulk, and strength. Other considerations beyond the motor examination include the assessment of kinesis and for tremor. These extrapyramidal elements are addressed in Chapter 12.1, “Parkinson’s Disease,” and Chapter 12.2, “Essential Tremor and Other Tremor Disorders,” respectively. Additional considerations include kinesis.

Testing cranial nerves IX and X • Listen to the patient’s voice—is it hoarse or nasal? • Ask the patient to swallow. • Ask the patient to say “Ah.” • Watch the movements of the soft palate and the pharynx. • Test the gag reflex (unconscious/uncooperative patient) (optional). 1 Stimulate the back of the throat on each side. 2 It is normal to gag after each stimulus.

Muscle bulk Generalized muscle atrophy can occur because of prolonged immobility and poor intake in dementia. Damage to the lower motor neuron causes focal muscle atrophy. This can occur as a result of direct trauma to the peripheral nerve, plexus, nerve root, or anterior horn cells in the spinal cord. Focal nerve injuries can also occur because of limb ischemia following trauma or from improper positioning or casting (for example, peroneal neuropathy with a foot drop from an excessively tight leg restraint).

Cranial nerve XI The spinal accessory nerve, innervating the ipsilateral stemocleidomastoid and trapezius muscles, is only rarely injured. Spinal accessory nerve injuries can cause limited neck rotation and shoulder abduction, affecting the ability to do activities above the head, such as reach for objects in a high cabinet.

Testing cranial nerve XI • From behind, look for atrophy or asymmetry of the trapezius muscles.

Muscle tone Spasticity is the most common abnormality of tone seen in patients with stroke, TBI, and spinal cord injury. Spasticity predominantly affects the flexor muscles of the arms and extensor muscles of the legs, while in spinal cord injuries, it predominates in the flexor muscles of both the arms and legs. Tone may also be increased in trunk muscles. Spasticity is caused by injury to the corticospinal tracts and is often accompanied by muscle weakness, hyperreflexia, and an extensor plantar reflex response.

Approach to the Geriatric Neurology Patient: The Neurologic Examination

Hypotonia may be seen in association with cerebellar lesions and also often occurs early following stroke and spinal cord injuries (spinal shock). In the latter, spasticity may develop later, after a period of days to weeks. A long period of hypotonia in this setting usually suggests a poorer likelihood of functional motor recovery. Rigidity generally results from injury to the basal ganglia. Common in Parkinson’s disease, rigidity also occurs in patients who have had subcortical strokes, trauma involving the basal ganglia, and anoxic brain injury. Paratonia is a consequence of bilateral frontal lobe injury or dementia. Spasticity and rigidity may be painful, can be accompanied by muscle spasms, and may affect nursing care by interfering with positioning, bracing, transfer, nursing care, and ADLs. Neck and head control can be affected, hampering feeding and grooming. Spasticity of laryngeal and pharyngeal muscles can affect breathing, articulation, phonation, and swallowing. Truncal spasticity can affect wheelchair positioning, standing, and ambulation. If spasticity is severe and prolonged, fixed joint contractures can develop, further impeding the care progress.

Testing muscle tone • Ask the patient to relax. • Flex and extend the patient’s fingers, wrist, and elbow. • Flex and extend the patient’s ankle and knee. • There is normally a small, continuous resistance to passive movement. • Observe for decreased (flaccid) or increased (rigid/ spastic) tone. The tone can be graded as normal, hypertonic, or hypotonic. Also indicate the type of hypertonia, include spastic, rigid, or gegenhalten. Spastic hypertonia, defined as velocity-dependent resistance to stretch, is referable to upper motor neuron lesions and occurs because of a lack of inhibition from the CNS, which results in excessive contraction of the muscles. Common considerations include residua from CVAs or spinal cord injury. Rigid hypertonia is seen in extrapyramidal disorders (such as PD; see Chapter 12.1). Rigidity, also called increased muscle tone, means stiffness or inflexibility of the muscles. Gegenhalten (also known as paratonia) refers to an involuntary resistance to passive movement as may occur in cerebral cortical disorders. It may occur as a symptom of catatonia, in which there is passive resistance to stretching movements, even when the patient attempts to cooperate. The effect may be psychogenic in origin or may be a sign of dementia or cerebral deterioration. Hypotonia is reduced muscle tone (the amount of tension or resistance to movement in a muscle, also known as flaccidity), and is usually associated with weakness (reduced muscle strength). Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve

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control by the brain or muscle strength. Diminished deep tendon reflexes also may be noted. Causes of hypotonia in the elderly include acute changes related to CVAs and spinal cord injury.

Muscle strength Assessing the muscle bulk is part of the motor exam. Atrophy of muscle groups is, by definition, decreased bulk. Atrophy can occur from myopathies, neuropathies, or radiculopathies and reflects lower motor neuron lesions. The most common patterns of weakness are hemiparesis or tetraparesis because of injury to the corticospinal tracts in the cerebral hemispheres or brainstem. Strokes typically result in hemiparesis, with the arm affected to a greater extent than the leg in middle cerebral artery distribution infarcts affecting cortical structures. In patients with anterior cerebral artery (ACA) distribution infarcts, the leg is predominantly affected. Subcortical strokes generally affect the arm and leg equally. Any deviation from an expected pattern should trigger a search for additional spinal cord or peripheral nerve injuries. Cervical spinal cord injuries often result in tetraparesis, while thoracic and lumbar spine injuries lead to paraparesis. The level of spinal cord injury is defined as the most rostral cord level innervating muscles with at least grade 3 strength.

Testing muscle strength • Test strength by having the patient move against your resistance. • Always compare one side to the other. • Grade strength on a scale from 0 to 5 out of 5 (see Table 3.2). • Test the following movements: 1 Flexion at the elbow (C5, C6, biceps). 2 Extension at the elbow (C6, C7, C8, triceps). 3 Extension at the wrist (C6, C7, C8, radial nerve). 4 Ability to squeeze two of your fingers as hard as possible (“grip,” C7, C8, T1). 5 Finger abduction (C8, T1, ulnar nerve). 6 Opposition of the thumb (C8, T1, median nerve). 7 Flexion at the hip (L2, L3, L4, iliopsoas). 8 Adduction at the hips (L2, L3, L4, adductors). 9 Abduction at the hips (L4, L5, S1, gluteus medius and minimus). Table 3.2 Grading motor strength Grade

Description

0/5 1/5 2/5 3/5 4/5 5/5

No muscle movement Visible muscle movement, but no movement at the joint Movement at the joint but not against gravity Movement against gravity but not against added resistance Movement against resistance, but less than normal Normal strength

Assessment of the Geriatric Neurology Patient

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10 11 12 13 14

Extension at the hips (S1, gluteus maximus). Extension at the knee (L2, L3, L4, quadriceps). Flexion at the knee (L4, L5, S1, S2, hamstrings). Dorsiflexion at the ankle (L4, L5). Plantar flexion (S1).

Testing pronator drift • Ask the patient to stand for 20–30 seconds with both arms straight forward, palms up, and eyes closed. • Instruct the patient to keep the arms still while you tap them briskly downward. • The patient will not be able to maintain extension and supination. Assessing the strength of all muscle groups in the upper and lower extremities is also part of the motor exam. Similar to younger patients, the motor examination should be assessed in detail. Focal weakness of a limb could reflect CVA (ACA infarct leads to monoparesis of the lower extremity), polyradiculopathy, or plexopathy. Weakness in a group of muscles could reflect radiculopathy or neuropathy.

Abnormal movements Abnormal motor movements or postures may result from dementia or brain injuries. Dystonia can occur because of basal ganglia injury (trauma or stroke) or may be seen as an adverse effect of neuroleptic medications and metoclopramide. Dyskinesias of the limbs or orofacial muscles and choreoathetosis may also result from basal ganglia injury or adverse effects of anticonvulsants, oral contraceptives, or antipsychotic medications. Ballismus may occur as a result of trauma or hemorrhage involving the subthalamic region. Tremor of the head or limbs may also result from brain injuries. Myoclonus can be focal, segmental, or generalized, and can occur as a direct consequence of brain injury, including anoxic encephalopathy. Myoclonus is also a common sequela of metabolic abnormalities, including hepatic and renal failure. Asterixis most commonly manifests as a wrist flap when holding the arms outstretched. This can occur in patients with injury to the thalamus, internal capsule, parietal cortex, and midbrain, but is often associated with liver failure. Post-traumatic parkinsonism can result from TBI or anoxic brain injury. Abnormal movements or postures interfere with normal coordinated movements, hampering a patient’s ability to perform ADLs, such as feeding and grooming, or to carry out mobility skills, including wheelchair positioning, sitting balance, standing, or ambulation.

Sensory examination The sensory examination encompasses assessing peripheral and central sensory elements. The primary peripheral sensory modalities include light touch, pinprick, vibration, and proprioception. Central sensory elements

include face–hand test for asimultagnosia, assessment of agraphesthesia, stereognosis, and assessment for neglect. (Also see Chapters 12.2 and 17.)

Sensory perception Sensory perception is commonly affected in patients with geriatric neurology, although sensory deficits are generally overshadowed by motor and cognitive deficits. Thalamic injuries result in loss of sensation on the contralateral side of the body. Parietal lobe injuries cause loss of ability to localize the site of sensory stimulation, with impaired joint position sense, stereognosis, and graphesthesia. Sensory neglect, including visual neglect, hemi-inattention, tactile extinction, and anosognosia, may also be present and is more common following nondominant parietal lobe involvement. Spinal cord injuries result in impaired sensation below the level of the injury, and even in the absence of weakness, bilateral lower extremity proprioceptive loss can significantly impair gait. Sensory deficits can lead to functional impairments. The inability of a patient to detect or localize pain or the presence of sensory neglect can result in injury, as patients may be unable to protect their affected limbs. The inability to control limb position in space because of impaired proprioception can cause problems with feeding and grooming. Lack of feeling in the hands can lead to difficulty with fine motor tasks such as buttoning or fastening snaps or zippers. Lower extremity sensory deficits can lead to problems with transfers and walking because of impairment in foot placement and balance. Patients with impaired sensation of the buttocks and lower extremities are at increased risk of developing decubitus ulcers, especially if spasticity, impaired mobility, and bowel and/ or bladder incontinence are present.

Testing sensory loss General • Explain each test before you do it. • Unless otherwise specified, the patient’s eyes should be closed during the actual testing. • Compare symmetrical areas on the two sides of the body. • Also compare distal and proximal areas of the extremities. • When you detect an area of sensory loss, map out its boundaries in detail. Vibration • Use a low-pitched tuning fork (128 Hz). 1 Test with a nonvibrating tuning fork first to ensure that the patient is responding to the correct stimulus. 2 Place the stem of the fork over the distal interphalangeal joint of the patient’s index fingers and big toes. 3 Ask the patient to tell you if he or she feel the vibration.

Approach to the Geriatric Neurology Patient: The Neurologic Examination

• If vibration sense is impaired, proceed proximally (optional): 1 Wrists. 2 Elbows. 3 Medial malleoli. 4 Patellas. 5 Anterior and superior iliac spines. 6 Spinous processes. 7 Clavicles.

Subjective light touch • Use your fingers to touch the skin lightly on both sides simultaneously. • Test several areas on both the upper and lower extremities. • Ask the patient to tell you if there is difference from side to side or if other “strange” sensations are experienced. Position sense 1 Grasp the patient’s big toe and hold it away from the other toes to avoid friction (optional). 2 Show the patient “up” and “down.” 3 With the patient’s eyes closed, ask the patient to identify the direction you move the toe. 4 If position sense is impaired, move proximally to test the ankle joint (optional). 5 Test the fingers in a similar fashion. 6 If indicated, move proximally to the metacarpophalangeal joints, wrists, and elbows (optional). Dermatomal testing If vibration, position sense, and subjective light touch are normal in the fingers and toes, you may assume the rest of this examination will be normal (optional). Pain • Use a suitable sharp object to test “sharp” or “dull” sensation. • Test the following areas: 1 Shoulders (C4). 2 Inner and outer aspects of the forearms (C6 and T1). 3 Thumbs and little fingers (C6 and C8). 4 Front of both thighs (L2). 5 Medial and lateral aspects of both calves (L4 and L5). 6 Little toes (S1). Temperature • Examination in this category is often omitted if pain sensation is normal (optional). • Use a tuning fork heated or cooled by water and ask the patient to identify “hot” or “cold.” • Test the following areas: 1 Shoulders (C4). 2 Inner and outer aspects of the forearms (C6 and T1). 3 Thumbs and little fingers (C6 and C8).

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4 Front of both thighs (L2). 5 Medial and lateral aspects of both calves (L4 and L5). 6 Little toes (S1).

Light touch • Use a fine wisp of cotton or your fingers to touch the skin lightly. • Ask the patient to respond whenever a touch is felt. • Test the following areas: 1 Shoulders (C4). 2 Inner and outer aspects of the forearms (C6 and T1). 3 Thumbs and little fingers (C6 and C8). 4 Front of both thighs (L2). 5 Medial and lateral aspects of both calves (L4 and L5). 6 Little toes (S1). Discrimination Because these tests are dependent on touch and position sense, they cannot be performed when the previous tests are clearly abnormal (optional). • Graphesthesia: 1 With the blunt end of a pen or pencil, draw a large number on the patient’s palm. 2 Ask the patient to identify the number. • Stereognosis: 1 Use this as an alternative to graphesthesia (optional). 2 Place a familiar object in the patient’s hand (coin, paper clip, pencil, etc.). 3 Ask the patient to tell you what it is. • Two-point discrimination: 1 Use this when more quantitative data are needed, such as following the progression of a cortical lesion (optional). 2 Use an opened paper clip to touch the patient’s finger pads in two places simultaneously. 3 Alternate irregularly with one-point touch. 4 Ask the patient to identify “one” or “two.” 5 Find the minimal distance at which the patient can discriminate. Reflexes Evaluation of muscle stretch reflexes helps localize the site of neurologic injury. Hyperreflexia suggests injury to corticospinal tracts in either the brain or the spinal cord and is often associated with spasticity and muscle weakness. Hyporeflexia is associated with lower motor neuron injuries and also occurs in the period of acute spinal shock below the level of injury. Hyporeflexia may also be seen in association with peripheral neuropathies and, at times, with cerebellar disease.

Deep tendon reflexes Reflexes are frequently diminished in the elderly. A global diminution might be associated with myopathy or neuropathy (see Chapter 21, “Neuromuscular Disorders”)

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Table 3.3 Tendon reflex grading scale Grade

Description

• Note contraction of the quadriceps and extension of the knee.

0 1+ or + 2+ or ++ 3+ or +++ 4+ or ++++

Absent Hypoactive Normal Hyperactive without clonus Hyperactive with clonus

Ankle (S1, S2) • Dorsiflex the foot at the ankle. • Strike the Achilles tendon. • Watch and feel for plantar flexion at the ankle.

Testing for clonus but might also be a reflection of aging. Focal loss of DTRs is indicative of radiculopathy (cervical or lumbar) or focal neuropathy (see Chapter 21).

Testing reflexes • The patient must be relaxed and positioned properly before starting. • Reflex response depends on the force of your stimulus. Use no more force than you need to provoke a definite response. • Reflexes can be reinforced by having the patient perform isometric contraction of other muscles (clenched teeth). • Reflexes should be graded on a 0–4 “plus” scale (see Table 3.3):

Biceps (C5, C6) • The patient’s arm should be partially flexed at the elbow with the palm down. • Place your thumb or finger firmly on the biceps tendon. • Strike your finger with the reflex hammer. • You should feel the response even if you cannot see it. Triceps (C6, C7) • Support the upper arm and let the patient’s forearm hang free. • Strike the triceps tendon above the elbow with the broad side of the hammer. • If the patient is sitting or lying down, flex the patient’s arm at the elbow and hold it close to the chest. Brachioradialis (C5, C6) • Have the patient rest the forearm on the abdomen or lap. • Strike the radius about 1–2 in above the wrist. • Watch for flexion and supination of the forearm. Abdominal (T8, T9, T10, T11, T12) • Use a blunt object such as a key or tongue blade. • Stroke the abdomen lightly on each side in an inward and downward direction above (T8, T9, T10) and below the umbilicus (T10, T11, T12). • Note the contraction of the abdominal muscles and deviation of the umbilicus toward the stimulus. Knee (L2, L3, L4) • Have the patient sit or lie down with the knee flexed. • Strike the patellar tendon just below the patella.

• If the reflexes seem hyperactive, test for ankle clonus (optional). 1 Support the knee in a partly flexed position. 2 With the patient relaxed, quickly dorsiflex the foot. 3 Observe for rhythmic oscillations. • Plantar response (Babinski) 1 Stroke the lateral aspect of the sole of each foot with the end of a reflex hammer or key. 2 Note movement of the toes, normally flexion (withdrawal). 3 Extension of the big toe with fanning of the other toes is abnormal. This is referred to as a positive Babinski.

Primitive reflexes Snout, root, grasp, palmomental, and glabellar can be examined. Primitive reflexes originate in the CNS and are exhibited by normal infants but not neurologically intact adults, in response to tactile stimuli. As the brain develops, these reflexes disappear or are inhibited by the frontal lobes (Primitive and Postural Reflexes, 2008). Primitive reflexes may reappear in adults because of certain neurologic conditions, including but not limited to degenerative neurologic conditions such as dementia, traumatic brain injuries, and cerebrovascular lesions (Schott et al., 2003; Rauch, 2006).

Coordination and cerebellar examination Coordination is modulated by a number of peripheral and central nervous system structures and can be affected by brain and spinal cord injuries. Injury to the corticospinal tracts results in muscle weakness with slowing of gross and fine motor tasks. Basal ganglia insults result in slowed initiation of movements. Cerebellar injuries can lead to truncal and limb ataxia, dysmetria, dysdiadochokinesia, dyssynergia, and intention tremor. Sensory ataxia can result from impaired proprioception due to either peripheral neuropathy or spinal cord injury involving the posterior columns. Truncal ataxia can affect sitting and standing balance, impairing the ability to sit upright in a wheelchair or to walk. Limb ataxia can make ADLs difficult. The assessment of coordination and cerebellar function is part of the geriatric neurologic examination. Impairment is referred to as dysmetria. Dysmetria refers to a lack of coordination of movement typified by the undershoot or overshoot (hypometria and hypermetria,

Approach to the Geriatric Neurology Patient: The Neurologic Examination

respectively) of intended position with the hand, arm, leg, or eye. It is sometimes described as an inability to judge distance or scale. Dysmetria occurs because of disorders of the cerebellum. Dysmetria of the extremities caused by hemispheric syndromes is manifested in two ways: dysrhythmic tapping of hands and feet and dysdiadochokinesis, which is the impairment of alternating movements (Schmahmann, 2004). The actual cause of dysmetria is thought to be caused by lesions in the cerebellum or lesions in the proprioceptive nerves that lead to the cerebellum that coordinate visual, spatial, and other sensory information with motor control (Townsend et al., 1999). Two types of cerebellar disorders produce dysmetria, specifically midline cerebellar syndromes and hemispheric cerebellar syndromes (Hain, 2002). Midline cerebellar syndromes can cause ocular dysmetria, a condition in which the pupils of the eye overshoot (Hain, 2002). Hemispheric cerebellar syndromes cause dysmetria in the typical motor sense that many think of when hearing the term dysmetria (Hain, 2002). A common motor syndrome that causes dysmetria is cerebellar motor syndrome, which is also marked by impairments in gait (also known as ataxia), disordered eye movements, tremor, difficulty swallowing, and poor articulation (Schmahmann, 2004). As stated earlier, cerebellar cognitive affective syndrome (CCAS) also causes dysmetria. Dysmetria is often found in individuals with ALS and persons who have suffered from tumors or strokes. Persons who have been diagnosed with autosomal dominant spinocerebellar ataxia (SCAs) also exhibit dysmetria. SCAs are rarely seen in the elderly. Dysmetria from sporadic causes should be considered first (Dysmetria, 2007).

Testing coordination Rapid alternating movements • Ask the patient to strike one hand on the thigh, raise the hand, turn it over, and then strike it back down as fast as possible. • Ask the patient to tap the distal thumb with the tip of the index finger as fast as possible. • Ask the patient to tap your hand with the ball of each foot as fast as possible. Point-to-point movements • Ask the patient to touch your index finger and his or her nose alternately several times. Move your finger about as the patient performs this task. • Hold your finger still so that the patient can touch it with one arm and finger outstretched. Ask the patient to move the arm and return to your finger with the eyes closed. • Ask the patient to place one heel on the opposite knee and run it down the shin to the big toe. Repeat with the patient’s eyes closed.

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Romberg • Be prepared to catch the patient if he or she is unstable. • Ask the patient to stand with the feet together and eyes closed for 5–10 seconds without support. • The test is said to be positive if the patient becomes unstable (indicating a vestibular or proprioceptive problem). Gait and posture Brain and spinal cord lesions in geriatric neurology often affect posture and gait because of injury to the sensory and motor pathways that affect ambulation. Patients with spastic hemiparesis due to stroke or other brain injuries often have weakness and spasticity of the chest and abdominal musculature, leading to trunk instability and difficulty with weight shifting. Gait deviation may be observed. Weakness of hip flexors and ankle dorsiflexors results in an impaired swing-through of the limb and inadequate toe clearance during the swing phase of gait, resulting in hiking of the hip and circumduction of the leg. Decreased arm swing on the paretic side may also occur. Spasticity may limit the range of motion of the hip, knee, and ankle. Patients with basal ganglia disorders often have a shuffling-type gait. Cerebellar disorders may result in gait ataxia. Patients with proprioceptive deficits may have problems with foot placement and balance. Spinal cord injuries typically result in spastic paraparesis or quadriparesis, with difficulty walking as a result. Patients with cervical spinal cord injuries may have weakness of chest and abdominal muscles, affecting their ability to sit upright and transfer without support, as well as compromising respiratory reserve. The evaluation of gait and the features of gait abnormalities of neurologic diseases are covered in detail in Chapter 6, “Gait Disorders in the Elderly.” Features to evaluate include base, stance, posture, turning, rising from a chair, arm swing, stride, toe, heel, and tandem. Disorders of gait are common in the elderly and falls are a huge risk. Identifying the different gait types helps identify the underlying etiology. For magnetic gaits, consider normal pressure hydrocephalus. For shuffling, festinating gaits, consider parkinsonism, dementia with lewy bodies (DLB), or idiopathic PD. For ataxic gaits, consider peripheral neuropathies or cerebellar disorders. For spastic or paraparetic gaits, consider spinal cord injuries, or spinal stenosis. For hemiparesis, consider focal CNS lesions such as CVAs or mass lesions. Peripheral pathology can affect gait. Antalgic gaits are attributable to orthopedic or arthritic changes of the hip, knee, and ankle. Foot drop from L5 radiculopathy or peroneal neuropathy can affect the gait also.

Testing posture and gait Ask the patient to perform the following activities. • Walk across the room, turn, and come back. • Walk heel-to-toe in a straight line.

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Assessment of the Geriatric Neurology Patient

Walk on the toes in a straight line. Walk on the heels in a straight line. Hop in place on each foot. Do a shallow knee bend. Rise from a sitting position.

Conclusion Careful attention to features of the physical and neurologic examination is essential in a geriatric patient. Careful examination can frequently point to root causes, prompting further investigation. A good geriatric neurologic examination with a focus on functional ability can allow for improving the quality of care in geriatric neurology.

References “Aphasia Symptoms, Causes, Treatment—How Is Aphasia Diagnosed?” Medicinenet.com, May 2011. http://www.medicinenet .com/ aphasia/page3.htm (accessed on August 26, 2011). Bickley, L.S., Szilagyi, P.G., and Bates, B. (2007) Bates’ Guide to Physical Examination and History Taking. Philadelphia: Lippincott Williams & Wilkins. de Jong, P.T. (2006) Age-related macular degeneration. N Engl J Med, 355 (14): 1474–1485. “Dysmetria.” Multiple Sclerosis Encyclopaedia, October 2007. http://www.mult-sclerosis.org/dysmetria.html (accessed on August 26, 2011). Hain, T.C. (2002) “Cerebellar Disorders.” http://www.dizzinessand-balance.com/disorders/central/cerebellar/cerebellar.htm (accessed on August 26, 2011).

Horton, J.C. (2005) Disorders of the eye. In: D.L. Kasper, E. Braunwald, S. Hauser, D. Longo, J.L. Jameson, and A.S. Fauci (eds), Harrison’s Principles of Internal Medicine, 16th edn. New York: McGraw-Hill. Iwamoto, Y. and Yoshida, K. (2002) Saccadic dysmetria following inactivation of the primate fastigial oculomotor region. Neurosci Lett, 325 (3): 211–215. Pavan-Langston, D. (2007) Manual of Ocular Diagnosis and Therapy. Philadelphia: Lippincott, Williams & Wilkins. “Primitive and Postural Reflexes.” The Institute for NeuroPhysiological Psychology, October 2008. http://www.inpp.org.uk/ intervention-adults-children/more-information/reflexes/ primitive-postural-reflex (accessed on August 26, 2011). Quillen, D.A. (1999) Common causes of vision loss in elderly patients. Am Fam Physician, 60 (1): 99–108. Rathe, R. (1996) “Neurologic Examination.” University of Florida. http://medinfo.ufl.edu/year1/bcs/clist/neuro.html (accessed on August 26, 2011). Rauch, D. (2006) “Infantile Reflexes on MedLine Plus.” MedlinePlus. www.nlm.nih.gov/medlineplus/ency/article/003292.htm (accessed on August 26, 2011). Rhee, D.J. (2008) “Glaucoma: Eye Disorders: Merck Manual Home Edition.” The Merck Manuals. www.merck.com/mmhe/sec20/ ch233/ch233a.html (accessed on August 26, 2011). Schmahmann, J.D. (2004) Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci, 16 (3): 367–378. Schott, J.M. and Rossor, M.N. (2003) The grasp and other primitive reflexes. J Neurol Neurosurg Psychiatr, 74 (5): 558–560. Townsend, J., Courchesne, E., Covington, J., et al. (1999) Spatial attention deficits in patients with acquired or developmental cerebellar abnormality. J Neurosci, 19 (13): 5632–5643.

Chapter 4 Assessment of Cognitive Status in Geriatric Neurology 4.1 Mental Status Examination in the Geriatric Neurology Patient

Papan Thaipisuttikul1,2 and James E. Galvin1,2 4.2 Neuropsychology in Geriatric Neurology

Donald J. Connor3 and Marc A. Norman4 1

Department of Neurology, New York University Langone Medical Center, New York, NY, USA Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA 3 Independent Practice, Consultant Clinical Trials, San Diego, CA, USA 4 Department of Psychiatry University of California, San Diego, CA, USA 2

Summary Mental Status Examination in the Geriatric Neurology Patient • Level of consciousness, general appearance, mood and affect, behavior, movement, speech and communication, thought form and content, perception, and insight should be observed during an assessment of cognitive status. • Performance testing provides an objective measure of cognitive performance and the ability to compare with previous and subsequent tests. • Individual cognitive domains can be tested including attention, working memory and concentration, orientation, memory, language, abstract thinking, judgment and problem-solving, visuospatial and construction skills, calculation, executive function, and world list generation. • Several brief scales used to detect depression in the elderly include the Geriatric Depression Scale (GDS), the Patient Health Questionnaire (PHQ-9), and the Hospital Anxiety and Depression Scale (HADS). • Performance-based cognitive evaluation tools include the mini-mental state examination (MMSE), Mini-Cog, short blessed test (SBT), and Saint Louis University Mental Status (SLUMS). • Informant-based tools provide assessments of changes in cognition and its impact on daily function. Questionnaires for informants include the AD8 and the IQCODE. Neuropsychology in Geriatric Neurology • Patient scores collected from standardized instruments are quantified using normative data in order to assess the individual’s performance relative to a demographically similar cohort. • Test results are integrated with observation and noncognitive factors that may influence the performance. • The relative performance on several tests is compared to create a profile of relative strengths and weaknesses. • Neuropsychological assessments play a role in differential diagnosis, assessment of function, and treatment. • Five domains of cognition are commonly tested. • Attention/Orientation: separated into selective, sustained, and divided attention for both verbal and spatial stimuli, awareness of the self and the environment. • Language and communication: assessment of aphasia in expression, comprehension, and repetition (e.g., Broca’s, Wernicke’s, or conduction aphasia). • Memory: several models exist for the concept of memory including temporal, characteristic, modality, and stage models. Within each model are unique terms classifying different types of memory. Neuropsychological tests rely heavily on verbal episodic memory, and visual episodic memory tasks to assess cognitive function. (Continued)

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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• Executive abilities: the abilities for initiation, organization, abstract thinking, and inhibition of impulsive behavior in order to complete a goal-oriented task. • Visuospatial abilities: visual information is separated into two pathways wherein the ventral pathway is involved with symbolic representation and the dorsal pathway is involved with spatial awareness. • Neuropsychological profiles of common disorders. • Mild cognitive impairment (MCI): impaired episodic memory and/or other cognitive functions insufficient to meet criteria for dementia. • Alzheimer’s disease (AD): pattern of impaired episodic memory (learning and free recall). As the disease progresses, impairments in executive functions and recognition memory are noted. • Frontotemporal dementia (FTD): executive dysfunction (e.g., primary progressive aphasia, semantic dementia). • Parkinson’s disease dementia (PDD): alterations or fluctuations in arousal and complex attention, impaired executive dysfunction, impaired memory retrieval. • Dementia with Lewy bodies (DLB): in mild stages, attentional, visuospatial, constructional, and executive dysfunction is greater than impairments in memory and naming compared to AD. • Progressive supranuclear palsy (PSP): characterized by a subcortical profile that includes deficits in attention, executive function, and visuospatial abilities. • Corticobasal ganglionic degneration (CBD): characterized by a subcortical profile. • Vascular dementia (VaD): clinical presentations and neuropsychological profiles vary widely due to the heterogeneity of the anatomical areas damaged. • Delirium: deficits in attention, orientation, and fluctuating levels of arousal caused by an underlying medical condition. • Depression: a risk factor for dementia but the diseases can be separate or comorbid. • Preclinical states of dementia are currently being studied in hopes of developing methods of slowing or temporarily halting the disease (disease modification).

Chapter 4.1 Mental Status Examination in the Geriatric Neurology Patient Papan Thaipisuttikul and James E. Galvin

The elements of a comprehensive mental status examination include observational, cognitive, and neuropsychiatric assessments. Although each of these elements is presented separately, they are inter-related and collectively characterize the neurobehavioral function of the patient. The initial contact with the patient affords the opportunity to assess whether a cognitive, attention, or language disorder is present. Questioning of an informant may bring to light changes in cognition, function, and behavior that the patient either is not aware of or denies. Because the frequency of cognitive disorders increases dramatically with advancing age, examination of mental status is one of the most important components of the neurologic examination. Unfortunately, it is often one of the parts of the examination most likely to be ignored and amongst the most difficult parts of the examination to be interpreted. In general, our fund of knowledge continues to expand throughout life and learning ability does not appreciably decline. Cognitive changes associated with normal aging include decrease in processing speed, cognitive flexibility, visuospatial perception (often in conjunction with decreased visual acuity), working memory, and sustained attention (Tarawneh and Galvin, 2010). Other cognitive abilities such as access to remotely learned information and retention of encoded new information appear to be relatively spared in aging; allowing their use as sensitive indicators for onset of cognitive impairment (Smith, 2003).

Observational and neuropsychiatric assessment In addition to detailed history taking and the more common components of the neurologic examination (motor and sensory function, gait, balance, etc.), careful and thoughtful observation of the patients’ appearance, behavior, and demeanor can provide insight into the nature of the cognitive status. Observation of the patient’s level of consciousness, general appearance, affect, movements, and speech provide important initial evaluation of the patient’s mental status, followed by asking probing questions to sample mood, thought, perception, and insight.

Level of consciousness An accurate assessment of a patient’s mental status and neurologic function must first document the patient’s alertness or level of arousal. Abnormal patterns of arousal include hypo-aroused or hyper-aroused states. Decreasing levels of arousal include lethargy, obtundation, stupor, and coma (Strub and Black, 2000). The lethargic patient is drowsy or fatigued and falls asleep if not stimulated; however, while being interviewed the patient will usually be able to attend to questioning. Obtundation refers to a state of moderately reduced alertness with diminished ability to consistently engage in the environment. Even in the presence of the examiner, if not stimulated, the obtunded patient will drift off. The stuporous patient requires vigorous stimulation to be aroused. Responses are usually limited to simple “yes/no” responses or may consist of groans and grimaces. Coma, which represents the end of the continuum of hypo-arousal states, is a state of unresponsiveness to the external environment. In the elderly, hypo-arousal states can be associated with systemic infection, cardiac or pulmonary insufficiencies, meningoencephalitis, increased intracranial pressure, toxic–metabolic insults, traumatic brain injury, seizures, or cerebrovascular disease. Coma requires either bilateral hemispheric dysfunction or brainstem dysfunction. Another important consideration is the role of polypharmacy (Samaras et al., 2010). Drug interactions are more common in older adults and can significantly impair consciousness (Samaras et al., 2010). Hyper-arousal states on the other hand, are characterized by anxiety, autonomic hyperactivity (tachycardia, tachypnea, hyperthermia), agitation or aggression, tremor, seizures, or exaggerated startle response (Strub and Black, 2000). In the elderly, hyper-arousal states are most often encountered in toxic–metabolic disorders including withdrawal from alcohol, opiates, or sedative– hypnotic agents. Other causes include tumors (both primary and metastatic), viral encephalitis (particularly herpes simplex), cerebrovascular, and hypoxemia (Caplan, 2010). Some patients, for instance, a patient with herpes simplex encephalitis may experience fluctuating periods of both hypo- and hyper-arousal (Ramrez-Bermdez et al., 2005).

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General appearance Assessment of a patient’s physical appearance should acknowledge body size and type, apparent age, posture, facial expressions, eye contact, hygiene, dress, and general activity level. A disheveled appearance may indicate dementia, delirium, frontal lobe dysfunction, or schizophrenia (Strub and Black, 2000). Wearing excessive makeup or flamboyant grooming or attire in an old individual should raise the suspicion of a manic episode or frontal lobe dysfunction (Sadock and Sadock, 2007). Patients with unilateral neglect due to dementia, stroke, or head injury may fail to dress, groom, or bathe one side of their body (Strub and Black, 2000). Patients with Parkinson’s disease (PD) may display a flexed posture, whereas patients with progressive supranuclear palsy (PSP) have an extended, rigid posture. The overall appearance of an individual should also provide information regarding their general health status. The cachectic patient may harbor a systemic illness (e.g., cancer), or have anorexia or depression (Sadock and Sadock, 2007). Mood and affect While mood is a subjective report of the patient’s emotional status that is sustained over time, affect is the patient’s present emotional response that can be inferred from facial expressions, vocal tone, and body movements (Sadock and Sadock, 2007). Affect can change during the interview, while mood usually remains stable during the office visit (Sadock and Sadock, 2007). Constriction or flatness is observed in apathetic states; for example, in the context of negative symptoms of schizophrenia, severe melancholic depression, or in demented patients with apathy (Sadock and Sadock, 2007). Increased intensity, on the other hand, is seen in mood disorders such as bipolar illness, and in personality disorders such as borderline personality (Sadock and Sadock, 2007). Lability is a disorder of emotional regulation. Patients with marked lability are irritable and shift rapidly among anger, depression, and euphoria commonly referred to a pseudobulbar affect (Schiffer and Pope, 2005). The emotional outbursts are usually shortlived. Labile mood is seen in mood disorders such as bipolar illness, and in certain personality disorders such as borderline personality. It also may occur in frontotemporal dementia (FTD), amyotrophic lateral sclerosis, cerebrovascular disease, multiple sclerosis, and head injury (Schiffer and Pope, 2005). In its full form as pseudobulbar palsy, it is commonly seen with lower cranial nerve (CN IX-XII) deficits and hyperactive reflexes (Gillig and Sanders, 2010). Depression is a common mood disorder in older adults and can occur in a variety of neurologic disorders, for example, cerebrovascular disease, Alzheimer’s disease (AD) and other types of dementia, PD, and epilepsy

(Lyness et al., 2006). Euphoria or full-blown mania occurs less often than depression in the course of neurologic illness. Euphoria is most common with frontal lobe dysfunction (trauma, frontotemporal degenerations, infections) and with secondary mania (Woolley et al., 2007). Even though geriatric-onset anxiety disorder is not common in older adults, anxiety symptoms occur in a variety of neuropsychiatric conditions, for example, depression, AD, PD, metabolic encephalopathies (hyperthyroid, anoxia), and toxic disorders (lidocaine toxicity) (Flint, 2005). Objective and subjective emotional components may be incongruent in certain psychiatric disorders (e.g., schizophrenia and schizotypal personality disorder), and in neurologic conditions such as pseudobulbar palsy due to a variety of underlying illnesses.

Behavior A variety of personality alterations can be encountered with focal brain lesions. Orbitofrontal dysfunction may be characterized by impulsiveness or undue familiarity with the examiner, lack of judgment or lack of social anxiety, and antisocial behavior (Newcombe et al., 2011). Individuals with dorsolateral frontal lobe dysfunction may be inattentive and distractible (Brooks et al., 2010). Apathy (lack of motivation, energy, emotional reciprocity, social isolation) may be caused by medial frontal dysfunction and injury to the anterior cingulate (Roth et al., 2007). The various dementias are associated with increased rigidity of thought, egocentricity, diminished emotional responsiveness, and impaired emotional control (Pulsford and Duxbury, 2006). Passivity, social withdrawal and apathy can be seen in Lewy body disorders (Galvin et al., 2007a). Movement Observation of patient’s movements may provide evidence of parkinsonism, chorea, myoclonus, or tics. Psychomotor retardation (i.e., slowed central processing and movement) may be indicative of vascular dementia (VaD), subcortical neurologic disorders, parkinsonism, medial frontal syndromes, or depression (Sadock and Sadock, 2007). Psychomotor agitation may be indicative of a metabolic disorder, choreoathetosis, seizure disorder, mania, or anxiety (Sadock and Sadock, 2007). Speech and communication Observation of spontaneous speech is the first step in formal language testing and can be assessed during history taking as well as in the course of the mental status examination. Mutism may be encountered in several neurologic conditions such as akinetic mutism, vegetative state, locked-in syndrome, catatonic unresponsiveness, or large left hemispheric lesions (Altshuler et al., 1986). Spontaneous speech is characterized by its rate, rhythm, volume, response latency, and inflection (Strub and Black, 2000). Accelerated speech may be encountered in mania,

Mental Status Examination in the Geriatric Neurology Patient

disinhibited orbitofrontal syndromes, or festinating parkinsonian conditions, whereas a reduced rate of speech output can occur as a component of psychomotor retardation (Sadock and Sadock, 2007). Response latencies may be prolonged or the patient may impulsively interrupt the examiner, anticipating the question. Perturbed speech prosody (loss of melody or inflection) can be encountered in brain disorders affecting the right hemisphere or the basal ganglia (Sidtis and Van Lancker Sidtis, 2003). Empty speech with hesitations or circumlocutions can be exhibited in patients with word-finding difficulties (Rohrer et al., 2008). Word-finding impairment may occur in dementia, aphasia, metabolic encephalopathies, physical exhaustion, sleep deprivation, anxiety, depression, or dorsolateral frontal lobe damage even in the absence of an anomia (Rohrer et al., 2008). Aphasia is characterized by impairment in oral and/ or written communication. Deficits will vary depending on the location and extent of anatomic involvement. Aphasias are generally characterized as nonfluent or fluent. Nonfluent aphasias are characterized by a paucity of speech, often with a hesitant quality (Strub and Black, 2000). In contrary, fluent aphasias are characterized by normal word production or may be increased, but there is a lack of comprehension about what words mean, often associated with impairment in reading ability (Strub and Black, 2000).

Thought form and thought content Thought form or thought process refers to the way of thinking, where a person puts ideas and associate them together. Examples of thought form disorders are circumstantial, tangential, derailment, flight of idea, thought blocking, loosening of association or incoherence. Perseveration (Sadock and Sadock, 2007) and incoherence are disorders of the form of thought that are common in neuropsychiatric conditions. Perseveration refers to the inappropriate continuation of an act or thought after conclusion of its proper context. Intrusions are a special case of perseveration with late recurrences of words or thoughts from an earlier context. Perseverations and intrusions can be seen in aphasias and dementing illnesses. Incoherence refers to the absence of logical association between words or ideas. It is observed in delirium, advanced dementias, and as part of the output of fluent aphasia. Thought content refers to what a person is actually thinking about, such as ideas, beliefs, preoccupations, and obsessions. Delusions are the most common manifestation of psychosis in neuropsychiatric disorders and are characterized by false beliefs based on incorrect inference about external reality. Common types of delusions encountered involve being followed or spied on, theft of personal property, spousal infidelity, or the presence of unwelcome strangers in one’s home. Theme-specific delusions such as

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the Capgras syndrome (the belief that someone has been replaced by an identical-appearing impostor) (Josephs, 2007) may also be observed in neurologic illnesses. Delusions are common in a number of dementia etiologies including AD and dementia with Lewy bodies (DLB), and may occur in VaD, FTD, and Huntington’s disease.

Perception Perceptual disturbances can be classified as hallucination or illusion/misperception. Hallucination is a false sensory perception that occurs without stimulation of the relevant sensory organ, while, illusion is a misperception or misinterpretation of real external sensory stimuli. Hallucinations and delusions frequently occur together in psychosis; hallucinations are nondelusional when the patient recognizes the sensory experience to be unreal. Hallucinations may involve any sensory modality (visual, auditory, tactile, gustatory, olfactory) and may be formed (e.g., people or things) or unformed (flashing lights or colors). Hallucinations occur with ocular and structural brain disorders as well as Charles Bonnet syndrome, epilepsy, narcolepsy, and migraine (Pelak and Liu, 2004). Well-formed visual hallucinations (children, furry animals) are a prominent early sign in DLB (Hanson and Lippa, 2009). Less well-formed visual hallucinations occur in the moderate-to-severe stages of AD with the patient typically not well able to describe what they saw. Gustatory or olfactory hallucinations are most common in seizure disorders, bipolar and schizophrenia, and with tumors located in the medial temporal lobe (Capampangan et al., 2010). Tactile hallucinations are most commonly associated with schizophrenia, affective disorders or drug intoxication, or withdrawal (Sadock and Sadock, 2007). Insight Insight is the patient’s ability to understand the true cause and meaning of his/her condition, as well as the implication of diagnosis and its prognosis. Patients with neuropsychiatric disease may display limited insight and be unaware of their medical conditions or limitations in function, thus assessment of a patient’s insight into the severity of their illness can yield useful diagnostic information and assist in developing a therapeutic plan. For example, AD patients have impaired insight into their memory and cognitive difficulties, whereas patients with VaD and DLB often exhibit more appropriate concern regarding their cognitive dysfunction (Del Ser et al., 2001). However, it should not be assumed that the patient is unaware of problems. Instead, they may be unable to attribute causality and are usually unable to rate the frequency and severity of their problems. Lesions of the right parietal lobe are associated with unawareness, neglect, or denial of the abnormalities of the contralateral side (anosagnosia) (Pia et al., 2004).

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Cognitive assessment Following observation, the clinician should begin a formal assessment of cognitive abilities. The assessment of cognitive function should be conducted methodically and should assess comprehensively the major domains of neuropsychological function (attention, memory, language, visuospatial skills, executive ability). The patient’s age, handedness, educational level, and sociocultural backgrounds may all influence the cognitive function and should be determined prior to initiating or interpreting the evaluation. In general there are two ways to assess the patient—informant assessments and performance testing. Using performance testing, the clinician may gain a sense of the objective performance of the patient in relation to published normative values, usually corrected for age and education. If the patient was previously assessed, comparison to previous tests offers the potential to measure change. Brief performance tests while providing a “snap shot” of abilities at the time of examination, are themselves unable to provide information regarding the change from previous abilities or how the scores on the tests interfere with the patients social and occupational functioning (i.e., their activities of daily living). Formal neuropsychological testing provides a more comprehensive assessment of cognitive abilities with estimates of premorbid intelligence (Section 4.2). However, neuropsychological testing is not practical in the office setting and may not be readily available outside major metropolitan areas. In this section, we take two approaches— (1) individual cognitive domains to create a brief 20–30 minute (depending on the level of dementia severity and language ability) battery of tests that could be done in the office setting (Table 4.1), and (2) brief global measures. Table 4.1 Example of a brief neurobehavioral status examination Verbal memory

Animal naming 15-item Boston naming

Working memory

Digit span forward Digit span backward

Episodic memory

Word list recall (Hopkins, California, CERAD) Paragraph recall

Visual construction

Clock drawing

Psychomotor speed

Trailmaking A

Executive function

Trailmaking B Digit symbol substitution

Abstraction

Similarities and differences Proverb interpretation

Concentration

Months in reverse order Counting backward from 20

Global measurement (Choose one)

Mini-mental status examination Short blessed test

Mood (Choose one)

Geriatric depression scale PHQ-9 Hospital anxiety and depression scale

Attention, working memory, and concentration Attention is very important in order to process other cognitive abilities. Two tests are useful in assessing attention: digit span and continuous performance tests. In the digit span forward (Strub and Black, 2000) test, the patient is asked to repeat increasingly long series of numbers (e.g., 1, 3-7, 4-6-3, 5-1-9-2, etc.). A normal forward digit span is seven digits; fewer than five is abnormal. Digit span backward (Strub and Black, 2000) is a test of mental control, and complex attention, as well as executive dysfunction. It entails saying increasingly long series of numbers and asking the patient to say them backward (give 2-5-8, response should be 8-5-2). A normal digit span in reverse is five digits; fewer than three is abnormal. Concentration is an ability to maintain attention. Concentration is evaluated by a continuous performance test, for example, ask the patient to count backward from 20, say months of the year backward, and serial subtraction (100−7 or 20−3). However, serial subtraction should be used with caution, because of its dependence on education and mathematical ability (Karzmark, 2000). Orientation Orientation to time is tested by asking the patient to identify the correct day of the week, date, month, and year. This could be followed by asking the patient to state the correct time of the day without looking at a watch or clock. The patient should be within 1 hour of the correct time. Orientation to place is assessed by asking about city, county, state, and current location. Orientation to situation can be assessed by asking the patient why they are in the clinic/hospital on the particular day. Memory Learning, recall, recognition, and memory for remote information are assessed in the course of mental status examination. Asking the patient to remember three words and then asking him or her to recall the words 3 minutes later can help assess learning, recall, and recognition. In general, the shorter the list, the easier it is to remember, particularly in high-functioning individuals. When told to remember items, patients will often remember the first two items heard (known as “primacy”) and the last two items heard (known as “recency”), therefore longer lists of 10 words may be preferable (Morris et al., 1989). After a delay, recall of less than five words is considered abnormal. Patients having difficulty with recall may be given clues (e.g., the category of items to which the word belongs or a list of words containing the target) to distinguish between storage and retrieval deficits. For example, giving clue to patient with AD will generally not help a patient to remember because of his/her primary storage disorder, while giv-

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Table 4.2 Useful screening tests for office setting Screening test

Numbers of items

Scoring system

Validity

Limitations

MMSE

30 items

Cutoff 23–24

Sensitivity 85–100% Specificity 66–100%

Mini-Cog

3 recall with clock drawing

SBT

6 items of orientation, memory and concentration

Recall 2/3 use clock to determine the problem 5–9/28 questionable 10 or over/28 dementia

SLUMS

11 items

MoCA

12 items,10 minutes administered, multicognitive domain assessing

Less than 26 detect MCI or dementia

Sensitivity of 90 for MCI and 100 for dementia

AD8

8 items

More than 2

Sensitivity 90% Specificity 68%

IQCODE

16 items

More than 3.44

Sensitivity 76–100% Specificity 65–86%

Score influenced by education, ethnicity, social class. Not ideal to identify mild impairment. Test focus on recall, visuospatial ability and construction. Test focus on orientation, memory and concentration. May not detect nonamnestic dementias. Limited validation on different groups of patients from original study. Tests are complicated and take time to use in an office setting. Takes 10 minutes or more for patients with more severe impairment. Not as extensively studied as MMSE. Depends on observant informant. In the absence of informant, the AD8 can be administered to the patient. Depends on observant informant.

Sensitivity and specificity comparable to MMSE High correlation of 0.52 between score and autopsy Cutoff of 21–26: mild cognitive Sensitivity 96–98% impairment (MCI), 20 and Specificity 61–100% below: dementia for high school education

ing clue to a patient with DLB may help the patient to recall since his/her primary deficit might be retrieval (Hamilton et al., 2004). To evaluate remote memory, information needs to be gathered on the patient’s life events and important historic events (marriage, birth of children). An informant may be helpful to verify the accuracy of the information. The pattern of memory loss in most forms of dementia usually starts with short-term (learning, recall, recognition) memory first, then gradually involving in long-term memory in the later stages of disease. However, psychogenic amnesia memory-loss patterns can be variable and typically involve both long and short memory (HennigFast et al., 2008).

Language Language assessment entails the evaluation of all aspects of communication including spontaneous speech, comprehension, repetition, naming, reading, and writing. Language comprehension is tested by asking the patient to follow increasingly complex verbal instructions. The easiest commands are one-step orders such as “close your eyes,” or “stick out your tongue” to multistep commands “take the piece of paper, fold it in half and place on the floor” to more complex questions, such as “If a lion is killed by a tiger, which animal is dead?” Impaired comprehension usually implies dysfunction of parietotemporal regions of the left hemisphere. In the elderly, it is important to establish that hearing is intact before testing

verbal comprehension. Failure to comprehend commands may reflect the inability to hear as opposed to impaired comprehension. Repetition is assessed by asking the patient to repeat increasingly long phrases or sentences. Repetition is impaired in Wernicke, Broca, conductive, and global aphasia but is generally preserved in transcortical aphasias. Naming tests involve asking the patient to name objects, parts of objects, and colors. Aphasic patients may use descriptive terms rather than give the proper name. Anomia, loss of naming ability, occurs in aphasia, dementia, delirium, and can sometimes be seen as a consequence of head trauma. Adequate vision and object recognition must be ensured before errors are ascribed to naming deficits. The 15-item Boston Naming Test (Mack et al., 1992) is an example of a brief measure of confrontational naming. When assessing reading, the patient’s ability to read aloud and to comprehend what is read should both be tested. Adequate vision must be ensured before failures are ascribed to an alexia. Many aphasias have concomitant alexias; however, the converse may not be true. In alexia with agraphia and alexia without agraphia, reading abnormalities may occur in the absence of other signs of aphasia (Maeshima et al., 2011). Patients with agraphia lose their ability to write/ draw things when asked by the examiner. Micrographia (Gangadhar et al., 2008) is a characteristic aspect of parkinsonism in which the script becomes progressively smaller as the patient writes a sentence or extended series

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of numbers or letters, and mechanical agraphias occur in patients with limb paresis, limb apraxia, or movement disorders such as tremor and chorea (Ferguson and Boller, 1977). Agraphias may accompany aphasic syndromes and errors found in written language are often similar to those noted in verbal output. In Gerstmann syndrome (agraphia, acalculia, right–left disorientation, finger agnosia), alexia with agraphia, and disconnection agraphia (occurring with injury of the corpus callosum), agraphia occurs without aphasia (Rusconi et al., 2010).

Calculation Patients are asked to add or multiply one or two digits mentally or to execute more demanding problems with pencil and paper. Calculation abilities are related to education and occupation. Acalculias may occur in association with a number of aphasic syndromes while visuospatial disorders lead to incorrect alignment of columns of numbers (Ardila and Rosselli, 1994). Primary anarithmetias (inability to do math) are produced by damage to the posterior left hemisphere (Grafman et al., 1982).

Abstract thinking Abstract thinking is the ability to deal with concepts. Similarities, differences, idioms, and proverb interpretation can all be used to assess abstracting capacity. These tests are influenced by culture and educational level. Abstraction abnormalities are a nonspecific indicator of cerebral dysfunction. Patients with neurodegenerative dementias typically offer concrete answers to abstract questions, thus comprehension should always be assessed before asking the patient to provide interpretations.

Executive function Executive function, or higher cortical function, has been mediated by frontal-subcortical system, complex neural circuits that include the dorsolateral prefrontal cortex, striatum, globus pallidus/substantia nigra, thalamic nuclei, and connecting white matter tracts. Patients with executive dysfunction manifest perseveration, motor programming abnormalities, reduced word list generation (left dorsolateral dysfunction), reduced nonverbal fluency (right dorsolateral dysfunction), poor set-shifting, abnormal recall with intact recognition memory, loss of abstraction abilities, poor judgment, and impaired mental control (Bullock and Lane, 2007). Simple executive function tests that are useful in clinical settings include Trail making A test that requires the patient to draw lines sequentially connecting 25 encircled numbers distributed on a paper. Trail making A (Corrigan and Hinkeldey, 1987) measures psychomotor speed with minimal executive function and if completed allows further testing with Trail making B (Corrigan and Hinkeldey, 1987) that requires alternating between numbers and letters (1-A-2-B…etc.).

Judgment and problem-solving abilities Assessing judgment assists in exploring the patient’s interpersonal and social insight. Damage to orbitofrontal subcortical circuit (e.g., in FTD, trauma, or focal syndromes) produces marked alterations in social judgment (Gleichgerrcht et al., 2010). Problem solving can be assessed by giving a scenario “If traveling in a strange town, how would a person locate a friend they wished to see?” Correct answers might include use of phone book, the internet, or city directory. Visuospatial and construction skills In the clinic, simple tests that are usually used to evaluate the patient’s visuospatial abilities are clock-drawing test and copying intersecting pentagons or cubes. The clock-drawing test (Libon et al., 1993) assesses the ability to plan and arrange the numbers on the clock face and to place the hands at the correct time. The hands should be of different lengths. Patients with executive dysfunction may draw a clock face that is too small to contain the required numbers (poor planning), whereas patients with unilateral neglect will ignore half of the clock face. There are a number of different scoring paradigms for the clock, although the simplest might simply be scoring the clock as normal or abnormal. Abnormalities of other copy tests (pentagons, cubes) include failures to reproduce the shapes accurately, perseveration on individual elements, drawing over the stimulus figure, or unilateral neglect. Drawing disturbances are common with many types of neurologic conditions including focal brain damage, degenerative disorders, and toxic and metabolic encephalopathies (Mechtcheriakov et  al., 2005).

Word list generation Ask the patient to think of as many members of a specific category (most commonly animals or vegetables) as possible within 1 minute. Typically, older adults can name approximately 18 animals within 1 minute; less than 14 is considered abnormal. Word lists can also be generated using the first letter (for example S and F (Brandt and Manning, 2009)). Word list generation deficits occur with anomia, frontal-subcortical systems dysfunction, and psychomotor retardation. It is a highly sensitive test for impairment but lacks specificity (Brandt and Manning, 2009).

Effects of mood and affect disorder on cognition Depression is common in older adults. Memory complaints are likely to be the chief complaints in this group of patients, as known as “pseudodementia” in the past. When depression improves, the cognitive impairment often improves as well. However, comorbid depression and cognitive impairment are a risk for the later emergence of AD (Alexopoulos et al., 1993). Therefore, early depressive symptoms with mild cognitive impairment

Mental Status Examination in the Geriatric Neurology Patient

(MCI) may represent a preclinical sign and should be considered a risk for impending dementia (Li et al., 2001). Concept of vascular depression or depression-executive dysfunction syndrome is also famous in older adults (Alexopoulos et al., 1997). The clinical presentations are psychomotor retardation, apathy, and severe disability related to impaired executive function. Depression in the elderly is not a unitary construct. There is a wide range of variations in etiologies and manifestations; therefore, early detection and appropriate management are important. Some brief scales that are usually used for detecting depression in the elderly are (1)  Geriatric Depression Scale (GDS), the 15-items and 30-items self-administered questionnaire that usually takes only 5–10 minutes, was first developed by Yeasavage in 1983 (Yesavage et al., 1983). GDS has shown a good sensitivity of 80% and specificity of 100% at the cutoff of 14/30 (Brink et al., 1982). (2) Patient Health Questionnaire (PHQ-9), the 9-item self-administered questionnaire that has been studied widely in primary care populations (Spitzer et al., 1999) was found to have overall 85% accuracy, 75% sensitivity, and 90% specificity for depression diagnosis. (3) Hospital Anxiety and Depression Scale (HADS), the 7-items depression combine with 7-items of anxiety self-administered questionnaire was first developed in the United Kingdom to use in general medical outpatient clinic settings (Snaith, 2003). HADS-D at cutoff of eight or over had 80% sensitivity and 88% specificity, while HADS-A at cutoff of eight or over had 89% sensitivity and 75% specificity from previous study (Olssn et al., 2005). Anxiety symptoms are common in the elderly, especially as a comorbid with late-life depression. In the past, experts believed that anxiety disorder usually have an onset in childhood or early adulthood; however, some researchers also found clinical samples with late-onset anxiety disorders (Blazer and Steffens, 2009). A preliminary study comparing generalized anxiety disorder (GAD) patients, major depressive disorder (MDD) patients, and healthy elderly individuals found that GAD patients had impaired short-term and delayed memory, but no executive deficits as seen in MDD patients (Mantella et al., 2007). Apathy, withdrawal or indifference is one of the most common behavioral symptoms in AD. Apathy defines as a reduction in a voluntary goal-directed behavior. Studies found that Alzheimer’s patients with apathy (lacks initiative) also have problem with multitasking (executive function) which can be an underlying factor of goaldirected behaviors (Esposito et al., 2010).

Performance-based tools for cognitive evaluation Though creating a unique, brief psychometric battery might seem appealing, administration of even a brief battery can take 20–30 minutes. Alternatively, there are

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a variety of brief, cognitive tests that were developed to help assess the general cognitive functions. Each has limitations, but in the setting of a busy office, practice may provide the quickest way to get a global assessment of the patients’ cognitive abilities (Table 4.2). The following are examples of general cognitive tests that are practical to use in geriatric patients in clinical setting.

Mini-Mental Status Examination The 30-item mini-mental state examination (MMSE) test, which takes around 10 minutes to complete, has been frequently used for initial assessment of memory problem, and its sensitivity increases if a decline of the score over time is taken into account (Folstein et al., 1975). The MMSE covers six areas: (1) orientation, (2) registration, (3) attention and calculation, (4) recall, (5) language, and (6) ability to copy a figure. However, although the MMSE is quick and easy to administer and can track the overall progression of cognitive decline, it is not considered to be a good test for definitive AD diagnosis (deSouza et al., 2009), particularly because of its greater emphasis on orientation (10 of 30 points) that is typically not impaired at the earliest stages of dementia. In addition, there are several issues associated with the MMSE, including bias according to age, race, education, and socioeconomic status (Caplan, 2010). There are also copyright issues that may limit its use. Several diagnostic tests are now available for use in primary care as alternatives to the MMSE; these are continually being updated and simplified in order to provide brief, easy to administer, and effective diagnostic tools.

Mini-Cog The Mini Cognitive Assessment Instrument (Mini-Cog) combines an un-cued 3-item recall test with a clockdrawing test that serves as a recall distractor; it can be administered in about 3 minutes and requires no special equipment. (Borson et al., 2005) The Mini-Cog, and the MMSE have similar sensitivity (76% vs. 79%) and specificity (89% vs. 88%) for dementia, correlating with findings achieved using a conventional neuropsychological battery. The Mini-Cog’s brevity is a distinct advantage when the goal is to improve recognition of cognitive impairment in primary care, particularly in milder stages of impairment. (Borson et al., 2005) It has also been suggested that cognitive impairment assessed by the Mini-Cog is a more powerful predictor of impaired activities of daily living than the disease burden in older adults. In addition, the Mini-Cog also has proven good performance in ethnically diverse populations of the United States, where widely used cognitive screens often fail, and is easier to administer to non-English populations.

Short Blessed Test Short blessed test (SBT), consisting of the items in the Blessed orientation–memory–concentration test, includes

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three orientation questions (month, year, and time of day), counting from 20 to 1, saying the months backward, and recalling a 5-item name and address memory phase (Katzman et al., 1983). This test was developed using scores from a validated 26-item mental status questionnaire of two patient groups in a skilled nursing home, patients in a health-related facility, and in a senior citizens’ center. There was a positive correlation between scores on the 6-item test and plaque counts obtained from the cerebral cortex of 38 subjects at autopsy. This test, which is easily administered by a nonphysician, has been shown to discriminate among mild, moderate, and severe cognitive deficits (Katzman et al., 1983). The SBT is quite sensitive to early cognitive changes due to AD. Based on clinical research findings from the Memory and Aging Project at Washington University in Saint Louis, the proposal of new cut-points, after adding weighting factors (total score of Katzman et al., 1983) were suggested: 0–4 normal cognition, 5–9 questionable impairment, and 10 or more impairments consistent with dementia (Morris et al., 1989).

The Saint Louis University Mental Status The Saint Louis University Mental Status (SLUMS) is a 30-point, 11-item, clinician-administered screening questionnaire that tests for orientation, memory, attention, and executive functions. The SLUMS is similar in the format of MMSE; however, it supplements the MMSE with enhanced tasks corresponding to attention, numeric calculation, immediate and delayed recall, animal naming, digit span, clock drawing, figure recognition/size differentiation, and immediate recall of facts from a paragraph. In particular, the clock-drawing test is designed to assess impairment in executive function (Schiffer and Pope, 2005). At a cut-off score of 27–30 normal, 21–26 mild neurocognitive disorder, and 1–20 dementia for high school education have 0.98 sensitivity and 0.61 specificity for MNCD and 0.96 sensitivity and 1.0 specificity for dementia diagnosis (Tariq et al., 2006). Therefore, the developer team suggests benefit of SLUMS over MMSE in order to identify minor neurocognitive disorders early. Due to copyright issues the Veterans Administration has stopped using the MMSE and now many use SLUMS. However, to date the SLUMS has not been validated outside of the original research sample.

The Montreal Cognitive Assessment The Montreal Cognitive Assessment (MoCA) is a 10-minute cognitive screening tool developed to assist physicians in the detection of MCI (Gillig and Sanders, 2010). MoCA is gaining credibility due to improvements in sensitivity, addressing frontal/executive functioning, and decreasing susceptibility to cultural and educational biases. It has high sensitivity and specificity for

detecting MCI in those patients who perform within the normal range of the MMSE. Compared with the MMSE, which had a sensitivity of 18% to detect MCI, the MoCA detected 90% of MCI subjects and, in patients with mild AD the MMSE had a sensitivity of 78%, whereas the MoCA detected 100% (Nasreddine et al., 2005). MoCA is also well-suited as a screening test for cognitive impairment in PD (Dalrymple-Alford et al., 2010), in which memory impairment may be involved later in the stage of disease compared to executive function. The limitation of the MoCA may be in its more complex interpretation.

Informant-based tools for cognitive evaluation The diagnosis of dementia is a clinical one, based on the principles of intraindividual decline in cognitive function that interferes with social and occupational functioning. The limitations to all brief performance measures is that they (1) fail to capture the “change” and “interference” when used as a dementia screen and (2) may be biased by age, gender, race, education, and culture. Informant-based instruments on the other hand rely on an observant collateral source to assess whether there have been changes in cognition and if said changes interferes with function. A particular strength compared to other cognitive screening tests is that informant assessments are relatively unaffected by education and premorbid ability or by proficiency in the culture’s dominant language. Because each person serves as their own control, there is little bias due to age, education, gender or race (Morales et al., 1997). The disadvantages of informant assessments are the reliability of the informant and the quality of the relationship between the informant and the patient. Because the informant assessments provide information complementary to cognitive tests, harnessing them together may improve screening accuracy. A gold standard in informant assessment is the Clinical Dementia Rating (CDR) used in many clinical trials and research projects. However, the length of the interview makes it impractical for use in the busy office setting. The value of including a reliable informant (spouse, adult child, caregiver) in the evaluation of cognitive and affective disorders in older adults has been incorporated into the following questionnaires.

AD8 AD8 screening interview is a brief, sensitive measure that reliably differentiates between individuals with and without dementia by querying memory, orientation, judgment, and function (Galvin et al., 2006). The AD8 comprises eight yes/no questions asked to an informant to rate changes, and takes approximately 2–3 minutes for the informant to complete (Table 4.3). In the absence of an informant, the AD8 can be directly administered to the patient as a self-rating tool (Galvin et al., 2007b) with

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Table 4.3 The AD8 Remember, “Yes, a change” indicates that there has been a change in the last several years caused by cognitive (thinking and memory) problems.

YES, A change

NO, No change

N/A, Do not know

1. Problems with judgment (e.g., problems making decisions, bad financial decisions, problems with thinking) 2. Less interest in hobbies/activities 3. Repeats the same things over and over (questions, stories, or statements) 4. Trouble learning how to use a tool, appliance, or gadget (e.g., VCR, computer, microwave, remote control) 5. Forgets correct month or year 6. Trouble handling complicated financial affairs (e.g., balancing checkbook, income taxes, paying bills) 7. Trouble remembering appointments 8. Daily problems with thinking and/or memory TOTAL AD8 SCORE Source: Adapted from Galvin, J.E. et al. (2005) The AD8, a brief informant interview to detect dementia. Neurology, 65: 559–564. Reproduced with permission of Washington University, St. Louis, MO.

similar large-effect sizes (Cohen’s d for informant = 1.66; for patient = 0.98 (Galvin et al., 2007b). Use of the AD8 in conjunction with a brief assessment of the participant, such as a word list, could improve detection of dementia in the primary setting to 97% and 91% for MCI (Galvin et al., 2006). The AD8 has a sensitivity of 84%, and specificity of 80% with excellent ability to discriminate between nondemented older adults and those with mild dementia (92%) regardless of the cause of impairment (Galvin et al., 2006). The AD8 is highly correlated with the CDR and neuropsychological testing. More recently the AD8 has been biologically validated against amyloid PET imaging and cerebrospinal fluid biomarkers of AD (Galvin et al., 2010). The AD8 has been translated into Spanish (Muoz et al., 2010), Korean (Ryu et al., 2009), and Chinese (Yang et al., 2011) with similar psychometric properties.

The Informant Questionnaire on Cognitive Decline in the Elderly The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) was developed as a way of measuring cognitive decline from a premorbid level using informant reports. Subsequently, the short version of 16-item correlated 0.98 with the full version and had comparable validity when judged against clinical diagnosis. Each item is rated on a 5-point scale from 1-“much better” to 5-“much worse” and the ratings are averaged over the 16 items to give a 1–5 score, with three representing no change on any item. In clinical situations, a screening cutoff of 3.44+ on the short IQCODE is a reasonable compromise for balancing sensitivity and specificity. The rating scale was deliberately designed to reflect cognitive improvement as well as cognitive decline, to allow for the questionnaire to be used in treatment trials and following acute illnesses (Form, 2004).

Summary Cognitive disorders are common in older adults; however, cognitive complaints may not be readily offered by patients due to denial, lack of insight, fear of stigma and/ or a general lack of knowledge about what is “normal” for an age. The elements of a comprehensive mental status examination include observational, cognitive, and neuropsychiatric assessments. In the absence of a comprehensive approach to evaluate cognitive abilities, it is unlikely that a clinician will detect impairment at the mildest stages when intervention may offer the greatest potential for benefit. In addition, the presence of cognitive impairment leads to poorer adherence, higher costs, and worse outcomes for other medical conditions compared with age-matched older adults without cognitive impairment. Whether the clinician designs their own unique assessments or utilizes one of the many standardized instruments available, failure to include a mental status examination in the assessment of older adults represents a missed opportunity.

Acknowledgments This work was supported by P30 AG008051 from the National Institute on Aging, National Institutes of Health.

References Alexopoulos, G.S., Meyers, B.S., Young, R.C., et al. (1993) The course of geriatric depression with “reversible dementia”: a controlled study. Am J Psychiatry, 150: 1693–1699. Alexopoulos, G.S., Meyers, B.S., Young, R.C. (1997) ‘Vascular Depression’ hypothesis. Arch Gen Psychiatry, 54: 915–922. Altshuler, L.L., Cummings, J.L., and Mills, M.J. (1986) Mutism: review, differential diagnosis, and report of 22 cases. Am J Psychiatry, 143 (11): 1409–1414.

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Ardila, A. and Rosselli, M. (1994) Spatial acalculia. Int J Neurosci, 78 (3–4): 177–184. Blazer, D.G. and Steffens, D.C. (2009) The American Psychiatry Publishing Textbook of Geriatric Psychiatry, 4th edn, Washington, DC: American Psychiatric Publishing Inc. Borson, S., Scanlan, J.M., Watanabe, J., et al. (2005) Simplifying detection of cognitive impairment: comparison of the Mini-Cog and Mini-Mental State Examination in a multiethnic sample. J Am Geriatr Soc, 53: 871–874. Brandt, J. and Manning, K.J. (2009) Patterns of world list generation in Mild Cognitive Impairment and Alzheimer disease. Clin Neuropsychol, 23 (5): 870–879. Brink, T., Yesavage, J., Lum, O. et al. (1982) Screening tests for geriatric depression. Clin Gerontologist, 1: 37–43. Brooks, J.O. 3rd, Bearden, C.E., Hoblyn, J.C., et al. (2010) Prefrontal and paralimbic metabolic dysregulation related to sustained attention in euthymic older adults with bipolar disorder. Bipolar Disord, 12 (8): 866–874. Bullock, R. and Lane, R. (2007) Executive dyscontrol in dementia, with emphasis on subcortical pathology and the role of butyrylcholinesterase. Curr Alzheimer Res, 4 (3): 277–293. Capampangan, D.J., Hoerth, M.T., Drazkowski, J.F., and Lipinski,  C.A. (2010) Olfactory and gustatory hallucination presenting as partial status epilepticus because of glioblastoma multiforme. Ann Emerg Med, 56 (4): 374–377. Caplan, L.R. (2010) Delirium: a neurologist’s view-the neurology of agitation and overactivity. Rev Neurol Dis, 7 (4): 111–118. Corrigan, J.D. and Hinkeldey, M.S. (1987) Relationships between part A and part B of the Trail Making Test. J Clin Psychol, 43 (4): 402–409. Dalrymple-Alford, J.C., MacAskill, M.R., Nakas, C.T., et al. (2010) The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology, 75 (19): 1717–1725. Del Ser, T., Hachinski, V., Merskey, S., and Munosk, D.G. (2001) Clinical and pathological features of two groups of patients with dementia with Lewy bodies: effect of coexisting Alzheimer type lesion load. Alzheimer Dis Assoc Disord, 15 (1): 31–44. deSouza, L., Sarazin, M., Goetz, C., and Dubois, B. (2009) Clinical investigations in primary care. Front Neurol Neurosci, 24,: 1–11. Esposito, F., Rochat, L., Van der Linden, A.C., et al. (2010) Apathy and executive dysfunction in Alzheimer disease. Alzheimer Dis Assoc Disord, 24 (2): 131–137. Ferguson, J.H. and Boller F. (1977) A different form of “pure agraphia”: syntactic writing errors in a patients with motor speech and movement disorders. Neurol Neurocir Psiquitr, 18 (Suppl. 2–3): 79–86. Flint, A.J. (2005) Anxiety and its disorders in late life: moving the field forward. Am J Geriatr Psychiatry, 13 (1): 3–6. Folstein, M.F., Folstein, S.E., and McHugh, P.R. (1975) Mini-mental State: a practical method for grading the cognitive status of patients for the clinicians. J Psychiatr Res, 12: 189–198. Form, A.J. (2004) The Informant Questionnaire on cognitive decline in the elderly (IQCODE): a review. Int Psychogeriatr, 16 (3): 275–193. Galvin, J.E., Roe, C.M., Xiong, C., and Morris, J.C. (2006) The validity and reliability of the AD8 informant interview for dementia. Neurology, 67: 1942–1948. Galvin, J.E., Malcom, H., Johnson, D., and Morris, J.C. (2007a) Personality traits distinguishing dementia with Lewy bodies from Alzheimer’s disease. Neurology, 68 (22): 1895–1901.

Galvin, J.E., Roe, C.M., Coats, M.A., and Morris, J.C. (2007b) Patient’s rating of cognitive ability: using the AD8, a brief informant interview, as a self-rating tool to detect dementia. Arch Neurol, 64 (5): 725–730. Galvin, J.E., Fagan, A.M., Holtzman, D.M., et al. (2010) Relationship of dementia screening tests with biomarkers of Alzheimer’s Disease. Brain, 133 (11): 3290–3300. Gangadhar, G., Joseph, D., and Chakravarthy, V.S. (2008) Understanding Parkinsonian handwriting through a computational model of basal ganglia. Neural Comput, 20 (10): 2491–2525. Gillig, P.M. and Sanders, R.D. (2010) Cranial Nerves IX, X, XI and XII. Psychiatry(Edgmont), 7 (5): 37–41. Gleichgerrcht, E., Torralva, T., Roca, M., et al. (2010) The role of social cognition in moral judgment in frontotemporal dementia. Soc Neurosci, 12: 1–10. Grafman, J., Passafiume, D., Faglioni, P., and Boller, F. (1982) Calculation disturbances in adults with focal hemispheric damage. Cortex, 18 (1): 38–49. Hamilton, J.M., Salmon, D.P., Galasko, D., et al. (2004) A comparison of episodic memory deficits in neuropathologically-confirmed Dementia with Lewy bodies and Alzheimer’s disease. J Int Neuropsychol Soc, 10 (5): 689–697. Hanson, J.C. and Lippa, C.F. (2009) Lewy body dementia. Int Rev Neurobiol, 84: 215–228. Hennig-Fast, K., Meister, F., Frodl, T., et al. (2008) A case of persistent retrograde amnesia following a dissociative fugue: neuropsychological and neurofunctional underpinnings of loss of autobiography memory and self-awareness. Neuropsychologia, 46 (12): 2993–3005. Josephs, K.A. (2007) Capgras syndrome and its relationship to neurodegenerative disease. Arch Neurol, 64 (12), 1762–1766. Karantzoulis, S. and Galvin, J.E. (2011) Distinguishing Alzheimer’s disease from other major forms of dementia. Expert Rev Neurother, 11 (11): 1579–1591. Karzmark, P. (2000) Validity of serial seven procedure. Int J Geriatr Psychiatry, 15 (8): 677–679. Katzman, R., Brown, T., Fuld, P., et al. (1983) Validation of a short orientation-memory concentration test of cognitive impairment. Am J Psyhciatry, 140: 734–739. Li, Y.S., Meyer, J.S. and Thornby, J. (2001) Longitudinal follow up of depressive symptoms among normal versus cognitive impaired elderly. Int J Geriatr Psychiatry 16: 718–727. Libon, D.J., Swenson, R.A., Barnoski, E.J., and Sands, L.P. (1993) Clock drawing as an assessment tool for dementia. Arch Clin Neurolpsychol, 8 (5): 405–415. Lyness, J.M., Niculescu, A., Tu, X., et al. (2006) The relationship of medical comorbidity and depression in older, primary care patients. Psychosomatics, 47 (5): 435–439. Mack, W.J., Freed, D.M., Williams, B.W., and Henderson, V.W. (1992) Boston Naming test: shortened versions for use in Alzheimer’s disease. J Gerontol, 47 (3): 154–158. Maeshima, S., Osawa, A., Sujino, K., et al. (2011) Pure alexia caused by separate lesions of the splenium and optic radiation. J Neurol, 258 (2): 223–226. Mantella, R.C., Butters, M.A., Dew, M.A., et al. (2007) Cognitive impairment in late-life generalized anxiety disorder. Am J Geriatr Psychiatry, 15: 673–679. Mechtcheriakov, S., Graziadei, I.W., Rettenbacher, M., et al. (2005) Diagnostic value of fine motor deficits in patient with low-grade hepatic encephalopathy. World J Gastroenterol, 11 (18): 2777–2780.

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Morales, J.M., Bermejo, F., Romero, M., and Del-Ser, T. (1997) Screening of dementia in community dwelling elderly through informant report. Int J Geriatr Psychiatry, 12 (8): 808–816. Morris, J.C., Heyman, A., Mohs, R.C., et al. (1989) The consortium to establish a Registry for Alzheimer’s disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology, 39 (9): 1159–1165. Muñoz, C., Núñez, J., Flores, P., et al. (2010) Usefulness of brief informant interview to detect dementia, translated into Spanish (AD8-Ch). Rev Med Chil, 138 (8): 1063–1065. Nasreddine, Z.S., Phillips, N.A., Bedirian, V., et al. (2005) The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc, 53: 695–699. Newcombe, V.F., Outtrim, J.G., Chatfield, D.A., et al. (2011) Parcellating the neuroanatomical basis of impaired decision making in traumatic brain injury. Brain, 134 (Pt3): 759–768. Olssøn, I., Mykletun, A., Dahl, A.A. (2005) The Hospital Anxiety and Depression Rating Scale: a cross sectional study of psychometrics and case-finding abilities in general practice. BMC Psychiatry, 5: 46. Pelak, V.S. and Liu, G.T. (2004) Visual hallucinations. Curr Treat Options Neurol, 6 (1): 75–83. Pia, L., Neppi-Modona, M., Ricci, R., Berti, A. (2004) The anatomy for anosognosia for hemiplegia: a meta-analysis. Cortex, 40 (2): 367–377. Pulsford, D. and Duxbury, J. (2006) Aggressive behaviour in residential care settings: a review. J Psychiatr Ment Health Nurs, 13 (5): 611–618. Ramírez-Bermúdez, J., Soto-Hernández, J.L., López-Gómez, M., et al. (2005) Frequency of neuropsychiatric signs and symptoms in patients with viral encephalitis. Rev Neurol, 41 (3): 140–144. Rohrer, J.D., Knight, W.D., Warren, J.E., et al. (2008) Word-finding difficulty: a clinical analysis of the progressive aphasias. Brain, 131 (Pt1): 8–38. Roth, R.M., Flashman, L.A., and McAllister, T.W. (2007) Apathy and its treatment. Curr Treat Options Neurol, 9 (5): 36–70. Rusconi, E., Pinel, P., Dehaene, S., and Kleinschmidt, A. (2010) The enigma of Gerstmann’s syndrome revisited: a telling tale of the vicissitudes of neuropsychology. Brain, 133 (Pt2): 320–332.

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Chapter 4.2 Neuropsychology in Geriatric Neurology Donald J. Connor and Marc A. Norman Basis of neuropsychological assessment Psychometric testing is based on the administration of standardized instruments, quantified using appropriate normative data, to produce a measurement of an individual’s relative cognitive strengths and weaknesses. Ideally, the normative transformation of the raw data will include factors that may influence test performance such as age, gender, education, premorbid intelligence, socioeconomic status, culture, and race (Mitrushina, 1999, pp. 24–27). This allows the examiner to estimate the relative probability that the test score is abnormal, and estimate the degree of impairment. Neuropsychological assessment involves the integration of the psychometric test results along with medical history, psychological/ psychiatric status, and subjective symptom report by the patient and family. This integration is done based on an intimate knowledge of brain–behavior–disease relationships that are the core of a neuropsychologist’s training. Neuropsychological testing is similar to a clinician’s mental status testing but differs quantitatively in the amount of testing and qualitatively in the integration of differential profiles and use of demographic-based normative data.

Normative data The issue of appropriate normative data is critical to the interpretation of the test profile. If the normative dataset is not appropriate to the individual patient’s demographic factors then the validity of the transformed data must be brought into question. Single cut points as commonly seen in mental status examinations are useful in clinical practice but can be misleading. Since the final interpretation of the data is a synthesis of all information available to the neuropsychologist, a valid and clinically useful conclusion may be reached despite the norms not accounting for all variables, but the decrease in the strength of the conclusions should be recognized (American Psychological Association Ethics standard 9.02, 2010). The subject’s performance is most commonly expressed as standard deviations (Z-scores), T-scores, standard scores, scaled scores, or percentiles. The differences between these transformations and their implications for interpretation are beyond the scope of this chapter. However, as a guideline, except for percentiles, these transformations of the raw scores assume a normal distribution of the data (e.g., standard

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bell curve). Z-scores have a mean of 0 with a standard deviation of 1; T-scores have a mean of 50 with a standard deviation of 10; standard scores such as those used in IQ tests have a mean of 100 and a standard deviation of 15; scaled scores have a mean of 10 with a standard deviation of 3. Percentiles are expressed somewhat differently as they are nonlinear and reflect the percentage of scores in a sample that fall at or below a given raw score. Because of this, conversion of percentiles into standardized scores (Z-scores, T-scores, etc.) assumes that the percentile distribution can reflect the normative curve which may not be the case in tests with a skewed distribution. However, assuming a normal distribution of the normative data, a Z-score = −1.0 (one standard deviation below the mean) would reflect a percentile score of sixteenth percentile, a Z-score of −1.5 would be in the seventh percentile and a Z-score of −2.0 would be in the second percentile. In general, cut scores of approximately −1 standard deviation may be taken as low average; scores of approximately −1.5 standard deviations may be taken as borderline or questionable; and scores of −2 standard deviations may be taken as impaired (Lezak et al., 2004; pp. 145–149) although there is significant variability in this and deficits of −1.0–1.5 have been used in the diagnosis of mild cognitive impairment (MCI) (Albert et al., 2011). The level of score that is indicative of a clinically relevant pathologic state is based on multiple factors (premorbid abilities, profile against other abilities, etc.) and is interpreted both as a probability that there is an impairment as well as the degree of impairment. The level of performance the practitioner uses to determine the clinical impairment may be greater or less than what may be considered statistically different depending on the factors mentioned above (premorbid abilities, demographics, sensory/motor deficits, distribution of the normative data, etc.) and the consequences of a false negative versus false positive result (Lezak et al., 2004; p. 148; Busch et al., 2006).

Standardized assessment In addition to limitations imposed by appropriateness of the normative data, other factors that may influence test performance must be taken into account. As detailed in a previous section on mental status testing, all psychometric testing should begin with at least a cursory examination of sensory and motor function. For example, if a subject demonstrates impaired performance on visual memory tasks but has significant uncorrected visual deficits, then

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the results of the testing must be carefully interpreted or discounted. The breadth of neuropsychological tests available allows the clinician some ability to measure cognitive function even in the presence of significant sensory or motor deficits, but ultimately the impact of the deficits on test performance, the effect on the cognitive profile and the validity of the results is determined by the clinical interpretation of the neuropsychologist. The basis of neuropsychological assessment is that test instruments are administered in a standardized manner so that appropriate normative data can be applied for a valid reflection of the patient’s abilities. Thus, neuropsychological tests tend to have detailed administration manuals and highly structured administration procedures. This quantitative approach emphasizes the final performance score as indicative of the patient’s abilities. However, observations made during the test session (apparent effort, level of consciousness, acute confusion, etc.) that may influence the validity of the results are also included in the interpretation. In some cases, a “process approach” may be used that emphasizes the method the patient uses to complete the task (Milberg, 1986). This approach involves a more sophisticated and complex analysis of the qualitative aspects of the test behavior and is integrated with the quantitative test scores. Some neuropsychological instruments have attempted to standardize the qualitative methodology as is reflected in tests such as the Wechsler Adult Intelligence Scale revised as a neuropsychological Instrument (Kaplan et al., 1991). However, the process approach method is seen as an adjunct to the quantitative method of analysis rather than a replacement for it.

Interpretation It is the integration of the test results into a cognitive profile that is the core feature of a neuropsychological assessment. This integration involves both the awareness of noncognitive factors that may influence the test results (mood, effort, sensory/motor, etc.) as well as the intertest patterns. Since no single test is a pure measure of any cognitive construct, using the relative performance of several tests compared to each other is necessary to define the impaired areas of function. One example of this is the Trail Making Test A/B (Reitan, 1958). This is a sequencing test consisting of two conditions. The first condition (Trails A) is a simple sequencing task where the patient is presented with a paper with numbers scattered over the page. The patient then draws a line from one number to the next—in order—with the time to completion and any errors recorded. The second condition (Trails B) is similar but involves alternating between numbers and letters (e.g., 1-A-2-B-3- etc.). Poor performance on Trails B can be due to visual–motor impairment or difficulties in maintaining the sequence set (executive dysfunction). By comparing the performance on Trials B to the performance on

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Trails A, the visual–motor component can be accounted for and a more accurate measure of executive function (EF) can be obtained. As mentioned in chapter 4.1, proficiency in mental status testing is a necessity in geriatric neurology. However, the abbreviated nature of the mental status tests tends to limit its sensitivity and specificity in very mild dementia (Tombaugh and McIntyre, 1992; Tariq et al., 2006) and the ability to detect relative levels of deficit in different cognitive domains (e.g., cognitive profiles). Many of the standard screening instruments (MMSE, MOCA, SLUMS) are useful for initial detection of clinical dementia based on their total score (Nasreddine et al., 2005; Ismail et al., 2010), but their reliability tends to decrease when individual items are interpreted. While these tests can be influenced by age, education, etc., this is often not taken into account when “cut” or threshold scores are used. In the MMSE manual (Folstein et al., 2001), a reference to an extensive normative study is given (Crum et al., 1993) as a way to take demographics into account. In particular, this study demonstrates the significant effect that age and education can have on what is considered a “normal” performance on the test. However, it should be noted that the administration procedures in the normative study are different from those described in the test manual, making use of the normative data questionable for the copyrighted version of the MMSE. Therefore, even when using abbreviated instruments it is necessary to ensure that the administration methods are appropriate to the normative data and that the normative data are appropriate for the individual patient. As mentioned previously, neuropsychological testing can be seen as a more extensive and expansive—albeit more time consuming—extension of mental status testing. Similarly to mental status testing, neuropsychological assessment can be done using a series of individual instruments chosen for the specific referral question or for appropriateness to the patient. Alternatively, a “comprehensive instrument” (Neurological Assessment Battery, Halstead–Reitan Neuropsychological Battery, Wechlser Adult Intelligence Scale, etc.) can be used in which the subtests are all designed to work together (e.g., minimize interference effects) and are co-normed which facilitates profile interpretation. A survey of the most common neuropsychological instruments can be found in Rabin et al. (2005).

Utility of neuropsychological assessment Neuropsychological assessment in a geriatric population can be used for many purposes, but the major applications fall into three broad categories: diagnosis, effect on function, and treatment.

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Diagnosis Incorrect diagnosis of an incurable degenerative disease (false positive) can cause unnecessary stress, pain and inappropriate choices (financial and social) to the patient and their family. Conversely, early detection of dementing disorders can have a significant positive effect on the patient and their family. It has been suggested that starting treatment early in the course of a dementia optimizes the treatment effects of medications and allows positive lifestyle changes that may slow the decline, although results of early treatment have been variable (Holt et al., 2009; Assal and van der Meulen, 2009). Accurate early detection also has the practical benefit of allowing the patient and their family to make future plans while the patient is still cognitively intact. Reaching early agreements on when to restrict driving, developing safe habits and routines that may carry forward into the moderate stages of dementia, and other social and treatment interventions can enhance the long-term quality of life of the patient and caregiver (Gessert et al., 2000; Papastavrou et al., 2007). Along with early and increased accuracy of detection of suspected dementia, neuropsychology can contribute to differential diagnosis of the underlying processes. While AD is the most common cause of dementia in the elderly, there are many other disease states that can cause dementia with significant implications for treatment and outcome. One of the most apparent differentials is when cognitive decline is caused by a delirium rather than a dementia. Delirium is often the result of an underlying medical condition that is often treatable (unlike most progressive dementias); however, if left undetected it may progress and be life-threatening. Differentiating between degenerative dementias can also have significant clinical utility. Perhaps the second most common cause of degenerative dementia is Lewy body disease (LBD). While it may often be found to have comorbidity underlying AD pathology, there are differences in presentation and cognitive profiles that can be used to increase the diagnostic certainty (McKeith et al., 2005). The clinical treatment implications are significant in those patients with LBD who show increased sensitivity to neuroleptics and, when used for treatment of agitation, can result in permanent rigidity (Weisman and McKeith, 2007). Treatment implications of differential diagnosis are of course not limited to medications, but include social interventions, rehabilitation, and family planning. For example, AD and FTD have different presentations, progressions, and treatments (Salmon and Bondi, 2009). Issues on what the family can expect through different stages, prediction of possible dangerous situations and behaviors, and coping programs can be quite different. Assessment of functional limitations The impact of the cognitive deficits on a patient’s ability to function and related safety issues can also be informed by neuropsychological assessment. While the structure of

most psychometric tests are geared toward measurement of cognitive abilities, some test batteries have attempted to include items that are ecologically valid measures of day-to-day functioning (Farias et al., 2003). However, while neuropsychological assessment can inform the level of function and track changes over time, it is not a replacement for direct evaluation (e.g., on road driving tests (Brown et al., 2005)). This in part may be due to the structured nature of the assessment instruments and the controlled environment in which the testing is administered. While this is necessary for accurate measurement of function, it does not reflect the complex and multimodal environment patients may find themselves functioning in. For example, in driving aspects of attention, reaction time, processing speed (monitoring the environment, observing traffic signals, traffic conditions), memory and orientation (getting lost), visual–spatial skills, and executive abilities (EA) (decision making with regard to other drivers and road conditions) are all involved in effective performance. Many patients with early Alzheimer’s disease (AD) may be able to drive safely in well-known areas as long as no confusing or conflicting elements occur in their environment since much of driving skill involves procedural memory that tends to be spared in the early stages of this disease. However, if the patient suddenly comes upon extensive road work with multiple lane restrictions or finds themselves in an unfamiliar area, other cognitive abilities that are affected by the disease (e.g., frontal executive) are necessary, and a dangerous situation could occur. Neuropsychological test results can be a useful adjunct to determination of functional problems, but are insufficient in and of themselves (Iverson et al., 2010). Competency is a legal term but is usually based on clinical information. In essence, it reflects the patient’s ability to make a decision, have a rationale for the decision and appreciate the consequences of that decision (Marson et  al., 2001; Moye and Marson, 2007). Competency itself can have multiple areas—such as the ability to make financial decisions, medical decisions and self-care—and a patient may be competent in one area and incompetent in another. As in other aspects of determination of function, neuropsychological assessment can aid in the determination of competency by providing information on deficits in various cognitive domains, but is not in and of itself sufficient.

Treatment The importance of neuropsychological testing for treatment extends beyond differential diagnosis or the detection of comorbid processes. While it is certainly important to determine the presence of a disorder before treating it (e.g., MCI), and it is important to make sure the correct disease is being treated (e.g., AD vs. LBD), the pattern of strengths and weaknesses a patient presents is important

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in any cognitive remediation or social intervention strategies. For example, if memory is a central issue, then electronic reminders to take medications along with written notes can prove helpful. Determination of the memory system affected can further guide intervention as the type of difficulty (encoding information vs. storage vs. retrieval) can have significant effects on the type of intervention that will prove most effective (Bayles and Kim, 2003). For example, written notes—while very useful in patients with AD—lose their impact if the patient develops an undetected Alexia. Most interventions in degenerative dementias concentrate on compensation and coping strategies, which will be under constant modification as the course of the disease progresses (Ptak et al., 2010). Patients who have had a stroke, traumatic brain injury (e.g., auto accident, falls), or who are post CNS surgery can benefit from more traditional rehabilitation treatments that seek to augment the normal recovery process. A critical step in this treatment is the identification of specific cognitive areas of impairment and remaining areas of strength (Yamaguchi et al., 2010).

Cognitive domains in neuropsychology Multiple approaches, models, and theories have been created to organize and explain mental processes. In clinical practice, five general cognitive domains that are widely recognized include: attention, language, memory, executive abilities, and visuospatial abilities.

Attention, orientation, concentration Assessment of attention varies from clinic screening to longer duration and precision computerized testing to inferential imaging (i.e., ERP, PET, fMRI, and SPECT). Attention is a primary component of multifactorial cognitive processing; however, there is no pure test for attention and there is no test that assesses all components of attention. Like other cognitive domains, attention is not a unitary construct and while some measures are very sensitive, attentional profiles lacks specificity; however, before interpreting attentional problems arousal and orientation must be adequate (see also previous section on mental status testing). Orientation in clinical use can range from a basic awareness of self, body, and immediate environment to understanding of time, place, and purpose. At its most basic, the construct of orientation overlaps with that of alertness and vigilance. Clinical assessment usually involves basic questions of person, place, and time (oriented × 3). Attention requires that sensory events must first be detected and oriented to, although at the most basic level this may

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be involuntary. This requires the individual to be sufficiently aroused and have sensory awareness. Those who are sedated or obtunded will have problems with the first step of attention. Attention is a complex construct and there exist many cognitive models dividing attention into subtypes (i.e., selective attention, sustained attention, and divided attention) and may overlap with the concept of alertness/vigilance on one end and working memory on the other. Selective attention is the process by which individuals preferentially select relevant, salient stimuli over less germane ones. Humans are remarkably facile in filtering irrelevant stimuli, but this may become compromised with normal aging, cerebral insults, or degenerative processes. After a stimulus is selected, sustained attention allows for the maintenance of vigilance, focused attention, and response persistence. In sustained attention, tasks measure the ability to hold information, concentrate, ignore other stimuli, and perform mental operations (see also working memory). In mental status testing, the “A” letter test can be used to test sustained attention where a list of random letters is read to the patient and is asked to tap the table every time they hear the letter “A”. Neuropsychologists use tests that may last from 5 (i.e., digit vigilance test) to 30 minutes (i.e., computerized continuous performance tests). These tests allow the patient to focus their attention on one task, but there are other measures that assess the ability to divide attention across two or more tasks, divided attention. Divided attention is not often challenged within the clinical setting, but some neuropsychological paradigms assess this (i.e., paced addition serial attention test, and consonant trigrams) (Gronwall, 1977; Morris, 1986). Intact attention is a prerequisite for cognitive function in any of the other domains. Clinically, impairment in attention may be reported by the patient or family as memory disturbance (encoding) or lack of effort. Patients with poor attention may complain that they are unable to remember information, but formal testing may reveal that they are unable to attend to verbal or visual information. For example, they may notice that after reading a page they are unable to “remember” what they have read; however, attentional impairment may render them unable to direct their attention to the information to be encoded, thus, it is not a true memory deficit. This level of differentiation (i.e., attention versus memory) may only be evident with detailed neuropsychological measures. Even within healthy aging, attentional resources lessen. This is typically noted in the diminished ability to attend to multiple stimuli at the same time (i.e., divided attention). Patients may complain of the inability to carry out conversations, because they are unable to focus or are easily distracted, but this may be a “normal” finding of healthy aging until it begins to affect function.

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Within a clinical population, attention can be used to distinguish general disorders within the elderly. For example, in AD, attention tends to be relatively better preserved than many other cognitive domains (i.e., memory and EF), but attention is more impaired than in healthy individuals (Rizzo et al., 2000a, 2000b; Peretti et al., 2008; Duchek et al., 2009). In contrast, attention is proportionately more impaired in Lewy body dementia (DLB) than in AD and significant fluctuation in attention are core characteristics of delirium (Ballard et al., 2001). Significant impairments of attention up to and including an acute confusional state, can be seen in metabolic disorders, intoxication, mania, fatigue, psychosis (distracted from internal stimuli), chronic sleep disorders (i.e., sleep apnea) and multifocal disorders (i.e., meningitis, encephalitis, acute traumatic brain injury). Because there are several components to attention, and models involve multiple neurosubstrates, lesions or neuropathology to almost any area of the brain may produce a disorder of attention (or a component of attention). Although most clinic attention assessment is within the verbal domain, spatial inattention may be evident in office screening. An example of verbal attention is a Digit Span task. Reciting a progressively longer sequence of digits (digits forward) is seen as a test of simple attention, and reciting the digit sequence in reverse order (digit backward) as a test of more complex attention, which overlaps with the construct of working memory. WORLD backwards and serial sevens in the mini-mental state examination (MMSE) are other examples of brief measures of attention. Information may be briefly held within working memory, but this is not necessarily stored for later memory retrieval. A simple spatial task that can be done within a few seconds is the line bisection test. The patient is asked to draw a perpendicular line in the center of the lines drawn on the paper. Figure 4.1 demonstrates left hemispatial inattention. Not only did the patient omit drawing the bisecting line in the page’s left hemispace, the lines they bisected in right hemispace were inaccurately bisected.

Figure 4.1 Line bisection test.

Language and communication Human expression and communication occurs through a variety of modalities including speech, writing, reading, drawing, and gestures. Three features can be used to generally classify broad aphasia subtypes: expression, reception, and repetition. Although the term aphasia (absence of speech) is commonly used and will be used in this section, in most cases dysphasia (impaired speech) is more accurate. Informal language assessment begins during the initial interaction and interview; however, subtle deficits may only be identified with further screening or a comprehensive, systematic approach. Practitioners should observe the quantity and quality of speech fluency, prosody, articulation, and grammar. As with any other part of the neurologic/neuropsychological examination, aberrant findings should be viewed in the context of other findings. For example, what may appear to be comprehension problems may be secondary to psychiatric or other factors (i.e., poor output secondary to depression, minimal motivation, negative attitude, poor hearing, etc.). Normal expressive speech should include fluent, spontaneous discourse. Expressive changes may range from mild to profound. Mild paraphasias may be subtle, but at the other end of the spectrum a patient may be completely unable to produce verbal language. Most language screening includes asking the patient to name items. Spontaneously naming items on confrontation requires aspects of object recognition, item identification, retrieval, and expression. It is also important to note that although a patient is unable to name an object, this may be due to a retrieval deficit, rather than anomia. In the case of a retrieval deficit, although the person is unable to spontaneously name the item, he/she would be able to do so with a phonemic cue (i.e., cuing them with “com…” for “computer”). In the latter case, anomia, they would be unable to generate the word even with a cue. Most clinical screening measures include some aspect of naming (i.e., MMSE, SLUMS, etc.). Neuropsychological assessments commonly include the Boston Naming Test (60 items) or other standardized naming tools. An often-overlooked aspect of language is automatic speech that includes overlearned sequences and phrases. Even when patients may have profound expressive language loss, automatic phrases like “hi”, or sequences like counting or singing the alphabet may be less impaired. Also, the automatic nature of overlearned songs (like “Happy Birthday”) can be performed when other speech is absent. Even when a patient is able to sing the alphabet, they may be unable to speak it without the prosodic tune. Comprehension deficits may be more difficult to identify than expressive ones. Patients display nonverbal communication (e.g., head nodding) that may mislead others to

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believe they understand what is being said when such is not the case. Practitioners may contribute to the problem in using their own gestures when asking a question (e.g., nodding affirmatively when asking if the person is having a good day or marriage). Comprehension can be assessed in several ways including, yes–no responses, responsive answers, pointing to responses, and simple commands; however, errors may not be apparent unless complex questions are asked. Simple yes–no questions may be needed for those with significant receptive aphasia (i.e., “Is your name Jane?”). Increasing complexity includes “Are the lights on in the room?” With greater complexity, responsive answers require greater understanding and expression (i.e., “the colors of the flag are red, white, and  _____”). However, when expression is impaired, patients may be unable to verbally respond to questions, so asking them to point toward objects and follow commands can be done. When asking a patient to point or follow commands, however, it is important to rule out pointing errors related to apraxia or agnosia. The third essential language area is repetition. Repetition of sounds, words, phrases, and sentences should be assessed. Like expression and reception, patients may display deficits with only complex items. On the simple end, noncomplex words can be repeated (i.e., car, house, etc.). Phrases and sentences offer a greater range of complexity (i.e., “Methodist Episcopal… The door to the office is closed… No ifs, ands or buts… The phantom soared across the foggy heath”). Because of the proximity of other cerebral structures to eloquent cortices, association cortices or fasciculi make it possible that other communication deficits may be present. Although not core pieces of subtyping aphasia, the neurologic examination may or may not include academic tasks of reading, writing, and arithmetic (functions associated with association areas around the supramarginal gyrus). Because of frontal and parietal proximity to language eloquent cortices, motor and sensory dysfunction is common. Reading, writing, and arithmetic may produce functional limitations, but are often not fully assessed, but changes may occur due to their proximity to association cortices. Alexia, apraxia, and agnosia are associated findings that are typically assessed in a neuropsychologist’s comprehensive aphasia battery. Also, neuropathologic correlates may be associated with alexia with (central) or without (posterior) agraphia. Many of the language tasks mentioned in the mental status examination section are used in neuropsychological screening (i.e., the Reitan–Indiana Aphasia Screening Test), but the neuropsychologist’s assessment armamentarium also includes comprehensive batteries including the Boston Diagnostic Aphasia Examination, Multilingual Aphasia Examination, Western Aphasia Battery, and a variety of other measures. Each tool assesses

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expression, reception, and repetition, but vary in their measures of apraxia, reading, writing, and agnosia. Also, some tasks are specific to one modality (i.e., comprehension). Neuropsychologists may use a tool like the Token Test to measure aspects of receptive dysfunction. For the Token Test, an array of various colored and sized shapes is presented, and the patient is asked to follow commands such as “touch the small red square with the large blue circle.” Once assessment of the disruption and/or preservation of language components is completed, an aphasia syndrome may be evident. Acute expressive and receptive changes are most commonly associated with vascular events; however, progressive changes can occur with degenerative disorders. There are many models and nosologies applied to language syndromes, and although described as discrete syndromes within the literature, they rarely occur in their purest forms. Generally, acquired language disorders can be separated into expressive, receptive, and mixed aphasias (Table 4.1). There are myriad models of language and aphasia with most language researchers identifying at least five types of aphasia. The distinctions vary in the presence or absence of deficits in expression, reception, and/or repetition. The most common term associated with expressive aphasia is Broca’s aphasia, a nonfluent aphasia. Because the underlying problem is language based, it differs from the articulation or motor aspects of speech, as in dysarthria or verbal apraxia. Agrammatism is the primary feature of Broca’s aphasia, where speech is labored and disjointed. Anatomically, Broca’s aphasia involves damage to Broca’s area (Broadmann area 44 and 45), which is within the dominant, posterior inferior frontal gyrus. In Broca’s Aphasia connector words are often omitted, making speech telegraphic. For example, a patient may describe their appointment as, “Hospital… two o’clock… Dr.  Smith.” Verbs and prepositions are omitted in this example. In Broca’s, comprehension is relatively preserved, but repetition is impaired. The latter point is the differential characteristic from Transcortical Motor Aphasia. Transcortical Motor Aphasia is a nonfluent aphasia, similar to Broca’s, but repetition is not impaired.

Table 4.1 Aphasias Expression Reception Expressive aphasias Broca’s or nonfluent aphasia Transcortical motor aphasia Receptive aphasias Wernicke’s or fluent aphasia Transcortical sensory aphasia Conduction aphasia Global aphasia + = intact; − = impaired.

Repetition

− −

+ +

− +

+ + + −

− − + −

− + − −

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Wernicke’s aphasia (a receptive aphasia) is a fluent aphasia, involving impairment of receptive language and repetition, but sparing in expressive speech. Anatomically, it is thought to involve Wernicke’s area (Broadmann area 22), an area in the posterior part of the superior temporal gyrus in the dominant hemisphere. Because the patient is unable to understand oral language, they fail to appreciate their own spoken language errors, tending to use real words, but their speech may be incomprehensible or frequent errors are evident. Their mixture of errors may produce a “word salad”. Similar to Wernicke’s aphasia, transcortical sensory aphasia produces fluent speech and impaired comprehension; however, repetition is not impaired. Conduction aphasia occurs when a patient has spared expression and reception, but repetition is impaired. This suggests a disconnection of primary expressive and receptive cortices and involvement of the arcuate fasciculus, although this has recently been brought into question (Bernal and Ardila, 2009). In these acquired aphasia syndromes, the most common etiologies of aphasia syndromes in the elderly are cerebrovascular accidents, and the most common vascular territory associated with aphasia is the middle cerebral artery. While cortical lesions are most commonly associated with aphasia, subcortical lesions may also produce aphasia. Aphasia can also occur as a primary or secondary feature of dementia. For example, primary progressive aphasia and semantic dementia may be categorized as subsets of FTD, and their primary presentation is that of language dysfunction.

Verbal and episodic memory Memory is a complex construct that has many different but overlapping conceptual models. Terminology varies widely depending on the orientation of the model and some are listed in Table 4.2. The major approaches to classifying memory and the associated terminology are discussed below.

Table 4.2 Examples of terminology used in conceptual models of memory Declarative Nondeclarative Episodic Semantic Procedural Skill learning Immediate Secondary Primary Working

Explicit Implicit Representational Dispositional Familiarity Reference Short-term Long-term Conditioning Priming

Temporal model One approach for classifying memory is to conceptualize it as an organization of systems for progressively longer periods of storage. In this approach, after attending to a stimuli (see attention, orientation, concentration section above) a representation of the material is kept in an immediate memory store. In immediate memory the information is stored for only moments. This memory store is limited not only in time but also can only hold a limited amount of information. This construct significantly overlaps with that of attention and working memory. For example, recalling a sequence of numbers immediately after presentation (e.g., digits forward) is  seen as a test of attention (“digit span” is sometimes used synonymously with attention span), but also meets the definition of immediate memory. Working memory is also seen as a very short-term store of information where bits of information are held while they undergo mental manipulation. Working memory can also overlap with concepts of attention and other constructs (e.g., some definitions of short-term memory). In a test sometimes used to measure “complex” attention, the patient is asked to repeat a sequence of numbers in reverse order (digit backward) that requires them to briefly hold the numbers in memory while manipulating their order. More complex versions of this (ordering sequences of numbers and letters, paced serial addition tasks) can detect subtle cognitive deficits, but tend to be nonspecific because of the overlapping constructs (sustained attention, immediate memory, working memory). Regardless, immediate memory can be conceptualized as a momentary memory that will be quickly degraded unless it is immediately refreshed (e.g., rehearsal) or transferred into a longterm memory store. A second temporal stage is short-term memory. This term is sometimes used synonymously with immediate memory in that it is the acquisition and retention of a memory trace for a measureable but brief period of time. The exact time period this term refers to is highly variable and some authors argue that it is not a meaningful construct as it may use the same neuroanatomic system as long-term memory, and therefore simply be a different stage of the same process (Brewer and Gabrieli, 2007). However, for clinical purposes short-term memory is usually defined as the retention of the material for a period of seconds to a few minutes. Thus, in a task requiring the patient to learn a list of words over a series of trials, the increase in the number of words recalled after each presentation (e.g., learning) is an aspect of short-term memory. The recall of the words after a delay of a few minutes—whether or not an interference list is given—has also been termed shortterm recall. The next temporal stage is long-term memory. As it implies, this term refers to the semipermanent to

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permanent storage of information over long periods of time. Again, there is no absolute minimum or maximum time frame that this term refers to. In clinical practice, retention of material after 20–30 minutes is said to enter long-term memory, although degeneration of the memory trace certainly continues after that point. Notably, significant disruption of long-term memory for hours or days prior to head injury (e.g., retrograde amnesia) indicating that the laying down of long-term memories (consolidation) is a continuing process. Remote memory is usually taken as a period of autobiographic memory (in geriatrics where the patient grew up, worked, was married, etc.), although this may also vary considerably between authors and often is simply considered an extension of long-term memory.

Characteristic model Another theoretical model has shown some success in parceling long-term memory into divisions based on the characteristics of the memory and the way they are expressed (Tulving, 1972; Schacter and Tulving, 1994; Squire and Knowlton, 1994). In this context, long-term memory is taken as the memory that has been consolidated and exists in a more stable form than immediate or short-term memory. The basic structure of this model is as follows. Declarative (explicit) memory: This type of memory involves the conscious recall of previous experiences. Two main divisions of this type of memory are episodic memory and semantic memory. • Episodic memory refers to the conscious recall of information linked to specific events (or episodes) that occurred in a specific context (time and place). Memories of specific instances from where someone grew up, went to school, a conversation with one’s spouse a week ago, what they had for breakfast today, or of a list of words they have read several minutes ago are examples of episodic memory. • Semantic memory refers to general knowledge about the world such as vocabulary, facts and concepts that are not contextually dependent. How we organize the world and its inter-relationships is an important aspect of this type of memory. For example, chairs may have very different forms, but we are able to associate them under the concept “chair.” Memories that have become generalized out of specific context (such as where one lived, who one’s relatives are) are also classified in this system (Warrington and McCarthy, 1988). Nondeclarative (implicit) memory: This type of memory is defined by a memory trace that is not consciously recalled and manifests in behavioral changes such as abilities (skill learning or procedural memory), habit formation, or priming effects. The ability of amnesic patients to alter behavior based on past

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events without conscious recall of those events has led to distinguishing this system from the episodic memory system (Mosccovitch, 2004). Several systems classified under implicit memory are clinically relevant, with procedural memory being perhaps the most important for patient functioning (Squire and Knowlton, 2000). • Procedural memory is based on learned abilities that we perform without conscious recall. Riding a bicycle, reading, writing, etc., are activities that we perform without conscious remembrance of the event or sequence. These abilities are often intact in dementia and other amnesic syndromes. • Priming phenomena can be seen as a nonconscious activation of memory traces that influence responses in ambiguous situations. The classic experimental demonstration of this is when subjects are asked to generate whole words from word fragments. Subjects tend to generate more words that they had been recently exposed to (primed) than other words that may be of higher frequency. • Classical conditioning is one of the earliest theories of learning in experimental psychology. It is based on the linking of a stimulus to an associated stimulus such that the presence of the associated stimulus alone will produce a similar response to that seen with the original stimulus. Animal studies and work with brain-damaged patients have indicated that different neural systems and structures underlie the different memory types above, supporting the validity of the model (Squire and Zola, 1996; Squire, 2009).

Modality model The nature of the stimulus can also be used to define memory systems. There is some evidence from imaging studies as well as patients with brain injury that different sensory systems use different storage networks in the brain (Wheeler et al., 2000). Clinically, verbal memory and visual memory are the modalities most often assessed. However, it should be noted that obtaining a “pure” measure of either is difficult as patients may verbalize the visual stimuli (e.g., describing drawings) and some may visualize the verbal material (e.g., visually linking items from a list). Other modalities have been assessed in the research literature, but are not commonly assessed separately in clinical practice. Stage model Clinically, a useful way of thinking of the memory process is by organizing it into a series of stages. Encoding (acquiring the memory), storage/consolidation (transferring into long-term stores) and retrieval (accessing the memory either into consciousness or as evidenced by

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behavior) is often used as a general guideline when conducting an assessment. Encoding: Seen as the initial stage in memory formation, encoding includes several processes. The patient must first attend to the particular stimuli to be encoded; this information is processed by the appropriate modality systems (e.g., verbal, visual, etc.) and linked with associated stimuli (context). This is usually seen as an active process as opposed to a passive reflection of sensory information (Blumenfeld and Ranganath, 2007). Storage: Consolidation is the transfer of the processed memory into a form that can be maintained over time without conscious rehearsal. Rather than a unitary process, consolidation appears to take place by multiple functional systems, molecular mechanisms, and structural changes. Further processing of the memory may occur at this stage and some authors have suggested that the postencoding process may continue to operate for years as new information is acquired and linked to previous memories (Brewer and Gabrieli, 2007). Delayed proactive interference and retroactive interference effects seen in normal individuals and retrograde amnesia that may occur for hours or days prior to brain injury appear to support this. Retrieval: Retrieval of an encoded and stored memory may take several forms in clinical assessment. Free recall is the ability to bring to consciousness a memory without any external or related associated stimulus (reminders). Cued recall involves the presentation of an associated stimulus to aid in recalling. Many mnemonic techniques will involve associating an external stimulus with an item to be remembered to both enhance encoding and recall (e.g., a person’s facial feature with their name). Clinically, cued recall may be done by providing semantic cues (the word was a type of fruit), phonemic cues (it began with the sound a…), or others (there were two figures on the page). Recognition is a third clinically useful construct where the patient is presented with the actual target item and several distracters and asked to identify the original item. Differences in the relative performance on free recall versus recognition tasks have been suggested to be useful in differentiating between some progressive dementias (see preclinical diagnosis of dementia section below). Familiarity is a related but slightly different construct. In familiarity the patient is aware of having encountered the stimulus before, but is not able to attach any context to the memory (e.g., source memory). Other terms and models exist for memory but they are less often used in clinical practice and some suggest the integration of several domains and complex neural circuits. Metamemory is a complex construct that includes judgment of learning, feeling of knowing, and other

memory self-monitoring-related phenomena (Pannu and Kaszniak, 2005). Prospective memory is the ability to remember to do something in the future (either time or event based), and involves not only declarative/episodic memory but also frontal EFs such as self-monitoring (Fish et al., 2010). While the above terms may be derived from different models of memory, they are complimentary and can be used together. In clinical practice, measurement of memory weighs heavily on verbal episodic memory tasks with visual episodic memory also assessed, but often to a lesser degree. Semantic memory can be assessed, but it is often done as part of the language examination (e.g., category fluency). In geriatric neuropsychology the most common tests of memory include learning lists of words (Rey Auditory Verbal Learning Test, California Verbal Learning Test, Hopkins Verbal Learning Test-Revised) or short stories (WMS logical memory), although there are multiple variations on administration (e.g., repeating the entire word list versus selective reminding—repeating only the words not recalled on the last trial) and the nature of the stimulus (unrelated word lists, semantically related word lists, etc.). Most of these tests follow the initial learning stage with a free recall after a few minutes delay (shortterm delay) and after a longer delay of 20–40  minutes (long-term delay). Multiple variations in delayed recall conditions are also present including cueing trials, recognition trials and/or forced choice trials (e.g., choose between the target word and one distractor word). In addition to individual instruments, most comprehensive memory batteries will contain these elements (Repeatable Battery for the Assessment of Neuropsychological Status; Wechsler Memory Scale; Wide Range Assessment of Memory and Learning, etc.).

Executive abilities/function The frontal lobes comprise about 30% of the cortical surface, and EAs/EFs are an important component of frontal lobe functioning. Many structures (i.e., temporal lobe, basal ganglia, cerebellum, etc.) have reciprocal projections to the frontal lobes, so damage or disconnection to or from these areas may result in executive dysfunction (Ravizza and Ciranni, 2002). There is no uniformity in the way EFs  are defined, conceptualized, or measured; however, EAs are broadly related to the higher-order functions that co-ordinate and manage other cognitive processes and allow individuals to engage in goal-oriented behavior. EF is measured by behavioral outflow, but involves the steps from ideation to behavioral execution. EF cannot be simply measured by asking patients what they would do in a certain circumstance, since ideation may be disconnected from the actual behavior. Patients may be able to verbalize what they should do, but they are unable to carry it

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out. Efficient EAs allow interaction with the environment by developing and implementing effective strategies while inhibiting impulsive, ineffective strategies. Behavior must be analyzed and modified according to internal and external feedback. There are discrete components to EF and as with other models of cognitive functioning there are multiple theoretical models of EF (Norman and Shallice, 2000; Miller and Cohen, 2001). Although separate from other cognitive domains, EAs are both independent and interdependent from other domains. Aspects of EF are included in Table 4.3. Neuropsychologists use different measures and techniques in attempting to isolate these features; however, task demands make this difficult or impossible. Most cognitive measures are multifactorial and require several aspects of EF in addition to other domains. Behavioral disturbance can be manifested in components of inhibition, problems stopping a behavior, difficulty in making mental or behavioral shifts, concrete thinking, and deficits in self-awareness assessment. Initiation involves spontaneously starting ideation and behavior. When there is severe impairment in ideation, patients fail to start thinking or acting. Family members describe that they have stopped doing activities that they once enjoyed (i.e., hobbies, reading, etc.), and they may sit for extended periods of time without doing anything. Within the clinical setting, they lack spontaneous speech and may appear lethargic and apathetic. Fluency is a common metric for assessing initiation within the clinic, but a poor score may be related to other factors (i.e., retrieval, aphasia, semantic loss, etc.). As it relates to initiation, verbal or design fluency may be diminished because of the lack of spontaneous creativity, and patients have slow, minimal output. Once a behavior is started, EAs then must stop the ongoing behavior. The established response tendency must be inhibited and unwanted responses resisted. Problems in suppressing activity can result from impulsivity, disinhibition, or over-reactivity. A simple clinical technique for assessing behavioral disinhibition is a go/no go paradigm. In screening, a patient can be told to tap his/her leg once when the examiner touches their leg twice and vice versa. The task requires the suppression of copying the examiner’s behavior as well as maintaining the alternate pattern. Several neuropsychological tests may pull for inhibition, including proximity errors on Trail Making B and commission errors on computerized continuous performance tests. Table 4.3 Functions subsumed under executive functioning (EF) Organization

Abstract thinking

Inhibition

Planning

Cognitive flexibility

Selecting relevant stimuli

Problem solving

Initiation

Strategizing

Managing time and space

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Individuals with executive dysfunction may also have a deficit in mental or behavioral shifting. Inflexibility, cognitive rigidity, being “stuck” in a response set, and perseveration are hallmarks. Asking patients to do a task and then having them shift their thinking can elicit evidence of inflexibility. Most neuropsychological tests of EF (i.e., Halstead Category Test, Wisconsin Card Sorting, etc.) do not tell patients what the rules are, and do not tell them when the rules have changed. Thus, the patient is not only required to solve the problem to find the correct response set, but they must then alter their thinking and behavior in response to negative feedback. When one examines the quality of error responses, a pattern of concrete thinking may be apparent. Concrete thinking may appear as literal explanations and interpretations. As opposed to “being stuck” in a response set, patient responses lack a deep understanding of concepts, and stimuli are taken at their obvious face value. Common clinical assessment involves asking the patient similarities, such as “In what way are an apple and orange alike”. Concrete answers involve obvious physical characteristics, like the fact that they are round or “can be different colors”. At times, patients will respond with how they are different (i.e., “one is red and one is orange”) or they may personalize the response (i.e., “I like apples, but I don’t like oranges”). A more integrated response will be the identification that they are edible and an abstract understanding will be that they are both fruits. Longer forms of the similarities task are found in neuropsychological testing, in addition to other tests such as the 20-questions and proverbs subtests of the Delis–Kaplan Executive Functions System (Delis et al., 2001). Self-monitoring and self-assessment are critical components for effectively appraising oneself and using the information to effectively alter behavior. In executive dysfunction, patients may be unable to perceive their performance errors, their impact on others, and lack social awareness. They make errors, but are unable to accurately recognize their poor performance. There is no formal test to measure this ability, but asking patients to evaluate their clearly poor performances is one way to assess this. For example in Figure 4.2, the patient was asked to draw a clock. After doing so, the patient spontaneously offered, “I’m sure you can’t tell what it is, but it looks right to me.” In this case, the patient appreciated that something seemed wrong, but perceived the drawing as correct. This lack of awareness of his impairment is anosognosia, and can create problems when a patient wants to continue activities in which they can no longer do well (driving, cooking, finances, etc.). Because patients may lack self-awareness or may inaccurately assess personality changes, collateral interviews may prove useful. Family members often raise this issue as the most disconcerting change in dementia and frontal cerebrovascular accidents. Social interactions may be

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Figure 4.2 Clock-drawing test.

marked with disinhibited, inappropriate responses, which are changes from the patient’s premorbid status, but the patient is unable to appreciate this. Also, sexual talk and sexual behaviors (including public masturbation) may occur. Rating scales, such as the Frontal Systems Behavior Scale (FrSBE; Grace and Mallow, 2001) can help to detect and group these behaviors, and provide some measure of the patient’s insight into them. The patient completes an FrSBE self-rating that can be compared to the ratings from an informant who is in regular contact with the patient. There is considerable variability to the behavioral manifestations of EAs. Not all facets of EF can be measured through psychometric testing, and there is considerable variability among patients. Different conceptualizations may have overlapping neuropathologic correlates and interconnections. Common frontal subcortical pathways mediate executive activities, speed of information processing and working memory where executive control is needed; however, these “frontal systems” may have subsystems. Miller and Cummings (1999) described three circuits within the frontal lobe—orbitofrontal, dorsolateral, and anterior cingulate. Persons with orbitofrontal injuries may not demonstrate impairment on neuropsychological testing, but they may display neurobehavioral manifestations of irritability, impulsivity, disinhibition, and they may show an inappropriate response to social cues, lack of empathy, and over-familiarity. Dorsolateral lesions have been associated with poor organizational strategies, poor memory search strategies, stimulus boundedness, and impaired set shifting and maintenance. Anterior cingulate lesions may manifest in apathy, poor response inhibition,

and poverty of speech (Miller and Cummings, 1999). These theoretical distinctions are infrequently seen in pure forms because injuries and degenerative processes involve multiple frontal areas, and damage to other connected areas may produce behavioral changes. Executive dysfunction can interfere with the functioning of other cognitive (particularly memory) domains. For example poor organization may be reflected in relatively poor learning on a memory test that benefits from the ability to organize a word list into semantic categories (e.g., California Verbal Learning Test-II and Hopkins Verbal Learning Test) (Delis et al., 2000; Brandt and Benedict, 2001). Thus, poor semantic organization (an EF) may be related to a poor learning score on the CVLT-II. In contrast, the same patient’s memory score may not be impaired on a test that does not benefit from this organizational strategy (i.e., Rey Auditory Verbal Learning Test, etc.) (Rey, 1964). Similarly, a patient’s visual drawing memory score for simple figures (i.e., Wechsler Memory Scale-III) (Wechsler, 1997b) may not be impaired, but their figure memory score may be impaired on a task with high organizational demand (i.e., Rey–Osterrieth Complex Figure) (Rey, 1941). Functionally, expression of executive dysfunction may be dependent on environmental demands. Older individuals who are still working may demonstrate changes in organizing time, space, and multitasking beyond what would be expected with normal aging. Colleagues, friends, and family may notice these changes before the person is aware of them. For those no longer working, subtle changes may only be noticed by those living with the patient, but subtle changes may affect self-care and safety awareness to the point of the person needing a higher level of care. Executive dysfunction may predict loss of autonomy independent of—or more than—memory loss (Royall et al., 2005; Tomaszewski et al., 2009).

Visuospatial abilities As with other domains, visual processing and construction dysfunction can occur due to complex and multifactorial reasons, including perceptual, spatial, or processing errors. For example, impairment in clock drawings may be secondary to conception, perception, spatial analysis, or construction. Efficient visuoconstruction relies on cerebral integration within the temporal–parietal–occipital association areas. Thus, lesions or dysfunction in any of these areas or within their interconnections by-produce visual misperceptions, such as agnosias (color, familiar or unfamiliar faces, and objects). In these instances, a patient may incorrectly name an item they see. It is not uncommon for misperceptions to be misconstrued as naming deficits. Visuoperception involves the detection, visual analysis, and synthesis. Ware (2004) offers a three-step model of

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visual perception based on detection, pattern analysis, and integration of attention and memory. In the first stage objects undergo detection for color, texture, shape, and spatial detection. In the second stage regional and simple pattern analysis occurs, and in the third stage objects are held in working memory by attention (Ware, 2004). Mishkin and Ungerleider 1982 theorized two pathways of visual analysis—the ventral stream and the dorsal stream. After visual information leaves the occipital lobe the ventral stream projects to the temporal lobe and is involved with object identification (the “what pathway”). Symbolic representation takes place within the ventral system, drawing from limbic and medial temporal memory areas. The dorsal stream projects from the occipital lobe to the parietal lobe where this “where pathway” processes spatial location. Spatial awareness from the dorsal stream then guides meaningful actions (Mishkin and Ungerleider, 1982). The ventral and dorsal streams are theorized to be interconnected, thus integrating visual information in meaning and space; however, this theory is controversial because of the complexity of the visuoperception. The complexity of this system necessarily means that it does not localize or lateralize. Both hemispheres are involved with aspects of visual synthesis. Visual images are processed as wholes and as parts. Delis et al., 1992 and others describe that in analyzing complex visual stimuli, the nondominant hemisphere analyzes configural (or global) features. In contrast, the dominant hemisphere processes visual stimulus details (or local features) (Delis et al., 1992). Differences in global–local errors were used to identify asymmetric profiles in AD and other cerebral changes, and this emphasizes the importance of qualitative visual analysis. Spatial cognition can be measured by many techniques (i.e., discrimination, recognition, drawing, 2D and 3D construction). Clock drawing and the MMSE figure are common clinical office drawing tasks. Errors on these relatively simple tasks can reveal qualitative subtleties, and these qualitative features may illuminate underlying conceptualization impairment or spatial inattention. For example, in Figure 4.3, the patient was unable to conceptualize the clock. This type of error is qualitatively different from errors in which all the numbers are present but misplaced (i.e., planning error). Also, perseveration is evident with three numbers being repeated, and the patient failed to appreciate how poor this drawing was. Expanded neuropsychological visuospatial testing may include noncomplex drawings (i.e., Benton Visual Recognition Test, WMS-III Visual Reproduction Copy) (Benton et al., 1983; Wechsler, 1997b) and complex drawings (i.e.,  Rey–Osterrieth Complex Figure, Taylor Complex Figure) (Rey, 1941; Taylor, 1969). Block construction (i.e., WAIS-III Block Construction) and other measures are commonly used for spatial cognition; however, the timed nature of these tasks may affect the score (Wechsler, 1997a).

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Figure 4.3 Clock-drawing test.

In Figure 4.4, the patient was not only unable to correctly draw the house and cube in three dimensions, they demonstrated left hemispatial inattention, although they had full visual fields. The left side of the house was missing, and the patient was unable to effectively scan to the left hemi space. This case highlights the difference between a field cut (i.e., homonymous hemianopsia) and hemi-inattention (also called visual inattention, visual neglect or visual extinction); however, the presence of the former increases the possibility of coexisting hemiinattention (De Renzi, 1978; Diller and Weinberg, 1977). Greater hemi-inattention deficits are generally more common in acute stages of traumatic event (i.e., CVA) than degenerative disorders.

Figure 4.4 House-drawing test.

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Clock, house, and cube examples of 2D and 3D constructional drawing are often used, but because they involve motor skills, clinicians may not be able to rule out a perceptual or motor deficit. Perception must be intact for accurate drawings. Neuropsychologists may use visual discrimination (Visual Form Discrimination Test) and line orientation (Judgment of Line Orientation) to assess nonmotor perception (Benton et al., 1983). Facial recognition is a complex process, although it is not typically assessed as part of the neurologic examination. Healthy adults can discriminate very subtle aspects of facial features and expressions. Prosopagnosia is the inability to recognize familiar faces, but impaired facial recognition can also occur in discriminating unfamiliar faces. Neuropsychological assessment can measure facial recognition through a Famous Faces Test, facial discrimination with the Benton Facial Recognition Test (Benton et al., 1983), and facial recognition with the Warrington Recognition Memory Test (Benton et al., 1983). Higher-level visual integration can be measured with the Hooper Visual Organization Test (Hooper, 1958), where pictures have been cut into pieces and must be mentally rotated and spatially integrated before being recognized.

Neuropsychological profiles of disorders in geriatric neuropsychology The basis of using cognitive profiles to diagnose disease, predict behaviors and guide treatment is the principle that the cognitive deficits accurately reflect a characteristic dysfunction or degeneration of the underlying neural network. For example, if the disease primarily affects the hippocampal system then the cognitive profile should reflect a primary episodic memory deficit. If the dorsolateral prefrontal regions are affected then an executive dysfunction should predominate (Cummings, 1993). A caveat to this concept is that if a morphologically defined disease such as AD (presence of neuritic plaques and neurofibrillary tangles) damages the brain in a distribution other than what is prototypical for that disease (e.g., as in a frontal variant of AD, with significant early neurodegeneration in the frontal lobes), then the cognitive profile can be expected to reflect the neural degeneration pattern rather than the disease etiology that underlies it. The following sections provide a brief neuropsychological overview of some common disorders that can affect cognitive function in the elderly. The reader is referred to individual chapters in this text for more details on each disease.

Mild cognitive impairment MCI is an attempt to detect dementia at an early stage, prior to the impairments becoming clinically significant. The basis for the diagnosis is performance in one or more cognitive domains that are lower than expected for an

individual, but do not yet indicate a significant decline in the ability to function. In the most widely utilized diagnostic guidelines (Petersen and Smith, 1999), four criteria are set out for the diagnosis of MCI. Two of these are based on interview (subjective memory complaint, no significant decline in daily function), one is based on cognitive assessment (objective impairment in one or more cognitive domains) and one synthesizes these elements (does not meet criteria for dementia). These elements have been retained and further refined in a recent set of diagnostic criteria from a joint effort of the National Institute on Aging and the Alzheimer’s Association (Albert et al., 2011). Sources of variability in standardization of this diagnosis include determining if a “significant decline in daily function” exists (e.g., in the case of a retired senior with multiple medical issues living in an assisted living environment) and in the criteria for detecting an objective impairment in cognition. Because of this, diagnosis of MCI has ranged from 10% to 74% depending on the criteria used (Portet et al., 2006; Jak et al., 2009). While the minimum level of objective cognitive impairment varies in different studies, cut points of 1.0 or 1.5 standard deviations below the mean are the most commonly used (Albert et al., 2011). MCI is not a unitary construct and various “MCI subtypes” exist. The classic MCI profile is characterized by impaired performance on standardized episodic memory tasks (word lists, paragraph recall, selective reminding test) and is denoted as amnesic MCI (aMCI). This profile is believed to lead to the most common form of dementia in the elderly, AD. MCI profiles that indicate nonmemory systems primarily affected are designated as non-aMCI and it has been suggested that the cognitive areas affected have some predictive value for the type of dementia that will develop (Petersen and Morris, 2005; Petersen, 2003). For example, if the frontal executive domain is the most severely impaired, then an FTD might be predicted. Often, more than one area may show impairment and when multiple cognitive areas are impaired, this is termed multidomain MCI. Multidomain MCI is sometimes further broken down into a multidomain aMCI (characterized by impairments in memory and at least one other domain) and multidomain non-aMCI (characterized by relatively intact memory performance, but impaired performance in two nonmemory domains) (Petersen, 2003). Since this diagnosis requires detection of deficits at an early stage, tests that are prone to ceiling effects (e.g., MMSE, Mini-Cog) are often insufficient. Since the predominant form of MCI is the amnesic type (single or multidomain), verbal delayed free recall tasks with greater sensitivity at the higher levels of function (e.g., Rey Auditory Learning Test, California Verbal Learning Test, Selective Reminding Test, WMS-R logical memory) tend to be most sensitive to the early deficits (Jak et al., 2009; Albert et al., 2011).

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While there is some probabilistic validity of using MCI as a predictor of incipient dementia, it is not entirely accurate. Studies have shown wide ranges of sensitivity (46–88%) and specificity (37–90%) in predicting conversion to AD (Visser et al., 2005; Rasquin et al., 2005). Identification of the underlying etiology by MCI subtype has also been shown to be questionable (Jicha et al., 2006). Longitudinal assessment showing further decline in cognitive function may add to the diagnostic certainty; advanced imaging techniques and biomarkers may further support the diagnosis, but are not yet suggested for clinical use (Albert et al., 2011).

Alzheimer’s disease AD is the most prevalent cause of dementia in the elderly. It frequently is the primary etiology of the cognitive decline, but also has a high co-occurrence with pathology seen in other diseases such as LBD and vascular ischemia. Its clinical diagnosis has traditionally been designated as either “possible AD” or “probable AD”, with a diagnosis of “definite” AD reserved for autopsy confirmation of the presence of the defining neuritic plaques and neurofibrillary tangles (McKhann et al., 1984; Storey et al., 2002; Hort et al., 2010; McKhann et al., 2011). Revision of the original NINCDS–ADRDA criteria (McKhann et al., 1984) by a joint work group of the National Institute on Aging and the Alzheimer’s Association kept the basic structure of the probable and possible definitions for their clinical criteria, while adding an additional division of research criteria that incorporates imaging and other biomarkers (McKhann et al., 2011). Cognitive testing with evidence of impairment in two or more areas is required, with neuropsychological testing recommended when bedside mental status testing is not sufficient for a “confident” diagnosis. AD has been called the prototypical “cortical” dementia because of the typical clinical presentation of impaired episodic memory as the first clinical sign. The overall cognitive decline is characterized by gradual onset and a progressive course. Neuropsychological tests sensitive to the typical AD presentation include learning and recall of word lists or paragraph-length stories, with impairments noted in learning, free recall, cued recall and recognition of the material. In the early stages free recall may be the most notably impaired, as recognition tasks often have low sensitivity due to ceiling effects. As the pathology spreads through the frontal lobes, executive dysfunction is typically noted on such tests as category fluency and Trails B. In the mild-to-moderate stages, performance on category fluency (e.g., animals) is typically seen to be more impaired than letter fluency, reflecting the early involvement of the frontal systems and the later spread to the language areas. Impairment in confrontation naming can be clinically observed in the moderate stages, but can be detected in earlier stages by instruments such as the Boston Naming Test.

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Frontotemporal dementia FTD encompasses several conditions that are characterized by degeneration of the frontal and/or temporal lobes (Pick’s disease, semantic dementia, primary progressive aphasia, dementia lacking distinctive histopathology). The most common presentation of FTD begins with personality and behavioral changes preceding or concurrent with the cognitive decline. The nature of the personality change varies, but may present as apathy (medial frontal/ anterior cingulated syndrome), disinhibition and inappropriate social interactions (orbitofrontal syndrome), loss of insight, or perseverative behaviors. The behavioral changes can sometimes be striking, and they represent an important factor in the diagnosis of the disease and as a target of treatment (Cummings, 1993; Kertesz, 2006). As would be expected, the profile of cognitive deficits reflects the distribution of the neuronal damage. FTD may present with executive dysfunction (dorsolateral prefrontal syndrome), a progressive decrease in speech output (primary progressive aphasia), or an impairment in understanding word meaning (semantic dementia) that is relatively more severe than the deficits in episodic memory—a profile opposite to that seen in AD (Cummings and Trimble, 2002). At the earliest stages of the dysexecutive syndrome a formal assessment of cognitive flexibility, multitasking, set switching, and higher-order conceptualization can detect deficits in the presence of only minor memory impairment. Performance on verbal fluency tasks may also show a pattern opposite to that seen in AD, with letter fluency being relatively more impaired than category fluency in FTD. The meaning of visuospatial deficits in FTD is somewhat ambiguous, as some tasks that involve complex stimuli (e.g., Rey–Osterrieth Complex Figure task) can show proportionate deficits, while others with a lower degree of complexity appear relatively spared (e.g., Block Design) (Salmon and Bondi, 2009). At the later stages of the disease, most cognitive functions can become affected and differentiation from other dementia types becomes dependent on an accurate history of the course of the disease. Primary progressive aphasia is a gradually progressing nonfluent expressive aphasia that initially presents with minimal impairment in memory or other cognitive functions, although most patients will progress to dementia with time (Mesulam, 1982; Rogalski and Mesulam, 2009). Clinically it is primarily characterized by a nonfluent expressive aphasia with phonemic paraphasias, anomia, and deficits in repetition (Neary et al., 1998). Comprehension and other cognitive areas are relatively intact in the initial stages, although the expressive impairments can make testing of verbal episodic memory difficult. Semantic dementia is a relatively rare condition that initially presents as a progressive fluent expressive aphasia. In this condition the patient begins to lose the meaning of words and concepts despite intact grammar and

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syntax (Snowden et al., 1996). Patients demonstrate fluent but empty spontaneous speech, semantic paraphasias, impaired naming, and comprehension due to loss of word meaning, while reading, writing, and repetition are typically intact (Neary et al., 1998).

Parkinson’s disease dementia Parkinson’s disease is initially a predominately motor disorder characterized by rigidity, bradykinesia, and tremor. The morphologic characteristics are defined by neuronal death and presence of Lewy bodies in brainstem nuclei (particularly the substantia nigra), and loss of dopaminergic inputs into the neostriatum and neocortex (Levy and Cummings, 2000). As the disease progresses, cognitive impairment becomes more prevalent, and estimates of dementia range from 25% to 40% prior to death (Hughes et al., 1993). Autopsy studies show that comorbid AD pathology occurs not infrequently, but the development of dementia is more strongly correlated to the presence of Lewy bodies in the cortex than AD pathology (Hurtig et al., 2000). Cognitive characteristics of PDD can include alterations/fluctuations in arousal and complex attention, impairment in EFs and memory retrieval deficits. Visuospatial deficits are also reported (Emre et al., 2007) but there is some controversy in the literature as to whether these are primary deficits or a consequence of other deficits (e.g., executive dysfunction) (Grossman et al., 1993). The pattern has been classified as a typical “subcortical” dementia because of the early prevalence of the attentional, visuospatial, and executive deficits combined with the type of memory impairment observed (Albert et al., 1974; Bondi et al., 1996). This memory deficit differs from the characteristic “cortical” amnesia (e.g., as in AD) in that the performance on recognition memory tasks appears relatively better than free recall, suggesting a problem with the retrieval mechanism rather than storage (as in AD). The executive dysfunction can be seen in tasks that involve set shifting (e.g., Wisconsin card sort, Trails B) and concept formation (Category test) (Duke and Kaszniak, 2000). Attempts to diagnose PDD at a MCItype stage have indicated significant early heterogeneity (Caviness et al., 2007; Adler, 2009). Notable AD pathology can occur in PDD and may result in a “mixed” cortical/ subcortical profile (Levy and Cummings, 2000).

Dementia with Lewy bodies The morphologic basis of DLB overlaps with that of Parkinson’s disease and the diseases can be difficult to distinguish at autopsy. Clinically, the disorders are distinguished by the relative appearance of significant motor signs sufficient for the diagnosis of Parkinson’s disease (PD) at least 1 year before the dementia (PDD), or the cognitive impairment is observed in the early stages of the extrapyramidal motor symptom onset (DLB). In DLB

eosinophilic intracytoplasmic neuronal inclusion bodies are present in both cortical and subcortical areas. Like PD, the Lewy bodies are prevalent in substantia nigra and locus coeruleus; however, the distribution tends to be more widespread across the cortical and limbic areas (McKeith, 2000). Clinical presentation includes mild parkinsonism (rigidity, bradykinesia, and masked facies), recurrent and well-formed hallucinations, and fluctuating cognition (McKeith et al., 2005; Weisman and McKeith, 2007). However, these clinical signs are not present in all patients with autopsy-confirmed DLB (Tiraboschi et al., 2006), and differential diagnosis with other conditions continues to be a challenge. Comorbid AD pathology is common, and can make the cognitive profiles difficult to be distinguished in individual patients (Hohl et al., 2000). However, at the mild stage, DLB may manifest greater attentional, visuospatial, constructional, and executive deficits relative to the memory and naming impairments than is typical for AD, and the pattern of impairments between category and letter fluency tend to be the reverse of that seen in AD (e.g., in DLB, letter fluency is as impaired or more than category fluency) (Metzler-Baddeley, 2007). Profiles on the subtests of the Mattis Dementia Rating Scale (Connor et al., 1998) and on the California Verbal Learning Test (Hamilton et  al., 2004) have been moderately successful in distinguishing the two diseases in autopsy-verified cases. Distinguishing LBD from other neurodegenerative disorders such as PDD, PSP, and corticobasal degeneration (CBD) is often based on the characteristic motor findings and clinical progression of each disease.

Progressive supranuclear palsy PSP is a tauopathy that is clinically diagnosed by the presence of a supranuclear gaze palsy, axial rigidity, pseudobulbar palsy, and falls. Tremor is not usually present. Autopsy results show neurofibrillary tangles, granulovacuolar degeneration, and cell loss in the midbrain, globus pallidus, and thalamus. Dementia is characterized by a subcortical profile including deficits in attention, EF, and visuospatial abilities early in the course of cognitive decline (Albert et al., 1974). While neuropsychological testing is useful for early detection of the cognitive deficit, differential diagnosis from other parkinsonian-like dementias (corticobasal ganglionic degeneration, multiple system atrophy, etc.) is usually based on the neurologic signs.

Corticobasal ganglionic degeneration Corticobasal ganglionic degeneration (CBGD) is a relatively rare disease with notable asymmetrical degeneration of the frontal–parietal cortex and substantia nigra degeneration. Clinically, it often presents with an asymmetrical, focal motor apraxia, and asymmetrical dystonia, rigidity, bradykinesia, and tremor. In a subset of patients,

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the cognitive changes may be evident prior to the motor signs (Murray et al., 2007). As mentioned for PSP, it presents with a subcortical profile and the cognitive profile is difficult to distinguish from other Parkinson-plus syndromes (Wadia and Lang, 2007).

Vascular dementia VaD is a heterogeneous dementia that can result from a single large stroke, multiple smaller infarctions (multiinfarct dementia), or small vessel diseases that cause ischemic damage to multiple areas of the brain. As such the clinical presentation and neuropsychological profile varies widely. A detailed history (step-wise pattern of deterioration), neurologic examination, and imaging combined with the psychometric testing can both solidify the diagnosis and provide valuable information regarding the nature of the cognitive deficits for treatment planning. Some forms of VaD may not show the step-wise decline and the results of imaging may be unclear (e.g., diffuse white matter pathology). In these cases a “subcortical” pattern of deficits on formal testing may help differentiate the etiology of the dementia. As such, impairments of EF that equal or exceed those of memory function are more indicative of a subcortical process than a cortical dementia (e.g., AD) (Reed et al., 2007). However, a broadbased neuropsychological battery that encompasses all cognitive domains (attention, language, visuospatial, memory, EF) is usually necessary to identify and characterize the impairments.

Delirium Delirium is an acute confusional state characterized by fast onset, deficits in attention, orientation, and fluctuating levels of arousal. It may present as a sudden change in a cognitively intact adult, or as a sudden decline in a cognitively impaired patient. It is important to diagnose this condition early and run a full medical work-up as a serious and life-threatening medical condition may underlay the delirium. Brief cognitive assessment is sufficient to detect most cases. Neuropsychological assessment may be of use in differentiating mild cases (medication interactions, low-grade infections, etc.) from the normal progression in a patient who already has dementia.

Depression There is a complex relationship between depression and dementia as each can be a risk factor for the other and they often co-occur (Wright and Persad, 2007). In the elderly, depressive symptoms often include memory complaints and the cognitive inefficiencies of depression can be difficult to distinguish from early dementia. However, quantitative and qualitative assessment can aid in the diagnosis and treatment of each as individual or comorbid diseases (Kaszniak and DiTraglia-Christenson, 1994; Potter and Steffens, 2007).

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Preclinical diagnosis of dementia Despite the advances in neurosciences of the last few decades, no treatment or intervention has been shown to halt or reverse the course of most progressive dementias. It has been suggested that if treatments are instituted before extensive damage has been done to the neural network, then disease progression is more likely to be slowed (disease modification) or even temporarily halted (DeKosky, 2003). In an elderly population, even a delay in onset of 5 years has been suggested to reduce the occurrence of the disease by half. The concept of diagnosing a disease before the clinical symptoms become apparent is not new and is used in many branches of medicine (e.g., cardiovascular, hepatic, etc.). In most of these conditions, a laboratory test indicates an abnormal value either in the presence of only minimal (or no) clinical complaints. As discussed in a previous section on MCI, a cluster of symptoms (MCI) have been suggested to be predictive of progression to a clinical dementia. However, most definitions of MCI require some clinical signs/impairments that, while not reaching the full criteria for dementia, may only be apparent after there has been significant damage to the underlying neural network. In the diagnosis of dementia, research into a preclinical diagnosis has several significant challenges including lack of a definition of “preclinical”, inability to sample brain tissue while the patient is alive, questionable specificity and sensitivity of noninvasive biomarkers in the general population, and poor prediction of progression to MCI or dementia in patients who may be positive for the biomarker (Backman et al., 2005). The accepted definitions of preclinical dementia vary widely and may overlap with those of MCI or similar classifications (e.g., cognitive impairment not demented) or may be seen as the stages preceding any abnormal cognitive measures (Backman, 2008; Guarch et al., 2008). This range of definitions has led to significant confusion in the literature and in estimates of prediction of progression to dementia. Recently a definition of preclinical dementia for AD has been published offered by a joint NIA–Alzheimer’s Association workgroup for Preclinical dementia (Sperling et al., 2011). As emphasized several times in their publication, this definition is for research purposes only and should not be used in clinical practice. In their conceptualization of preclinical dementia there are no notable declines in the patient’s ability to function and no evidence of significantly impaired cognitive function, thus it prestages MCI. The three-stage categorical model suggested by the workgroup reflects the current beliefs in the development of the pathology underlying AD. Briefly, the first stage reflects detection of amyloidosis in the brain (by CSF- or PET-amyloid imaging), in the second stage there is additional evidence of neuronal degeneration (by FDG-PET, volumetric MRI, etc.) and the third evolutionary stage

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includes the presence of the previously mentioned markers along with “subtle cognitive decline”. As the authors point out, this third stage approaches the border of the definition of MCI, the main differential being that the subtle cognitive decline here may only be evident as a change from the individual patient’s previous level of functioning and not be abnormally below the performance of an age and education-matched cohort. This general approach of identifying changes in the basic elements that define the disease (amyloid for AD, Lewy bodies for LBD, etc.) followed by the physical/physiologic consequences of those elements (disruption of neural transmission, neuronal cell death, etc.) and finally by subtle clinical signs (decline in function from previous abilities) appear a reasonable approach toward guiding the investigation into the “preclinical” evolution of various dementias. It should be emphasized that the preclinical diagnosis of any of the dementing disorders (AD, vascular, Lewy body, FTD, etc.) is a vital and important research area. However, until appropriate definitions can be agreed on, clarification of concepts provided (e.g., determining if a marker is a risk factor or an early stage of the disease) and predictive values assessed for the individual patient, it appears far too early to utilize the research results in clinical guidelines.

Conclusion Neuropsychological assessment utilizing well-established techniques can be a useful addition to the physician’s resources in geriatric neurology. Assistance in early diagnosis, differential diagnosis, assessment of the patient’s deficits and remaining strengths as well as information to help guide the treatment may be obtained from a proper assessment. While there are many theories and models in cognitive psychology, several that address five major domains of cognition (attention, language, memory, EF, visuospatial skills) have shown to be useful in modeling the functions affected in dementia and brain dysfunction. As technology advances and biomarkers (e.g., biochemical and imaging) of the central nervous system disorders become a more important part of the clinician’s resources, careful direct assessment of cognitive functions will continue to offer complementary information for the best treatment of the patient.

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Chapter 5 Cognitive Reserve and the Aging Brain Adrienne M. Tucker1 and Yaakov Stern2 1

Cognitive Science Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands Cognitive Neuroscience Division, Department of Neurology, Columbia University Medical Center, New York, NY, USA (Financial support provided by National Institute of Aging (NIA)—grants T32 AG00261 and R01 AG026158) 2

Summary • Cognitive reserve, which is often estimated with education and IQ, is the ability to make flexible and efficient use of available brain reserve during tasks. It has been found to be protective against the cognitive outcomes of brain injury. • Cognitive reserve is reflected in neural reserve and neural compensation. • Neural reserve allows healthy individuals more efficient processing (processing which requires less neural activity) as well as higher processing capacity (the ability to recruit more neural activity when task demands are high). • Neural compensation is the activation of alternate brain regions to compensate for deficiencies in individuals with brain impairments. • Young adults with high cognitive reserve display greater neural efficiency. This may be a result of better or more efficient use of strategies. • Neural markers for cognitive reserve may differ between younger and older adults. This may be an indication of compensatory reorganization during aging. • Activation patterns related to cognitive reserve are reversed between healthy older adults and individuals with Alzheimer’s. • Individuals with high cognitive reserve may present with pathology without functional deficits. Thus, accounting for cognitive reserve in addition to the underlying pathology may aid clinical judgment.

Introduction The theory of reserve against brain insult arose to explain individuals who continue to function clinically despite brain pathology (Gertz et al., 1996; Davis et al., 1999; Gold et al., 2000; Jellinger, 2000; Riley et al., 2002). In an early example, the brains of 10 cognitively normal elderly women were found to have Alzheimer’s plaques at autopsy (Katzman et al., 1988). These women’s brains were heavier and contained more neurons, which were thought to provide “reserve,” to help the women function despite their pathology. Indeed, later studies found that 25–67% of subjects characterized as cognitively normal throughout longitudinal assessments meet pathologic criteria for dementia at autopsy (Crystal et al., 1988; Morris et al., 1996; Price and Morris, 1999; Ince, 2001; Mortimer et al., 2003). Two types of reserve contribute to maintaining functioning after brain insult: brain reserve and cognitive reserve. Standard proxies for brain reserve include brain size (Katzman, 1993) and/or neuronal count (Mortimer et al., 1981). For any level of pathology, more brain reserve is associated with better functional outcomes (Satz, 1993; Graves et al., 1996; Jenkins et al., 2000). The brain reserve model posits a threshold at which functional deficits

manifest and suggests that individuals with more brain reserve will accumulate more pathology before reaching that threshold. For example, in the case of Alzheimer’s, the disease will advance longer and additional pathology will be acquired before deficits are seen in individuals who start with more neurons and/or a bigger brain. The initial brain reserve model was entirely quantitative: a given brain injury affects each individual in the same manner, and brain injuries throughout the lifespan sum together. Evidence indicates that some brain deficits do sum across the lifespan. For example, the risk for Alzheimer’s rises with each psychiatric episode (Kessing and Andersen, 2004) and/ or concussion (Guskiewicz et al., 2005). A limitation of this model, however, is that brain reserve is thought to constitute the only meaningful difference between individuals, with the idea that accumulated damage either does or does not reach the threshold necessary for functional deficits. Although the brain reserve model explains some observations, the generalization that more is better may be too simple. As one example, autism is associated with a brain that is bigger than normal, perhaps reflecting a failure of pruning mechanisms that eliminate unused or faulty neural connections, or a larger glia/neuron ratio (Redcay and Courchesne, 2005). Furthermore it has been

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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found that in healthy children, young adults, and elderly samples, more gray matter is associated with worse memory performance (Salat et al., 2002; Van Petten, 2004). This strongly suggests that those with the biggest brains are not always at the biggest advantage. Another limitation of brain reserve theory is that it does not explain the counterintuitive finding that, once Alzheimer’s is diagnosed, higher IQ and more education are associated with faster deterioration and more rapid death (Stern et al., 1994; Stern et al., 1995; Teri et al., 1995; Stern et al., 1999; Scarmeas et al., 2006; Hall et al., 2007; Helzner et al., 2007). By contrast, cognitive reserve refers to the ability to make flexible and efficient use of available brain reserve when performing tasks (Stern, 2002). Cognitive reserve has been most often estimated using education (Stern et al., 1992) and IQ (Alexander et al., 1997), although other variables have also been used, including literacy (Manly et al., 2003; Manly et al., 2005), occupational complexity (Stern et al., 1994; Richards and Sacker, 2003; Staff et al., 2004), participation in leisure activities (Scarmeas et al., 2001; Wilson et al., 2002; Scarmeas et al., 2003a), and the cohesion of social networks (Fratiglioni et al., 2000; Bennett et al., 2006). Recently, personality variables have also been incorporated (Wilson et al., 2006; Wilson et al., 2007). Those with higher cognitive reserve tend to have better clinical outcomes for any level of pathology and brain reserve. As one example, Mortimer et al. (2003) found that those with smaller brain reserve, operationalized with head circumference, were at increased risk of Alzheimer’s. Yet this relationship was moderated by cognitive reserve such that those with smaller heads and more education were not at increased risk. This suggests that cognitive reserve allowed individuals to compensate for any pathology present in their smaller brains by making more optimal use of that brain reserve present. It further suggests that the threshold of brain reserve necessary to maintain functioning is not fixed, but instead varies among people such that those higher in cognitive reserve can maintain functioning at lower levels of brain reserve. Although cognitive reserve is discussed most often in the context of Alzheimer’s disease and normal aging, it has also been demonstrated to provide benefit in vascular injury (Dufouil et al., 2003; Elkins et al., 2006), Parkinson’s disease (Glatt et al., 1996), traumatic brain injury (Kesler et al., 2003), HIV (Farinpour et al., 2003), and multiple sclerosis (Sumowski et al., 2009). While it has been established in these diverse conditions that cognitive reserve is protective against brain injury for cognitive outcomes, it remains to be determined whether cognitive reserve is similarly protective for affective or psychiatric outcomes. One report found that higher cognitive reserve is not protective against the depressive symptoms that arise with the early stages of Alzheimer’s (Geerlings et al., 2000); however, other reports of healthy individuals have found

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that higher cognitive reserve does protect against psychiatric diseases such as depression (Barnett et al., 2006; Koenen et al., 2009). Many aspects of cognitive reserve are intercorrelated. For example, people with higher IQs obtain more education, which, in turn, increases IQ (Ceci, 1991). Yet, although they are intercorrelated, these aspects of cognitive reserve impart both independent and interactive effects that accrue over the lifespan. Richards and Sacker (2003) examined how cognitive reserve variables collected at different points in the lifespan affected cognitive function at midlife. The authors found that the earliest point, childhood IQ, had the strongest effect; a later point, educational attainment by early adulthood, less effect; and the latest point, occupation in middle age, the least strong effect. These results suggest that while early childhood factors are crucial for the buildup of cognitive reserve, cognitive reserve continues to be influenced by circumstances throughout the lifespan. It has been pointed out that many of the variables used to measure cognitive reserve, such as education, are conflated with socioeconomic status (SES). However, Karp et al. (2004) found that while less education and lower SES are independently associated with higher risk for Alzheimer’s disease, with both in the model simultaneously, only education is significant. Thus, the lower risk for Alzheimer’s in those more highly educated is not mediated by SES. Furthermore, Turrell et al. (2002) found that a relationship between more years of education and better cognitive outcomes in middle age was independent of both childhood and current SES. Thus, the benefits arising from cognitive reserve are not reducible to SES. Another potential limitation is that individuals with more education and higher IQ display superior performance on the tests used to measure cognitive decline and diagnose dementia; this has been called the ascertainment bias (Tuokko et al., 2003). In other words, although an individual high in cognitive reserve might slip from the previous high level of performance as a result of pathology or aging, this deterioration might go unnoticed in testing, because performance may still be average. Yet cognitive reserve still provides benefit even when dementia is diagnosed with measures of daily functioning instead of neuropsychological tests (Liao et al., 2005). Further, cognitive reserve has been demonstrated even in longitudinal studies with a clear baseline for each subject from which to assess performance (Scarmeas and Stern, 2004). Unlike brain reserve, cognitive reserve makes clear why those with higher IQ, more education, and/or more participation in leisure activities have poorer outcomes, in that they deteriorate more quickly and proceed to death soon after Alzheimer’s is diagnosed (Stern et al., 1994; Stern et al., 1995; Teri et al., 1995; Stern et al., 1999; Scarmeas et al., 2006; Hall et al., 2007; Helzner et al., 2007). The cognitive reserve model posits that those with higher

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reserve are able to compensate for pathology early on in the course of Alzheimer’s disease. Not until the pathology is more advanced and the patient is nearer to death are deficits observable in an individual with high cognitive reserve. This also implies that, for any given functional level, those higher in reserve will have more pathology (Bennett et al., 2003; Bennett et al., 2005; Serra et al., 2011). Although the initial conception of brain reserve was entirely quantitative, recent evidence suggests that this concept is more nuanced. First, brain and cognitive reserve share some overlap. For example, IQ and brain volume show a small but significant correlation (McDaniel, 2005). More importantly, stimulating environments–-a component of cognitive reserve measured in humans by variables such as engagement in leisure activities and occupational attainment–-foster the growth of new neurons (Churchill et al., 2002) and upregulate brain-derived neurotrophic factor (BDNF), which fosters neural plasticity. Furthermore, animal studies suggest that enriching environments may reduce Alzheimer’s pathology directly (Costa et al., 2007). In humans, it has been demonstrated that higher IQ reflects higher metabolic efficiency in the brain, which may slow the development of neuropathology (Yeo et al., 2011). Nonetheless, although they are in some ways interdependent, brain reserve and cognitive reserve make independent yet synergistic contributions to understanding individual differences in clinical resilience to brain pathology. In terms of cognitive performance, cognitive reserve may help by enabling more flexible strategy usage, a skill tapped by executive function tasks. In support of this, structural equation modeling performed in nondemented older adults aged 53–97 revealed that cognitive reserve–-as measured using years of education, Wide Range Achievement Test (WRAT) score or, for Spanish speakers the Word Accentuation Test (WAT) score, and picture vocabulary from the Peabody Picture Vocabulary Test, 3rd edition (PPVT-III)–-overlapped greatly with executive functioning measured using the letter-number (LN) sequencing subtest of the third version of the Wechsler Adult Inventory Scale (WAIS-III), the odd-manout task, and the difference score from the Color Trails Test (Siedlecki et al., 2009). In healthy adults aged 20–81, cognitive reserve measured as mentioned previously (education, WRAT, and picture vocabulary) was found to entirely overlap with executive functioning as measured using the same LN sequencing subtest and also the Wisconsin Card Sorting Task and the Matrix Reasoning Test. These results suggest that cognitive reserve could involve fluid executive abilities. In terms of neuroimaging, cognitive reserve is thought to be reflected in neural reserve and neural compensation. Neural reserve provides young, healthy individuals the ability to process tasks with more efficiency and greater capacity. For tasks of low-to-moderate difficulty,

those higher in cognitive reserve may display less neural activation, because they are able to process the task with greater neural efficiency. Opposingly, when tasks involve high levels of difficulty, those higher in cognitive reserve may display more neural activation, because they have a greater neural capacity to use when performing the task. Attending to difficulty is thus vital for understanding the meaning of differences in neural activation between groups. Neural reserve operates similarly to mitigate the effects of aging and brain pathology. Those higher in neural reserve are expected to perform better than or equivalently to those with lower neural reserve. Neural compensation is defined as the activation of alternate brain regions not often used by healthy young adults, to compensate for deficiencies in primary routes to effectual task performance. As defined, then, neural compensation occurs not in healthy young adults, but only in those with brain deficits. As for neural reserve, attending to difficulty is vital for accurately identifying neural compensation. For example, neural compensation may be suspected if a region is activated in older adults and not in younger adults. Yet in a more difficult version of the task, this region might also be activated by the young adults. Sometimes, it is even the case that young adults are using the brain area, but this is missed because of the statistical threshold chosen to define brain activation. Neural compensation can sometimes be accompanied by worse performance, although this is not always the case. In some instances, neural compensation could act like a cane, which enables individuals to walk but will not return the ability to sprint. As this metaphor suggests, neural compensation is sometimes associated with slower performance (Zarahn et al., 2007; Steffener et al., 2009). Some think that this happens because, with neural compensation, processing travels across more brain regions, each of which may take some additional amount of time. An alternate idea is that, with neural compensation, processing shifts from a primary network to a slower secondary network. It should be remembered that neural compensation has been found to correlate with better performance in terms of accurately remembering more words (Stern et al., 2000). To sum, neural compensation can accompany performance that is either enhanced or degraded. A further consideration is that when additional brain areas are activated in the presence of pathology, this does not always indicate compensation. The activation of additional regions can be malfunctional when it arises from detrimental processes such as dedifferentiation (blurring) of sensory maps (Park et al., 2004), deficits in handling competition between brain regions (Logan et al., 2002), or a deficit in the ability to inhibit the default network (Lustig et al., 2003). Thus when performance is worse, it is necessary to rule out these detrimental processes before labeling the activation of neural compensation.

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An implicit assumption is that neural compensation differs from task to task (that is, it is an emergent property of the task at hand). Yet, as cognitive reserve protects functioning on a wide variety of tasks, it is possible that one generic cognitive reserve network subserves one general cognitive function. Some evidence in support of this idea (Stern et al., 2008) is reviewed in the next section. If this is true, activation of this network would likely indicate a positive, helpful form of neural compensation.

Neural markers of cognitive reserve in young, healthy adults Stern et al. (2003) conducted an event-related fMRI analysis of young adults performing a nonverbal serial recognition task, looking for regions whose activation changed with difficulty. Low-difficulty trials involved one shape to remember, while the number of shapes to remember for high-difficulty trials was customized for each subject to achieve 75% accuracy. Univariate analyses were performed to find regions where the change in activation with difficulty was associated with cognitive reserve, here measured using the National Adult Reading Test (NART) IQ score. Such regions were found for both study and test task phases. These results indicate that cognitive reserve is linked to differential task-related activation (neural reserve) even in healthy young adults. These differences in task-related processing may provide benefits to those higher in cognitive reserve when they become challenged by age-related brain changes or pathology. The previous data were re-examined using multivariate analyses (Habeck et al., 2003). For this study, first a network of regions was sought that changed activation with difficulty. Next, it was investigated whether this network showed differential expression as a function of cognitive reserve. First, a difficulty-related network was found in the study phase. As hypothesized, individuals higher in cognitive reserve expressed this network less (r2 = 0.24), demonstrating higher neural efficiency. Then forward application of this network to the test phase similarly found that those higher in cognitive reserve had lower network activation (r2 = 0.23). Thus, even with this more conservative method, young adults higher in cognitive reserve displayed evidence for greater neural efficiency. Habeck et al. (2005) explored the same question on another task: delayed letter recognition. In this task, memory set sizes of one, three, and six letters constituted the manipulation of difficulty. At the study phase, the difficulty-related network was not associated with cognitive reserve as measured by NART IQ. At the retention phase, or 7-second delay over which items had to be actively held in mind, a difficulty-related network was found that was expressed less by those higher in cognitive reserve (r2 = 0.15). In a second task, then, neural efficiency

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was again detected in young adults higher in cognitive reserve, here during retention. To some extent, individuals higher in cognitive reserve may have higher neural efficiency as a result of employing better performance strategies. This idea is supported by a study that failed to find the usual neural efficiency advantage with intelligence after controlling for strategy usage (Toffanin et al., 2007). Further support comes from a study that found that more activation was associated with trying out more strategies. The idea is that those with higher intelligence are able to decide on a good strategy more quickly and, as a result, show less activation (Jaeggi et al., 2007). Gray et al. (2003) examined healthy young adults performing a three-back working memory task. In this study, event-related activation differed as a function of fluid intelligence, as measured with the Raven’s Advanced Progressive Matrices, for trials at various levels of difficulty, here manipulated through high-interference as opposed to low-interference items. Although this was not explicitly a study of cognitive reserve, fluid intelligence would be expected to be a good proxy for cognitive reserve (Siedlecki et al., 2009). The authors found that activation on the most difficult trials was greater for those higher in fluid intelligence. Higher fluid intelligence was also associated with improved accuracy for lure trials. Interestingly, the increase in activation from nonlure to lure trials mediated the intelligence–accuracy relationship on lure trials by 99%. These results provide support for the idea that those higher in cognitive reserve have greater neural capacity to use, which provides an advantage when tasks are highly difficult. One limitation of these studies is that the tasks used did not have the range of difficulty needed to see neural efficiency and neural capacity operating in the same individuals. There is thus an outstanding research need to find neural efficiency and neural capacity operating with higher cognitive reserve in the same task in young people. Our group has one such report (Stern et al., 2012).

Neural markers of cognitive reserve in healthy young and older adults In older as compared to younger adults, the neural activation associated with cognitive reserve is sometimes the same but can be altered as well. Scarmeas et al. (2003b) examined PET activation in healthy younger and older adults on a nonverbal serial recognition task; cognitive reserve was measured by a factor score extracted from years of education, NART, and age-scaled vocabulary scores from the revised version of the Wechsler Adult Intelligence Scale (WAIS-R). The low-difficulty condition was a single shape, while the high-difficulty condition was adjusted to each subject so that they achieved 75%

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accuracy. Univariate analyses were used to find regions associated with cognitive reserve for each group separately and next to find regions differentially associated with cognitive reserve between the young and the old. The first analyses found some regions associated with cognitive reserve only for the young and other regions associated with cognitive reserve only for the old. The second analyses found three types of differential expression between the two groups: some regions were positively expressed with higher cognitive reserve in the young and negatively expressed with higher cognitive reserve in the old; some regions showed the opposite pattern; and some regions were positively expressed with cognitive reserve in the young and positively, albeit more faintly expressed with cognitive reserve for the old. The authors posit that these differences between young and old in cognitive reserve expression indicate that compensatory reorganization happens with aging. Stern et al. (2005) re-examined the data with multivariate analyses to find regions that were differentially activated with difficulty and age. The authors found a network of brain regions that were activated differently between young and older individuals. Expression of this network was positively associated with cognitive reserve in the young (r = 0.45), indicating higher neural efficiency, and negatively associated with cognitive reserve in older individuals (r = −0.50), indicating higher neural capacity. To sum, young and older individuals expressed the cognitive reserve pattern in opposite ways. The authors posit that this difference reflects helpful reorganization of brain networks in aging, or neural compensation. Stern et al. (2008) next examined in young and older adults whether cognitive reserve might operate similarly in different tasks. Event-related fMRI was used to probe for a cognitive-reserve-related network shared by two different tasks: delayed letter and shape Sternberg. Cognitive reserve was measured with the NART and the vocabulary subtest of the WAIS-R. The letter task contained difficulty levels of one, three, and six letters, while the shape task contained difficulty levels of one, two, and three shapes. On the whole, the shape task was considerably more challenging than the letter task. Two networks were found for the study phase. While the first network was used only during the letter task, the second network was used during both the letter and shape tasks. For young subjects, network activation in both tasks was negatively associated with cognitive reserve, indicating higher neural efficiency in those with greater cognitive reserve. For older subjects, network expression was negatively associated with cognitive reserve only for the less challenging letter task. These results suggest a generic “cognitive reserve network” that can be utilized for performing many tasks. This is concordant with the observation that cognitive reserve provides benefits against brain pathology for many different tasks and real-world functions.

Steffener et al. (2009) examined event-related fMRI activation between young and older subjects performing a delayed letter recognition task. Memory set sizes of one, three, and six letters comprised three levels of difficulty; networks were found that changed expression with increasing difficulty during retention. While young adults utilized a single network, older adults utilized this network along with an additional network. The authors demonstrated that greater pathology in the primary network, operationalized here as more atrophy in the precentral gyrus, was associated with greater utilization of the secondary network in the elders. Because the young subjects did not use the secondary network, it can be presumed to reflect neural compensation in the older subjects. Importantly, older individuals with more cognitive reserve were able to tolerate greater pathology before having to employ the secondary network.

Neural markers of cognitive reserve in healthy elderly and Alzheimer’s patients Scarmeas et al. (2004) examined PET activation in healthy older and Alzheimer’s patients performing a nonverbal serial recognition task. The low-difficulty condition involved a single shape, while the high-difficulty condition was adjusted so that each subject achieved 75% accuracy; cognitive reserve was measured using a factor score extracted from years of education, NART IQ, and the vocabulary subtest of the WAIS-R. Activation patterns differed between healthy older and Alzheimer’s patients. In some regions, Alzheimer’s patients with higher cognitive reserve displayed greater activation, while healthy older individuals with higher cognitive reserve displayed less activation, while in other regions, the relationships were reversed. These region-specific differences were posited to reflect compensatory reorganization of brain networks in Alzheimer’s patients. Solé-Padullés et al. (2009) compared cognitive-reserverelated fMRI activation on a recognition task between healthy old, mild cognitive impairment patients and Alzheimer’s patients. Stimuli were images of landscapes and people engaging in outdoor activities; cognitive reserve was measured with a composite score of the vocabulary subtest of the WAIS-III, an education–occupation scale, and a scale of participation in leisure activities. Univariate analyses were performed after adjusting for the differential performance between the groups. In healthy older individuals, more cognitive reserve was associated with less activation, indicating higher neural efficiency. Conversely, in mild cognitive impairment and Alzheimer’s disease, those with more cognitive reserve displayed greater activation, thought to indicate greater neural capacity. Taken together with the previous study, reverse cognitive-reserve-related brain activation is seen between healthy and diseased older individuals.

Cognitive Reserve and the Aging Brain

Implications of cognitive reserve for diagnosis and prevention Individuals with greater cognitive reserve create a diagnostic challenge, as pathology may be present without functional consequences. Furthermore, for patients with dementia at any stage of clinical severity, individuals with greater cognitive reserve will have more advanced pathology. Neuroimaging biomarkers are currently being developed to assist in early detection of Alzheimer’s pathology, even prior to clinical consequences. Complicating this endeavor, individuals with greater cognitive reserve can tolerate more decreases in cortical thickness (Querbes et al., 2009), levels of amyloid peptides in cerebrospinal fluid (Shaw et al., 2009) and plasma (Yaffe et al., 2011), and more regional atrophy (Hua et al., 2008) before clinical consequences emerge. For these reasons, the predictive accuracy of biomarkers is improved when adding cognitive reserve variables to the model (Roe et al., 2011). More generally, clinical status can best be understood when both underlying pathology and cognitive reserve are taken into account. With the future growth of the aging US population, the number of dementia cases will triple by 2050 if interventions are not applied (Hebert et al., 2003). Katzman (1993) reasoned that as higher education staves off Alzheimer’s for 5 years, it may considerably lessen its prevalence. Thus, cognitive reserve interventions may constitute a chief nonpharmacologic approach for preventing this disease (Stern, 2006). Although Alzheimer’s has a large genetic component (Gatz et al., 2006), behavioral and environmental factors still exert considerable influence over its expression and timing of onset. Even in early-life onset Alzheimer’s, which has a stronger genetic component than does late-life onset Alzheimer’s, cognitive reserve has recently been demonstrated to play a protective role (Fairjones et al., 2011). Future studies might elucidate optimal strategies for augmenting cognitive reserve in order to delay or prevent Alzheimer’s disease and other age-related afflictions.

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Chapter 6 Gait Disorders in the Graying Population Joe Verghese and Jessica Zwerling Department of Neurology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

Summary • Gait disorders can increase the risk of falls, disability, and mortality in the elderly. Gait dysfunction is also common in individuals with cognitive impairment. • Gait disorders can be classified as neurologic or non-neurologic. Within these classifications, the disorder can also fall under different subtypes. Gait is assessed by standard neurologic examinations, visual screens, and the Romberg test for balance. • Neurologic gait disorders can have several underlying etiologies including myelopathy, Parkinson’s disease (PD), vascular or other structural causes, normal pressure hydrocephalus (NPH), strokes, disorders of the cerebellum, and subacute or chronic sensorimotor axonal neuropathy. • Prevention strategies and treatment should be tailored to each individual according to their underlying etiology.

Introduction: a historical perspective

Epidemiology

What has four legs in the morning, two legs in the afternoon, and three legs at nighttime? Man. This riddle illustrates three phases of life. The first phase represents an infant crawling. In the second phase, the child progresses to walking. The third stage then describes a phase in which man requires assistance for walking. In this latter stage, identifying gait disorders is crucial to prevent morbidity and mortality in the elderly. The locomotor system of the animal is based on a spinal neural network (Grillner, 1975; Mor and Lev-Tov, 2007). From the four-legged animal in early evolutionary stages to modern upright man, the advantage of bipedalism has enabled humans to have a unique interaction with the environment. The upright structure has both advantages and disadvantages. The “three legs at nighttime” represents the downside of bipedalism. This locomotor strategy can be fraught with “slipped disks, dislocated hips, wrenched knees, fallen arches, and a whole catalog of associated woes” (Tattersall, 1998). Identifying gait disturbances is crucial. It enables efficient diagnosis of neurologic illnesses in clinical settings as well as facilitates the identification of high-risk older individuals to institute interventions to prevent outcomes such as falls that are associated with high personal and societal costs.

In older adults, gait disturbance is common and can be associated with pain, functional impairment, and falls. The ability to ambulate independently is a major contributor to overall well-being and autonomy in elderly individuals. In the “oldest-old” (over age 85) living in the community, the prevalence of walking limitations approaches more than 50% (Ostchega et al., 2000). In an urban community-based study, abnormal gaits were reported in one-third of older persons and accounted for 58% of the overall number of deaths and institutionalizations over 5 years in this sample (Verghese et al., 2006). The prevalence of clinically diagnosed gait abnormalities was 35% in this sample (Verghese et al., 2006). Incidence of abnormal gait was 168.6 per 1000 person years, and increased with age (Verghese et al., 2006).

Gait and adverse outcomes Falls Falls are a significant health concern because they cause significant morbidity and mortality in the elderly and result in a significant burden on a socioeconomic level. Over age 65, falls are the leading cause of fatal injuries (Stevens et al., 2008). About one-third of the community population over age 65 falls each year (Gillespie et  al.,

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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2009). Emergency departments are frequently overwhelmed with older adults who have unintentional falls. In 2005, 1.8 million elderly people were admitted in emergency rooms across the country (Stevens et al., 2006). Falls are predictors of future falls; in other words, patients who have fallen are more likely to fall again, especially if there are detected abnormalities of gait (Ganz et al., 2007). The latter fact underscores the importance of identifying patients who fall with simple screening questions. In addition, falling occurs in the setting of “fear of falling”; therefore identification of patients with this particular “fear” is also essential. Fear of falling is a well-known independent risk factor for falls (Delbaere et al., 2010). Race has no preference when it comes to falls; African Americans and White elderly individuals fall at the same rate. However, African Americans are more likely to have a traumatic brain injury, and women are more likely to experience a fracture (Ganz et al., 2007; Delbaere et al., 2010). Clinical gait abnormalities predict future risk of falls (Tinetti et al., 1994, 1995; Verghese et al., 2006; DeMott et al., 2007; Ganz et al., 2007). In a prospective study of community-residing elderly, the presence of neurologic gaits was a strong risk factor for falls and was associated with a 49% increased risk of falls over a 20-month period (Verghese et al., 2010). Unsteady and neuropathic gait were the two gait subtypes among the six studied that predicted risk of falls (risk ratio: 1.52, and 1.94, respectively) (Verghese et al., 2010). This study showed that classifying gait disorders is crucial to identifying individuals at risk for falls, as well as to identifying gait problems to institute preventative measures. Gait should be treated as a potential modifiable risk factor for falls (Tinetti et al., 1994, 1995; Mor and Lev-Tov, 2007; Delbaere et al., 2010; Verghese et al., 2010).

Gait and disability The risk of developing disability can be predicted in community elders by lower-extremity performance tests, of which gait speed is the main factor in community-based cohort studies (Verghese et al., 2010). Gait speed is a key component of the clinical definition of frailty (Gill et al., 2010), which is conceptualized as a state of heightened vulnerability to stressors and increases the risk of disability in older adults. Gait speed is a potentially modifiable risk factor to prevent disability and related outcomes. Gait and survival Gait speed and survival are associated (Markides et  al., 2001; Boyle et al., 2005; Louis et al., 2005; Stevens et  al., 2006; Ganz et al., 2007; Cesari et al., 2009; Gillespie et al., 2009; Delbaere et al., 2010). In a pooled analysis, Studenski et al. found that slower gait speed is an absolute risk for shorter survival in older adults (Studenski et al., 2011). Improvement in gait speed by 0.1 m/s over 1 year has been termed as a meaningful clinical difference, and

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this change has been associated with reduced mortality in prospective cohort studies (Perera et al., 2006; Hardy et al., 2007). Variability in gait is an important predictor of mobility difficulty in older adults. In a small sample of subjects in the Einstein Aging cohort, meaningful changes in various quantitative indices of gait were determined (Brach et al., 2010). Preliminary criteria for meaningful change are 0.01 seconds for stance time and swing time variability, and 0.25 cm for step length variability (Perera et al., 2006).

Cognition and gait Gait disorders are common in the elderly, particularly in patients with cognitive impairment (Verghese et al., 2008). Studies have shown that there is likely a link between the cognitive and motor systems (Verghese et al., 2008). Furthermore, Verghese et al. underscored that clinical and quantitative gait dysfunction is common in mild cognitive impairment (MCI) and is associated with poorer status (Verghese et al., 2007). In this same elderly cohort, subjects with amnestic-MCI (a-MCI) had worse swing time and stride length variability than those with nonamnestic-MCI (na-MCI) (Verghese et al., 2008). Subjects with a-MCI had worse performance on rhythm and variability gait domains than age-matched and sex-matched controls and those with na-MCI (Verghese et al., 2008). Neurologic gaits were more common in subjects with a-MCI (Verghese et al., 2008). Parkinsonian signs in MCI were related to the severity and type of cognitive impairment in another elderly cohort (Boyle et al., 2005) Another community-based study reported that mild parkinsonian signs were associated with a-MCI but not na-MCI (Louis et al., 2005; Verghese et al., 2008).Motor decline as indexed by gait speed declined up to 12 before other cognitive domains in patients with MCI (Buracchio et al., 2010).

The “aging” of walking Changes that are seen with aging include shorter and broad-based strides, as well as a reduction in pelvic rotation and joint excursion (Sudarsky, 1990, 2001). In the Einstein Aging Study cohort, gait velocity and stride length decreased with advancing age (Oh-Park et al., 2010). However, the aging effect on walking was less pronounced when clinical and subclinical disease influence on gait was taken into account. These results suggest that gait changes with aging are better explained by age-related diseases than they are age-associated. Hence, underlying causes for gait changes need to be investigated regardless of the age of the patient. In a study of community elders, the most important factors associated with walking speed were leg extensor power, standing balance, and physical activity, regardless of body mass index or gender (Sallinen et al., 2011). These

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are all potentially modifiable risk factors that interventions aimed at improving lower extremity impairments can improve (Sallinen et al., 2011). Cross-sectional conventional norms may underestimate gait performance in aging (Oh-Park et al., 2010). Longitudinal robust norms provide more accurate estimates of normal gait performance and thus may improve early detection of gait disorders in older adults (Oh-Park et al., 2010). Robust norms consider subjects with prevalent or “in transition” gait abnormalities to develop clinical gait abnormalities and exclude them (Oh-Park et al., 2010). This allows for a gait to reflect more of the “normal” elderly population, so that targeted interventions can be more accurately guided (Oh-Park et al., 2010). The following sections contain a discussion of clinical gait evaluation and classification, quantitative indices of gait, and performance-based measures.

Clinical gait classification Several different clinical classification systems exist for gait and have been described. All these clinical gait classifications rely on the clinician’s observation of walking patterns. Nutt and colleagues proposed a system that classifies clinical gait abnormalities based on abnormal sensorimotor levels as low, middle, and high (Nutt et al., 1993). Higher-level gait disorders are thought to stem from pathology in the frontal lobes and their connections with parietal lobes, subcortical structures (cerebellum and basal ganglia), and the upper brainstem (Nutt et al., 1993). Lower-level gait disorders can be divided into motor and sensory systems. Lower-level gait disorders are thought to arrive from perturbation of the muscle or peripheral nerve. An example of lower-level gait disorder is neuropathic gait secondary to neuropathy (see the description in the Section Case Discussions, later in this chapter). Lower-level gait dysfunction is also classified secondary to disorders of vision, vestibular sensation, and proprioception (Nutt et al., 1993). The middle-level gait disorder is thought to originate from “motor” dysfunction. This level includes causes such as spasticity due to spinal cord pathology, cerebellar ataxia, and dystonia. Patients with Parkinson’s disease (PD) have dysfunction at the high or cortical level of processing and the middle level (subcortical structures), as they may have rigidity and bradykinesia. The higher-level disorders primarily involve problems integrating information in the environment (Nutt et al., 1993). For example, the execution of locomotion is the main higher-level disturbance in the “freezing” phenomenon during walking seen in patients with PD. Gait is evaluated as part of the standard neurologic examination to test cranial nerves, strength, sensation, and deep tendon reflexes. Visual screening should be

included, along with evaluation for range of motion. The Romberg test is used to assess standing balance with visual cues removed or eyes closed. A positive test refers to a patient’s inability to maintain balance when standing erect with feet together and eyes closed. Cognitive screening is also important to include, given the correlation between the motor and cognitive functions (Verghese et al., 2008). We have been using a clinical gait classification during our clinical evaluation at the Einstein Aging Study for the past two decades. In the Bronx Aging Study (now known as the Einstein Aging Study), clinicians blinded to the gait evaluation of the subjects showed 89% agreement (κ = 0.6) on gait classification, specifically whether the gait was neurologic or non-neurologic (Verghese et al., 2002b). Inter-rater reliability (normal vs any abnormal gait), studied prospectively, between two study clinicians who independently assessed gait in 30 subjects was good (κ = 0.8) (Verghese et al., 2004). At each visit, study clinicians observe gait patterns and turns while subjects walk up and down a well-lit path (Verghese et al., 2002b, 2006, 2010; Oh-Park et al., 2010). The first step in clinical gait analysis is the recognition that gaits are either normal or abnormal; then abnormal gaits are subtyped as either neurologic (one of eight subtypes discussed shortly) or non-neurologic (arthritic, vascular claudication, or secondary to cardiopulmonary issues, and so on). In our large community-based study (the Bronx Aging Study, now known as the Einstein Aging Study (Verghese et al., 2002b, 2006, 2010; Oh-Park et al., 2010), neurologic gaits are subtyped. Neurologic gait abnormalities are subtyped as unsteady if subjects experienced marked swaying or lost balance under two or more of the following conditions: while walking in a straight line or in tandem or while making turns. Ataxic (cerebellar) gait is wide based, with other cerebellar signs such as intention tremor. Ataxic and unsteady gaits were combined, because they share clinical features such as wide base and poor balance. Patients with neuropathic gaits have foot drop, sensory loss, and depressed deep tendon reflexes. Short steps, wide base, and difficulty lifting the feet off the floor characterize frontal gait. Older people with parkinsonian gaits have small shuffling steps, flexed posture, absent arm swing, en bloc turns, and festination. Frontal gait is characterized by short steps, wide base, and difficulty in lifting the feet off the floor. Patients with hemiparetic gait swing a leg outward and in a semicircle from the hip (circumduction). In addition to lower motor neuron/lower-level causes of foot drop, ankle dorsiflexion can be affected in patients with upper motor neuron disorders. Ankle dorsiflexion plays a role in the initial stance phase of the gait cycle and the wing phase, and can be impaired in upper motor neuron lesions, as part of the hemiparetic gait (Verghese et al., 2007). In spastic gait, both legs circumduct and, when severe, cross in front of

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one another (scissoring). See web links (Verghese et al., 2002b) to videos of abnormal neurologic gait subtypes.

Psychogenic gait disorders Gait disorders that are nonorganic/nonphysiologic/ functional are called psychogenic gait disorders. Astasiaabasia is a Greek term that means “inability to stand and to walk.” Paul Blocq described this phenomenon in the late 1800s, which he characterized in a series of patients who did not have the ability to maintain an upright posture, despite normal function of the legs in bed (Blocq, 1888). Sudarsky et al. found that, in elderly patients, 3.3% of gait disorders were psychogenic (Sudarsky and Tideiksaar, 1997). A functional disorder has several features, such as momentary fluctuations, excessive slowness of movement or hesitation, “psychogenic” Romberg with a silent delay or improvement with distraction, uneconomic postures (wasting of energy), small cautious steps with fixed ankle joints (“walking on ice”), and sudden buckling of knees with and without falls. The caveat is that gait disorders develop over time, and repeated examination and history taking is necessary to truly characterize a gait disorder as psychogenic. Elderly patients may showcase a “cautious gait,” with reduced stride, widened base, and lowered center of gravity (Sudarsky and Tideiksaar, 1997). Cautious gait may be a reaction to a previous fall, may be psychogenic, or may be a representation of a larger gait disorder that has not manifested yet. The main risk factors for developing the fear of falling are at least one fall, female sex, and increasing age (Tinetti and Mendes de Leon, 1994; Sudarsky and Tideiksaar 1997; Scheffer et al., 2008). This can cause significant psychosocial limitations for an individual. Treatment relies on a multidisciplinary team, including psychiatry and rehabilitation experts. An additional syndrome important to discuss is camptocormia, or “bent spine syndrome.” This syndrome is characterized by forward flexion of the trunk in the erect position and reduced flexion when in the supine position (Azher and Jankovic, 2005). The etiology was originally thought to be a form of “conversion” or psychogenic disorder; however, the underlying cause encompasses many aspects of the neuraxis. The etiology involves neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD), mitochondrial myopathy, and dysferlinopathy, as well as PD and dystonia (Van Gerpen, 2001; Schabitz et al., 2003; Azher and Jankovic, 2005; Gomez-Puerta et al., 2007; Seror et al., 2008).

Quantitative assessment of gait: creating a scorecard for prediction of falls Walking is the repetitive sequence of limb motion to push the body forward while maintaining stance and stability

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(Perry, 1992). Although clinical observation alone is an important component of gait analysis, it depends on the examiner’s expertise. On the other hand, criticisms of quantitative gait analysis methods may state that the assessment protocols are cumbersome and vary in the level of detailed analysis required. Recent technologic advances in quantitative assessment of gait have enabled faster acquisition of kinematic data and an in-depth measurement of various gait variables (Verghese et al., 2002b; Abellan van Kan et al., 2009). It is important to measure variables such as normal gait measures, as well as variability within these measures. Gait speed has been associated with good health and functional status (Cesari et al., 2005; Rolland et al., 2006; Rosano et al., 2008; Abellan van Kan et al., 2009; Verghese et al., 2009). Normal older adults with increased stride-to-stride or stance time variability at baseline assessments were reported to have increased risk of falling, mobility disability, and dementia (Brach et al., 2005; Cesari et al., 2005; Perera et al., 2006; Verghese et al., 2009; Verghese and Xue, 2011).

Timed gait Simple timed gait is recommended by a number of studies and can be done in most clinical settings (Abellan van Kan et al., 2009; Studenski, 2009; Verghese et al., 2009). An abundance of gait norms exist for elderly individuals, which presents difficulty for clinical application because of the variation in the reported values. Mean gait velocity varied in older adults from 89  cm/s to 141  cm/s in previous community-based studies (Murray et al., 1969; Winter et al., 1990; Oberg et al., 1993; Samson et al., 2001; Bohannon, 2008). Gait velocity decreased with advancing age in the Einstein Aging cohort (Verghese et al., 2009). In this prospective study of a large, well-characterized cohort of community-residing elders, quantitative gait markers were independent and strong predictors of incident falls (Verghese et al., 2009). Each 10  cm/s decrease in gait speed was associated with a 7% increased risk for falls (Verghese et al., 2009). Participants with slow gait speed (≤70  cm/s) had a 1.5-fold increased risk for falls, compared with those with normal speed (Verghese et al., 2009). Computerized assessments for gait are varied. Subjects in the Einstein Aging Study protocol are asked to walk on a mat at their normal pace for two trials in a quiet, well-lit hallway with comfortable footwear on the GAITrite system. Footfalls are recorded and gait variables are recorded over two trials. Eight gait parameters are reported, based on previous studies of their associations with adverse outcomes: velocity (cm/s), cadence (steps/min), stride length (cm), swing time (s), stance time (s), and double support phase (%). (See Table 6.1 for definitions.) The standard deviation (SD) of stride length and swing time is used for variability (Verghese et al., 2007). Gait variability in each measure of gait was defined as the within-

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Table 6.1 Definition of quantitative gait parameters. Variable

Unit

Definition

Velocity Stride length

cm/s cm

Cadence Double support

steps/min s

Swing time

s

Stance time

s

Distance covered on two trials by the ambulation time Distance between heel points of two consecutive footfalls of the same foot. Variability in length between strides is reported as standard deviation (SD). Number of steps taken in a minute Time elapsed between the first contact of the current footfall and the last contact of the previous footfall, added to the time that elapsed between the last contact of the current footfall and the first contact of the next footfall Duration when the foot is in the air and is the time taken from toe-off to heel strike of the same foot. Variability in swing time is reported as SD. Duration when the foot is on the ground and is the time taken from heel strike to toe-off of the same foot

Source: Adapted from Snijders et al. (2007), with permission from Elsevier. All quantitative parameters described are automatically calculated as the mean of two trials by the gait software.

subject SD derived from all the right steps recorded over two trials (Brach et al., 2005). Gait variability is an important indicator of impaired mobility in older adults (Brach et al., 2005).

Performance-based tests A number of performance-based assessments can be used in any office setting to assess risks for falls. A quick tool that has been well validated is the Timed Up and Go test (Podsiadlo et al., 1991). The patient is timed from rising from a chair, walking 3 m, turning, and returning to the chair. A timing of 14 seconds or more has been shown to be an indicator for a fall risk (Podsiadlo et al., 1991). A unipedal stance of less than 5 seconds has been associated with increased risk of falls in the elderly (Vellas et al., 1997). Walking while talking The task of walking while talking (WWT) requires divided attention and harnesses the bridge between cognitive and motor disorders. Although walking at a normal pace is thought to be “reflexive,” WWT requires a shift of attentional resources and places cognitive demands on individuals. In subjects with imbalance, this can lead to postural instability and falls (Verghese et al., 2002a; Beauchet et al., 2009). In a review of dual-task conditions such as WWT, the pooled odds ratios showed a statistically significant increase in the risk of falls while performing the dual task of WWT (5.3 (95% CI, 3.1–9.1)) (Beauchet et al., 2009). Etiology of gait disorders: a window into diagnosis and workup General medical examinations, especially during visits to emergency rooms, often neglect gait examination. Yet it is a crucial part of the neurologic examination. The following discussion includes etiologies of six main subtypes of neurologic gait disorders, described in our

clinical gait classification in the previous sections and related investigations. The cause of spasticity can be multifactorial in the elderly. Myelopathy from structural causes such as spondylotic ridges and ligamentous hypertrophy contribute to spinal canal narrowing and cord impingement. As a result of cord compression, especially in the posterior columns, which contain vibration and proprioception fibers, patients often complain of imbalance. The physical examination includes mild spasticity (especially in the legs), hand numbness, reports of urinary urgency and incontinence, and a positive Romberg test. The gait is described as stiff-legged with reduced toe clearance and a tendency toward circumduction. Patients may also have pseudoathetosis, or abnormal writhing movements, usually of the fingers, caused by a failure of joint position sense (proprioception). It is important to keep in mind that presentations may be asymmetric or may appear as a central cord syndrome with possible associated syringomyelia, with sensory deficits in a cape-like distribution. Nonstructural causes of myelopathy can be caused by demyelinating diseases such as multiple sclerosis, vitamin B12 deficiency, trauma to the spinal cord, vitamin E deficiency, post-radiation, herpes zoster infection, or copper deficiency. Further evaluation of the brain and spine with MRI, as well as screening bloodwork for nonstructural causes, may be indicated. Parkinsonism is characterized by bradykinesia, resting tremor, rigidity, and loss of postural reflexes. PD is common in the elderly population, with a prevalence of approximately 0.5–1% among persons 65–69 years of age, rising to 1–3% among persons 80 years of age and older (Tanner and Goldman, 1996). Other disorders, including those from neuroleptic drugs and arteriosclerotic parkinsonism as a result of multiple subcortical infarcts, may cause similar gait and balance problems mimicking idiopathic PD. If idiopathic PD is suspected, no further workup is necessary unless secondary causes are suspected.

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Hemiparetic gait is characterized by asymmetric weakness and may be attributable to vascular causes; however, other structural causes, such as AVM, subdural hematoma, metastases, must be ruled out with imaging of the head. Frontal gait includes the disorders of normal pressure hydrocephalus (NPH), as well as multiple strokes. As previously discussed, patients may have a “magnetic gait,” with difficulty lifting the feet off the floor (Sudarsky and Simon, 1987). Imaging of the brain often reveals extensive white matter disease when the etiology is vascular. NPH is characterized by frontal gait disorder, urinary incontinence, and cognitive impairment. This syndrome requires a lumbar puncture for diagnosis, and improvement in gait monitored by the clinician underscores the NPH diagnosis. The response to the removal of 30–50 cc or a large volume of the cerebrospinal fluid is characterized by improvement of gait. The response or rating of improvement to spinal tap is not well standardized. Treatment requires shunting of the cerebrospinal fluid. Ataxic gait includes unsteady gait and includes disorders of the cerebellum. The disorders can be because of neurodegenerative causes, as in olivopontocerebellar degeneration, a disorder that is within the category of Parkinson’s plus syndromes. Paraneoplastic degeneration of the cerebellum associated with antibodies against different cells can cause ataxic gaits. One example includes Anti-Yo antibodies, found mostly in women with cerebellar degeneration accompanying gynecologic and breast malignancies (Peterson et al., 1992). The antibodies recognize cytoplasmic proteins of Purkinje cells, contributing to their degeneration. Anti-Hu antibody, found predominantly in paraneoplastic neurologic syndromes associated with small-cell carcinoma of the lung, reacts with proteins present in nuclei and cytoplasm of virtually all neurons (Mason et al., 1997). Chronic alcoholism can contribute to atrophy of the anterior vermis of the cerebellum (Victor et al., 1959). Treatment includes elimination if thought to be because of toxins. Screening for underlying malignancy and with labwork to identify antibodies is crucial in ataxia as a result of paraneoplastic degeneration. Individuals with neuropathic gait have unilateral or bilateral foot drop and may have a “stocking” pattern of sensory loss and absent deep tendon reflexes. Etiology depends on the type of neuropathy. Several causes of subacute/chronic sensorimotor axonal polyneuropathy include, but are not limited to, diabetes, hypothyroidism, vitamin B12 deficiency, connective tissue disease (Sjorgren, rheumatoid arthritis), paraproteinemia, and toxic neuropathy (alcohol). Clinical cues must be taken from the history and examination. Workup as suggested for the first tier by Herskovitz et al. is complete blood count, chemistry, HgA1C, oral glucose tolerance test, vitamin B12 (methylmalonic acid/homocysteine), ESR, serum protein immunofixation, and toxic exposure his-

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tory (Herskovitz et al., 2010). The authors encourage consideration of urinalysis, chest X-ray, thyroid testing, lipid profile, antinuclear antibody (ANA), rheumatoid factor, Lyme disease, hepatitis C titre, and angiotensin-converting enzyme (ACE) level (Herskovitz et al., 2010).

Summary A detailed history taking that includes an assessment of home safety, complemented with a complete cognitive and gait examination, is crucial to identifying patients with gait disorders. Prevention strategies should be tailored to each individual, depending on the etiology such as stroke, neurodegenerative, neuropathic, psychogenic, or ataxic. Treatment is targeted at controlling underlying conditions that have caused the gait disturbance. Close follow-up is important to ascertain changes in gait patterns over time. Gait disorders follow the same evolutionary principle as the development of man. They evolve over time. The astute clinician must help the patient identify the underlying problem, highlight the obstacles, and help the patient adapt to the environment.

Suggested citations Nutt, J.G., Marsden, C.D., and Thompson, P.D. (1993) Human walking and higher-level gait disorders, particularly in the elderly. Neurology, 43: 268–279. Snijders, A.H., van de Warrenburg, B.P., Giladi, N., and Bloem, B.R. (2007) Neurological gait disorders in elderly people: clinical approach and classification. Lancet Neurol, 6: 63–74. Sudarsky, L. (1990) Geriatrics: gait disorders in the elderly. N Engl J Med, 322 (20): 1441–1446. Verghese, J., Lipton, R., et al. (2002) Abnormality of gait as a predictor of non-Alzheimer’s dementia. N Engl J Med, 347: 1761–1768. Verghese, J., Wang, C., Lipton, R.B., et al. (2007) Quantitative gait dysfunction and risk of cognitive decline and dementia. J Neurol Neurosurg Psychiatry, 78: 929–935. Verghese J., Holtzer, R. et al. (2009) Quantitiative gait markers and incident fall risk in older adults. J Gerontol A Biol Sci Med Sci, 64: 896–901.

Case discussions The following section illustrates the major subtypes of gait disorders. It is a useful tool for teaching and can be utilized with the videos from Verghese et al. ( 2002b).

Case 1: history The patient is a 65-year-old right-handed man with a four-year history of intermittent distal symmetric paresthesias of the legs. Over the past year, the

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paresthesias has caused his legs to become numb to the mid-calf at all times. He had a recent fall in which he “tripped over the curb.” Over the last several months, he has complained of difficulty buttoning his shirt and opening jars. He denies bowel/bladder symptoms or autonomic symptoms. There is no allodynia. There are no constitutional symptoms. He remarked that although it is winter, he finds it uncomfortable to sleep with the sheet on the bed. He denies a family history of neuropathy, high arches, or hammer toes. He has significant thirst, but he attributes it to the use of his inhaler for chronic obstructive pulmonary disease (COPD).

The general medical examination is unremarkable except for poor dentition. The mental status examination was normal. Cranial nerves were normal. The strength examination was normal. Deep tendon reflexes were absent at the toes and brisk 3+ knees but present and normal at the arms. Plantar responses were extensor. There was no tremor or other adventitious movements. Light touch and pinprick were affected to midshin bilaterally. Vibration was decreased to anterior iliac spine, and proprioception required large excursions. Tone was increased throughout. Romberg was positive. There was significant pseudoathetosis.

Physical examination

Gait

The general medical examination is unremarkable. The mental status examination was normal. Cranial nerves were normal. The strength examination revealed a weakness of toe flexion and extension, with an MRC grading of 4, with slight asymmetry or worsening on the right. Deep tendon reflexes were absent at the toes and knees but were present and normal at the arms. Plantar responses were flexor. There was no tremor or other adventitious movements. Light touch and vibration were decreased to midshin bilaterally with pinprick and proprioception mildly affected. There was sensitivity to touch at the soles of the feet. He was able to toe-walk and heel-walk but had extreme difficulty. Romberg showed swaying. There was no pseudoathetosis. Tone was normal. The lower legs were significantly atrophic.

Sways slightly while walking with occasional misstep. Worse with tandem. Wide-based ataxic gait with spasticity.

Gait Bilateral foot drop—neuropathic. There is a “stocking” pattern of sensory loss and absent deep tendon reflexes. Comment on case: Upon further questioning, there was significant erectile dysfunction for 5 years beforehand. Labwork revealed significantly elevated HgA1C.

Case 2: history This is an 85-year-old woman with a history of “unsteadiness” for several months. She reports intermittent paresthesias of the hands, which began several months ago and now has affected the feet. She reports that when she is in the shower, she is unable to wash her hair with her eyes closed. She feels as though she will fall over, and she reports “electricity” in both arms with tilting of her head and neck in a certain direction. There are no bowel/bladder symptoms or constitutional symptoms. She reports recent dental work with injection only (no gas) for poorly fitting dentures. There are no falls. She is on Coumadin for an “abnormal heart rate. She also notes that she has been forgetting where she put her keys a lot more often and got lost driving home on her usual route.

Physical examination

Diagnosis Myeloneuropathy secondary to hyperzincemia causing hypocupremia (Kumar et al., 2004; Nations et al., 2008). Comment on case: Vitamin B12 levels were normal. The patient admitted to using denture cream in significant amounts over the past several months (Herskovitz et al., 2010). Copper levels were low. Serum zinc levels were high. There was an associated anemia on complete blood count. The previous discussion includes description of two subtypes of gait: ataxic and spastic gait.

Case 3: history This 78-year-old right-handed writer presents with a two-year history of changes in his handwriting. He used to take notes throughout the day and night to keep track of new book ideas. His handwriting has become progressively smaller. He notes that, at nighttime, he has increasing difficulty turning in bed. While watching television, he also noted a right-hand tremor. He has lost his balance occasionally but has no falls. He denies hallucinations or autonomic symptoms. Family history is noncontributory. Past medical history is significant for depression without neuroleptic use.

Physical examination The general medical examination is unremarkable. The mental status examination was normal. Cranial nerves were normal. The strength examination was normal. Deep tendon reflexes were normal. Plantar responses were flexor. There was a rest tremor on the right hand. Light touch, pinprick, vibration, and proprioception were normal. There was cogwheeling with activation of the right upper extremity. Pull test was positive. Romberg was negative. He pushed with arms to elevate from a seat. Frontal release signs were negative. Fine finger movements were slowed throughout.

Gait Disorders in the Graying Population

(a)

(b)

(c)

(d)

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Figure 6.1 Footfall patterns recorded on an

instrumented walkway: (a) frontal gait; (b) parkinsonism; (c) ataxic gait; (d) left hemiparetic.

Gait Small shuffling steps, flexed posture, absent arm swing on right, turns en bloc, and festination (acceleration while walking). He does not swing his arms and has difficulty with initiating a turn. (See Figure 6.1.)

Diagnosis Idiopathic PD. Comment on case: The patient exhibits typical features of PD that hallmark symptoms of tremor, bradykinesia, rigidity, and postural instability. His gait was parkinsonian.

Case 4: history This 85-year-old right-handed woman presents with a two-year history of difficulty walking. She feels as though she just cannot move forward or that there is glue under her feet. She is independent at home; however, she recently stopped going to the movies with friends because of incontinence over the last several months. She spends her time reading multiple books at a time and has no trouble keeping up with them.

Physical examination The general medical examination is unremarkable. The mental status examination was normal. Cranial nerves were normal. The strength examination was normal. Deep tendon reflexes were normal. Plantar responses were flexor. There were no adventitious movements. Light touch, pinprick, vibration, and proprioception were normal. Tone and bulk were normal. Pull test was positive. Romberg was negative. She pushed with arms to elevate from a seat. Frontal release signs showed positive snout and palmomental. Fine finger movements were slowed throughout. No pseudobulbar affect.

Gait Frontal gait is characterized by short steps, wide base, and difficulty lifting the feet off the floor (magnetic response).

Diagnosis NPH (Figure 6.1–-the wide base can be visualized).

Case 5: history This is a 65-year-old left-handed woman with history of hypertension who had acute onset of “inability to speak” and weakness of her right-side arm/leg. She was unable to lift her right leg and arm at first. She noted that her drink was coming out of her mouth. She went to the emergency room after 48 hours of symptoms. After further questioning, she noted an increasing headache over the past several weeks, with a “worse” headache the day of maximal symptoms. She has a remote history of melanoma. She was noted to have an elevated blood pressure.

Physical examination The general medical examination is unremarkable. The mental status examination was normal. Cranial nerves revealed a right central facial. Strength examination showed right triceps, right hamstring, psoas weakness grade 4/5. There was a positive fixed arm roll, as well as pronator drift. Coordination showed difficulty with finger–nose–finger test not out of proportion to weakness. Deep tendon reflexes were hypoactive on the right. Plantar responses were extensor on the right. There were no adventitious movements. Light touch and pinprick were decreased on the right upper and lower extremity. Vibration and proprioception were normal. Tone and bulk were normal.

Gait She swings her leg outward and in a semicircle from the hip (circumduction) and displays external rotation of the right foot. She does not swing her right arm, and her right leg is slower than the left (see Figure 6.1).

Diagnosis Hemiparetic gait. Imaging revealed a hemorrhage in the left basal ganglia; detailed imaging with MRI revealed an underlying lesion with hemorrhage, likely because of metastatic melanoma.

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Seror, P., Krahn, M., et al. (2008) Complete fatty degeneration of lumbar erector spinae muscles caused by a primary dysferlinopathy. Muscle Nerve, 37: 410–414. Snijders, A.H., Van De Warrenburg, B.P., Giladi, N., and Bloem, B.R. (2007) Neurological gait disorders in elderly people: clinical approach and classification. Lancet Neurol, 6: 63–74. Stevens, J.A., Mack, K.A., et al. (2006) The costs of fatal and nonfatal falls among older adults. Inj Prev, 12 (5): 290–295. Stevens, J.A., Mack, K.A., et al. (2008) Self-reported falls and fallrelated injuries among persons aged > or = 65 years–-United States, 2006. J Safety Res, 39 (3): 345–349. Studenski, S. (2009) Bradypedia: is gait speed ready for clinical use? J Nutr Health Aging, 13 (10): 878–880. Studenski, S., Perera, S., et al. (2011) Gait speed and survival in older adults. J Am Med Assoc, 305 (1): 50–58. Sudarsky, L. (1990) Geriatrics: gait disorders in the elderly. N Engl J Med, 322 (20): 1441–1446. Sudarsky, L. (2001) Gait disorders: prevalence, morbidity, and etiology. Adv Neurol, 87: 111–117. Sudarsky, L. and Simon, S. (1987) Gait disorder in late-life hydrocephalus. Arch Neurol, 44: 263–267. Sudarsky, L. and Tideiksaar, R. (1997) The cautious gait, fear of falling, and psychogenic gait disorders. In: Gait Disorders of Aging. Philadelphia: Lippincott Raven. Tanner, C.M. and Goldman, S.M. (1996) Epidemiology of Parkinson’s disease. Neurol Clin, 14: 317–335. Tattersall, I. (1998) Becoming Human: Evolution and Human Uniqueness. New York: Harcourt Brace and Company. Tinetti, M. and Mendes de Leon, C. (1994) Fear of falling and fallrelated efficacy in relationship to functioning among community elders. J Gerontol, 49 (3): M140–M147. Tinetti, M.E., Baker, D.I., et al. (1994) A multifactorial intervention to reduce the risk of falling among elderly living in the community. N Engl J Med, 331: 821–827. Tinetti, M.E., Doucette, J., et al. (1995) Risk factors for serious injury during falls by older persons in the community. J Am Geriatr Soc, 43 (11): 1214–1221.

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Chapter 7 Imaging of the Geriatric Brain 7.1 Structural Neuroimaging in Degenerative Dementias

Liana G. Apostolova1 7.2 Functional Imaging in Dementia

Adam S. Fleisher2 and Alexander Drzezga2 7.3 Amyloid Imaging

Anil K. Nair3 and Marwan N. Sabbagh4 1

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

2

Banner Alzheimer’s Institute, Department of Neurosciences, University of California, San Diego, CA, USA and Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany 3Clinic

for Cognitive Disorders and Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA

4Banner

Sun Health Research Institute, Sun City, AZ, USA

Summary Structural Neuroimaging in Degenerative Dementias • Neurodegenerative disorders cause brain changes that can be detected with structural imaging. • Hippocampal atrophy, cortical atrophy, ventricular enlargement, and white matter changes are structural biomarkers for the presence of AD. • Structural biomarkers for frontotemporal dementias (FTDs) (differ by phenotype) are as follows: • fvFTD: frontal atrophy, which is often asymmetrical. • Nonfluent PPA: left perisylvian atrophy. • Fluent PPA: anterior temporal lobe involvement. • Structural biomarkers for dementia with Lewy bodies (DLB): • Mild-to-moderate, nonspecific, generalized brain atrophy. • Atrophy of dorsal midbrain, hypothalamus, and substantia innominata. • Structural biomarkers of Parkinson’s disease dementia: • Widespread cortical atrophy of the limbic, temporal, parietal, frontal, and occipital regions. • Atrophy of caudate nuclei and lateral and third ventricular enlargement. • Structural biomarkers of corticobasal degeneration: • Asymmetric frontoparietal atrophy that involves the sensorimotor strip. • Structural biormarkers of progressive supranuclear palsy: • Atrophy of the midbrain tegmentum, enlargement of the third ventricle. • Structural biomarkers in Creutzfeldt–Jakob disease: • Increased T2, fluid attenuation inversion recovery (FLAIR) and diffusion-weighted abnormalities in the cortical ribbon and basal ganglia.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Functional Imaging in Dementia FDG-PET • Currently a complementary procedure in the diagnostic evaluation of dementia. • Progressive reduction of complete metabolic response (CMR) in hippocampal, temporoparietal, and posterior cingulate areas occur years before the onset of clinical AD. • It is 94% sensitive and 73% specific for AD and shows reduced temporoparietal glucose utilization may be detectable before notable amyloid pathology. • In frontotemporal dementias (FTDs), it shows frontal or temporal hypometabolism with relative sparing of the parietal lobes. • In dementia with Lewy bodies (DLB), glucose utilization is impaired in the primary visual and occipital association cortices in addition to the precuneus and posterior cingulate areas; and dopamine PET scans may show reduced striatal dopaminergic activity. SPECT • Shows decreased temporoparietal perfusion in AD with sparing of primary sensorimotor strip and basal ganglia. • Isoflupane(IFP)-CIT-SPECT shows nigrostriatal hypoperfusion and is useful to distinguish DLB from Alzheimer’s disease (AD) and Parkinson’s disease (PD). • Metaiodobenzylguanine(MIBG)-SPECT may be a good measure of cardiac sympathetic denervation in DLB. • Vascular dementia shows nonspecific patchy hypoperfusion in the neocortex, subcortical regions, and cerebellum. • Frontal blood flow has 80% sensitivity and 65% specificity in distinguishing FTDs from AD. fMRI • Research tools such as blood-oxygenation-level-dependent (BOLD) imaging and arterial spin labeling (ASL) are magnetic resonance imaging (MRI) techniques to magnetically tag blood and may have superior temporal and spatial resolution compared with PET and SPECT. • Hippocampal and parahippocampal regions show reduced BOLD activations during episodic encoding tasks in clinical AD. • In early mild cognitive impairment (MCI) and in APOE4 carriers, there may be a compensatory increase in hippocampal BOLD response that precedes clinical worsening. • Default mode networks (DMNs) show reduced resting state connectivity as well as alterations in task-induced deactivation in MCI, AD, and in APOE4 carriers. Amyloid Imaging • Amyloid imaging may help identify individuals at high risk for AD as well as test the efficacy of anti-amyloid therapeutics in clinical trials. • It uses two types of radio-labeled agents, (11)C—Pittsburgh Compound B (PiB) and (18)F— florbetapir, florbetaben, flutemetamol. • Plasma or cerebrospinal fluid (CSF) amyloid measurements indirectly estimate the extent of cerebral amyloidosis, but imaging can directly assess amyloid plaque pathology. • Amyloid imaging will soon supplement clinical evaluation in the diagnosis of AD, while MRI and FDG-PET may supplant cognitive tests as markers of disease progression. (11)C LABELED AGENTS • (11)C has a half-life of only 20 minutes, making large-scale distribution difficult. • PiB, the most extensively studied isotope, is an analog of the amyloid-binding dye Thioflavin-T. • It has an on-and-off accumulation pattern unlike the progression of pathologic brain changes. • BF227 labels dense amyloid deposits like Abeta plaques in AD as well as Lewy bodies in PD. (18)F LABELED AGENTS • The 2-hour half-life allows distribution from regional cyclotron facilities to local scanners for up to 10 hours post manufacture. • FDDNP-PET provides detailed visualization of both Abeta plaques and neurofibrillary tangles (NFTs) in AD. • Florbetapir, florbetaben, and flutemetamol show high affinity specific binding to amyloid deposits in the brain.

Chapter 7.1 Structural Neuroimaging in Degenerative Dementias Liana G. Apostolova Disclosures: This project was supported by a grant from the National Institute on Aging for the UCLA Alzheimer’s Disease Research Center (P50 16570) and the Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development.

Dementia is the persistent state of serious cognitive, functional, and emotional deterioration from a previously higher level of functioning, leading to impaired abilities of self-care and independent living. Dementia most commonly results from insidiously progressive neurodegenerative disorders such as Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). These disorders invariably cause irreversible brain parenchymal changes, which can be frequently detected with structural imaging. In recent decades, the predementia stages of neurodegeneration have attracted significant attention and have led to the recognition of a state called mild cognitive impairment (MCI). MCI (Petersen et al., 2001) and the related construct of prodromal AD (Dubois and Albert, 2004; Dubois et al., 2007) are increasingly important foci of research and clinical attention in our efforts to identify and treat patients early. The 2001 American Academy of Neurology (AAN) guidelines (Knopman et al., 2001) recommend structural neuroimaging as part of the routine clinical evaluation of patients with cognitive impairment supported by class II evidence of nondegenerative lesions, such as a slowgrowing brain neoplasm, subdural hematomas, or normal-pressure hydrocephalus, being the culprit for cognitive decline (Chui and Zhang, 1997). Although magnetic resonance imaging (MRI) is preferred, if MRI technology is not available or an MRI is contraindicated (such as in patients with pacemakers), computed tomography (CT) should be used. Recently, the role of structural and functional neuroimaging in the initial assessment and outcome prediction for subjects with cognitive decline has expanded with the newly proposed prodromal AD diagnostic criteria. This criteria is based on a combination of characteristic cognitive features and a well-established positive disease biomarker such as hippocampal atrophy or cerebrospinal fluid Abeta, and tau levels or a positive amyloid PET scan suggestive of AD (Dubois et al., 2007).

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The role of structural neuroimaging in Alzheimer’s disease Hippocampal atrophy Atrophy of the medial temporal lobe structures—the entorhinal cortex and the hippocampus—are considered the classic structural imaging hallmark of AD (Jack et al., 2004; Apostolova et al., 2006b; see Figure 7.1). These changes can be easily appreciated as early as the prodromal AD stages. As the disease evolves into a full-blown dementia syndrome, significant global brain atrophy with temporoparietal predilection and ventricular enlargement develops (see Figures 7.1 and 7.2; Thompson et al., 2003; Apostolova et al., 2007). These are easily appreciated on conventional CT or structural MRI sequences. In addition, MRI gradient echo sequences can reveal another common finding in AD patients—multiple small hemorrhages in the brain and spinal cord. These are due to accompanying amyloid angiopathy, which can also result in large, lifethreatening lobar hemorrhages in late life. The hippocampal imaging research field has been particularly productive in the past decade. Imaging biomarkers are presently being developed as diagnostic and prognostic biomarkers and as surrogate biomarkers for clinical trials. Hippocampal atrophy, the most validated structural biomarker, is already being accepted as a biomarker criterion for AD presence in the prodromal AD stages (Dubois et al., 2007). The hippocampus undergoes age-related structural changes. Hippocampal atrophy has been found to accompany normal aging with an estimated volume loss rate of around 1.6–1.7% annually (Jack et al., 1998, 2000). MCI subjects who eventually convert to dementia and AD subjects show a hippocampal volume loss of 3.7% and 3.5–4% per year, respectively, but MCI subjects who remain cognitively stable show an annual atrophy rate of 2.8% (Jack et al., 1998, 2000). Although this volumetric measure is seemingly useful and intuitive, it cannot capture the complex pattern of disease progression within the hippocampal structure (Schonheit et al., 2004).

Structural Neuroimaging in Degenerative Dementias

AD

Coronal view hippocampal head

Mid-sagittal view

NC

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images from a normal elderly person (normal control (NC), left column) and an advanced AD patient (right column). Significant hippocampal atrophy can be easily appreciated in the sagittal (top row) and coronal sections through the hippocampal head (middle row) and body (bottom row). Cortical thinning of the entorhinal and parahippocampal cortex is also evident in AD.

Coronal view hippocampal body

Figure 7.1 7T structural MRI hippocampal

Figure 7.2 Brain atrophy in prodromal and advanced AD. In the

prodromal stages, mild hippocampal and global brain atrophy and mild ventriculomegaly are noted. In advanced AD, severe hippocampal and global brain atrophy and ventriculomegaly are easily identified.

New and advanced methodologies provide a unique opportunity to study the earliest AD-associated changes in the hippocampal structure. Advanced computational anatomy, hippocampal shape, and deformation techniques allow us to study the subregional hippocampal changes (Csernansky et al., 2000; Thompson et al., 2004). For example, the hippocampal radial distance mapping approach (which models the hippocampal structure in 3D) computes hippocampal thickness at each surface point. Using the radial distance or other conceptually related approaches, researchers have now mapped the progression of AD pathology through the hippocampal structure in vivo (Csernansky et al., 2000, 2005; Apostolova et al., 2006a, 2006b, 2010c) and documented the spread of hippocampal atrophy from the subiculum and CA1 subfield to the CA2-3 region—a pattern that was previously captured in only postmortem studies (Schonheit et al., 2004). The unsurpassed precision of surface-based approaches has allowed us to also document subtle hippocampal structural changes years before the onset of cognitive decline, suggesting a potential role of such technologies in presymptomatic diagnosis and risk assessment. For example, subtle atrophy can be readily detected in the prodromal AD stages as early as 3 years before evident cognitive impairment, warranting a diagnosis of MCI in cognitively normal elderly patients who eventually

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Figure 7.3 3D hippocampal atrophy maps showing the amount of atrophy (in %) accumulated over a 3-year period in cognitively normal elderly patients who remained cognitively normal for 6 years or longer since baseline (NL–NL) and cognitively normal elderly patients who were diagnosed with amnestic MCI at 3 years and AD at 6 years (NL–MCIAD). (For a color version, see the color plate section.)

develop full-blown dementia syndrome of the Alzheimer’s type (Apostolova et al., 2010b; see Figure 7.3). In addition, CA1 atrophy of the hippocampus at baseline was recently shown to increase the future risk of conversion to dementia in the MCI stage (Apostolova et al., 2010c). The next major advance in structural hippocampal imaging is the recent development of automated hippocampal segmentation techniques (Fischl et al., 2002, 2004; Yushkevich et al., 2006; Morra et al., 2008a), which has allowed rapid and successful analyses of very large datasets such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI; Morra et al., 2009a). ADNI data analyses have confirmed previous findings from smaller studies and helped us map the expected associations between hippocampal atrophy and cognitive deterioration (Apostolova et al., 2006d; Morra et al., 2008b; Mormino et al., 2009; Beckett et al., 2010). Important observations from the ADNI study have also linked genetic risk factors and rates of hippocampal atrophy. The hippocampi of APOE ε4 allele carriers were reported to atrophy faster than those of noncarriers (Morra et al., 2009b; Schuff et al., 2009; Beckett et al., 2010). MCI subjects with a maternal history of dementia had greater atrophy at baseline and greater 12-month atrophy rates relative to those who had a negative maternal history of dementia (Andrawis et al., 2012).

Cortical atrophy Cortical atrophy, a classic feature of AD, has also been heavily researched in recent years with advanced and more precise techniques and approaches. The contemporary cortical thickness approaches currently offer the most precise cortical mapping (Fischl et al., 1999; Fischl and Dale, 2000; Thompson et al., 2003). Using these techniques has allowed us to document in vivo the progressive spread of cortical atrophy in subjects with AD

(Thompson et al., 2003), to identify the excess cortical damage in subjects with very mild AD compared with those with MCI (see Figure 7.4; Apostolova et al., 2007), and to ascertain the cortical subregions that most sensitively predict AD type dementia in the elderly (Lerch et al., 2005; Bakkour et al., 2009). Cortical areas that are affected early include the entorhinal, parahippocampal, inferior, and lateral temporal cortices, with disease changes spreading next to the parietal and frontal association cortices (see Figure 7.4; Thompson et al., 2003). It is now well established that MCI subjects have intermediate cortical thickness relative to cognitively normal elderly and AD subjects in the normal aging–dementia continuum (Singh et al., 2006). Similar to hippocampal atrophy, cortical atrophy shows robust correlations with cognitive impairment (Thompson et al., 2003; Apostolova et al., 2006c, 2008a). Because the association cortex is highly specialized, the observed brain–behavioral associations have been very insightful. Global measures of cognitive decline, such as the mini– mental state examination (MMSE), show a widely distributed pattern of association with cortical atrophy, including the entorhinal, parahippocampal, precuneal, superior parietal, and subgenual cingulate association cortices (Apostolova et al., 2006c). However, impaired language function showed associations with the perisylvian cortical areas thought to play an important role in lexical and semantic storage and retrieval and language processing (Apostolova et al., 2008a). Investigating the effects of APOE4 genotypes on cortical atrophy has resulted in several interesting reports. Several groups recently reported that APOE4 carriers show a more aggressive involvement of the temporal association cortices relative to noncarriers (Filippini et al., 2009; Gutierrez-Galve et al., 2009; Pievani et al., 2009).

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Figure 7.4 Cortical atrophy in AD. Relative to patients with amnestic MCI, patients with very mild AD show extensive cortical atrophy of the entorhinal, parahippocampal, inferior, and lateral temporal cortices, with disease changes spreading next to the parietal and frontal association cortices (left column). The pattern is strikingly similar to the amyloid deposition described in Braak and Braak amyloid stage B (right column). (For a color version, see the color plate section.)

Ventricular enlargement Ventricular enlargement is another consistent finding in AD. The radial distance approach has also been applied to study the changes in the ventricular system in AD. Although ventricular enlargement is largely nonspecific and occurs in many degenerative and nondegenerative neurologic conditions, it is a robust imaging biomarker in AD. MCI subjects show a posterior-predominant enlargement of the lateral ventricles; however, when subjects are in the dementia stages of AD, a panventricular enlargement is readily observed (Chou et al., 2008). APOE4 carriers show a frontal-predominant dilatation pattern relative to APOE4 noncarriers. Cognitive measures show the expected strong linkage in an AD-like pattern (Chou et al., 2008). White matter changes White matter changes have been long implicated in neurodegeneration (Bartzokis et al., 2004; Bartzokis, 2007) and have been associated with cognitive decline in the elderly (Debette et al., 2010). In the ADNI sample, greater white matter hyperintensity burden at baseline was associated with greater cognitive decline during the following 12 months (Carmichael et al., 2010). Diffusion-weighted imaging (DWI) sequences have been recently utilized to study white matter integrity. Microstructural changes in the myelin sheath result in greater diffusivity and reduced fractional anisotropy on DWI sequences, and are positively correlated with worsening cognition in MCI and AD (Wang et al., 2010). A comprehensive meta-analysis recently revealed that the white matter changes in AD are nonuniform. The greatest changes in fractional anisotropy and mean diffusivity were seen in the uncinate fasciculus (the white matter

tract connecting the hippocampus and amygdala with the anterior temporal lobe) and the superior longitudinal fasciculus (a white matter tract connecting the anterior (frontal) with the posterior (temporal, parietal, and occipital) association cortices; Sexton et al., 2011.). Medium effect size was seen in the genu and splenium of the corpus callosum and the frontal and temporal white matter (Sexton et al., 2011). Among subjects with MCI, the most pronounced differences relative to normal controls were seen in the hippocampus and parietal white matter (Sexton et al., 2011). Decreased fractional anisotropy has been reported in preclinical presenilin mutation carriers in the fornix and orbitofrontal white matter, suggesting that brain parenchymal changes begin years and possibly decades before dementia onset (Ringman et al., 2007).

The role of structural neuroimaging in the frontotemporal dementia (FTD) spectrum The FTDs are a group of neurodegenerative disorders affecting the frontal or temporal lobes disproportionately to the rest of the brain with variable post-mortem pathologic findings. The group comprises several distinct phenotypes: the classic frontal or behavioral variant FTD (fvFTD), two language variants—primary progressive aphasia (PPA) and semantic dementia (SD)—and one variant with associated motor neuron disease (MND), FTD-MND. At the time of diagnosis patients with fvFTD usually reveal substantial frontal or temporal (often asymmetrical) atrophy (see Figure 7.5). The classic MRI feature of nonfluent PPA is left perisylvian atrophy, particularly in

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Figure 7.5 Brain atrophy in FTD. Frontal variant FTD is characterized by prominent frontal lobe atrophy. Primary progressive aphasia subjects have asymmetric left-predominant perisylvian atrophy most pronounced in the posterior portions of the inferior frontal gyrus. SD patients characteristically present with left-predominant anterior temporal atrophy.

the inferior frontal cortex and insula; however, fluent PPA patients tend to show inferior, middle, and polar temporal lobe involvement. SD patients usually present with bilateral anterior temporal lobe involvement (Gorno-Tempini et al., 2004; Chao et al., 2007). DWI imaging in FTD has also shown abnormalities. Reduced fractional anisotropy has been reported in the frontal and temporal lobe white matter and the anterior cingulate (Zhang et al., 2009). Reduced fractional anisotropy in the uncinate fasciculus and the occipitofrontal fasciculus have recently been reported in still asymptomatic Progranulin mutation carriers, suggesting that brain parenchymal changes begin years and possibly decades before the onset of dementia (Borroni et al., 2008).

The role of structural neuroimaging in dementia with Lewy bodies On the basis of structural imaging alone, DLB is difficult to distinguish from AD. Upon visual inspection of clinical CT or MRI scans, patients with DLB often have mild-tomoderate nonspecific, generalized brain atrophy. Hippocampal involvement may be present. After a larger number of DLB subjects scans are analyzed, some atrophy patterns emerge. DLB has been associated with diffuse temporal, parietal, and frontal cortical atrophy (Burton et al., 2002; Ballmaier et al., 2004; Beyer et  al., 2007b), as well as with atrophy of the dorsal midbrain, hypothalamus, and substantia innominata (Whitwell et al., 2007). Diffusion tensor imaging (DTI) signal changes in DLB are somewhat similar to patients with AD. Decreased fractional anisotropy was found in the inferior longitudinal fasciculus—the white matter tract connecting the temporal with the occipital lobes—in both disorders (Kantarci et al., 2010). In the DLB group, this finding showed a strong association with visual hallucinations (Kantarci et al., 2010). Another study compared the DTI characteristics between DLB and Parkinson’s disease dementia (PDD). Relative to the PDD group, DLB subjects showed more severe and more extensive abnormalities, with fractional

anisotropy decreases in the posterior cingulate and visual cortices (Lee et al., 2010).

The role of structural neuroimaging in Parkinson’s disease dementia Cognitive impairment is arguably the most understudied nonmotor syndrome in Parkinson’s disease (PD). Yet as many as 90% of all PD subjects develop dementia during the disease course (Buter et al., 2008). In PD, the clinical indications for obtaining an MRI would be to rule out basal ganglia strokes, diffuse white matter ischemic changes, features associated with other parkinsonian disorders, such as midbrain atrophy, which is commonly seen in progressive supranuclear palsy (PSP), or an asymmetric frontoparietal atrophy that could suggest corticobasal degeneration (CBD). Yet widespread cortical atrophy in PDD- and PD-associated MCI does occur and involves the limbic, temporal, parietal, frontal, and occipital cortical regions and caudate nuclei (Burton et al., 2004; Beyer et al., 2007a; Meyer et al., 2007; Apostolova et al., 2010a; Hwang et al., 2013). These cortical changes are also accompanied by atrophy of the caudate nuclei and lateral and third ventricular enlargement (Meyer et al., 2007; Apostolova et al., 2010a). As previously mentioned, PDD subjects also show decreased fractional anisotropy in the frontal, temporal, and parietal white matter (Lee et al., 2010).

The role of structural neuroimaging in other parkinsonian dementias and Creutzfeldt–Jakob disease The frequently asymmetric clinical cortical features of CBD—cortical sensory loss, and limb apraxia—are reflected in often strikingly asymmetric contralateral frontoparietal atrophy, with clear involvement of the motor and sensory cortices. High T1 signal intensity of the subthalamic nucleus, midbrain atrophy, and T2 striatal hypointensity can also be seen (Sitburana and Ondo, 2009; Tokumaru et al., 2009).

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promising disease-modifying agents in the pharmaceutical pipeline, AD researchers are hopeful to soon be able to cure and prevent this most devastating neurodegenerative disorder.

References

Figure 7.6 Diffusion-weighted imaging findings in CJD. Extensive cortical hyperintensities can be identified in the right temporal, the bilateral insular and frontal cortex, and the caudates.

The classic structural MRI abnormalities of PSP are atrophy of the midbrain tegmentum, enlargement of the third ventricle, hyperintensity of the midbrain, and inferior olives (Oba et al., 2005; Boxer et al., 2006). Some studies have also reported frontal and temporal cortical atrophy and hypointensity of the red nucleus and putamen (Gupta et al., 2010). The classic MRI findings in Creutzfeldt–Jakob disease (CJD) are increased T2, fluid attenuation inversion recovery (FLAIR), and diffusion signal of the basal ganglia and the cortical ribbon. Such findings are essentially pathognomonic for CJD (see Figure 7.6; Milton et al., 1991; Hirose et al., 1998; Yee et al., 1999; Zeidler et al., 2000; Matoba et al., 2001).

Conclusions Structural neuroimaging almost invariably shows significant abnormalities in most neurodegenerative disorders. The most prevalent neurodegenerative disorder—AD— is one of the leading health concerns of the twenty-first century, with an increasing elderly population and its exponentially increasing social and economic impact. Researchers are already tuned into developing powerful biomarker strategies that can potentially identify the cognitively normal elderly who have entered the presymptomatic (prodromal) AD stages, as these subjects would be the ideal therapeutic target for any disease-modifying drug. In the recent two decades, neuroimaging researchers have developed major revolutionary technologic advances in both structural and functional neuroimaging fields. The rapid development of new promising techniques capable of reliable, sensitive, and powerful detection of focal disease-induced changes instills optimism that disease course and therapeutic response could be carefully monitored and appraised. With several

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Chapter 7.2 Functional Imaging in Dementia Adam S. Fleisher and Alexander Drzezga Alzheimer’s disease (AD) is pathologically manifested as synaptic loss and neuronal death, with subsequent reduction of metabolic activity and brain volume loss. Although the specific neurodegenerative pathway in AD is unknown, it is believed to predominantly be an amyloid protein-mediated process (Braak and Braak, 1991, 1994; Selkoe, 2000). It is most widely accepted that beta amyloid (Aβ) is poorly cleared in AD patients, leading to increased soluble and insoluble extracellular Aβ, also leading to fibrillar amyloid plaque deposition and downstream neurotoxic pathways (Selkoe, 2008). According to this hypothesis, excess Aβ leads to loss of neuronal synapses, intracellular neurofibrillary tangles (NFTs), and cellular toxicity, resulting in mitochondrial dysfunction and, ultimately, cell death (Mirra et al., 1991, 1993). This pathologic process progresses in predictable regional patterns predominantly involving structures in the basal forebrain, medial temporal lobes (MTLs), and parietal cortex (Braak and Braak, 1996). In addition, neuropathology and synaptic dysfunction may occur several decades before clinical manifestations (Braak and Braak, 1991; Reiman et al., 2004; Engler et al., 2006; Mintun et al., 2006). And it is likely that neuronal synaptic dysfunction precedes Aβ plaque deposition and the gross pathologic changes associated with AD (Selkoe, 2002). If physiologic changes can be identified before clinical and gross pathologic changes, this provides a potential opportunity for sensitive presymptomatic imaging biomarkers of disease. Standards for the diagnosis of dementia today are based entirely on clinical symptoms (McKhann et al., 1984). Medical history of progressive cognitive decline consistent with AD, ruling out active confounding comorbidities, and neuropsychological evaluations are the mainstays for establishing a diagnosis of dementia. Neuropsychological evaluations, however, have a relatively low sensitivity and specificity of 80% and 70%, respectively, for identifying pathologically confirmed dementia of the Alzheimer’s type (Jobst et al., 1998; Knopman et al., 2001; Silverman et al., 2002b; Lopponen et al., 2003; Petrella et al., 2003; Zamrini et al., 2004). Guidelines recommend imaging predominantly as a tool for excluding other causes of dementia, such as cerebrovascular disease, infection, normal pressure hydrocephalus, and other structural lesions (Knopman et al., 2001; http://www. aan.com/professionals/practice/pdfs/dementia_guideline. pdf). New advancements in functional imaging may provide tools for identifying neurodegenerative brain disease

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for clinical decision making and treatment development. Recently, the European Federation of the Neurological Societies (EFNS) recommended the use of functional imaging as part of the routine diagnostic workup of clinically questionable dementia cases (Hort et al., 2010).

What is functional imaging? Unlike imaging of gross brain structures or even micropathology, functional imaging is defined as any imaging modality that represents an underlying physiologic process. This type of imaging can capture static average brain function while a participant is resting with eyes open or closed, or can identify dynamic brain activity in response to a task being performed during image acquisition. Such tasks may be cognitive in nature, such as with memory or language, or reflect sensory-, motor-, visual-, or even smell-related brain activity. Common physiologic targets of functional imaging include brain oxygen utilization, blood perfusion, and glucose metabolism. Various modalities of imaging can be used to identify these physiologic brain functions. In dementia, the most frequently utilized imaging modalities include magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). All three of these techniques are capable of imaging brain pathology and functional brain physiology. In addition, imaging methods that identify pathologic and physiologic changes associated with disease progression may be superior to neuropsychological testing regarding early and reliable diagnosis of AD (Lim et al., 1999; Hoffman et al., 2000; Silverman et al., 2001). But many techniques in dementia imaging are predominantly used for research and are not approved for clinical purposes. Therefore, this chapter focuses on functional imaging techniques that are available and practical in clinical dementia evaluations for the purpose of guiding physicians in clinical decision making. Structural MRI and amyloid imaging are addressed elsewhere.

Positron emission tomography in dementia PET imaging facilitates the detection of subtle changes in brain physiology. PET uses positron emitters to label

Functional Imaging in Dementia

target physiologic or pathologic brain processes. Positrons are positively charged unstable particles that interact with electrons while traveling through brain tissue. This interaction produces photons. These coincident tissue interactions are detected by sensitive detector rings in the PET scanner that make it possible to identify both spatial and intensity information. Various types of positron-emitting nuclei can be used to label tracers to identify physiologic targets of interest in vivo. The most common are 15O, 11C, and 18F, with 18F being the most widely used in clinical practice, mostly because its longer half-life makes it a more practical molecular isotope. In particular, PET imaging with a glucose analog, 18F fluorodeoxy glucose (FDG), has been used to identify subtle changes in metabolic glucose utilization in the brain. In AD, reductions in regional glucose metabolism, representing cellular metabolic activity, may be one of the earliest detectable brain dysfunctions accompanying the onset of AD pathology. In fact, there is reason to believe that FDG-PET may be able to detect brain dysfunction prior to notable amyloid pathology in the brain (Reiman et al., 2001; Alexander et al., 2002; Caselli et al., 2008; Langbaum et al., 2009). However, this idea is somewhat controversial, given our poor understanding of the relationship between amyloid deposition and glucose metabolism. In fact, there are examples of comparable FDG-PET uptake in amyloid PET positive healthy patients compared with amyloid negative patients, and areas of increased glucose metabolism associated with increased amyloid binding in mild cognitive impairment (MCI) patients (Cohen et al.,

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2009). Currently, the use of FDG-PET is recommended as only an optional complementary procedure in the diagnostic evaluation of dementia. However, as more information becomes available, it is more likely that functional imaging will play a more prominent role in early clinical diagnosis, risk assessment, and treatment–response monitoring. As a measure of neuronal dysfunction, radiolabeled glucose using FDG-PET allows tracking of glucose metabolism in the brain. It is well understood that glucose utilization parallels neuronal activity as its primary energy source. After intravenous injection, FDG is phosphorylized and incorporated into cells. The amount of regional FDG uptake then provides a spatial and intensity representation of brain cell cerebral metabolic rates of glucose metabolism (CMRgl; Phelps et al., 1983). Synaptic activity of neurons drives glucose utilization, perhaps indirectly, with increased glucose uptake in surrounding glial cells. Lactate is subsequently transferred to neurons for energy metabolism (Magistretti and Pellerin, 1999). In the resting state, FDG uptake is driven mostly by basal neuronal activity. In general, basal state FDG-PET imaging represents underlying neuronal integrity, with decreased function leading to regional reduction in glucose turnover (Rocher et al., 2003). In AD, patients have characteristic patterns of glucose hypometabolism. This consists of reduced FDG-PET signal in temporal–parietal, posterior cingulated, and frontal cortices (see Figure 7.7). These regions are well known to be associated with cognitive function such as memory

92 AD < 104 NC

Figure 7.7 FDG-PET in 92 AD and 184 MCI participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; Mueller et al., 2006; Jack et al., 2008a), compared with 104 cognitively normal elderly controls. Top images show typical patterns of glucose hypometabolism in Alzheimer’s disease (AD), compared with normal. Bottom images show similar AD-like patterns, but to a less spatial and intensity extent in MCI. See Langbaum et al. (2009) for methodology details. (For a color version, see the color plate section.)

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and spatial orientation. Likewise, brain regions spared of early hypometabolism in AD include the primary visual, sensory, and motor cortices, consistent with spared associated symptoms in clinical AD (Herholz, 1995; Silverman et al., 2001; Minoshima, 2003). This pattern is also consistent with known patterns of AD pathology (Braak and Braak, 1996; Klunk et al., 2004). Minoshima et al. (2001) found that patients with postmortem histopathologic proof of AD showed typical temporal–parietal, posterior cingulate, and frontal hypometabolic changes in prior FDG-PET scans. Hoffman et al. (2000) reported that temporal–parietal hypometabolism is the typical abnormality in patients with pathologically verified AD. Recently, one autopsy comparison study demonstrated longitudinal decline in FDG-PET CMRgl in cognitively normal individuals followed an average of 13 years (Mosconi et al., 2009b). Two of four patients declined to clinical AD in that time period. The authors observed that progressive CMRgl reductions on FDG-PET occurred years in advance of clinical AD symptoms in patients with pathologically verified disease. Deficits in CMRgl demonstrated progressive AD-like patterns, with most prominent reductions in the hippocampus, temporal–parietal, and posterior cingulate cortices. The FDG-PET profiles in life also were consistent with the postmortem diagnosis of AD. This small case series supports the idea that FDG-PET is a valuable preclinical marker of AD pathophysiology.

Disease severity and cognitive decline is strongly associated with glucose hypometabolism in AD (Kawano et al., 2001; Alexander et al., 2002; Bokde et al., 2005; Langbaum et al., 2009). In fact, regions of brain glucose hypometabolism that correlate with measures of global cognition are similar to patterns characteristic for AD (Langbaum et al., 2009). Figure 7.8 shows patterns of glucose hypometabolism correlated with the mini–mental state examination (MMSE) scores (Folstein et al., 1975), a brief global test of cognition commonly used in clinical practice, and the Clinical Diagnostic Rating scale (CDR; Berg, 1988), which is a functional and global cognitive assessment tool commonly used as an endpoint measure in AD clinical treatment trials. FDG-PET is highly sensitive and moderately specific for dementia of the Alzheimer’s type, with superior accuracy compared with neuropsychological testing. In a large multicenter trial, Silverman et al. (2001) found a sensitivity of 94% and a specificity of 73% for identifying histopathologically proven AD. Comparatively, when using pathologically confirmed AD as a diagnostic gold standard, neuropsychological testing has shown a sensitivity of 85% and specificity of 55% (Lim et al., 1999; Hoffman et al., 2000). These studies provide convincing evidence that diagnostic workups for AD that include FDG-PET are more accurate than neuropsychological and medical evaluation alone. In addition, it has been demonstrated

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Figure 7.8 FDG-PET in 298 participants with varying degrees of MCI and AD, and cognitively normal elderly from ADNI ( Mueller et al., 2006; Jack et al., 2008a). (a) Areas of correlated FDG-PET binding representing glucose hypometabolism associated with CDR scores. (b) Areas of correlated FDG-PET binding representing glucose hypometabolism associated with MMSE scores. Regions associated with cognitive impairment are similar to those associated with a diagnosis of clinical AD (Figure 7.7). See Langbaum et al., 2009 for methodology details. (For a color version, see the color plate section.)

Functional Imaging in Dementia

that FDG-PET is cost-efficient and can lead to improved management, including therapeutic decision-making and overall patient care (Silverman et al., 2002a, 2002b; Moulin-Romsee et al., 2005). Although there is some controversy regarding whether glucose hypometabolism is a cause or consequence of AD, FDG-PET represents a valuable tool for early diagnosis and differential diagnosis in AD (Silverman et al., 2002b; Minoshima, 2003). FDG-PET is the most validated functional imaging technique available to most clinicians for evaluating dementia patients. AD is a clinical diagnosis in evolution, with a push to define the disease by pathologic biomarkers as part of clinical diagnostic criteria (Dubois et al., 2007). Efforts are currently underway by the National Institute on Aging and the Alzheimer’s Association to revise existing NINCDS-ADRDA diagnostic criteria to better reflect this emphasis on biomarker evidence of disease. Recent recommendations from the EFNS include use of FDG-PET or perfusion SPECT in patients where there is diagnostic doubt in clinical dementia presentation (Hort et al., 2010). Functional imaging also may play an important role in identifying the earliest clinical stages of the disease processes. FDG-PET has been shown to be valuable in detecting early disease such as MCI, as a transitional stage between normal aging and clinical dementia. In addition, FDG-PET may be capable of identifying AD-like hypometabolism in asymptomatic people at increased risk factors for AD, suggesting its potential use as a presymptomatic predictor of future cognitive decline.

FDG-PET in MCI A clinical diagnosis of MCI is defined as a loss of cognitive function that exceeds common age-associated changes but does not meet the diagnostic criteria for dementia (Petersen et al., 1999, 2001; Petersen, 2000). Thus, MCI is regarded as a risk population for AD. Consequently, current guidelines of the American Academy of Neurology recommend that patients with MCI be identified and monitored for progression to AD (Knopman et al., 2001). Glucose hypometabolism occurs in MCI patients in patterns similar to those with AD, but to a lesser degree (see Figure 7.7). A number of studies have evaluated the value of FDG-PET in the diagnostic assessment of MCI. Several cross-sectional studies (some of them large, multicenter studies with more than 100 MCI subjects) have consistently demonstrated that FDG-PET imaging can reliably differentiate groups of MCI patients from healthy controls and on the basis of specific hypometabolic patterns (Minoshima et al., 1997; Drzezga et al., 2003, 2005; Del et al., 2008; Nobili et al., 2008). A number of studies have identified a predictive value of FDG-PET as a biomarker for determining future AD (Herholz et al., 1999; Arnaiz et al., 2001; Silverman et al., 2001; Chetelat et al.,

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2003; Drzezga et al., 2003, 2005; Mosconi et al., 2004; Hunt et al., 2007; Nobili et al., 2008; Landau et al., 2011). All these studies were able to identify typical hypometabolic changes in FDG-PET baseline examinations of MCI patients, associated with later conversion to AD dementia, whereas stable subjects showed fewer or no abnormalities. Generally, high sensitivity and specificity values were calculated (75–100%). Drzezga et al. (2005) demonstrated a sensitivity of 92% and a specificity of 89% (positive predictive value 85%, negative predictive value 94%) for predicting conversion to AD within 16 months. A number of studies were also able to demonstrate higher accuracy of FDG-PET for prediction of AD dementia in MCI patients, compared with neuropsychological examination (Silverman et al., 2001; Mosconi et al., 2004). While postmortem neuropathologic evaluation was considered as the gold standard, it is clear that adding FDG to the diagnostic evaluation improves prediction accuracy (Silverman et al., 2001). It is commonly agreed that brain pathology in AD begins many years prior to clinical symptoms of cognitive impairment. In fact, this pathologic burden may begin as many as 20 years before clinical manifestations (Mintun et al., 2006; Fagan et al., 2007). Functional imaging therefore affords us the opportunity to potentially identify AD before clinical symptoms develop. This is critically important for developing treatments to prevent future dementia and screening for individuals at increased risk for AD. Current diagnostic guidelines recommend against cognitive screening in asymptomatic individuals. Therefore, use of known risk factors for AD in healthy elderly individuals may provide guidance in determining which individuals should be screened for the pathologic hallmarks of AD. For example, patients with a strong family history of dementia and those with known genetic risk factors may have detectible presymptomatic biomarkers of AD pathology and represent such a risk population (Fratiglioni et al., 1993; Corder et al., 1998; Ghebremedhin et al., 1998).

FDG-PET in the evaluation of presymptomatic risk for AD Early-onset familial Alzheimer’s disease (FAD) is associated with autosomal-dominant inheritance of mutations in the presenilin and amyloid precursor protein genes (Goate, 1997; Ermak and Davies, 2002). Regional glucose hypometabolism on FDG-PET has been associated with asymptomatic FAD gene carriers, consistent with the typical AD PET pattern in the relative absence of structural brain atrophy (Mosconi et al., 2006; Nikisch et al., 2008). However, cases of FAD with autosomal-dominant inheritance represent only a small percentage of all AD cases and have a very different clinical onset and course

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compared with the more common late-onset sporadic AD (LOAD). Thus, findings obtained in this population may not be generalizable to LOAD. The apolipoprotein E (APOE) e4allele (ε4) is currently the most potent known genetic risk factor for LOAD (Corder et al., 1993; Farrer et al., 1997). It is associated with the subsequent presence of NFTs and amyloid plaques in the brain (Corder et al., 2004) and plays a key role in coordinating the mobilization and redistribution of cholesterol, phospholipids, and fatty acids. It also is implicated in the mechanisms of neuronal development, brain plasticity, and repair (Mahley, 1988; Mahley and Rall, 2000). Evidence indicates that it promotes formation of the beta-pleated sheet conformation of Aβ peptides into amyloid fibers and inhibits the neurotoxic effect of Aβ in an allele-specific manner (E3 > E4; Strittmatter et al., 1993; Ma et al., 1996; Jordan et al., 1998). The APOEε4 gene also appears to modulate Aβ toxicity to vascular endothelium (Folin et al., 2006). Having a family history of dementia is independent and additive to the risk associated with the APOE ε4 allele (Cupples, Farrer et al., 2004). For these reasons, presymptomatic pathologic and physiologic brain changes may be identifiable in individuals with genetic risk factors for AD by using FDG-PET. Several studies have been able to demonstrate hypometabolic abnormalities in cognitively impaired individuals at increased risk for AD, including carriers of the APOE ε4 allele and those with family histories of AD. For example,

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Reiman et al. (1996) showed reduced glucose metabolism in ε4 homozygotes, compared with age- and educationmatched noncarriers (ages 50–65 years). This occurred in the same brain regions as in patients with probable AD (posterior cingulate, parietal, temporal, and prefrontal regions). These same authors later demonstrated that even relatively young (20–39 years) ε4 homozygotes had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex, and that the ε4-gene dose is correlated with lower glucose metabolism in each of these brain regions (see Figure 7.9; Reiman et al., 2004, 2005). Furthermore, in several studies, decline of glucose metabolism over time in AD-typical regions has been demonstrated in cognitively healthy ε4 carriers (Small et al., 2000; Reiman et al., 2001). Correspondingly, more pronounced hypometabolism was detected in ε4-positive subjects with clinical AD, compared with age-matched ε4–negative AD patients (Drzezga et al., 2005). Recent studies have also shown hypometabolic changes in subjects with maternal history of AD who are at higher risk for dementia, suggesting additional genetic or environmental risks for LOAD (Mosconi et al., 2007, 2009a). For these reasons, functional brain imaging may be useful for evaluating putative AD prevention therapies in cognitively normal individuals at increased genetic risk for AD near the age of mean clinical dementia onset (Reiman, 2007; Fleisher et al., 2009a; Reiman et al., 2010).

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Figure 7.9 Regions of the brain with abnormally low CMRgl in young adult carriers of two copies of the APOE ε4-allele and their relationship to brain regions with abnormally low CMRgl in patients with probable AD. Purple areas are regions in which CMRgl was abnormally low only in patients with AD. Bright blue areas are regions in which CMRgl was abnormally low in both the young adult e4 carriers and patients with probable AD. The muted blue areas are regions in which CMRgl was abnormally low only in the ε4 carriers. Source: Reiman et al. (2004). Reproduced with permission from National Academy of Sciences. (For a color version, see the color plate section.)

Functional Imaging in Dementia

FDG-PET and other dementias FDG-PET may be particularly useful to clinicians in distinguishing AD from other dementias. As seen, typical patterns of hypometabolism can be identified in patients with AD. Likewise, other dementias show patterns of glucose metabolism that distinguish them from normal controls and AD patients. These disease-specific patterns can be used for differential diagnosis decisions and subsequent clinical management. However, much less data is available on other neurodegenerative dementias, given their relatively low prevalence compared with AD. FDG-PET can often be useful for diagnostic differential conclusions based on patterns of hypometabolism in individual patients. Yet, in common clinical dementia evaluation guidelines(Knopman et al., 2001), routine FDG-PET scans are not recommended in dementia evaluations because the added value over structural imaging has not been well established in individual patients. However it is reimbursable under Medicare, as noted, to distinguish clinically ambiguous cases of AD versus frontal temporal lobar dementia (FTLD). The EFNS guidelines now support its use in such cases (Hort et al., 2010).

Frontal temporal lobar dementia FTLD is a heterogeneous disorder representing a mix of pathologies and clinical presentations (Rabinovici and Miller, 2010). Pathologic features in FTLD syndromes include either tau-positive (FTLD-TAU) or TAR DNAbinding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLDs are clinical syndromes of progressive dysfunction of the frontal and/or temporal lobes, bilaterally or unilaterally, with clinical decline in behavior and/ or language, resulting in dementia. It is recognized as one of the leading causes of dementia before age 65. These disorders are clinically distinct from AD in most cases, but have overlapping syndromes with atypical parkinsonism, such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as with amyotrophic lateral sclerosis. Three primary types of FTLD syndromes exist, including behavioral variant (bvFTD), FTD associated with motor neuron disease (FTD-MND), and primary progressive aphasia (PPA). PPA is subsequently broken down into three aphasia variants: semantic, logopenic, and nonfluent/agrammatic. It has been demonstrated that forms of AD with atypical clinical appearance can be confused with the FTLD syndromes. Diagnosis based on neuropsychological criteria alone cannot assess underlying pathology or reliably differentiate such cases of nonamyloid pathology in atypical AD clinically presenting with FTLD-like symptoms (Neary et al., 1998). Postmortem studies demonstrate that clinical diagnosis alone may lead to confusion of FTLD and AD in some cases (Godbolt et al., 2005). With this degree of clinical and pathologic

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variability, it is not surprising that functional imaging may be just as heterogeneous in presentation. In many cases, functional neuroimaging can improve diagnostic accuracy in distinguishing clinical syndromes of FTLD with AD. Typical patterns of hypometabolism in FTLD include a combination of frontal or temporal predominant CMRgl reductions. At least early on in the course of the disease, these patterns show relative sparing of the parietal lobes, distinguishing them from AD (Ishii et al., 1998, 2000; Silverman et al., 2001; Ishii, 2002; Foster et al., 2007). When seen in individual patients, these patterns are useful in distinguishing FTLD from AD (see Figure 7.10). Foster et al. (2007) demonstrated that adding FDG-PET to clinical diagnostic criteria can significantly increase the accuracy of diagnosis. In comparison of 31 AD patients to 14 FTD patients, they were able to achieve a specificity of 97.6% and sensitivity of 86% for distinguishing AD from FTD. This was particularly true with visual inspections of individual images projected onto stereotactic brain surface projections. Unfortunately, this holds true at the group level but cannot always be identified in individual patients (Silverman et al., 2001). Nonetheless, when typical frontal and/or anterior frontal hypometabolism is seen, it can improve clinical diagnostic accuracy. Figure 7.10D demonstrates an example of frontal hypometabolism on FDG-PET in a patient with bvFTD.

Dementia with Lewy bodies Approximately 15% of dementias occurring over the age of 65 result from dementia with Lewy bodies (DLB), as the second most common type of late-onset dementia (Heidebrink, 2002). DLB involves widespread neuronal degeneration with deposition of Lewy bodies and Lewy neurites, which contain alpha-synuclein as a major filamentous component (Galvin et al., 1999). Similar to AD in its progression with prominent memory dysfunction, DLB also typically presents with fluctuations in cognitive impairment, prominent visuospatial dysfunction and visual hallucinations, and early parkinsonism (McKeith et al., 2005). In fact, DLB is often an overlap syndrome with the majority of DLB patients also meeting pathologic CERAD criteria for AD, with the addition of diffuse cortical Lewy bodies (Fleisher and Olichney, 2005). There have been relatively few investigations of DLB with functional imaging, compared with AD. But consistent with structural findings, there appears to be a relative sparing of the MTL and an overall pattern of glucose hypometabolism, similar to AD (Burton et al., 2002; Weisman et al., 2007). In addition to precuneus and posterior cingulated hypometabolism, decreased glucose utilization is often seen in the primary visual and the occipital association cortices, consistent with the clinical presentation of DLB (see Figure 9.4; Minoshima et al., 2001; Gilman et al., 2005). This pattern of hypometabolism is consistent with a finding of diffuse

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Lewy bodies on autopsy (Albin et al., 1996; Minoshima et al., 2001; Gilman et al., 2005; Mosconi et al., 2009b). One such study by Minoshima et al. (2001) comparing 11 DLB with 10 AD patients, showed significant metabolic reductions in DLB compared with AD, with 90% sensitivity and 80% specificity. In addition, dopaminergic loss and dopamine transport loss in the striatum has been demonstrated at autopsy to be similar in magnitude in DLB to that seen in Parkinson’s disease (PD) (O’Brien et al., 2004). Experimentally, PET ligands that bind to dopamine ([18F] fluorodopa) and monoamine transporters ([11C]DTBZ) have demonstrated reduced striatal dopamine activity in DLB compared with AD, consistent with the high prevalence of parkinsonism in this dementia (Hu et al., 2000; Koeppe et al., 2008; Klein et al., 2010). These dopamine PET imaging techniques are not widely available and are not recommended for routine evaluations of DLB. However, SPECT tracers for imaging of dopamine transporters may have clinical value and have recently been demonstrated to reliably differentiate between DLB and AD.

Vascular dementia Vascular dementia is typically diagnosed with a combination of clinical and MRI findings (van Straaten et al., 2003). Functional imaging would be used only for cases with equivocal findings. In addition, 15–20% of vascular dementia patients will have a combination of AD and vascular pathology (Chui et al., 2000). Findings of patchy deficits rather than typical patterns of parietotemporal dysfunction may help distinguish vascular dementia from AD (Talbot et al., 1998; Jagust et al., 2001). However, MRI imaging for ischemic disease is routinely recommended over functional imaging for diagnostic evaluation.

FDG-PET in the clinic FDG-PET scanning, in general, is approved for clinical use. However, Medicare in the United States has specific National Coverage Determinations for use of FDG-PET as a diagnostic test for dementia and neurodegenerative diseases (Medicare Manual Section Number 220.6.13). In general, Medicare covers FDG-PET scans for the differential diagnosis of frontotemporal dementia (FTD) and AD. An FDG-PET scan is considered reasonable and necessary in patients with a recent diagnosis of dementia and documented cognitive decline of at least 6 months who meet diagnostic criteria for both AD and FTD. These patients have been evaluated for specific alternate neurodegenerative diseases or other causative factors, but the cause of the clinical symptoms remains uncertain. Coverage varies from state to state, and there is no guarantee that a private insurance carrier will cover the cost or approve the imaging procedure. Costs can be as high as $4000 if not covered

by the patient’s insurance, so it is important to have these discussions with patients before ordering scans. When used in individual patients in the clinic, the typical pattern of glucose hypometabolism for MCI, AD, FTLD, and DLB is often identifiable and potentially useful for diagnosis and clinical decision-making (see Figure 7.10).

Single photon emission computed tomography SPECT imaging uses gamma photon–emitting radioisotopes attached to biologically relevant molecules that have been injected intravenously and distributed throughout the body. As gamma-emitting molecules are dispersed in the body, they are attenuated as they pass through different types of tissue. This attenuation is assumed to be homogenous throughout the brain. A gamma camera is used to detect the photon signal, and collimators funnel photon activity to the camera as they are emitted in defined directions, allowing for the detection of spatial patterns. This directional filtering allows only a small portion of photons to be detected, which limits the sensitivity of SPECT compared with PET. The gamma camera rotates around the patient, generating 2D images projected from various angles. Three-dimensional reconstruction of these 2D images facilitates the modeling of biologically meaningful physiologic processes such as blood flow and receptor-binding capacity. Modern cameras use dual- or triple-head cameras to reduce acquisition times. With regard to neurologic indications, SPECT most commonly is used to measure cerebral blood flow by using common gamma-emitting tracers such as Technetium 99-hexamethylpropylene amine oxime (99mTcHMPAO) and 99mTc-ethylenedicysteine-folate (99mTcEC-folate; Shagam, 2009). SPECT has historically been widely available and well studied in AD (Silverman, 2004). It continues to be widely available and somewhat less expensive than FDG-PET scanning. It is approved by the FDA for general medical use but has no specific Medicare indication for dementia. Insurance coverage for use in dementia is therefore variable but generally good. Similar to hypometabolism seen on FDG-PET imaging, SPECT shows decreased cerebral perfusion in bilateral temporalparietal lobes (Table 7.1). As in PET, the frontal lobes are also affected in AD (often in the later stages of dementia), but the primary sensorimotor strips and basal ganglia are typically spared (Silverman et al., 2001; Dougall et al., 2004; Pakrasi and O’Brien, 2005). SPECT in MCI has likewise revealed consistent patterns of cerebral hypoperfusion, though to a lesser degree than that seen in AD, and has shown some predictive value for AD (Johnson et al., 1998; Huang et al., 2002; Staffen et al., 2006). One recent study demonstrated a limited

Functional Imaging in Dementia

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Figure 7.10 Individual FDG-PET

scans in a patient with (a) normal cognition, (b) MCI, (c) AD, (d) bvFTLD, and (e) DLB. Images on the left are individual FDGPET CMRgl binding, showing areas of significant glucose hypometabolism compared with normal controls (blue). An automated algorithm was used to transform individual patient images into the dimensions of a standard brain and compute statistical maps of significantly reduced glucose metabolism relative to 67 normal control subjects (mean age 64 years). Redoutlined regions represent areas of mean hypometabolism seen in FDG-PET scans from 14 patients with AD (mean age 64 years), compared with the same 67 normal controls. On the right are raw FDG-PET color maps from the same corresponding patients. Here we can see the use of FDGPET for identifying diseasespecific patterns of glucose metabolism for clinical use in individual patients, to assist with diagnostic decision-making. (For a color version, see the color plate section.)

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utility of SPECT for predicting progression to AD from MCI. The authors found that visual ratings of SPECT in the temporal and parietal lobes did not distinguish eventual MCI converters to AD (N = 31) from nonconverters (N = 96), whereas a global rating of dementia did (41.9% sensitivity and 82.3% specificity, Fisher’s exact test p = 0.013; Devanand et al., 2010). Only when dichotomized at the median value of the patients with MCI did low flow increase the hazard of conversion to AD for parietal (hazard ratio: 2.96, 95% CI: 1.16–7.53, p = 0.023) and medial temporal regions (hazard ratio: 3.12, 95% CI: 1.14–8.56, p = 0.027). In a 3-year follow-up sample, low parietal (p <0.05) and medial temporal (p <0.01) flow predicted conversion to AD, with or without controlling for age, MMSE, and APOE ε4 genotype. However, these measures lost significance when other strong predictors were included in logistic regression analyses such as verbal memory and social/cognitive functioning. Overall, the literature on predementia and risk for dementia is considerably scarce for perfusion SPECT compared with that for FDG-PET.

Other dementias show similar regions of hypoperfusion on SPECT scanning to glucose hypometabolism. FTLD patients often show expected patterns of frontal and anterior temporal lobe hypoperfusion (Coulthard et al., 2006; McNeill et al., 2007). McNeill et al. (2007) found that frontal blood flow had a sensitivity of 80% and specificity of 65% in distinguishing AD from FTD. DLB shows expected patterns of cerebral hypoperfusion similar to AD, but as with FDG-PET, it reveals relatively more blood flow reduction in the visual cortex (Donnemiller et al., 1997; Lobotesis et al., 2001). However, modest sensitivity and specificity of around 60–65% suggest limited usefulness of HMPAO SPECT to distinguish AD from DLB (Lobotesis et al., 2001). Yet, DLB offers an opportunity to explore other molecular targets with SPECT imaging. As noted previously, dopaminergic loss in the striatum is present in DLB on autopsy with a similar magnitude as seen in idiopathic PD(O’Brien et al., 2004). 123ioflupane (IFP)-CIT (DAT-SCAN) is a SPECT ligand that enables visualization of nigrostriatal dopaminergic neurons. Studies have demonstrated IFP-CIT SPECT imaging to have  an overall accuracy of

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around  86%, with a sensitivity of 78% and specificity of 90% for distinguishing DLB from other dementias (primarily AD), and 78% sensitivity and 94% specificity for distinguishing it from PD (O’Brien et al., 2004; McKeith et al., 2007). Another interesting SPECT finding is reduced cardiac uptake of metaiodobenzylguanine (MIBG) in DLB patients, compared with normal controls and AD. MIBG SPECT is thought to be a measure of cardiac sympathetic denervation in DLB patients. MIBG cardiac imaging has shown sensitivities of 95–100%, and specificity of 87–100% for distinguishing DLB from AD and normal controls (Hanyu et al., 2006a, 2006b; Yoshita et al., 2006; Kobayashi et al., 2009). This association also appears to be related to clinical symptoms of orthostatic hypotension (Kobayashi et al., 2009). For these reasons, dopamine imaging has been included as a “suggestive feature” in the International Consensus criteria for diagnosis of DLB. MIBG SPECT and perfusion SPECT have been included as “supportive features” (McKeith et al., 2005; McKeith, 2006). Dopaminergic SPECT is also now recommended, with strong evidence for clinical evaluations to distinguish AD from DLB by the EFNS (Hort et al., 2010).

Table 7.1 FDG-PET and SPECT perfusion findings in dementia

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Functional magnetic resonance imaging

In general, diagnostic accuracy of SPECT is not as good as that of PET (Silverman, 2004). This is partly due to the reduced magnitude of changes in cerebral perfusion compared with glucose hypometabolism in AD, and partly due to reduced spatial resolution compared with modern PET scanners (Masterman et al., 1997; Silverman, 2004). One review of SPECT literature in AD revealed 71% sensitivity and 90% specificity for AD versus normal elderly controls, with 76% specificity for other dementias (Dougall et al., 2004). As previously noted, PET studies have shown sensitivity of 94%, with specificity similar to SPECT at 73% (Silverman et al., 2001). One study comparing FDG-PET with HMPAO SPECT in distinguishing AD (n = 20), nonAD dementias (n = 12), and cognitively normal elderly found a 90% diagnostic accuracy with FDG-PET and 67% accuracy using SPECT. When looking at patients with MMSE scores greater than 20, SPECT accuracy did not improve (Herholz, 1995). Consistent with this, several studies utilizing high-resolution SPECT and PET systems have suggested 15–20% increased sensitivity with FDG-PET, compared with perfusion SPECT for detecting AD (Messa et al., 1994; Mielke et al., 1994; Mielke and Heiss, 1998). PET and FDG SPECT and HMPAO SPECT changes are highly correlated with each other (r = 0.90), particularly in the posterior cingulated and temporoparietal regions, with significantly more pronounced abnormalities in tracer uptake of FDG, compared with HMPAO (Herholz et al., 2002). Despite the reduced cost and wide availability of SPECT, its limitations and the increasing

MRI can generate images of the brain with superior spatial and temporal resolution, compared with SPECT or PET scanning. It also has the advantage of generally being less costly to perform and does not use any form of radiation, unlike SPECT, PET, and computed tomography (CT). MRI measures variance in magnetic fields and changes produced by radio frequency pulses against the magnetic dipoles of hydrogen molecules in the body and brain. By measuring the various magnitudes and directions of magnetic field distortion, MRI scanners can reconstruct 2D and 3D images of the brain. By adjusting the radio frequency pulses and assessing the amount of time it takes the magnetic dipole distortion to return to its equilibrium state, MRI imaging can be adjusted to measure specific types of tissue. Not only can this be done to produce highresolution anatomic images, but it can be used to measure physiologic processes as well. The most common types of functional MRI (fMRI) are blood-oxygenation-leveldependent imaging (BOLD) and arterial spin labeling (ASL). Despite the high potential of fMRI as a tool for clinical diagnosis of early functional biomarkers in AD, it has yet to be proven useful in individual patients. These techniques require sophisticated statistical data analysis and are plagued by intra- and intersubject and scanner variability. For these reasons, fMRI is currently used only as a research tool in the field of dementia. fMRI can measure brain physiology during the resting state or in response to a cognitive task, such as memorization. When a region of the brain is active or stimulated,

Dementia type

Deficits in nuclear imaging

Alzheimer’s disease (AD)

Early regional hypoperfusion and glucose hypometabolism in parietal, temporal, and posterior cingulated cortices, with relative sparing of primary visual and sensorimotor cortex, striatum, thalamus, and cerebellum. Findings can be asymmetric in early disease. Dementia with Lewy Similar deficits as seen in AD, plus hypoperfusion bodies (DLB) and hypometabolism in the primary visual cortex. Frontotemporal lobar Hypoperfusion and hypometabolism in the dementia frontal, anterior temporal, and mesiotemporal regions early in disease, with later involvement of parietal cortex. Sensorimotor and visual cortices are typically spared. Vascular dementia Patchy hypoperfusion and hypometabolismin nonspecific patterns within the neocortex, subcortical regions, and/or cerebellum. Source: Adapted from Silverman (2004).

availability of advanced PET scanners and tracers have made PET imaging much more prominent both in clinical research and for diagnostic evaluations by clinicians.

Functional Imaging in Dementia

the metabolic rate of oxygen consumption (CMRO2) is increased locally. This drives a perfusion response to increase oxygenated blood flow to that region of the brain (Fox and Raichle, 1986). This influx of oxygenated blood effectively decreases the local level of deoxygenated hemoglobin (Buxton et al., 2004). As deoxygenated hemoglobin levels go down, the fMRI signal goes up. In short, increasing oxygenated blood increases the local fMRI signal, which can be detected at a volumetric resolution of about 1–3 mm3. This allows determination of variable levels of brain activity in disease states such as AD. ASL imaging allows quantifiable measures of cerebral blood perfusion in physiologic units ([ml of blood]/[100 gm of tissue]/min). First developed in 1992, ASL was later modified for human use (Alsop and Detre, 1996). The principles of ASL are similar to those underlying PET studies with H215O. In this fMRI technique, blood is magnetically “tagged” before entering the brain; after waiting for a predetermined time and distance for the tagged spins to arrive at the brain region of interest, an MRI image is collected (tag image). A second image is then collected in an identical way, but without tagging the blood (the control image). A subtraction of the tagged image from the control image results in an fMRI signal that represents the magnitude and quantity of blood perfused to the brain in each MRI voxel.

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hippocampal BOLD response predicted rate of clinical decline over the next 4 years in MCI patients and subsequent loss of hippocampal signal over time (Miller et al., 2008b; Dickerson and Sperling, 2009). These authors hypothesized that hyperactivation in MTL regions may reflect a compensatory response to accumulating AD pathology and may be a harbinger of hippocampal degeneration, serving as a marker for impending clinical decline. Similarly, increased encoding-associated MTL BOLD activity has been demonstrated in cognitively normal elderly carriers of the APOE ε4 allele, perhaps representing a similar compensatory response (Bookheimer et al., 2000; Fleisher et al., 2005). However, depending on age and the memory task used, some studies have shown decreased or mixed BOLD responses to encoding (Bondi et al., 2005; Johnson et al., 2006b; Trivedi et al., 2006). Also, simply having a family history of AD may influence the fMRI signal (Fleisher et al., 2005; Johnson et al., 2006b). Notably, one must be careful in interpreting BOLD because increased BOLD activation does not translate directly to increased neuronal activity (Fleisher et al., 2009b). Due to these complexities in interpreting task-related BOLD fMRI, these techniques remain predominantly used for research purposes. New, simplified uses of fMRI during the resting state are being explored.

Resting state fMRI fMRI in response to a memory task fMRI has been used to identify patterns of brain abnormalities in AD, MCI, and genetic risk for AD based on the presence of the apolipoprotein epsilon4 (APOE4) genotype. A number of fMRI studies in patients with clinically diagnosed AD have identified reduced BOLD activations in hippocampal and parahippocampal regions, compared with control subjects during episodic encoding tasks (Small et al., 1999; Rombouts et al., 2000; Machulda et al., 2003; Sperling et al., 2003). Overall, the BOLD response to a memory task is consistently decreased in AD (Dickerson et al., 2005; Dickerson and Sperling, 2009). However, increased activation has been reported in prefrontal regions performing memory tasks (Sperling et al., 2003). In MCI, fMRI studies have reported similar reductions in MTL BOLD activation, compared with controls (Small et  al., 1999; Machulda et al., 2003; Johnson et al., 2006a). Yet, there may be an early phase of the disease in which the MTL BOLD signal is increased in MCI, compared with controls (Dickerson et al., 2005; Hamalainen et al., 2007). One study of 32 MCI patients showed an increase in MTL BOLD activation, which correlated with better memory performance. Increased right parahippocampal activation also was associated with greater clinical decline over 2.5 years (Dickerson et al., 2004). A later study demonstrated that increased

The default mode network (DMN) represents a network of coordinated low-frequency fluctuation in specific functional neuronal networks. It is manifested in key brain regions that are elevated in states of relative rest, which are responsible for attention to environmental stimuli, review of past knowledge, and/or planning of future behaviors (Binder et al., 1999; Raichle et al., 2001). These regions predominantly consist of midline and lateral frontal regions, and medial and lateral parietal regions extending into posterior cingulate/retrosplenial cortex (Buckner and Vincent, 2007). These same regions that are activated at rest appear to be suppressed during various cognitive activities, including encoding of new memories (Rombouts et al., 2005; Sorg et al., 2007; Pihlajamaki et al., 2008). For this reason, two strategies have been developed utilizing the DMN to identify diseases of cognition and risk for dementia in the BOLD fMRI literature. One strategy explores task-related deactivations; the other focuses on differences in resting state BOLD networks. These default networks may be particularly affected by the neurodegenerative process of AD (Buckner et al., 2008). With this, several groups have reported both reduced resting state connectivity (Buckner et al., 2005) and alterations in fMRI task-induced deactivation responses in aging (Lustig et al., 2003; Andrews-Hanna et al., 2007), MCI (Rombouts et al., 2005; Sorg et al., 2007), and AD patients (Lustig et al.,

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2003; Greicius et al., 2004; Rombouts et al., 2005; Wang et al., 2006, 2007; Buckner and Vincent, 2007; Persson et al., 2008), compared with healthy controls. Additionally, older adult APOE4 carriers have reduced DMN deactivation, compared with noncarriers (Persson et al., 2008) and alterations in resting state connectivity differences in both older adults (Fleisher et al., 2009c) and in APOE4 carriers as young as 20–35 years of age (Filippini et al., 2009). Abnormalities of the DMN seen with fMRI may signify underlying physiologic defects associated with AD. Evidence that supports this includes findings that the cortical regions that make up the DMN are similar to areas of early brain atrophy, hypometabolism, decreased perfusion, and fibrillar amyloid deposition in early AD and MCI (Minoshima et al., 1997; Johnson et al., 1998; Klunk et al., 2004; Buckner et al., 2005, 2009; Edison et al., 2007; Forsberg et al., 2008; Jack et al., 2008b), as well as in cognitively normal elderly (Sperling et al., 2009). In particular, the posterior cingulate and precuneus cortex are regions that have the most prominent deactivations during cognitive tasks and are increased during the resting state (Greicius et al., 2004; Buckner et al., 2005). Furthermore, failure to deactivate medial posterior DMN during encoding is associated with worse memory performance (Miller et al., 2008a). Also, suppression of the DMN during a memory task is associated with increased cortical fibrillary amyloid in cognitively normal elderly individuals (Hedden et al., 2009; Sperling et al., 2009) and reduction of structural white matter integrity (Greicius et al., 2009). Overall, these findings suggest that “suspending” the default network during working memory is necessary for successful encoding, is impaired in AD, and is potentially associated with preclinical amyloid pathology. For these reasons, resting state fMRI techniques may hold great potential as sensitive preclinical biomarkers of AD pathology.

Summary Functional imaging has become an important tool for understanding the pathophysiology of dementia. Because most dementias stem from underlying pathology that is present many years before clinical symptoms, identifying biomarkers of disease is critical for preventative treatment development. In the clinic, PET and SPECT scanning are currently available as tools to assist in diagnostic decision-making, with a vast amount of research data supporting their utility. More recently, additional biomarker tools have been emerging that will soon play an important role in clinical management, diagnosis, and ultimately screening for presymptomatic disease. Spinal fluid levels of Aβ and tau proteins have proven to be sensitive predictors of disease and progression (De Meyer et al., 2010) and are becoming more readily accessible and cost-effective for clinicians and patients. The advent of amyloid imaging using PET ligands is a promising research technique that provides an opportunity to identify Alzheimer’sassociated pathology in patients and will likely be available in the clinic in the near future. Combining these pathologic markers of disease with functional markers of impaired brain physiology will ultimately provide important tools for clinicians to accurately diagnose dementing diseases at the earliest possible stages. In fact, there has been increasing emphasis on including pathologically linked biomarkers of AD as part of clinical diagnostic criteria (Dubois et al., 2007), with efforts currently underway by the National Institute on Aging and the Alzheimer’s Association to revise existing NINCDS-ADRDA diagnostic criteria to include functional imaging in diagnostic decision-making. Use of biomarkers such as functional imaging likely will become standard practice in dementia care.

Perfusion fMRI using arterial spin labeling

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ASL has been used to distinguish AD and MCI subjects from normal controls (Alsop et al., 2000; Johnson et al., 2005). Small studies also have been able to use ASL perfusion MRI to distinguish cognitively normal individuals based on family history of AD and APOE ε4 allele status (Fleisher et al., 2009b). This technique has not been widely studied, and little is known about its sensitivity for distinguishing AD, MCI, and healthy elderly controls. This technique does have advantages over SPECT perfusion, with improved spatial and temporal resolution, the ability to measure resting perfusion as well as change in perfusion with a functional task, relatively inexpensive cost, and absence of radiation in testing. For these reasons, it has potential as a useful future biomarker of AD pathophysiology.

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Chapter 7.3 Amyloid Imaging Anil K. Nair and Marwan N. Sabbagh

Introduction The diagnosis and treatment of Alzheimer’s disease (AD) are hampered by the lack of noninvasive biomarkers of the underlying pathology. There is a need for a diagnostic biomarker to help clinicians separate patients who have AD pathology from those who do not. Biomarkers of brain amyloid deposition can be measured either by cerebrospinal fluid beta amyloid (Aβ)42 or by radiolabeled markers on positron emission tomography (PET) imaging. In this chapter, we survey the current amyloid imaging techniques using 11C-labeled (11C) agents such as Pittsburgh compound B (11C-PiB) or 18F-ligands (18F) such as Florbetapir F 18 (18F-AV-45), 18F-flutemetamol (18FGE067), Florbetaben (18F-BAY94-9172), 18F-FDDNP, and NAV. Among these, PiB is the most studied Aβ-binding PET radiopharmaceutical in the world. The histologic and biochemical specificity of PiB binding across different regions of the AD brain was demonstrated by showing a direct correlation between Aβ-containing amyloid plaques and in vivo (11C)PiB retention, measured by PET imaging. Because 11C is not ideal for commercialization, (18F)3’-F-PiB (Flutemetamol), 18F-AV-45 (Florbetapir), and 18F-AV-1 (Florbetaben) are undergoing extensive Phase II and III clinical trials. Clinical trials have clearly documented that PET radiopharmaceuticals capable of assessing Aβ content in vivo in the brains of AD subjects and subjects with mild cognitive impairment (MCI) will be important as diagnostic agents to detect in vivo amyloid brain pathology. In addition, early PET amyloid imaging will help test the efficacy of anti-amyloid therapeutics currently under development in clinical trials. AD is the most common cause of dementia in the elderly, affecting more than 4 million people in the USA and approximately 7.3 million people in Europe (Wilmo and Prince, 2010). Although diagnosis based on consensus criteria (McKhann et al., 1984; American Psychiatric Association, 2000) is reasonably accurate by comparison with the gold standard of pathology at autopsy (Jobst et al., 1998; Knopman et al., 2001), approximately 10% of community-dwelling elderly still have undiagnosed dementia (Solomon et al., 2000; Lopponen et al., 2003). Community physicians may fail to diagnose up to 33% of mild dementia cases (Lopponen et al., 2003). Additionally, the medical system does not have the resources to routinely send all

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elderly subjects with memory complaints for comprehensive expert evaluation. Furthermore, upon comprehensive diagnostic testing, many patients are found to have cognitive impairment but are not demented, and thus, do not meet diagnostic criteria for AD (for example, people with MCI). Some, but not all, of these patients will go on to develop AD within 3–5 years (Petersen et al., 2001a). A reliable biomarker might aid diagnosis by documenting the presence or absence of disease-related pathology. A biomarker could also be useful for early identification of subjects at risk for developing AD (Thal et al., 2006). Although the underlying etiology of AD is not established, the Aβ peptide is important in the pathogenesis of the disease. Accumulation of Aβ in the form of amyloid plaques is one of the hallmarks of the disease and is a key component of the preclinical neuropathologic criteria for diagnosis (Mirra et al., 1991; Hyman and Trojanowski, 1997; Albert et al., 2011; Pontecorvo and Mintun, 2011). Most cases of AD are thought to occur sporadically, but rare familial mutations are known to produce an autosomal dominant form of the disease. All forms directly or indirectly increase production or accumulation of specific forms of Aβ peptide and lead to the formation of amyloid plaques (Hardy and Higgins, 1992; Hardy and Selkoe, 2002). Transgenic mice that express one or more of these mutant human genes develop amyloid plaque, and behavioral/cognitive deficits that are similar in some respects to those seen in AD (Hsiao, 1998; Hock et al., 2003; Gotz et al., 2004). Finally, experimental treatments that reduce Aβ peptide production or increase the clearance of Aβ from amyloid plaques have been successful in reversing behavioral deficits in these mice; some of these treatments are now being tested in patients with AD (Hock et al., 2003). The most widely accepted and validated biomarkers in AD fall into two categories: imaging and CSF chemical analytes (Shaw et al., 2007; Hampel et al., 2008). Different biomarkers serve as in vivo indicators of specific pathologies. Measures of brain atrophy on a magnetic resonance imaging (MRI) are biomarkers of neurodegenerative pathology (Bobinski et al., 2000; Gosche et al., 2002; Jack et al., 2002; Silbert et al., 2003; Jagust et al., 2008; Vemuri et al., 2008; Whitwell et al., 2008), while both PET amyloid imaging (Klunk et al., 2004; Edison et al., 2007; Rowe et al., 2007; Drzezga et al., 2008; Ikonomovic et al., 2008; Leinonen et al., 2008; Frisoni et al., 2009; Tolboom et al., 2009)

Amyloid Imaging

and decreased CSF Aβ 42 (Clark et al., 2003; Strozyk et al., 2003; Schoonenboom et al., 2008; Buchhave et al., 2009; Tapiola et al., 2009) are indicators of brain Aβ amyloidosis or Aβ load. A variety of biomarkers for amyloid plaque accumulation have been proposed (Thal et al., 2006). The clinical utility of Aβ imaging at the present time may be particularly useful in the evaluation of complicated or atypical cases of neurodegenerative diseases. In the future, the life cycle plan for broader application of Aβ imaging will likely include sufficient data to permit thorough examination of its potential utility in the differential diagnosis of neurodegenerative diseases, in monitoring disease progression, in therapy monitoring (and for tailoring therapy to individual patients), and in predicting at-risk patient populations.

Individual amyloid imaging agents In contrast to techniques designed to indirectly estimate levels of brain amyloid plaques from Aβ levels in plasma or cerebral spinal fluid, imaging techniques utilizing radiolabeled PET tracers that bind to the aggregated Aβ peptides in amyloid plaques have the potential to directly assess relative brain amyloid plaque pathology. The first successful amyloid-imaging agent employed in humans was 18 fluoro labeled 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile (FDDNP), a fluorinated derivative of a nonspecific cell membrane dye (Agdeppa et al., 2001). FDDNP binds in vitro to amyloid conformations of Aβ, tau, and prion protein (Agdeppa et al., 2001; Bresjanac et al., 2003). In 2002, Shoghi-Jadid and coworkers demonstrated increased tracer binding on PET in nine patients with AD, compared with seven matched controls (Shoghi-Jadid et al., 2002). Tracer retention was highest (30% greater than the pons reference region) in the medial temporal cortex, hippocampus, and amygdala, regions that typically show dense neurofibrillary tangles (NFTs), and was also increased 10–15% above baseline in the frontal, temporal, and parietal cortex, regions that typically show both Aβ plaques and NFTs. In one patient who later came to autopsy, increased FDDNP-PET signal during life co-localized to regions with significant plaque and tangle pathology postmortem (Small et al., 2006).

11C-labeled agents Most imaging studies of Aβ have been conducted using [11C] PiB. The half-life of the 11C isotope is 20 minutes, which makes the manufacturing and wide-scale distribution to institutions with PET scanning facilities limited and impractical. PiB The most widely studied amyloid-imaging agent is PiB, an analog of the amyloid-binding dye Thioflavin-T. It

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was the first tracer to show a clear correspondence to the known regional distribution of postmortem Aβ pathology in AD. To date, more [11C]PiB scans (>2000) have been performed at more PET centers worldwide (more than 40 sites) than any other Aβ imaging tracer. In vitro, PiB binds specifically to extracellular and intravascular fibrillar Aβ deposits in postmortem AD brains (Bacskai et al., 2003; Klunk et al., 2003; Lockhart et al., 2007; Ikonomovic et al., 2008). At PET tracer concentrations, PiB does not appreciably bind to other protein aggregates such as NFTs or Lewy bodies (Fodero-Tavoletti et al., 2007; Lockhart et al., 2007; Ikonomovic et al., 2008). PiB does bind nonspecifically to white matter, likely due to delayed clearance of the lipophilic compound from white matter (FoderoTavoletti et al., 2009). In 2004, Klunk et al. reported the first human study of PiB-PET . Preliminary studies show that higher levels of radioactivity can be imaged in the cortex of patients with AD than in the cortex of healthy controls, presumably reflecting the elevated accumulation of Aβ pathology and consequent binding of PiB in the cortex of patients with AD (Lopresti et al., 2005). Despite these encouraging results, the short half-life (20 minutes) of the 11C isotope may limit the utility of 11C-PiB as a tool for community-based diagnostic screening and therapeutic evaluation. PiB accumulation as AD progresses (such as from controls and from MCI to AD) follows a pattern that has been described as an “on and off” pattern that is typically not found in pathology specimens (Mintun et al., 2006; Kemppainen et al., 2007). Moreover, PiB has signals in AD in most brain regions except medial temporal, compared with control patients (Shin et al., 2008), but a significant number of controls do present positive PiB binding (Mintun et al., 2006). Some AD subjects also present negative PiB binding (Leinonen et al., 2008).

BF227 [C-11] BF-227 (2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)- 6-(2-[fluoro]ethoxy) benzoxazole) is a novel family of benzoxazole compounds that have shown promise as Aβ imaging agents for detection of dense amyloid deposits. It was developed at Tohoku University. BF227 labeled both Aβ plaques and Lewy bodies in immunohistochemical/fluorescence analysis of human AD and Parkinson’s disease (PD) brain sections, respectively. This study suggests that [(18)F]-BF227 is not Aβ selective. AD showed higher accumulation of BF-227 in the parietotemporal, medial frontal, precuneus, and posterior cingulate areas than NCn11 (p <0.05, ext >200). MCI showed intermediate binding between AD and NCn11 in voxel-based and region of interest (ROI) analyses. The standardized value uptake ratio (SUVR) ROI value was inversely correlated with MMSE (p <0.05) and logical memory II (p <0.05). BF227 is also being investigated as a potential biomarker for PD.

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18F-labeled agents 18F-radiotracers (such as [18F]FDG) are commercially viable and can be made available through regional cyclotron facilities that distribute the radiotracers to local scanners. The half-life of 18F (almost 2 hours) allows its distribution (subject to shelf-life) for up to 10  hours post-manufacture. The longer half-life also allows imaging at longer intervals after injection, and this can be useful when the optimal signal-to-noise ratio of a tracer is reached more than 90 minutes after injection. In addition, 18F tracers can often be labeled at higher specific activities than 11C tracers; hence, extremely low levels (typically less than 5 μg) of unlabeled ligand is injected. Flutemetamol Flutemetamol, a GE Healthcare PET imaging agent currently in Phase III development, is being studied to identify the uptake of Aβ via imaging of the brain tissue in live humans (Vandenberghe et al., 2010). In 2002, GE Healthcare acquired a license to access the patent rights and know-how behind the Thioflavin-T derivatives. 18F Flutemetamol performs similarly to the (11)C-PiB parent molecule within the same subjects and provides high test–retest reliability and potentially much wider accessibility for clinical and research use. In a Phase II study of 27 patients with early-stage clinically probable AD, 20 with amnestic MCI, and 15 cognitively intact healthy volunteers (HVs) above, and 10 HVs below 55 years of age, blinded visual assessments of (18)F-Flutemetamol scans assigned 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly HVs to the raised category; this corresponds to a sensitivity of 93.1% and a specificity of 93.3% against the SOT. Correlation coefficients between cortical (18)F-Flutemetamol SUVRs and (11) C-PiB SUVRs ranged from 0.89 to 0.92. Test–retest variability of regional SUVRs was 1–4%. FDDNP FDDNP or 2-(1-{6-[(2-[F-18]Fluoroethyl)(methyl)amino]2-naphthyl}ethylidene) malononitrile (Agdeppa et al., 2001; Small et al., 2006; Liu et al., 2007; Shin et al., 2008) PET provides detailed visualization (Braskie et al., 2010) of the pattern of beta-amyloid plaques (Aβ) and NFTs in the living brain of progressive AD. FDDNP cortical binding is to NFTs and may help determine whether a given FDDNP brain pattern is compatible with possible AD. This scan is likely to be complementary to amyloid scans. PiB binding pattern is different from that of FDDNP and does not follow the progressive nature demonstrated by neuropathologic evaluation of autopsy specimens (Braak and Braak, 1991). One of the explanations for the difference may be attributed to the fact that PiB does not bind to NFTs, while FDDNP does (Shin et al., 2008; Tolboom et al., 2009).

Florbetapir In contrast, Florbetapir F 18 is a novel amyloid-binding agent (Zhang et al., 2005, 2006) labeled with 18F. Because 18F has a radioactive half-life of 110 minutes, regional preparation and shipping of doses is possible, thereby reducing the cost and increasing the number of potential imaging centers. Studies conducted to date suggest that Florbetapir F 18 may label amyloid plaques in a manner similar to PiB and may have the potential to serve as an agent for in vivo imaging of Aβ pathology in humans with AD. Florbetapir F 18 exhibits high affinity, specific binding to amyloid plaques with a Kd of 3.1 nM and thus has the potential to be an imaging biomarker for amyloid deposits in subjects with cognitive impairment. In vitro autoradiography studies further confirm that, when applied at tracer concentrations, Florbetapir F 18 labels Aβ amyloid plaques in sections from patients with pathologically confirmed AD. The nonradioactive version of Florbetapir F 18 (referred to as “AV-45”) can be prepared at high concentrations and shows very low to no affinity for all other central nervous system and cardiovascular receptors tested, including the hERG potassium channel binding site (Avid Radiopharmaceuticals, Inc., 2008). The potential toxicity of AV-45 was tested in rats with single acute doses (up to 100×) and 28 days of repeated doses (up to 25×) of the maximum human dose (MHD) of 50 μg. No clinically relevant adverse effects were observed on behavior, gross pathology, or histology in either study. Thus, in both studies, the no observed adverse effect level (NOAEL) was at or above the highest dose level tested (100× MHD for acute, 25× MHD for repeat dose, allometrically scaled). In Beagle dogs, 14- and 28-day repeat-dose intravenous toxicity studies were performed, and there were no significant adverse effects based on clinical observations, weight, gross pathology, or histopathology at any dose studied (the highest dose levels were 8.7× and 25× MHD, respectively, allometrically scaled). In each rat and dog toxicity study conducted, the NOAEL was determined to be equal to or higher than the highest dose level tested. Potential genetic toxicity has been tested in both in vitro and in vivo assays. Bacterial reverse mutation assay results showed positive responses in two out of five tested strains. The human peripheral lymphocyte chromosomal aberration assay showed no statistically significant test article-related increases in the percent of cells with structural aberrations after 3 hours of treatment, but a statistically significant positive result was seen after 22 hours of exposure. In the in vivo micronucleus assay, Florbetapir F 18 produced no evidence of genotoxicity when administered at doses up to the highest practically achievable dose (83× MHD) for 3 consecutive days. The different results in the in vitro bacterial mutation and chromosome aberration assays and the in vivo micronucleus study are likely related to differences in the exposure conditions encountered by the target cells in the different test systems. AV-45 is cleared rapidly in vivo, whereas the in vitro experiments employ static, prolonged exposure of cells to the test article and/or

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metabolites. Cardiovascular safety and respiratory functions were tested in Beagle dogs implanted with subcutaneous telemetry units to monitor cardiac and respiratory functions and given doses of AV-45 corresponding to 25, 50, and 100× MHD (allometrically scaled). No test article-related adverse cardiovascular or respiratory effects were observed. No biologically significant prolongation of QTc was observed in any animal on any study day. To determine the possible effects of commonly used drugs and drug candidates on Florbetapir F 18 binding to Aβ, an in vitro drug–drug interaction study was conducted using tissue binding assay and in vitro film autoradiography techniques. The studies showed that none of the drugs tested interfered with Florbetapir F 18 binding to Aβ at therapeutically meaningful concentrations. Florbetapir was FDA approved for clinical use in 2012 under the trade name “Amyvid.”

Florbetaben Florbetaben (BAY 94-9172 or ZK 6013443) is another PET imaging agent for detection/exclusion of cerebral betaamyloid when compared with postmortem histopathology. Florbetaben (18F) is also a promising 18F-labeled amyloidβ-targeted PET tracer in clinical development (Villemagne et al., 2011). Eighty-one participants with probable AD and 69 healthy controls were assessed. Independent visual assessment of the PET scans showed a sensitivity of 80% (95% CI 71–89) and a specificity of 91% (84–98) for discriminating participants with AD from healthy controls (Barthel et. al., 2011). The SUVRs in all neocortical gray matter regions in participants with AD were significantly higher (p <0.0001), compared with the healthy controls, with the posterior cingulate being the best discriminator. Linear discriminant analysis of regional SUVRs yielded a sensitivity of 85% and a specificity of 91%. Regional SUVRs also correlated well with scores of cognitive impairment, such as the MMSE and the word-list memory and word-list recall scores (r 0.27 –0.33, p ≤0.021). APOE P4 was more common in participants with positive PET images compared with those with negative scans (65% vs. 22% [p = 0.027] in patients with AD; 50% vs. 16% [p = 0.074] in healthy controls). No safety concerns were noted. NAV4694 NAV4694 (2-(2-fluoro-6-methylaminopyridin-3-yl)-1benzofuran-5-ol or [18F]NAV4694 or AZD4694) is another promising 18F-labeled PET tracer targeting fibrillar Aβ. The initial clinical studies with [18F]NAV4694 determined the tracer to be well tolerated with a good signal-to-noise ratio and appears to have less white matter uptake compared with other Aβ tracers under development. A phase 2 study involving 24 subjects (10  AD, 10 older HVs, and 4 young HVs), various analysis methods, including the simple SUVR, were utilized to quantify Aβ deposition with [18F]AZD4694 and effectively distinguished subjects diagnosed with AD from older HVs and young HVs. There was excellent test–

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retest reliability (3–5%, and intraclass correlation coefficient was 0.96–1.00 for most regions and methods). The tracer was well tolerated and no adverse events were considered to be related to [18F]NAV4694. Studies have demonstrated that [18F]NAV4694 binds specifically to regions known for Aβ binding with relatively high specific Aβ-to-white matter binding. The tracer therefore may have increased sensitivity in detecting subtle amounts of Aβ plaque and changes in plaque burden over time. This may offer an advantage over other tracers currently under development and may permit the acquisition of an image that can be read more easily and reliably by nuclear medicine physicians.

Case studies using amyloid imaging We describe three clinical cases where Amyloid imaging was of great value. The thealzcenter.org clinic uses Montreal Cognitive Evaluation (MOCA) for regular clinical assessments, which are more suited in patients with mild memory loss.

Case 1: Ms. JW, MOCA 18, amyloid negative Patient Ms. JW, 77, arrived at the thealzcenter.org clinic with MCI or early dementia of uncertain etiology and a family history of AD. Her husband had also been previously diagnosed with AD. The patient was on prescribed opiate medications for pain; psychiatric medications including quetiapine, doxepin, and lorazepam for bipolar depression with anxiety and she suffered from sleep apnea. Upon assessment, the patient showed signs of mild parkinsonism. She also had prior restless leg syndrome. She also experienced visual hallucinations during a hospital admission, but did not have these regularly. At the time of the scan, her MOCA score had declined to 18 from a prior baseline of 25/30 even after a reduction of psychiatric medications and controlling sleep apnea. Underlying dementia was considered, as the deficits significantly interfered with day-to-day functional independence. Her Clinical Dementia Rating (CDR) was 0.5; Clock Drawing Test Score (CDT) was 3/ 3 ADL 12/12, IADL 15/16. (Figure 7.11 top row). An Amyloid PET scan study was negative (Figures 7.12 and 7.13 top row). The diagnosis of AD was excluded clinically after incorporating the amyloid information. She was initiated on Parkinson medications. Patient improved mentation with MOCA, with an improved score of 25/30 and was transitioned into living on her own in the community with assistance from VNA and an automated pillbox. Case 2: Mr. PS, MOCA 22, amyloid PET scan positive Mr. PS, 76, had a longstanding history of (h/o) depression, uncontrolled sleep apnea, diarrhea and urinary incontinence, and was presented to the alzcenter.org memory clinic with progressive decline in function at home. His

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Figure 7.11 Details of Montreal Cognitive Assessment (MOCA) test subsets for cases 1, 2 and 3. Top row is tests performed by Ms. JW,

middle row by Mr. PS and bottom row by Ms.EC. The executive function and memory test performance might have misclassified the patients without the amyloid imaging test information. Amyloid positive patients outperformed the amyloid negative subject on executive function. Immediate memory was preserved in all subjects. Short term free delayed recall was impaired in all subjects, and cued recall was present, contributing to clinical uncertainty. These clinical settings are appropriate to use amyloid imaging for furthering the diagnosis.

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Figure 7.12 Amyloid Imaging for Cases 1, 2

and 3. Top row is images from Ms. JW, middle row from Mr. PS and bottom row from Ms.EC. Even with significant accumulation of amyloid in their brain, the amyloid positive patients outperformed the amyloid negative subject on executive function tests. Memory evaluations were worse, contributing to clinical uncertainty. The amyloid scans facilitated early diagnosis and appropriate treatment for all three patients.

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Figure 7.13 Falsely colored amyloid images for cases 1, 2 and 3. Top row is images from Ms. JW, middle row from Mr. PS and bottom row from Ms. EC. Even though there images further highlight the significant differences in accumulation of amyloid, it is recommended that black and white images be used in diagnostic visual evaluation and rating of amyloid images. This is to minimize machine and operator factors involved in producing false color images leading to greater inter rater variability. (For a color version, see the color plate section.)

MOCA was 22/30, CDR 1.0; CDT 2/3; activities of daily living (ADL) was 12/12, and instrumental ADL (IADL) was 15/16. (see Figure 7.11 middle row). Neuropsychological tests were inconclusive, but supportive of AD or dementia with deficits in orientation, attention, language, memory, visual–spatial functioning, depression, and executive functioning. However, family and patient disagreed with the diagnosis, as he was able to compensate for these deficits, achieving day-to-day functional independence. He was also running his own business, and the diagnosis had significant financial consequences. Vascular etiologies were negative on MRI, which only showed mild to moderate small vessel disease. Labs were negative for thyroid problems, Lyme, and other reversible causes of dementia. A spinal tap measured CSF amyloid and tau, but was inconclusive for AD diagnosis. As he was high risk for side effects on acetyl cholinesterase inhibitors due to coexisting cardiac issues, an amyloid scan was pursued and found to be positive for brain amyloidosis. (see Figures 7.12, 7.13 middle row). Using the additional information, a clinical diagnosis of early AD was made using the new criteria. The patient was started on acetyl cholinesterase inhibitors, but diarrhea prevented dose escalation. Eventually the patient elected to join a clinical trial for early AD. The patient was able to close his business without financial ruin, preserved his wealth, even negotiated a settlement from the IRS and is now retired happily. After 2 years of stability, he is still able to do most IADLs, however he gave up driving after the scan information was discussed with him.

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Case 3: Ms. EC, MOCA 20, amyloid scan positive Ms. EC, 62, arrived at the thealzcenter.org clinic with memory complaints. She had significant deficits in multiple domains such as orientation, attention, language, memory, visual–spatial functioning, and executive functioning. These did not appear to significantly interfere with her day-to-day functional independence. Her MOCA was 20/30, CDR 0.5; CDT 2/3. (see Figure 7.11 bottom row). While the underlying etiology could include AD, there was significant uncertainty due to her higher functional ability at home. No features of Lewy body dementia, vascular dementia and reversible causes of dementia such as in thyroid, infectious or demyelization processes were found clinically. Additionally, her labs and MRI did not reveal any additional information, and her neuropsychology tests were inconclusive. At subsequent visits the MOCA improved spontaneously to 25. As the patient and family wanted to know the underlying etiology precisely and did not want a lumbar puncture, an amyloid scan was pursued. The scan was positive. (Figures 7.12 and 7.13 bottom row) The clinical diagnosis was revised to MCI due to AD. As she was of altruistic nature, the patient elected to join a clinical trial for preventing AD even though the trial included serial lumbar punctures. She felt joining the trial may not help herself, but may help others, including her children or grandchildren. After 2 years, she continues to have amnestic MCI, and no significant decline on clinical memory testing.

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Conclusion Amyloid imaging of the brain and classification of cognitively normal subjects into a high-risk category based on this imaging represent a major advance in neuroscience. The detection and quantification of pathologic protein aggregations in the brain may help advance early detection and eventual treatment of this group with new biologics. Multiple tracers that mark PiB binding, specifically to fibrillar beta-amyloid (Aβ) deposits, is a sensitive marker for Aβ pathology in cognitively normal older individuals and in patients with MCI and AD. Amyloid PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid-imaging studies support a risk-evaluation model similar to cholesterol or hypertension in cardiac disease; amyloid deposition is an early event on the path to dementia. This begins insidiously in cognitively normal individuals, accompanied by subclinical or subtle cognitive decline, leading eventually to functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation, which may be irreversible. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression than cognitive tests.

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Chapter 8 Clinical Laboratory Investigations in Geriatric Neurology Geoffrey S. Baird1 and Thomas J. Montine2 1 2

Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA Departments of Pathology and Neurological Surgery, University of Washington, Seattle, WA, USA

Summary • Bayes’ Theorem dictates that the value of a test is highly correlated with the prior probability of disease. • Tests with high clinical sensitivity are most useful in screening when prior probability of disease is low. Positive screening results must be followed by a confirmatory test with high clinical specificity. • Body fluids (blood, urine, cerebrospinal fluid) are preferred samples for neurological testing. Peripheral nerve biopsies are generally well-tolerated, but brain biopsies are generally avoided for non-neoplastic cases because of morbidity, mortality, and low clinical yield. • In dementia, laboratory testing is primarily used to identify secondary dementias, i.e. resulting from a systemic disorder. • A reasonable secondary dementia screening panel could include: complete blood count with differential, plasma or serum sodium, potassium, chloride, bicarbonate, glucose, creatinine, blood urea nitrogen, calcium, vitamin B12, TSH, folate. • Alzheimer’s disease (AD): Cerebrospinal fluid (CSF) Aβ42 and tau concentrations are known to vary significant between normal, mild cognitive impairment, and clinical AD. • Vascular brain injury (VBI): Standard dementia screening panel is recommended, as well as tests for inflammatory conditions • Lewy body disease (LBD): No specific laboratory tests are available to rule in this disorder. • Frontotemporal lobar degeneration (FTLD): No specific laboratory tests are available to rule in this disorder. • Creutzfeldt–Jakob disease (CJD) and prion disorders: Recommended tests depend on the clinical presentation, but could include complete blood counts, serum electrolytes, urinalysis, assessment of liver function and injury, thyroid function testing, serum B12, folate assays, humanimmunodeficiency virus (HIV), RPR/syphilis screening, and paraneoplastic antibody testing. CSF testing can include 14-3-3 and tau. • Normal pressure hydrocephalus (NPH): No specific laboratory tests are available to rule in this disorder. • Parkinson’s disease (PD): Laboratory testing is useful for ruling out other possible causes of the clinical phenotype. • “PD plus” syndromes: Rare genetic causes can be identified with molecular tests. • Infarction: Standard testing usually includes serum or plasma electrolytes/renal function tests and glucose, Troponin I or T, complete blood count including platelet count, and coagulation testing including PT/INR and aPTT. Additionally, hepatic function tests, toxicology screen, blood alcohol assay, pregnancy test, arterial blood gas analysis, and lumbar puncture may also be useful. • Hemorrhage: Standard testing usually includes complete blood count, electrolytes, blood urea nitrogen and creatinine, glucose, PT/INR and aPTT. Toxicology screens and pregnancy tests may also be useful. Some evidence supports increased neutrophil counts and plasma fibrinogen as biomarkers. • Vasculitis: Standard testing usually includes complete blood count with differential, serum electrolytes and glucose, renal and hepatic function markers, erythrocyte sedimentation rate and C-reactive protein, CSF analysis, and urinalysis to investigate potential secondary causes. Tests of autoimmunity may reveal underlying connective tissue disease or systemic vasculitis. • Headache: Laboratory testing is rarely indicated; specific details of presentation should dictate the testing algorithm if unusual headache features are found at presentation. Lumbar puncture with analysis of CSF could be indicated if common headache syndromes are unlikely. • Depression: Frequently used tests to screen for secondary causes of depression include complete blood count, serum electrolytes and glucose, urinalysis, blood urea nitrogen and creatinine, liver function tests, TSH, serum B12, folate concentration, and RPR testing. The benefit of laboratory testing in idiopathic depression is unclear. • Delirium: many potential causes but selected laboratory tests can identify the most serious or prevalent causes. • HIV: in addition to HIV testing, cardiovascular risk assessment should not be neglected in the elderly HIV patient. • Paraneoplastic disorders: Many exist, and specific testing for antibodies associated with the specific presentating syndrome is recommended. • Genetic disorders: High costs of large genetic testing panels should be avoided by testing serially. One should seek expert advice from neurogeneticists in order to select the most appropriate testing for a given patient. • Cerebral injury: S100B protein and neuron-specific enolase are highly studied markers of brain injury—however, no FDA-approved assays are available. Quantitation of CK-BB in CSF is an alternate test.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Laboratory test interpretation Laboratory tests have become essential components of physicians’ armamentaria to approach and manage diseases in their patients. These tests can effectively rule out some disease processes in apparently healthy patients (screening) and establish a specific diagnosis in ill patients with nonspecific signs and symptoms. Indeed, the ubiquity of clinical laboratory testing attests to its utility but also cautions that laboratory tests need to be used judiciously. Laboratory tests are often classified by clinical specificity and sensitivity; the concepts are represented graphically in Figure 8.1. One of the most important statistical concepts related to the utility and interpretation of laboratory testing is Bayes’ theorem (Equation 8.1). P(A|B) =

P(B | A) ⋅ P(A) P(B)

(8.1)

This equation states that the conditional probability of event A, given the occurrence of event B, is equal to the conditional probability of B, given A times the prior probability of A divided by the prior probability of B. Applied to laboratory testing, Bayes’ theorem indicates that the probability of having a disease, given a

Test result

Disease Present Absent Positive

True positive (TP)

False positive (FP)

Negative

False negative (FN)

True negative (TN)

Sensitivity =

TP TP + FN

Specificity =

Positive predictive value = Negative predictive value =

TN TN + FP

TP TP + FP TN TN + FN

Figure 8.1 Definitions of test performance metrics.

positive laboratory test, P(A|B)—also known as the posterior probability—is proportional to the prevalence or prior probability of the disease, P(A), times the probability that the test is positive in those with the disorder, P(B|A)—the clinical sensitivity—divided by the probability that the test result is positive in a population, P(B). The posterior probability is what clinicians desire—the probability that a patient has a disease after getting a test result. Bayes’ theorem states that this probability depends not only on the test’s clinical performance characteristics, but also on the likelihood that the patient had the disorder before any testing was done. Therefore, when testing for conditions that are very unlikely, (P(A)~0), a positive result still corresponds with a low posterior probability and is likely a “false positive.” Conversely, testing for highly likely conditions with highly sensitive tests is most likely to produce a true positive result that simply confirms what was already clinically suspected. Testing in either of these situations is unlikely to be beneficial or cost-effective. Bayes’ theorem provides the mathematical underpinning to the obvious but important directive that laboratory testing must be applied in concert with clinical assessment. When applied in the setting of a low prior probability, a sensitive but nonspecific test used to rule in a diagnosis is unlikely to provide a true positive result. A more appropriate use of a test with high clinical sensitivity in the setting of low prior probability is to rule out a disease. This is known as screening, in which negative results are trusted and positive results are considered only presumptive and must be followed by a confirmatory test (see Figure 8.2). The best tests for confirmation of positive screening tests are those with high clinical specificity. Few tests have sufficient clinical specificity and sensitivity to perform well in both screening and confirmatory roles. Additionally, highly reliable confirmatory assays are usually too costly to employ in the screening setting. Bayesian analysis is a useful tool for assessing the information content provided by laboratory testing, but it should not be used in isolation to determine the utility of testing. To the contrary, one should always consider whether the result from a laboratory test—positive or

Clinical sensitivity High Low Clinical specificity

This chapter focuses on the clinical laboratory examinations used to screen, diagnose, predict, and monitor neurologic disorders in geriatric patients. Because the goals of laboratory testing in this population overlap those of general laboratory testing, a brief section on test interpretation and general laboratory considerations precedes the sections devoted to neurologic disorders of geriatric patients.

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High

Screening or confirmation

Confirmation

Low

Screening

Do not use

Figure 8.2 Most appropriate use of laboratory testing based on

clinical test performance.

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negative—would influence clinical management. Especially for a disease for which no therapies currently exist, identifying a root cause with a diagnostic test may not provide any actionable information. Although there exist numerous valid reasons to order tests that are not associated with a specific clinical action–-such as identifying a genetic defect to aid in family counseling–-the stress, cost, potential consequences for medical insurability, and other potentially deleterious consequences of laboratory testing should always be considered prior to embarking on a laboratory testing odyssey.

General considerations Clinical laboratory testing is most easily accomplished on body fluids because they are most easily manipulated by automated quantitative instruments. Table 8.1 describes body fluids relevant to geriatric neurologic disorders. Correctly choosing a specimen collection container, preservative or anticoagulant, and storage condition— such as immediately freezing at –70°C versus holding at room temperature–-is of utmost importance in obtaining accurate laboratory results. Mistakes in the sampling process, known as preanalytical errors, are frequent sources of unwanted variability in the clinical laboratory. Although biopsy is a key diagnostic procedure in cases of suspected central nervous system (CNS) neoplasia (such as gliomas), solid tissue is rarely sampled when evaluating chronic neurologic disorders in the elderly because of the morbidity, and even mortality, of sampling procedures. Peripheral nerve biopsies to investigate neuropathies are generally well tolerated, but brain biopsy has significant morbidity and is generally avoided in non-neoplastic cases unless other diagnostic modalities have failed to produce a clear diagnosis. Examples in which brain biopsies have clinical utility include rapidly progressive or atypical neurodegenerative diseases (Schott et al., 2010).

Table 8.1 Body fluids used in laboratory testing Fluid type

Preservative or anticoagulant

Whole blood

Many possible

Gases, culture, cell counts and analyses, DNA from white blood cells

Plasma

Heparin

Electrolytes, plasma proteins

Plasma

EDTA

Preferred for proteomics

Plasma

Citrate

Coagulation studies

Serum

None

Serum proteins, electrolytes

Cerebrospinal fluid (CSF)

None

Glucose and protein, pathogen culture or PCR, proteomics

Urine

Numerous

Culture, electrolytes, proteins (electrophoresis)

Target analyses

Dementias Dementia is a clinically defined state with multiple causes that, either alone or in combination, lead to profound cognitive and behavioral deficits. The most common diseases contributing to the dementia syndrome in the elderly are chronic: Alzheimer’s disease (AD); vascular brain injury (VBI), especially small vessel disease; and Lewy body disease (LBD). Although each is considered a disease, they really are clinicopathologic entities that likely have multiple etiologies. In other words, dementia in the elderly may be viewed as a syndrome of commonly comorbid chronic syndromes. Further complexity is added by the many less common diseases that also can cause dementia in the elderly, including frontotemporal lobar degenerations (FTLDs) and prion diseases. Although history, physical examination, and cognitive testing are the current cornerstones in evaluating suspected dementia, developing clinical laboratory tests for primary causes of dementia is an area of active research. A limited number of clinical laboratory tests are available to aid in diagnosis, such as cerebrospinal fluid (CSF) concentrations of 14-3-3 protein and tau in Creutzfeldt–Jakob disease (CJD), or CSF concentrations of amyloid Aβ42 and tau in AD. Currently, the major role of clinical laboratory testing in dementia is to investigate the possibility that the patient’s dementia is a secondary manifestation of a systemic disorder or to identify a rare but treatable cause of dementia (Feldman et al., 2008).

Secondary dementia The list of metabolic conditions associated with secondary dementia is long and includes dysfunction of nearly every major organ system in the body: hepatic dysfunction, renal dysfunction, cardiopulmonary failure, anemia or blood disorders, endocrine or vitamin deficiencies, and toxic injury by medications or other toxins such as alcohol. A variety of malignancies can also produce paraneoplastic cognitive disorders, as can infections, inflammation, or trauma. The complete evaluation of all these possible contributors to dementia is beyond the scope of this chapter. A standard screening panel of laboratory tests intended to identify common occult causes of secondary dementias based on recommendations from the Third Canadian Consensus Conference on Diagnosis and Treatment of Dementia (March 2006) is as follows. Laboratory tests suggested for comprehensive evaluation of dementia are the following: • Complete blood count with differential. • Plasma or serum sodium, potassium, chloride, carbon dioxide, fasting glucose, creatinine, blood urea nitrogen, and calcium. • Serum vitamin B12. • Thyroid stimulating hormone. • Serum or red blood cell folate (optional).

Clinical Laboratory Investigations in Geriatric Neurology

Generally, more testing that further interrogates additional metabolic pathways is indicated in the context of increased clinical suspicion, such as folate testing in patients with evidence of malabsorptive gastrointestinal disease. The same organization that made the recommendations in Table 8.2 also recommends against specific tests, such as serum homocysteine concentration or determination of APOE genotype, citing insufficient evidence for homocysteine testing and poor positive and negative predictive value of APOE testing. However, it should be stressed that these are only recommendations and that history, presentation, and physical findings should always guide decisions on the appropriateness of laboratory tests. If a toxic cause is suspected on clinical grounds, additional testing for heavy metals may be warranted; if an infectious cause is suspected, testing for the human immunodeficiency virus (HIV) or syphilis might be essential.

Alzheimer’s disease As mentioned earlier, clinical laboratory testing for AD is an area of active research, but no test or set of tests has achieved widespread application in the primary care setting. Despite the obvious convenience to patients, research efforts have yet to identify reliable blood or urine biomarkers of AD. One reason for this is the blood–brain barrier (BBB), a selectively permeable barrier between the CNS and the peripheral circulation. In contrast, CSF partially derives from brain and spinal cord extracellular fluid and so does not filter through the BBB prior to sampling (Wood, 1980; Milhorat, 1983), making it more reflective of CNS metabolism. Although there may be other reasons, the practical outcome is that research efforts so far have identified reliable biofluid biomarkers for AD in CSF, but not in blood or urine. The most widely studied CSF biomarker of AD is the combination of Aβ42 and total tau or some subset(s) of phosphorylated tau isoforms (Sonnen et al., 2010). Current research findings indicate that as AD progresses from latent to prodromal to clinically overt stages, CSF Aβ42 concentration decreases while CSF tau concentration increases. Association with neuroimaging studies strongly suggests that decreasing CSF Aβ42 concentration in patients with AD reflects Aβ42 accumulation in brain parenchyma. The mechanisms underlying increased CSF tau concentration are less clear but are not specific to AD because increased CSF tau concentration also occurs in other brain diseases. Other CSF biomarkers of AD have been reported in the literature, and although several show promise as sensitive indicators of different stages of AD, none have been validated for routine clinical use. A major problem in CSF AD biomarker discovery efforts has been cross-platform inconsistencies–-“hits” determined using one technology (such as mass spectrometry) commonly have not been validated with another (such as immunoassay).

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Vascular brain injury VBI can manifest as cognitive decline or dementia, conditions referred to in aggregate as vascular cognitive impairment (VCI). Our understanding of VCI has advanced substantially from the caricature of multi-infarct dementia with stereotypical “stepwise” decline in cognitive abilities. Although classic multi-infarct dementia clearly does occur, more subtle forms of VCI, especially from small vessel disease, can produce a pattern of injury and functional impairment that is difficult to distinguish from other common causes of dementia. The situation is further complicated because, as with Lewy body dementia (LBD), VCI is commonly comorbid with AD. Initial clinical laboratory investigation of VBI should include tests listed in Table 12.2, and additional testing for possible inflammatory conditions such as vasculitis (C-reactive protein (CRP)) and hyperlipidemia (cholesterol and triglycerides) should be performed if the clinical presentation warrants further investigation. Although no current clinical laboratory assays exist to definitively rule in VCI, differentiation among dementia subtypes is an active area of research. Discrimination between AD and VCI in small studies has been proposed using ADassociated CSF biomarkers such as Aβ and phosphorylated tau isoforms (Paraskevas et al., 2009), as well as markers of oxidative damage such as malondialdehyde (Gustaw-Rothenberg et al., 2010). Lewy body disease LBD is a spectrum of clinicopathologic entities that includes Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies (DLB); all these entities form intraneuronal α-synuclein-immuonoreactive inclusions called Lewy bodies, but in different regions of the brain. DLB is a complex entity because it can exist in a pure form but is more commonly comorbid with AD. No current clinical laboratory tests can confirm the diagnosis of LBD or adequately distinguish DLB from AD. Research studies have identified potential CSF biomarkers of DLB in small cohorts of patients, such as CART (Schultz et al., 2009) and α-synuclein (Kasuga et al., 2010). Frontotemporal lobar degeneration FTLD is a class of degenerative diseases that include Pick’s disease. These disorders share some clinical features with AD but differ in others, such as the marked change in personality observed early in the course of disease. No current clinical laboratory tests are able to distinguish clearly between AD and FTLD, but small research studies have suggested several CSF biomarkers such as agoutirelated protein (AgRP), adrenocorticotropic hormone (ACTH), eotaxin-3, Fas, and interleukin 17 (IL-17) (Hu et al., 2010b). Other studies suggest that the AD markers Aβ42 and tau, especially their ratio (de Souza et al., 2010; Hu  et  al., 2010a), can help discriminate between FTLD

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and AD. At the time of this writing, however, clinical validation for these analytes is lacking.

Creutzfeldt–Jakob disease and prion disorders The prion disorders are caused by misfolded fragments (prions) of a protein called the prion precursor protein, and they can present with rapidly progressive dementia. The United States National Prion Disease Pathology Surveillance Center maintains a helpful website with links to information on prion diseases, research studies, and testing information, at www.cjdsurveillance.com. CJD is the most common prion disorder, and it occurs in several forms (Gambetti et al., 2003): sporadic CJD (sCJD) with no known cause, familial CJD (fCJD) caused by mutations in the gene that encodes the prion precursor protein, and acquired forms of CJD called iatrogenic (iCJD) and variant (vCJD) that are transmitted from contaminated instruments or tissues (iCJD) or by ingestion of tainted animal products (vCJD). A thorough workup for rapidly progressive dementia should include complete blood counts, serum electrolytes, urinalysis, assessments of liver function and injury, thyroid function testing (thyroid stimulating hormone), serum B12 and folate assays, and tests for potential HIV and syphilis infection (RPR assay). Additional testing may include paraneoplastic antibody testing (vida infra). Laboratory testing of sporadic prion disorders may also include CSF analysis. Because routine CSF test values in prion disorders are usually normal (protein, glucose, and cell count), aberrant values for these analytes should prompt efforts to find a secondary cause for the patient’s rapid deterioration. One CSF analyte commonly assayed in suspected prion disorders is 14-3-3 protein, a member of a family of ubiquitous regulatory proteins released into CSF as a consequence of the rapid brain tissue destruction caused by the disorder. Concentrations of CSF 14-3-3 (Chohan et al., 2010) and tau (Wang et al., 2010) are elevated in prion disorders, but because they can also be elevated in other neurologic diseases, testing is useful clinically when other causes of rapidly progressive dementia have been sufficiently ruled out with the screening tests noted earlier. Initial reports found that the clinical sensitivity and specificity of CSF 14-3-3 for CJD were both 96% (Hsich et al., 1996), although these values are somewhat misleading because the value of the CSF 14-3-3 test is highly dependent on clinical presentation and, hence, prior probability. In addition, subsequent reports have indicated lower sensitivity of the CSF 14-3-3 test for CJD associated with alternate prion protein molecular phenotypes (Castellani et al., 2004; Gmitterova et al., 2009). Normal pressure hydrocephalus Normal pressure hydrocephalus (NPH) is a clinical syndrome that typically presents with gait or balance disturbance, cognitive impairment, and sometimes urinary

incontinence. Although clinical examination, radiologic exams (CT and MRI), and response to large-volume CSF tapping via lumbar puncture have been found to aid in diagnosis and increase the accuracy of predicting a response to surgical treatment (Gallia et al., 2006), no current clinical laboratory tests help distinguish NPH from other causes of dementia (Tarnaris et al., 2009). Selected studies have indicated that phosphorylated tau or total tau (Kapaki et al., 2007), or combinations of neurofilament protein (low molecular weight), phosphorylated tau, and Ab42 may have utility in distinguishing AD from NPH (Agren-Wilsson et al., 2007).

Movement disorders Parkinson’s disease Parkinsonism describes a syndrome of akinetic-rigid movement disorders; the most common idiopathic form is PD. As with other idiopathic neurodegenerative diseases, PD is a clinicopathologic entity. Clinically, it is characterized by bradykinesia, rigidity, and a type of tremor; pathologically, it is characterized by dopaminergic neuron loss in the substantia nigra with Lewy body formation, among other features. The current role of clinical laboratory testing is primarily to rule out other possible causes of the clinical phenotype. The search for CSF biomarkers of PD is an active area of research, driven primarily by the desire to aid clinicians when the diagnosis in unclear. However, there is also a need in research studies for surrogate markers of response to therapy to provide more objective outcome measures in clinical trials. DJ-1 protein concentration, in both plasma (Waragai et al., 2007) and CSF, has been investigated as a possible PD biomarker. Study results have been conflicting, with earlier studies indicating elevated CSF DJ-1 in PD (Waragai et al., 2006) and later studies indicating lower CSF DJ-1 in PD (Hong et al., 2010). α-synuclein, the primary component of Lewy bodies, has also been measured in CSF. Although results have been conflicting, a large study that controlled for blood contamination in CSF observed a lower α-synuclein concentration in patients with PD than in controls or in patients with AD (Hong et al., 2010). Progress in this area has been limited by several confounding factors, such as the use of different assays by different research groups and the high content of DJ-1 and α-synuclein in blood cells that may be lysed during serum preparation or may contaminate CSF samples (Shi et al., 2010). Parkinson-plus syndromes The Parkinson-plus syndromes include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal ganglionic degeneration (CBGD); all have the hallmark of sharing clinical features with PD but

Clinical Laboratory Investigations in Geriatric Neurology

are less common and difficult to diagnose because of clinical overlap. Rarely, specific Parkinson-plus disorders have been associated with genetic causes that can be identified with specific testing, such as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which is linked to both mutations in the MAPT gene that encodes for tau protein and the PGRN gene that encodes progranulin (Boeve and Hutton, 2008). Although these two genes are closely linked to chromosome 17, mutations in each appear to trigger different pathophysiologies, and it is not well understood why mutations in these distinct genes lead to similar phenotypes.

Cerebrovascular disorders Infarction Infarction of CNS tissue is a highly prevalent cause of morbidity and mortality, second only to heart disease in the Western world and responsible for 10% of all deaths. Pathophysiologically, CNS infarction from reduced blood flow (ischemia) can be caused by a variety of mechanisms, such as thrombus formation on a ruptured cerebral artery atherosclerotic plaque, embolism from a cardiac or carotid artery source, cerebral artery rupture as a result of hypertension, or arterial injury from inflammation. Of possible causes, the most important clinical distinction is whether the infarct is complicated by hemorrhage because this determines whether anticoagulant or fibrinolytic therapy can be used. Although radiology plays a far greater role than clinical laboratory testing in making this diagnosis, and immediate noncontrast brain CT or brain MRI is indicated in all patients suspected of having an acute stroke, laboratory testing can be helpful. American Heart Association/American Stroke Association guidelines 2007 (Adams et al., 2007) indicate that all patients suspected of having an ischemic stroke should undergo laboratory testing for blood glucose; serum or plasma electrolytes/renal function tests; cardiac markers such as Troponin I or T; a complete blood count, including platelet count; and coagulation testing, including the prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT). In selected patients with clinical indications for more targeted testing, the guidelines recommend hepatic function tests, a toxicology screen, a blood alcohol assay, a pregnancy test, arterial blood gas analysis, and lumbar puncture if subarachnoid hemorrhage is suspected and if CT scan is negative for correlates of hemorrhage. Unless a bleeding disorder is suspected or the patient is known to be, or suspected to be, on anticoagulants, thrombolytic therapy should not be delayed while waiting for the results of these tests. Blood glucose testing warrants specific attention because of the results of several studies pertaining to stroke. Immediate assessment of blood glucose is

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necessary in suspected stroke because hypoglycemia can mimic the signs and symptoms of stroke. However, elevated blood glucose has been identified as a poor prognostic marker in several studies (Kruyt et al., 2010), so correction and continued monitoring of glucose should be considered in all stroke patients.

Hemorrhage American Heart Association/American Stroke Association guidelines 2010 (Morgenstern et al., 2010) indicate that patients with intracranial hemorrhage should have  the following tests ordered: complete blood count, electrolytes, blood urea nitrogen and creatinine, glucose, PT or INR, and aPTT. Further specific recommendations include a toxicology screen for young or middle-aged persons to rule out cocaine use, as well as a pregnancy test in women of childbearing age. Several additional tests have been shown to have prognostic value in the setting of intracranial hemorrhage. Elevated serum glucose has been correlated with poor outcomes (Kruyt et al., 2009), and increased INR as a result of warfarin anticoagulation has been (unsurprisingly) correlated with expansion of hematomas (Cucchiara et al., 2008; Flaherty et al., 2008). In fact, the risk of any major bleeding–-intracranial or elsewhere–-increases dramatically in patients on warfarin as the INR increases, approaching 10% if the INR is greater than 9 (Garcia et al., 2006). Ages older than 65 have also been associated with a higher risk of bleeding in this setting (Landefeld and Goldman, 1989). Other prognostic biomarkers in hemorrhage include increased neutrophil counts and plasma fibrinogen, both of which are correlated with early neurologic deterioration (Leira et al., 2004). Many other serum markers of intracranial hemorrhage are currently under investigation (Maas and Furie 2009) but are not yet available in the routine clinical laboratory setting. These include matrix metalloproteinase-9 (Abilleira et al., 2003) (concentrations 24 hours after onset of bleeding correlate with edema), matrix metalloproteinase-3 (Alvarez-Sabín et al., 2004) (concentrations at 24–48 hours after bleeding correlate with risk of death), c-Fibronectin and interleukin-6 (Silva et al., 2005) (each associated with expanding hemorrhage), tumor necrosis factor-α (Castillo et al., 2002) (correlated with perihematomal edema), glutamate (Abilleira et al., 2003) (correlated with residual hematoma cavity size), and many others. Vasculitis CNS vasculitis can be idiopathic, as in primary angiitis of the CNS (PACNS), a cerebral manifestation of a systemic disorder such as lupus, or it can be caused by infectious agents (Hajj-Ali, 2010). Clinical manifestations commonly include cognitive decline, headache, and seizures. Because these disorders are rare, there is little evidence to

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Assessment of the Geriatric Neurology Patient

support the utility of any specific panel of laboratory tests in the diagnostic approach. Nonetheless, basic laboratory tests–-complete blood count with differential, serum electrolytes and glucose, renal and hepatic function markers, erythrocyte sedimentation rate (ESR) and CRP, CSF analysis, and urinalysis–-can provide information that helps determine the likelihood of other secondary causes for the neurologic presentation. Erythrocyte sedimentation rate and CRP are often elevated in systemic vasculitis but not in PACNS. These markers can also be elevated in infectious vasculitis; because the therapies for infectious and noninfectious vasculitis are markedly different, additional testing is required to evaluate for the presence of specific pathogens. Specific pathogens associated with CNS vasculitis include HIV, syphilis, Varicella zoster virus, mycobacteria, fungi, Borrelia spp. (Lyme disease), Bartonella spp., Herpes viruses, hepatitis C, and Taenia parasites (cysticercosis). Tests for autoimmunity may also help reveal the presence of an underlying connective tissue disease or systemic vasculitis such as lupus, Sjögren’s syndrome, Wegener’s granulomatosis, or Behcet’s disease. Such tests include antinuclear antibodies (ANAs); rheumatoid factor; antibodies to Ro/SSA, La/SSB, Sm, and RNP antigens; double-stranded DNA antibodies; antineutrophil cytoplasmic antibodies (ANCAs); serum C3 and C4; serum cryoglobulins; and serum/urine protein electrophoresis/immunofixation. Anticardiolipin and antiphospholipid antibodies as part of a hypercoagulability profile may also help detect an underlying disorder. Although standard CSF analyses are usually abnormal in PACNS–-demonstrating modest pleocytosis, normal glucose, elevated proteins, and occasional oligoclonal bands on electrophoresis–-no specific test can yet confirm this diagnosis. Giant cell arteritis, a cause of headache in older adults, is addressed in the subsequent section on headache.

Other disorders Headache Headaches are common in adult patients. Common categories of idiopathic headache include migraine, tension-type headache, and cluster headaches. Diagnostic classification of headaches is accomplished by history and physical examination to detect signs of an underlying condition that requires prompt medical attention, such as a cerebral aneurysm, intracranial hemorrhage, or brain tumor. Typical “red flags” in the investigation of headache include a previous head or neck injury, a new onset/ type/pattern, a patient self-reporting the “worst headache ever,” an abrupt onset, a “trigger” caused by Valsalva/ exertion/sexual activity, a concurrent pregnancy, an onset late in life, any coexisting neurologic signs or symptoms not classically associated with common headaches,

and any sign of systemic illness or infection. Additional indications that a more thorough workup is warranted include concurrent cancer of any sort, immunosuppression (including HIV infection), and recent travel to an area with endemic CNS-tropic viruses. Therefore, laboratory testing for headache is reserved for cases in which common headache syndromes are judged unlikely, offending medications have been ruled out as potential causes, and specific primary etiologies are suspected. Specifically, when subarachnoid hemorrhage, CNS infection, CNS neoplasia, or CNS inflammation is suspected, lumbar puncture with relevant analyses on CSF (glucose, protein, cell counts, tests for infectious agents, flow cytometry, and so on) is advised, following appropriate radiologic studies. A relevant consideration in the differential diagnosis of headache in the geriatric population is giant cell arteritis; if this is suspected, serum CRP and ESR may be helpful diagnostic tests, although temporal artery biopsy and histologic analysis are the preferred modalities used to confirm the diagnosis. Table 8.2 gives other, less common causes of headache, along with appropriate diagnostic tests. Note that the routine evaluation of headache with laboratory tests is not likely to yield benefits commensurate with the associated costs, so testing should be directed to patients with suspicious clinical presentations. Laboratory analyses for headache also can pose risks to patients because CSF sampling by lumbar puncture can rarely result in persistent CSF leakage, a syndrome characterized by severe postural headaches.

Depression Depression is prevalent in the elderly population, found at a rate of 6.8% in the United States between 2006 and 2008 ((CDC) CfDCaP 2010). However, the prevalence increases dramatically in the setting of comorbid illnesses such as acute coronary syndrome (Amin et al., 2006) or stroke (Robinson, 2003), and in hospitalized patients (Cullum et al., 2006), in whom the disorder is often unrecognized. Late-life depression is often undetected in primary care settings, in men, and in ethnic minorities, and can be associated with poor quality of life, poor functioning, worsening of other chronic medical problems, and increased morbidity and mortality (Unützer, 2007). In addition, depression commonly can present in concert Table 8.2 Laboratory evaluations for unusual causes of headaches Suspected disorder

Laboratory test

Pheochromocytoma Drug overdose or abuse Carbon monoxide poisoning Hypothyroidism

Plasma or urine metanephrines Toxicology screening Hemoglobin CO oximetry Thyroid stimulating hormone, thyroid hormones

Clinical Laboratory Investigations in Geriatric Neurology

with other neurologic disorders prevalent in the elderly, such as VBI or AD. Diagnostic criteria in the Diagnostic and Statistical Manual (Association AP, 2000) for major depression include numerous historical factors and the requirement that idiopathic depression be distinguished from depression secondary to another underlying medical condition. Depending on the clinical presentation, tests to evaluate for possible depression-related conditions in the elderly population with suspected comorbidities could include complete blood count, serum electrolytes and glucose, urinalysis, blood urea nitrogen and creatinine, liver function tests, thyroid stimulating hormone, serum B12 and folate concentration, or serologic evaluation for syphilis (RPR testing). However, there is little evidence to support the practice of using laboratory test screening in all patients who present with suspected depression, and a study has demonstrated that thyroid stimulating hormone testing, generally accepted as a screening test in patients with depression, is of little clinical value in elderly patients with depression (Fraser et al., 2004). In the research setting, several biomarkers of depression have been identified. These include decreased platelet imipramine binding, decreased 5-HT1A receptor expression, increased serum-soluble interleukin-2 receptor and interleukin-6, decreased serum brain-derived neurotrophic factor, hypocholesterolemia, decreased blood folate, and both hypercortisolemia and impaired suppression on the dexamethasone suppression test (Mössner et  al., 2007). However, many of these biomarkers are associated with other conditions; none are specific, nor are they currently used in diagnosing major depression. In addition to fluid biomarkers of depression, pharmacogenomic studies have illuminated the possible role of polymorphisms in the serotonin transporter-linked polymorphic region (5-HTTLPR) in assessing possible resistance to therapy or risk of side effects with serotonin-selective reuptake inhibitors (SSRIs) (Gerretsen and Pollock 2008). Early studies indicate that pretreatment testing for polymorphisms at this locus may lead to earlier remissions during SSRI therapy (Smits et al., 2007). A norepinephrine transporter polymorphism (NET-T182C) has also been shown in a study of Han Chinese subjects to have a link to susceptibility to depression (Min et al., 2009).

Delirium Delirium is defined by several key features, including rapid onset of reduced consciousness, changing cognition not explained by coexisting dementia, and evidence of a medical condition, intoxication, or medication causing the disorder. Delirium is commonly encountered in patients with significant medical illness, especially older patients. The list of possible etiologic causes of delirium is long and includes numerous drugs and medications, infections,

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Table 8.3 Specific laboratory tests addressing causes of delirium Cause

Specific test(s)

Hypoxia/hypercarbia Hypoglycemia Poisoning Medication effect Meningitis/encephalitis Thyroid dysfunction Electrolyte disturbance Liver failure Uremia Myocardial infarction Adrenal failure Other infections Paraneoplastic syndrome

Blood gas analysis Blood glucose Urine toxicology Therapeutic drug monitoring CSF analysis/culture/PCR Thyroid stimulating hormone Serum electrolytes Hepatic function tests, ammonia Blood urea nitrogen, creatinine Plasma troponin I or T Cortisol with ACTH stimulation Blood/urine/respiratory culture Specific antibodies

organ system failures, trauma, metabolic disorders, and primary brain disorders. With so many potential causes, it is obvious that no single set of laboratory tests will suffice for diagnosis in all cases. Nonetheless, several diagnostic tests can be of value in identifying either the most serious or the most prevalent causes of delirium (Han et al., 2010), listed in Table 8.3.

Human immunodeficiency virus HIV infection was historically prevalent in older adults who received blood transfusions before 1985, when routine testing of the blood supply began. Currently, the prevalence and incidence of HIV in adults older than 50 is lower than for adults younger than 50 ((CDC) CfDCaP. 2008), but progress in therapy means that the number of older patients with HIV should rise in the coming years. Because HIV is less common in older patients, however, a delay in diagnosis is more likely because the disease is not suspected. Neurocognitively, older HIV patients have been found to be at increased risk for HIV-associated neurocognitive disorders, including HIV dementia (Jayadev and Garden 2009). Although laboratory testing to diagnose HIV in older patients is essentially identical to that in younger patients, it is important to consider cardiovascular risk assessments in these patients. HIV is commonly comorbid with diabetes, hyperlipidemia (Malvestutto and Aberg 2010), and cardiovascular risks that are also more prevalent in older populations. Thus, identifying these risk factors with appropriate testing (such as blood glucose/hemoglobin A1c, or lipid and cholesterol panel) in older HIV patients, and taking appropriate action on the results, should be a primary concern. Paraneoplastic disorders Paraneoplastic neurologic syndromes (PNS) are increasingly recognized as causes of neurologic dysfunction in patients with both clinically apparent and occult

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malignancies (Didelot and Honnorat 2009). Often the neurologic manifestations of these disorders antedate the recognition of an underlying malignancy and thus may represent the presenting symptoms. Understanding of these disorders has advanced substantially in recent years as a result of the identification of specific autoantibodies associated with selected syndromes, many of which can be tested for clinically. It is worth noting that neurologic symptoms accompanying cancer are most often not because of paraneoplastic syndromes but instead because of metastatic or direct involvement of neoplasic disease with the CNS or because of complications from toxic therapies or infections. Nonetheless, several associations between specific antibodies, neoplasms, and syndromes have been identified and reviewed (Didelot and Honnorat 2009); one of the more common is the Hu antibody, which has been found in patients with small-cell lung carcinoma and associated with subacute cerebellar ataxia, limbic encephalitis, and sensory neuropathy. Testing for paraneoplastic inflammatory syndromes begins with a high clinical index of suspicion. Routine CSF analyses indicate mild inflammatory changes and often oligoclonal banding on electrophoresis. Testing for specific antibodies, singly or in panels, is also available from specialized laboratories. Because clinical presentations differ for these syndromes, it is often helpful to provide the laboratory with a summary of the clinical phenotype, to aid in interpreting the results of these assays. Because PNS are all, by definition, associated with malignancy, the next step after confirming a diagnosis is to find the related malignancy. The specific paraneoplastic syndrome identified can often guide this search–-for example, paraneoplastic encephalomyelitis because of anti-Hu antibodies is highly associated with small-cell lung cancer–-but often a whole-body search for a primary malignancy is required.

Genetic disorders Diseases caused by inherited mutation are rarely assessed in the geriatric population, as they tend to manifest in the young. Nonetheless, some neurologic diseases caused by inherited mutations impact older patients. Examples of these include Huntington’s disease, dominant cerebellar ataxias, certain muscular dystrophies, and autosomal dominant inherited forms of AD, PD, or FTLD. Although specific management and therapy are often lacking for these disorders, correctly diagnosing these diseases is not merely an academic exercise. Identifying a genetic cause in patients with complicated neurologic disorders can prevent an otherwise lengthy and costly workup, inform relatives about genetic risks, and aid researchers who study these conditions (Bird et al., 2008). The requirements for diagnosing these diseases in the elderly include both a high index of suspicion and an available clinical genetic assay. Complex genetic

assays–-both those that search for specific mutations and those that sequence large spans of introns or exons–-are becoming increasingly available in commercial and academic laboratories. A helpful online resource for clinical genetics testing is the website www.genetests.org, which is hosted by the United States National Center for Biotechnology Information. It provides both literature references and clinical testing sources for thousands of genetic diseases. Two general considerations about neurogenetic testing are helpful in deciding on an appropriate diagnostic approach. First, test costs may be highly variant depending on the laboratory used, so it is important to pay attention to which component tests comprise a large panel of assays that are “bundled” together. A second consideration is that parallel testing for numerous possible etiologies of a suspected genetic disorder, so-called “shotgun testing,” may not be the most cost-effective approach. After consulting with the laboratory performing the tests, it is often possible to identify a sequential testing algorithm in which the most likely genetic alterations are assayed initially with a lower-cost technique, and only after these tests come back normal are more expensive large-scale sequencing tests performed. Because the diagnostic yield of these tests is increased greatly when they are ordered in an appropriate setting, many laboratories that send these tests out to reference laboratories have moved to testing formularies so that only specific physicians (neurogeneticists instead of family practice physicians) can order these complex and often expensive tests.

Assessment of cerebral injury Often cases arise in which the underlying diagnosis accounting for a clinical presentation is not in question, such as a subarachnoid hemorrhage that is confirmed by neuroimaging, or traumatic brain injury (TBI). Outside of immediate management issues, the primary concern in such cases may shift to prognostication about when or whether the patient will regain consciousness or physical independence after the current acute injury is resolved. Numerous studies have identified CSF and serum biomarkers of the severity of brain injury. Two of the most widely studied biomarkers of injury include S100B protein and neuron-specific enolase, both of which may be assessed in either the CSF or serum and are highly correlated to the severity of brain injury following a number of insults (Kochanek et al., 2008). However, the primary problem for using these markers in the United States is that no Food and Drug Administration (FDA)-approved assays are available, meaning that only laboratories willing to develop in-house tests provide this testing in the United States.

Clinical Laboratory Investigations in Geriatric Neurology

An alternate test for which an FDA-approved method exists is quantitation of the BB isoform of creatine kinase in CSF, so-called CK-BB. CK exists as several isoenzymes inside cells, including MM (predominantly from muscle), MB (present in cardiac muscle and used for detecting myocardial infarction), and BB (the primary isoenzyme in brain). CK-BB is usually concentrated intracellularly and is at low concentration in CSF (<10 U/L) so that elevated CSF CK-BB activity indicates brain tissue destruction and enzyme leakage from cells. The activity of CK-BB, determined after electrophoretic separation of CK isoenzymes, has been correlated with prognosis after a CNS insult in several studies and can accurately predict whether patients will regain consciousness or independence (Kärkelä et al., 1993; Coplin et al., 1999). Acknowledgements: This work was supported by AG05136 and the Nancy and Buster Alvord Endowment.

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Hu, W., Chen-Plotkin, A., Grossman, M., et al. (2010b) Novel CSF biomarkers for frontotemporal lobar degenerations. Neurology, 75 (23): 2079–2086. Jayadev, S. and Garden, G. (2009) Host and viral factors influencing the pathogenesis of HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol, 4: 175–189. Kapaki, E., Paraskevas, G., Tzerakis, N., et al. (2007) Cerebrospinal fluid tau, phospho-tau181 and beta-amyloid1-42 in idiopathic normal pressure hydrocephalus: a discrimination from Alzheimer’s disease. Eur J Neurol, 14: 168–173. Kärkelä, J., Bock, E., and Kaukinen, S. (1993) CSF and serum brainspecific creatine kinase isoenzyme (CK-BB), neuron-specific enolase (NSE), and neural cell adhesion molecule (NCAM) as prognostic markers for hypoxic brain injury after cardiac arrest in man. J Neurol Sci, 116: 100–109. Kasuga, K., Tokutake, T., Ishikawa, A., et al. (2010) Differential levels of alpha-synuclein, beta-amyloid42 and tau in CSF between patients with dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry, 81: 608–610. Kochanek, P., Berger, R., Bayir, H., et al. (2008) Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making. Curr Opin Crit Care, 14: 135–141. Kruyt, N., Biessels, G., de Haan, R., et al. (2009) Hyperglycemia and clinical outcome in aneurysmal subarachnoid hemorrhage: a meta-analysis. Stroke, 40: e424–e430. Kruyt, N., Biessels, G., Devries, J., et al. (2010) Hyperglycemia in acute ischemic stroke: pathophysiology and clinical management. Nat Rev Neurol, 6: 145–155. Landefeld, C., and Goldman, L. (1989) Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med, 87: 144–152. Leira, R., Dávalos, A., Silva, Y., et al. (2004) Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology, 63: 461–467. Maas, M. and Furie, K. (2009) Molecular biomarkers in stroke diagnosis and prognosis. Biomark Med, 3: 363–383. Malvestutto, C. and Aberg, J. (2010) Coronary heart disease in people infected with HIV. Cleve Clin J Med, 77: 547–556. Milhorat, T. (1983) Cerebrospinal fluid as a reflection of internal milieu of brain. In: J. Wood (ed.), Neurobiology of Cerebrospinal Fluid. New York: Plenum Press. Min, W., Li, T., Ma, X., et al. (2009) Monoamine transporter gene polymorphisms affect susceptibility to depression and predict antidepressant response. Psychopharmacology (Berl), 205: 409–417. Morgenstern, L.B., Hemphill, J.C. III, Anderson, C., et al. (2010) Guidelines for the management of spontaneous intracerebral

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Part 3 Neurologic Conditions in the Elderly

Chapter 9 Cognitive Impairment and the Dementias 9.1 Mild Cognitive Impairment

Ranjan Duara1,2,3, Miriam Jocelyn Rodriguez1, and David A. Loewenstein1 9.2 Alzheimer’s Disease

Martin R. Farlow4 9.3 Dementia with Lewy Bodies

Clive Ballard5 9.4 Vascular Cognitive Impairment

Helena C. Chui6 and Freddi Segal-Gidan6 9.5 Frontotemporal Dementia

David Perry7 and Howard Rosen7 9.6 Primary Progressive Aphasia

Maya L. Henry8, Stephen M. Wilson9, and Steven Z. Rapcsak10 9.7 Prion Diseases

Michael D. Geschwind8 and Katherine Wong8 9.8 Normal Pressure Hydrocephalus

Norman R. Relkin11 1Wien

Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, FL, USA of Neurology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA 3University of Florida, College of Medicine, University of Florida, Gainesville, FL, USA 4Department of Neurology, Indiana University, Indianapolis, IN, USA 5Wolfson Centre for Age-Related Diseases, King’s College London, London, UK 6Department of Neurology, Keck School of Medicine and University of Southern California, Los Angeles, CA, USA 7Memory and Aging Center, Department of Neurology, School of Medicine, University of California, San Francisco, USA 8Department of Communication Sciences and Disorders, University of Texas at Austin and Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA 9Department of Speech, Language, and Hearing Sciences, University of Arizona, Tucson, AZ, USA 10Department of Neurology, University of Arizona, Tucson, AZ, USA 11Memory Disorders Program, Department of Neurology and Brain Mind Research Institute, Weill Cornell Medical College, New York, NY, USA 2Department

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Summary Mild Cognitive Impairment OVERVIEW

• The term MCI was introduced as a stage in the Global Deterioration Scale to describe the progression from normal aging to dementia, and later studies showed an increased risk of progression from MCI to dementia. • The widely used Mayo Criteria for MCI is based on prodromal amnestic features typical of AD, requiring impairment of memory on at least one standard test. • Subsequently, amnestic and nonamnestic types of MCI affecting single and multiple domains were described, and the term now applies to the predementia phase of any disease that may progress to cause a full-blown dementia. • Other predementia entities include benign senescent forgetfulness, age-associated memory impairment (AAMI), ageassociated cognitive decline (AACD), and cognitive impairment no dementia (CIND). • Mild MCI is likely to be reversible, and this has created some controversy regarding the relevance of the term to clinical practice and the appropriateness of the term to define a predementia state. DEFINITION

• Memory complaints, preferably corroborated by an informant. • Evidence of objective memory impairment for the age of the patient, as assessed by neuropsychological testing. • Preserved global cognition. • Essentially intact activities of daily living (ADLs). • Absence of dementia. SUBTYPES

• The most commonly used classification divides MCI into amnestic and nonamnestic types and further into single domain and multidomain MCI. • Significant etiologic overlap occurs between these classes, but in general amnestic MCI is more specific for AD and is characterized by hippocampal and/or entorhinal cortex atrophy. • Predementia conditions other than prodromal AD which may be present as MCI include vascular cognitive impairment, Lewy body disease, and various forms of frontotemporal lobar degeneration. • MCI due to LBD has features of episodic confusion, poor performance on fluency tests requiring attention, visuospatial deficits, REM sleep behavior disorder, and motor dysfunction, with relatively good performance on memory tests. • Multiple-domain MCI is the most common type in vascular MCI, corresponding to the presence of multiple lacunar infarcts in the basal ganglia, thalamus, and/or subcortical white matter. • MCI may also be due to medical illnesses, toxins, and neuropsychiatric disorders. DIAGNOSIS

• Structural imaging is mainly used to rule out conditions like stroke, hydrocephalus, and tumors but may show atrophy of the hippocampus, parahippocampal gyrus, and amygdala. • Functional imaging by PET, SPECT, and fMRI may become an integral part of management of MCI in the future. • Cerebrospinal fluid (CSF) biomarkers and genetic assays can be done to estimate the risk for progression to AD. TREATMENT

• Donepezil, rivastigmine, and galantamine have shown no effectiveness in decreasing the rate of progression from MCI to dementia. • ApoE4 carriers may benefit from treatment with donepezil at the MCI stage. • Biomarkers may better identify groups which will respond favorably to pharmacologic treatment. • Nonpharmacologic treatment which is perhaps more effective at this stage includes regular cognitive and physical activity. • The effective use of biomarkers as screening tools to identify patients who will benefit the most from early intervention will make the benefits of treating MCI worth the cost of current treatments. Alzheimer’s Disease • General symptoms include poor recall, visuospatial difficulties, executive functioning deficits, possible apathy or depression, decline in episodic memory, and difficulty with daily activities as symptoms pregress. • DSM-IV and NINCDS-ADRDA criteria, clinical examinations, lab studies, and scans including MRI and PET are used to help diagnose. • Biomarkers associated with Aβ deposition, biomarkers for neuronal injury, and biomarkers associated with biochemical change are included in criteria for MCI diagnosis.

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• Biomarkers are also incorporated into criteria for probable and possible AD as two groups: indicators of amyloid-β protein deposition in the brain and indicators of neuronal degeneration with decreased FDG uptake in temporal lobes. High total tau and phosphorylated-Tau (pTau) levels in CSF is another indicator. • While genetic components are associated with developing AD such as ApoE which is the highest risk factor, there are other factors that put patients at risk for developing AD. Dementia with Lewy Bodies • Two of the three core symptoms define patients with DLB: motor features of Parkinson’s, visual hallucinations, and cognitive fluctuations. Other symptoms consist of sleep disturbances, attentional and executive dysfunction. Its loss in cognition and function is similar to that of AD but differs for DLB derives from associated motor and autonomic impairments. • α-synuclein is a protein present in patients with DLB, found in Lewy neurites. DLB patients also have concurrent amyloid pathology with Aβ-positive plaque, similar to those with AD. • Similarities in symptoms of DLB and Parkinson’s have led them to be defined as on a spectrum instead of being completely distinct conditions. Vascular Cognitive Impairment • Cerebrovascular disease (CVD) is the second leading cause of dementia. In late life, the two most common causes of CVD are arteriosclerosis (including atherosclerosis and arteriolosclerosis) and cerebral amyloid angiopathy. CVD is the primary disease process that leads to vascular brain injury (VBI) and vascular cognitive impairment (VCI). • VCI is an umbrella term that includes mild cognitive impairment and dementia attributed to CVD and VBI, and includes previous labels including multi-infarct dementia, post-stroke dementia, vascular dementia, ischemic vascular dementia and Binswanger syndrome. • Currently there are several consensus criteria for VCI, but as yet no well established pathologic criteria. • The clinical presentation (e.g., cognitive profile, focal neurologic signs, symptom progression) is heterogeneous. • The subtype of subcortical vascular dementia tends to be associated with greater impairment in executive function than memory. • The best treatment for VCI associated with arteriosclerosis is prevention, through early identification and management of vascular risk factors. Frontotemporal Dementia Clinical syndromes of FTD include: • Behavioral variant of FTD (bvFTD) mainly describes personality and socioemotional function changes, like disinhibition, apathy, changes in eating behaviors, compulsive behaviors. MRIs depict atrophy in the frontal and/or anterior temporal lobes. • Depending on whether atrophy exists in the left or right temporal pole, semantic variant primary progressive aphasia (svPPA) is distinguished by progressive deterioration in knowledge about words and objects or behavior changes as seen in bvFTD and difficulties in recognizing famous icons. • Nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) is characterized by articulation and agrammatism difficulties. • As there are no pharmacologic treatments, studies have implemented other drugs, such as antidepressants, sertraline, trazodone, to control behavioral symptoms. Primary Progressive Aphasia • There is a gradual deterioration in communication ability the absence of general cognitive impairment. Several variants of PPA are associated with impairment of specific speech-language domains. • Nonfluent/agrammatic: • Agrammatic language, halting, effortful speech, and speech-sound errors. • Neuroimaging reveals atrophy of left anterior perisylvian regions. • Common underlying pathologies include FTLD spectrum disorders (tauopathies and TDP-43 proteinopathies). • Semantic: • Gradual deterioration of semantic memory and a reduction in expressive and receptive vocabulary. • Neuroimaging reveals asymmetrical (left > right) anterior and inferior temporal lobe atrophy. • TDP-43 FTLD is the most common underlying pathology. • Logopenic: • Slow rate of speech, impaired single-word retrieval, and difficulty with repetition. • Neuroimaging reveals neurodegeneration of left posterior perisylvian cortex. • AD pathology is most common. • Behavioral speech-language treatments may result in improved communication abilities in PPA. (Continued)

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Prion Diseases • Prion diseases can develop spontaneously (sporadic), genetically, and through transmission (acquired). • Classic EEG finding in sCJD consists of sharp waves (PSWCs) occurring about once every second. CSF biomarkers are also examined but have been found to vary in sensitivity and specificity. Brain MRIs with DWI and FLAIR sequences should be examined when CJD is suspected. • PRNP mutations can cause fCJD, GSS, and FFI. • Prions are not highly infectious or contagious as an estimated several thousand proteins are necessary to transmit prion disease. • There is currently no treatment for prion diseases, and all cases are fatal. Normal Pressure Hydrocephalus • NPH is a chronic neurologic disorder characterized by enlargement of the cerebral ventricles, shuffling gait, urinary incontinence, and dementia. • It frequently develops in the absence of a macroscopic obstruction to the flow of CSF; however, it is unclear how disturbances in the CSF compartment translate into brain dysfunction and clinical symptoms in NPH. • Brain imaging is necessary to identify ventricular enlargement and verify obstruction to CSF flow in NPH. MRI is the preferred modality for evaluation though CT scans are also common. • Symptoms fall on a continuum, gait, and balance are typically described as “shuffling”; urinary frequency is part of urination control problems; and cognitive disturbances manifest in executive dysfunction as NPH often occurs with AD. • NPS symptoms can be reversed by diverting CSF out of the CNS. Neurosurgical implantation of a ventricular shunt is the standard of care for NPH.

Chapter 9.1 Mild Cognitive Impairment Ranjan Duara, Miriam Jocelyn Rodriguez, and David A. Loewenstein

Development of the concept of mild cognitive impairment The concept of mild cognitive impairment (MCI) entity stemmed from the observation that diseases causing cognitive and functional impairment generally go through a transitional stage between a cognitively normal state and a dementia syndrome. “Prediabetes” and “prehypertension” are examples of conditions that grew to be established in the medical lexicon after it became apparent that these prodromal conditions conferred a very high risk for developing diabetes and hypertension, respectively. Moreover, the complications and management of these prodromal states were found to be similar to the fullblown conditions. It is well recognized that cognitive deficits and atrophic changes in the brain begin long before a diagnosis of dementia, in conditions such as Alzheimer’s disease (AD), Lewy body disease, frontotemporal lobar dementia (FTLD), and vascular dementia. In fact, the pathology of a disease such as AD is probably detectable in the brain several decades before the clinical onset of the disease becomes evident (Braak and Braak, 1991). One of the earliest terms used to classify cognitive changes in the elderly is benign senescent forgetfulness, introduced in 1962 by Kral, who believed it represented a variant of normal aging instead of being a predementia term entity. The Clinical Dementia Rating (CDR) scale, which was reported in 1982, included the term questionable dementia, or CDR 0.5 (CDR 0 was equivalent to normal cognition and CDR 1 equated to mild dementia in this scale; Hughes et al., 1982; Morris, 1993). The term mild cognitive impairment was introduced as a stage in the Global Deterioration Scale in describing the progression from normal aging to dementia by Reisberg et al. (1982). Later studies showed an increased risk of MCI progressing to dementia (Flicker et al., 1991). The National Institute of Mental Health (NIMH) introduced the term age-associated memory impairment (AAMI; Crook et al., 1986) as a variant of normal aging in which cognitive performance was substantially worse than in younger healthy individuals. Subsequently, the International Psychogeriatric Association introduced the term age-associated cognitive decline (AACD; Levy, 1994) as a variant of normal aging with dysfunction in multiple cognitive domains, relative to normal elderly individuals.

The Canadian Study of Health and Aging introduced the term cognitive impairment no dementia (CIND; Graham et al., 1997) to enable clinicians to describe a stage of cognitive and/or functional impairment—not as criteria for dementia but without the requirement of formal tests of cognition to characterize the level of cognitive impairment. The Mayo Criteria for MCI (Petersen et al., 1999, 2003), which have been adopted widely as the standard criteria for identifying MCI, are based on prodromal amnestic features typical of AD, requiring, at minimum, impairment of memory on a single standard test. Subsequently, single- and multidomain nonamnestic forms of MCI and multidomain amnestic MCI (amnestic MCI (aMCI) and nonamnestic MCI (naMCI)) were described (Petersen, 2004). The term MCI is now widely used to describe the predementia phase of any disease that may ultimately progress into a dementia syndrome. The primary benefit of diagnosing a disorder in the MCI stage is to recognize the risk for progression to a full dementia syndrome and to exercise the opportunity for early therapeutic interventions that may prevent or delay progression and improve quality of life (Mosconi et al., 2007). Among the interventions that may be considered are earlier institution of pharmacologic treatments for the suspected cause of the MCI syndrome, secondary prevention methods that may delay progression, and management of a variety of psychosocial issues that may complicate or aggravate the underlying disease entity and its management. Individuals identified to be in the milder stages of MCI are more likely to have readily reversible factors, such as anxiety and attentional disorders, depression, metabolic or nutritional disorders, and medication side effects. However, MCI does not merely represent a point in the transition from normal aging to dementia; instead, it involves a spectrum of cognitive and subtle functional impairments. The reversibility of MCI has given rise to a measure of uncertainty regarding the utility of the term to describe a predementia state and its relevance to clinical practice and research studies. In studies with high base rates of AD, the rate of progression to AD is approximately 12–15% per year, with a low rate of reversal (Luis et al., 2003), whereas in epidemiologic studies there is a lower rate of progression and a high rate of reversal to a normal state (Larrieu et al., 2002; Ganguli et al., 2004).

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How is MCI defined? A transitional, predementia state between normal cognition and established dementia is likely to exist for most recognizable dementing disorders. The best cognitive biomarker of AD in its predementia state appears to be impairment of episodic memory, even among asymptomatic, community-dwelling elders (Howieson et al., 1997; Grober et al., 2000; Assal and Cummings, 2002; Small et al., 2003). Although memory-related symptoms are by far the most common presentation of early AD, variations in the onset and progression of AD are also well known, including aphasic/anomic, visual agnosic, and frontal (abulic or disinhibited) onset (Galton et al., 2000). In contrast to the cognitive deficits seen in dementias, which, by definition, are acquired, the deficits in MCI, as defined here, may or may not be acquired. Especially in community studies, individuals with or without subjective memory complaints may be found to have cognitive deficits upon evaluation, and it may be challenging to determine whether a clear history of cognitive deterioration is present. Correct rates of classification in cross-sectional studies are ultimately related to the sensitivity and specificity of particular test measures and the thresholds for diagnosing impairment, as well as the underlying base rates of the underlying condition causing these impairments in any population (see Brooks and Loewenstein, 2010, for a more extensive review). Although diseases that currently require dementia as a criterion for diagnosis (such as AD) could be diagnosed at an earlier stage by lowering current thresholds for cognitive and/ or functional impairment, lowering these thresholds may also enhance false positive diagnoses. Formal criteria for aMCI proposed by Petersen et al. (1999) require the following features: (1) memory complaints, preferably corroborated by an informant; (2) evidence of objective memory impairment for the age of the patient, as assessed by neuropsychological testing; (3) preserved global cognition; (4) essentially intact activities of daily living (ADLs); and (5) absence of dementia. The specific neuropsychological tests to be used, the thresholds for defining impairment, the specific ADLs to be assessed, and the decision regarding whether these ADLs are intact are left to the judgment of the clinicians. Nevertheless, subjects diagnosed to have MCI using these criteria have been found to have a high likelihood of progression to probable AD in specialty memory disorder clinics. In a follow-up study of a cohort of 220 subjects who were diagnosed at baseline to have MCI, about 80% progressed to develop dementia (Petersen et al., 2003). Grundman et al. (2004) proposed an adaptation of Petersen’s MCI criteria for use in clinical trials by specifying the cognitive and functional tests to be used and the scores for determining impairment in these areas. They proposed that (1) memory complaints should be

corroborated by an informant; (2) abnormal memory functioning should be documented by the delayed recall score for a single standard paragraph from the Logical Memory II subtest of the Wechsler Memory Scale (WMS), using 1.5 SD below age and education equivalent cognitively normal subjects as the threshold for impairment; (3) normal general cognitive functioning should be based on clinical judgment and an MMSE score of 24 or above; and (4) no evidence exists of impairment or minimal impairment in activities of daily living, documented by a CDR global score of 0.5 or higher. Other predementia entities include CIND (Graham et al., 1997), the criteria for which are less restrictive and merely require evidence of cognitive impairment in a nondemented individual. Galvin et al. (2005) and Storandt et al. (2006) have suggested that a targeted clinical history that provides evidence of cognitive and functional decline, relative to previously attained abilities, can identify nondemented subjects who will progress and be found to have histopathologic AD on autopsy. These impressive findings may partly be related to the clinical environment in which these criteria were implemented; the process of referral may have resulted in them being preselected to have AD. Evidence of progression of cognitive deficits, either by history from an informant or by longitudinal examination, allows a tentative classification of MCI cases into progressive versus nonprogressive (even reversible) MCI. It remains important to consider predementia conditions other than prodromal AD, which may be present as MCI or CIND, including vascular cognitive impairment, Lewy body disease, and various forms of frontotemporal lobar degeneration. Neuropsychological tests commonly used to assess performance in multiple cognitive domains required to assess MCI include word list tests (such as FAS and COWAT), logical memory from the WMS third and fourth editions, memory-delayed recall, and the Stroop color word test to measure different areas of cognitive functioning (Grober et al., 2000; Small et al., 2003; Backman et al., 2004). Various cut-off scores have been used for these tests, although 1.5 SD below age- and educationadjusted norms for domains of episodic memory, executive functioning, and perceptual speed appears to be most effective in identifying MCI (Loewenstein et al., 2006), even among asymptomatic, community-dwelling elders (Assal and Cummings, 2002). In some studies, the earliest deficits have been noted to be in executive functioning and perceptual speed, as well as memory and learning (Vanderploeg et al., 2001; Backman et al., 2004; Loewenstein et al., 2004). The use of multiple memory measures to identify memory impairment, using a cut-off score of 1.0 SD on at least two cognitive tests in the same cognitive domain, may decrease the false positive rate in classification (Jak et al., 2009). As a consequence of the variety of

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cognitive tests and cut-off scores are in use to establish cognitive impairment, considerable variability exists in the prevalence and incidence rates of MCI in studies conducted in the last decade (see Luis et al., 2003; Brooks and Loewenstein, 2010).

MCI subtypes The heterogeneity of MCI is a consequence of a number of factors, including the methodology used to classify MCI, the underlying etiology of the MCI syndrome, and the premorbid status of the patient. Items of particular importance are the level of education, cultural background, cognitive reserve in various domains, and general medical, neurologic, and psychiatric status. MCI may be classified on the basis of the presenting cognitive syndrome (amnestic, nonamnestic, multidomain), the suspected aetiology (AD, cerebrovascular disease, Lewy body disease), and the progression rates to dementia (rapid and slow progressors, nonprogressors, and reversers). Disproportionate involvement in memory, language, visual-spatial, or other functions results in the two basic subtypes of aMCI or naMCI. Each of these can be single-domain or multiple-domain MCI. Multidomain aMCI requires impairment in memory and one or more nonmemory domains; multidomain naMCI requires impairment in two or more nonmemory domains, such as attention/executive functioning, language, and visuospatial processing (Petersen et al., 2003; Kantarci et al., 2008). Nevertheless, considerable overlap occurs between aMCI and naMCI, depending on the criteria used to classify impairment. Methodological factors may result in different frequencies of MCI subtypes, thereby contributing substantially to the heterogeneity of MCI. The prevalence rates for MCI subtypes depend on the use of different cut-off scores for memory and nonmemory impairment, as well as the use of different normative data bases to derive such cut-off scores. For example, it is evident that the greater the number required to classify an individual as being impaired, the lower will be the prevalence rates of aMCI; a correspondingly higher prevalence rate of naMCI may then become evident. Reducing the threshold for classifying impairment in a memory test from 1.5 to 1.0 SD will increase the frequency of aMCI relative to naMCI. Further complicating the field of MCI research is the heterogeneity and plethora of memory and nonmemory test measures employed. Individuals with high premorbid educational attainment or cognitive reserve may be able to compensate for their deficits because of their greater knowledge base and familiarity with the test-taking process and by employing various strategies that allow them to perform well on cognitive measures, in spite of their deficits. Those with low cognitive reserve may perform far worse than would be expected, not only

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because of a lower knowledge base, possibly resulting from a lower educational level, but also because of lack of familiarity with test taking and the associated anxiety and attentional problems. The clinical features of etiologic subtypes of MCI would be expected to be similar to those of the corresponding dementia subtype; however, this may depend on a number of factors, including the duration of the MCI stage of the dementing disease and the saliency of the clinical features that generally occur in that stage. For example, one of the distinguishing clinical features used for diagnosing AD is gradually progressive impairment in recent memory, as opposed to remote memory. This feature is generally most apparent in the earlier phases of AD and becomes less distinct in the later stages of the disease. The most useful distinguishing features of Lewy body disease in the MCI stage (MCI-LBD; occurring in 79–86% of cases) are (1) episodic confusion; (2) impaired performance on fluency tests requiring sustained attention and on visuospatial tests, with relatively preserved performance of memory tests in spite of frequent memory-related complaints; (3) REM sleep behavior disorder; and (4) motor dysfunction (Ferman et al., 2002; Claassen et al., 2010). It has been suggested that aMCI is more likely to reflect underlying AD pathology, whereas naMCI is more indicative of non-AD pathologies (Petersen, 2004). Indeed, in the Leipzig Longitudinal Study of the Aged, Busse et al. (2006) found that naMCI was associated with progression to dementia of the non-AD type, whereas aMCI was associated with progression to AD. Other studies have shown that memory impairments are common among individuals with underlying vascular disease and that the severity of vascular disease is related to the degree of impairment in executive function. This makes multiple-domain MCI the most common subtype among those with vascular MCI (Villeneuve et al., 2009). Among all MCI subtypes, the presence of mild parkinsonian signs was associated with increased dysexecutive function and increased probability of a vascular dementia diagnosis (Mauri et al., 2008). Among 1346 patients with Parkinson’s disease (PD), from eight different cohorts, 25.8% were found to have MCI. Among them, amnestic impairment (13.3%) was most common, followed by visuospatial impairment (11%), and then attention/executive impairment (10.1%; Aarsland et al., 2010). The frequencies of different MCI subtypes were as follows: aMCI single domain (8.9%), aMCI multiple domain (4.8%), naMCI single domain (11.3%), and naMCI multiple domain (1.3%). The pattern of cognitive impairment and the number of domains involved may have diagnostic and prognostic implications (Bozoki et al., 2001). Patients with aMCI, especially those with impairment in more than one memory test, have a higher risk of progression to dementia, as compared to normal elderly individuals or those with naMCI. Patients in the prodromal stages of AD may

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present with pure memory impairment, but those who progress more rapidly are likely to have more widespread disease, with impairment in cognitive and noncognitive domains. These noncognitive domains include psychiatric symptoms such as anxiety, depression, paranoia, apathy or disinhibition, and motor symptoms such as parkinsonism and abnormalities in posture and gait. Although not typically considered a noncognitive domain, radiological findings do contribute important diagnostic and prognostic information. MCI-Vasc usually has evidence of multiple lacunar infarcts in the basal ganglia, thalamus, and/or subcortical white matter. MCI-AD is characterized by the presence of hippocampal and/or entorhinal cortex atrophy without obvious cerebral infarctions (Luis et al., 2003; Burton et al., 2009). MCI-FTD is characterized by predominant frontal and/or anterior and lateral temporal atrophy. Cognitive impairment among nondemented elderly individuals may also be caused by a variety of systemic medical conditions, effects of medications and toxins, neuropsychiatric disorders, educational and sociocultural deprivation, and “frailty related” factors.

Diagnostic issues The classification of subjects as normal, MCI, or mild dementia, according to neuropsychological and functional evaluation, is more challenging for MCI than it is for dementia cases because MCI patients have much milder and more subtle cognitive and functional deficits (Luis et al., 2003). The diagnosis of cognitive states relies on two elements of clinical assessment: the history from the subject (and/or one or more informants), providing information about the presence, severity, and course of functional impairment; and an objective cognitive (neuropsychological) assessment. Especially in the early phase of MCI, the reliability of both these elements is likely to be suboptimal, for two reasons: (1) It is difficult to distinguish functional impairment associated with normal versus abnormal aging, especially in the presence of agerelated conditions such as arthritis or visual and hearing impairment. (2) Objective assessment of cognitive deficits tends to be obscured when impairment is mild because the relative impact is greater for factors such as low or very high educational levels, practice effects, recruitment/referral bias, cultural and linguistic diversity, premorbid cognitive and functional deficits, and coexisting psychiatric, medical, or neurologic conditions, including attention deficit disorder and dyslexia. The two elements in the clinical evaluation of MCI cases have been combined to provide a summary score in the CDR scale (Morris, 1993), although there is often wide discrepancy, especially in the early stages of cognitive and functional impairment, between the results of objective cognitive assessment and the history of functional

impairment. Diagnostic variability between individual clinicians and diagnostic teams (Rockwood et al., 2000) reduces reliability of diagnoses in cross-sectional and especially longitudinal studies. As a consequence, large number of subjects may be required to power studies in order to obtain significant results, particularly for subjects who have been recruited from the community and not the clinic. Most patients who present to a clinic come with a reliable informant who can provide a reasonably unambiguous account of the mode of onset of the cognitive syndrome, its relationship to other events (such as a stroke, a medical illness, or a surgical procedure), its mode of progression, the presence of fluctuations, REM sleep behavior disorder, and so on. Subjects recruited from the community typically are not accompanied by an informant, and any available informant is unlikely to have the knowledge or the motivation to provide the requisite information. These issues can be problematic in clinical trials that require independent assessments of the history and functional status and clinical interview of the research subject (usually performed by a physician) and the cognitive assessment performed by a neuropsychologist. The individual assessments of the patient are then reconciled by a consensus process, which requires reconciliating discrepancies between the diagnoses of the two assessments. The thresholds used for distinguishing normal aging from any form of MCI and MCI from mild dementia are arbitrary. Consensus diagnosis also can be time consuming and labor intensive to produce, resulting in an increased overall expense to the diagnostic process. The individual views and the personality of a single clinician on a consensus conference team may sway the consensus diagnosis in a particular direction. Although the reliability of a consensus diagnosis of dementia or MCI has been assessed only infrequently (Hogervorst et al., 2003; Schafer et al., 2004), in the few studies that have been done, the results have not been impressive. To address these aforementioned issues, an algorithmic consensus diagnosis has been proposed and used effectively to reconcile the different perspectives of individual sources of data and to systematize the process of making the distinctions between cognitively normal and MCI subjects and MCI and mild dementia subjects (Duara et al., 2010). After a global cognitive diagnosis of MCI or dementia is determined, an etiologic diagnosis, which is based on the same clinical, neuroimaging, and laboratory features required to make a series of dementia diagnoses, may be assigned. Examples of such MCI etiologic diagnoses are MCI-AD (early AD), MCI-vascular or vascular cognitive impairment (early vascular dementia), and MCI-LBD (early Lewy body dementia), MCI-FTD (early frontotemporal dementia). Cognitively impaired subjects seen in a memory disorder center are much more likely to have AD than those recruited from a community study. Subjects found to have cognitive impairment in a stroke clinic, a renal clinic, a

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cancer center, or a sleep center are unlikely to be referred for cognitive assessment because of the (often correct) assumption that the cognitive impairment is associated with the medical condition or its treatment at that clinic. Diagnostic criteria for the individual causes of dementia generally require the exclusion of all other identifiable neurologic, psychiatric, and medical causes of dementia or cognitive impairment. As such, the dominant medical illnesses present in each individual should be emphasized as possible etiologic factors for an MCI syndrome. The methods that are available for making the diagnosis and the expertise of the diagnosticians at a particular venue also determine the accuracy of the diagnosis. In community practice, the time and expertise to administer and even brief cognitive tests may not be available. Culture, education, socioeconomic factors, and attitudes regarding the aging process may determine the importance given to cognitive symptoms and the effort in diagnosing the cause of such symptoms. The availability of neuropsychological evaluation, brain imaging, and CSF evaluation may be determined by prevailing healthcare regulations and regional biases toward the use of certain tests. Diagnostic accuracy may also be influenced by the specific tests used and how they are interpreted (e.g., currently only the exceptional radiologist assesses and comments on the severity of medial temporal atrophy on a magnetic resonance imaging (MRI) scan). The challenge in assigning an etiologic diagnosis to an MCI syndrome, especially in general practice, is that symptoms mimicking early dementia and performance on cognitive tests may be related not only to a variety of medical conditions or the effects of medications but also to psychosocial factors, developmental cognitive disorders such as attention deficit disorder and dyslexia, and psychiatric conditions such as anxiety, depression, and personality disorders (Budson and Price, 2005). The relationship between depression and dementia is a complex one. The results of some studies suggest that depression may often be a prodrome to AD. Other studies suggest that impaired attention and executive function are associated with geriatric depression (Lockwood et al., 2002) and that these deficits may persist even after successful treatment of depression. Among 1777 subjects in the National Alzheimer Coordinating Center (NACC) database (Beekly et al., 2004), subjects with MCI who had prominent deficits in executive functioning were found to have greater severity of depression (Rosenberg et al., 2011), but there was no association between the presence of aMCI or naMCI and depression. In another study, patients with four or more neuropsychiatric symptoms were more likely to be diagnosed with aMCI, and patients diagnosed with aMCI were more likely to exhibit depressive symptoms than other symptoms and to have an increased risk of developing dementia (Edwards et al., 2009). Although clinicians must be aware that memory complaints may be symptomatic

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of underlying depression, it is especially important for psychiatrists to be aware that depressive symptoms in an individual who has demonstrable amnestic deficits often suggests a diagnosis of an early form of dementia.

Pathology of MCI The pathologic changes of AD may begin many years before the patient is diagnosed with dementia (Crystal et al., 1988; Braak and Braak, 1997; Silverman et al., 1997). The earliest known event in the pathophysiology of AD is the deposition of amyloid beta protein in the neocortex (Oddo et al., 2003). This, by itself, may result in subtle cognitive deficits (Rentz et al., 2010). The neurodegenerative phase of AD begins with selective involvement of the anterior aspects of the transentorhinal and entorhinal cortex (ERC), the CA1 sector, and subiculum of the hippocampus (HP; Leverenz and Raskind, 1998). About 30% of individuals who meet neuropathologic criteria for AD and are classified as Braak and Braak stage V or VI at autopsy remain nondemented during life (Snowdon et al., 1997); this suggests that the disease can reach a relatively advanced pathologic stage without significant symptoms of dementia. Among elderly clinically normal individuals (in the Mayo ADRC) who have been classified pathologically as Braak and Braak stage IV or less, amyloid or diffuse plaques are frequently present, but neuritic plaques are rare (Jack et al., 2002). Subjects diagnosed with MCI during life have greater tau and neurofibrillary pathology (which correlates closely with cognitive function) than cognitively normal subjects but have cortical plaque densities that are similar to those in patients with AD. Although AD pathology is almost universally present among subjects classified clinically to have MCI, about 30% also have other pathologies such as Lewy bodies, argyrophilic grain disease, or hippocampal sclerosis affecting the medial temporal lobe (Forman et al., 2007). Biochemical alterations in cortical tau, Aβ, and isoprostanes correlate with plaque and tangle burden but do not distinguish MCI subjects from those with clinical dementia. Markers of lipid peroxidation, F2-isoprostanes (F2-IsoP), and F4-neuroprostanes (F4-NP) have been found to be similar in the cerebral cortex and hippocampus of MCI and AD subjects but are elevated compared to normal controls. Cognitive function has also been found to correlate with the loss of synaptic markers and white matter pathology, even among normal individuals (Markesbery et al., 2005).

Biomarkers in MCI As described previously, the assessment of memory and other cognitive deficits, typically affected by diseases such as AD, may be influenced by a variety of demographic,

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psychosocial, medical, and psychiatric factors, as well as hearing and visual deficits (Lopez et al., 2000; Manly et al., 2005; Acevedo et al., 2007; Dilworth-Anderson et al., 2008). In contrast, such factors do not influence the accuracy of biomarkers for the detection and diagnosis of diseases. In general, biomarkers become detectable years or even decades preceding the onset of the clinical syndrome of the disease in question. Biomarkers may be indices of specific underlying pathologies such as the accumulation of amyloid (Aβ1-42) in the brain (as indicated by low levels of CSF Aβ1-42 or elevated levels of fibrillar amyloid on amyloid positron emitting tomography (PET) scans). Biomarkers may also be downstream indices of degenerative changes in the brain (such as regional atrophy or synaptic loss/dysfunction). Both specific and downstream biomarkers are surrogates of underlying pathology and can be used as aids in the diagnosis, potentially even in the preclinical stage of diseases such as AD and FTLD. They may also predict the rate of progression of the clinical syndrome. Alterations in the structure of the brain can be detected and quantified by several structural imaging techniques, including computed tomography (CT) and MRI, especially in the medial temporal lobes, where AD and FTLD-related degenerative pathology appear to be most prominent early in the disease process. Functional changes in the brain can be assessed with PET and single photon emission computed tomography (SPECT), as well as by functional MRI (fMRI). Amyloid deposition in the brain can be detected using PET scans with either C-11 or F-18 labeled ligands that bind to fibrillar amyloid beta protein. Genetic markers, such as APOE genotypes, can identify subgroups of individuals who are at elevated risk for cognitive decline and the development of AD pathology (Cosentino et al., 2008). Genetic markers for AD that are sensitive to autosomaldominant transmission include amyloid precursor protein (chromosome 21; onset at 40–65 years), presenilin 1 (chromosome 14; onset at 25–60 years), and presenilin 2 (chromosome 1; onset at 45–84 years). The most common genetic risk factors for late-onset AD, the ApoE-e4 allele, are associated with a greater prevalence and an earlier age of onset of AD in most racial/ethnic groups. The epsilon 4 allele for the apolipoprotein E (APOE) gene on chromosome 19 is a risk factor that explains about 20% of late-onset cases. Those heterozygous for the e4 allele have increased risk for AD by two- to threefold, and those homozygous for the e4 allele have 10- to 15-fold increased risk for AD. The SORL1 gene on chromosome 11 and a host of other candidate genes (see www.alzgene.org) also explain small percentages of the variance with regard to risk for AD. Relatively high prevalence of the APOE e4 allele, but with a lower risk for AD, has been reported among nondemented African Americans (Kamboh et al., 1989; Srinivasan et al., 1993), relative to non-demented

Hispanic, and even more so among non-Hispanic Caucasian groups (Pablos-Mendez et al., 1997; Harwood et al., 2004). The presence of the APOE e4 genotype combined with clincal features has been used to increase the predictive accuracy of the diagnosis AD, especially in its predementia phase (Jobst et al., 1998; Visser et al., 2002). Cerebrospinal fluid (CSF) biomarkers of AD pathology are CSF Aβ1-42 (the 42 amino acid form of Aβ), as an early marker of the amyloid phase of the disease; and CSF total tau—that is, T-tau, phosphorylated tau associated with tangle formation phospho tau (P-Tau181P)—as a marker of the later neurodegenerative phase of the disease associated with neuronal/axonal degeneration. Low CSF Aβ42 has also been reported several years before the onset of clinical symptoms, suggesting its potential utility for preclinical diagnosis (Fagan et al., 2007; Stomrud et al., 2010). The CSF Aβ42/tau ratio differentiated patients with subjective cognitive complaints, with naMCI, and with aMCI from healthy controls (Visser et al., 2009). Currently, the most promising biomarkers that could assist in the diagnosis of early AD are the ratios of CSF tau protein to CSF Aβ levels (Sunderland et al., 2003) and CSF phosphotau-231 (ptau-231) (Buerger et al., 2002, 2003, 2006; Hansson et al., 2006). CSF biomarkers have been shown to have utility in predicting cognitive decline in cognitively normal older adults (Fagan et al., 2007) and progression to an MCI state (Li et al., 2007), as well as progression of aMCI to AD (Li et al., 2007; Diniz et al., 2008; Visser et al., 2009). Using the US Alzheimer’s Disease Neuroimaging Initiative (ADNI) data set, a marked increase in CSF T-tau and P-tau together with a marked decrease in CSF Aβ42 is found in AD (De Meyer et al., 2010), providing 85% sensitivity at a specificity level of 90%. In this study, a separate analysis derived an “AD signature” consisting of specific ratios of CSF β-amyloid (1:42) to CSF phosphorylated tau181P. This signature was present among 90% of AD patients, 72% of MCI subjects, and 36% of cognitively normal elderly normal subjects. While the proportion of cognitively normal subjects with the AD signature was unexpectedly high, the APOE e4 allele frequency was markedly increased in this subgroup of normal subjects with the AD signature (De Meyer et al., 2010), suggesting that the signature was able to detect preclinical AD. A meta-analysis of the diagnostic and predictive utility of CSF phosphorylated tau levels showed it was satisfactory for diagnosing MCI and predicting progression of MCI to dementia but was less capable of differentiating AD from other types of dementia (Mitchell, 2009). In many European specialty centers (which is the main location for diagnosis and treatment of dementing diseases), lumbar puncture and CSF assays are performed routinely. In countries where nonspecialists provide diagnosis and treatment of dementia, CSF biomarkers are less likely to become the prevailing standard for diagnosis of AD.

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Structural neuroimaging is used routinely in the evaluation of dementia/MCI, primarily for the purpose of excluding conditions such as stroke, hydrocephalus, and brain tumors. MRI is vastly superior to CT scanning as a structural imaging technique, as it has greater resolution, provides far greater soft tissue contrast in the brain and also has the advantage of avoiding ionizing radiation. Assessment of hippocampal and entorhinal cortex atrophy in structural brain images could be an inclusive test for the diagnosis of prodromal and probable AD. Entorhinal cortex and hippocampal volume loss on MRI scans are highly correlated with the rate of progression of MCI to AD. The presence of MCI or mild dementia versus normal cognition has been associated specifically with atrophy of the left hippocampus, parahippocampal gyrus, and amygdala (Bobinski et al., 2000; Wolf et al., 2001; Jarvenpaa et al., 2004; Salamon et al., 2004). Smaller hippocampal and entorhinal cortical size on MRI (de Leon et al., 1993, 1997) has been related to relatively poor performance of memory function in normal aging and future AD risk (Killiany et al., 2000; Xu et al., 2000). The histopathologic correlate of these imaging findings appears to be the accumulation of neurofibrillary tangles, neuritic plaques, and the loss of neurons and dendritic arbor in the transentorhinal cortex and the hippocampus cortex (Bobinski et al., 1996, 2000; Gosche et al., 2002; Jack et al., 2002; Burton et al., 2009). The presence of medial temporal atrophy is not specific for AD, and conditions such as FTLD, vascular dementia, and hippocampal sclerosis may also demonstrate brain atrophy in these regions. However, because of the high prevalence of AD in the elderly, 85–90% of all degenerative pathology in the medial temporal lobe in elderly subjects is AD pathology (Barker et al., 2002), either alone or in combination with other diseases. An early effort demonstrating the importance of combining structural MRI with other risk factors in the assessment of risk of progression of aMCI to AD was the study by Petersen (2004). They found that, among aMCI subjects, those who were APOE e4 allele carriers had the greatest deficits on cued memory tasks and reduced hippocampal volumes on structural MRI, as well as the greatest risk for rapid progression to dementia. Two functional imaging techniques, PET and SPECT, are sensitive methods for providing quantitative evaluation of physiologic functions, protein pharmacokinetics, and distribution of receptors in the brain (CedazoMinguez and Winblad, 2010). Radiolabeled glucose FDG (fluoro-2-deoxy-d-glucose)-PET can be used to measure cerebral glucose metabolism, which indirectly indicates synaptic activity. Metabolic or perfusion deficits detected on PET or SPECT scans in AD patients distinguish them from normal control subjects and from patients with other types of dementia and correlate with the severity of cognitive impairment in MCI patients (Small et al., 2008). Using FDG-PET, with an automated method of image

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analysis to study the medial temporal regions and hippocampus, de Leon and colleagues showed that baseline FDG-PET measures predicted decline from normal to MCI or AD 6–7 years in advance of symptoms with 71% and 81% accuracy, respectively. An extrapolation of these results suggests that AD can be identified 12 years before the patient is symptomatic. A functional imaging technique (fMRI) can provide measures of regional cerebral blood flow in various brain areas with high temporal resolution, allowing assessment of changes in blood flow in association with a cognitive task. By using fMRI, Sperling (2007) studied cognitive-behavioral functions in the early phases of neurodegenerative disorders and identified neuroanatomic networks affected by these diseases (Sperling, 2007). The results of an fMRI study of verbal short-term memory comparing healthy controls to AD patients showed that alternate functional networks and greater overall activation occurred in AD patients during memory processing (Peters et al., 2009).

Predictors of outcomes in MCI The importance of recognizing individuals at high risk for developing AD is based on the concept that such individuals may benefit from early therapeutic interventions (Mosconi et al., 2007). The design of primary and secondary prevention trials and of pharmacologic and nonpharmacologic treatment trials could be influenced by the profile of neuropsychological, functional, and biomarker tests that facilitate prediction of the rate at which individual MCI subjects will progress to dementia. By factoring in these profiles and the predicted rates of decline without any treatment for individual subjects participating in a clinical trial, it may be possible to better determine the effect of a specific intervention for a group of subjects. In clinical settings, the rate of progression from aMCI to dementia is generally 10–15% per year (Petersen et al., 1999, 2001; Boyle et al., 2006). Morris et al. (2001) reported that 100% subjects diagnosed with MCI (CDR score = 0.5) progressed to dementia over a 9.5-year period, of which 84% received a neuropathologic diagnosis of probable AD. Alexopoulos et al. (2006) found that 25% of subjects with aMCI, 38% of subjects with naMCI, and 54% of individuals with mixed amnestic and nonamnestic impairment progressed to dementia over a 3.5-year follow-up period. On the other hand, Rountree et al. (2007) found no differences in the rates of progression between those with aMCI (56%) and those with naMCI (52%) over a 4-year follow-up. The degree of impairment on both amnestic and nonamnestic measures is associated with the likelihood that individuals with MCI will progress to dementia versus revert to a normal state over time (Loewenstein et al., 2009). As might be expected, the prevalence rates

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of MCI and the rates of progression to dementia among subjects diagnosed in a community settings appear to be considerably lower than for subjects seen in a clinical setting (Larrieu et al., 2002; Ganguli et al., 2004). Although aMCI and naMCI are generally diagnosed on the basis of a cut-off point of 1.5 SD below age- and education-corrected means on a single neuropsychological test, it is apparent that, for aMCI, impairment in more than one memory measure or a combination of deficits in memory and nonmemory measures is much less susceptible to reversion to a normal state and faster progression to dementia than when only a single amnestic or nonamnestic cognitive impairment is present (Manly et al., 2005, 2008; Jak et al., 2009; Loewenstein et al., 2009; Brooks and Loewenstein, 2010). Individual tests evaluate unique aspects of cognitive function, and subjects with deficits on multiple tests are likely to have more advanced or widespread underlying pathology and be further along in the disease process. As a result, it is not surprising that these individuals progress to dementia at much greater rates as well as show less reversion rates to a normal state of cognition. Longitudinal studies suggest that patients with naMCI are likely to have far more variability in terms of symptomatology and progression to various forms of dementia (such as frontotemporal dementia and primary progressive aphasia; Nordlund et al., 2010; Ritchie and Tuokko, 2010). Non-neuropsychological measures that may predict a high rate of progression of MCI to dementia include the subjects’ age (older subjects are more likely to progress), the presence of medial temporal lobe atrophy and white matter hyperintensities on neuroimaging, low beta-amyloid, and high tau levels in the CSF. Abnormal neuropsychiatric features including extrapyramidal signs, gait disorders, and the presence of psychopathology also predict the rate of progression of MCI to dementia (Kantarci et al., 2008; Jack, 2010). A recent meta-analysis of approximately 50 different studies suggested that depression is a risk factor for AD. However, while the presence of co-morbid anxiety predicts progression to dementia (Edwards et al., 2009), neither depression nor anxiety has been found to predict the likelihood of reversion to a normal cognitive state (Beekly et al., 2004; Budson and Price, 2005). Visser et al. (2002) created the Predementia Alzheimer’s Disease Scale (PAS) by combining demographic, cognitive, and biomarker profiles and performing a multivariate analysis of various predictors of AD among clinic patients diagnosed with MCI who were participants in a large-scale European study. Variables shown to be associated with an increased risk of progression from normal cognition to MCI in the PAS included age, memory scores, hypertension, APOE e4 genotype, and presence of hippocampal atrophy. The PAS was found to correlate with beta amyloid levels in CSF (Schoonenboom et al., 2005). In a retrospective validation study, the optimal cut

score of the PAS had a sensitivity of 82%, specificity of 85%, and positive predictive accuracy of 75% (Visser et al., 2002) for predicting progression from MCI to AD over a 2–5-year follow-up period. The order in which the items were included in the analysis of the PAS data (demographic, medical, cognitive, biomarker) reflected the order used commonly in clinical practice. Based on much of the afore-mentioned information, guidelines for a diagnosis of AD in a predementia stage have been proposed based on the PAS score (Dubois et al., 2007, 2010). The “Dubois criteria” for “prodromal AD” are based on criteria similar to those used for aMCI, with the additional requirement that a positive biomarker be present (medial temporal atrophy on MRI, parietotemporal deficits of PET or SPECT scanning, or abnormal CSF analysis of amyloid β or tau proteins. A more elaborate classification of preclinical AD and MCI due to AD has been proposed by workgroups convened by the National Institute on Aging and the Alzheimer’s Association (www.alz.org/research/diagnostic_criteria). They issued their recommendations for new diagnostic criteria for AD based on the following proposed clinicopathologic stages of preclinical AD: • Stage 1: asymptomatic cerebral amyloidosis. Evidence of cerebral amyloid-β accumulation, by either low CSF Aβ42 measures or elevated PET amyloid tracer retention, with normal performance on all measures of cognitive function. • Stage 2: cerebral amyloidosis with evidence of early neurodegeneration. Stage 1 plus evidence of an AD-like pattern of abnormality on downstream markers of neurodegeneration and synaptic dysfunction (increased CSF tau or phospho tau, cortical volume loss, gray matter loss, or thinning or hippocampal atrophy), with or without normal cognition. • Stage 3: cerebral amyloidosis with evidence of neurodegeneration plus subtle cognitive change. Stage 2 plus definite evidence of subtle decline over time on standard cognitive tests but not meeting criteria for MCI. • Stage 4: cerebral amyloidosis with evidence of neurodegeneration plus evidence of MCI. The workgroup developed the following criteria for a diagnosis of MCI due to AD. These are similar but slightly different from the original criteria for MCI because they include intra-individual changes in cognition and function: • Concern regarding a change in cognition. The patient, an informant, or a skilled clinician can identify concern about a change in cognition. • Impairment in one or more cognitive domains. Performance is lower than would be expected, considering the patient’s age and education (impairment is typically 1–1.5 standard deviations below the mean of the individual, adjusted for age and education). Impairments may present in more than one domain and may be amnestic or nonamnestic.

Mild Cognitive Impairment

• Preservation of independence in functional abilities. The criterion allows mild problems with complex tasks to be present, as long as independence of functions, such as paying bills, preparing meals, and shopping, is maintained, albeit with minimal aids and assistance. • Not demented. The cognitive changes should be sufficiently mild that there is no evidence of impairment in social or occupational function. Using these criteria for MCI, the workgroup developed the following criteria for a diagnosis of MCI due to AD. Biomarkers classify MCI patients into three groups, with increasing levels of certainty of underlying AD pathology: • MCI of a neurodegenerative etiology. The patient fulfills MCI criteria, but no biomarker evidence is present (biomarkers may not have been tested—or, if tested, results are ambiguous or negative). • MCI of the Alzheimer type. The patient fulfills MCI criteria and has positive findings from at least one “downstream” biomarker, such as MRI evidence of hippocampal atrophy or FDG PET alterations. • Prodromal Alzheimer’s dementia. The patient fulfills MCI criteria and has positive biomarker evidence of amyloid accumulation in the brain, such as low CSF Aβ42, or amyloid accumulation on PET imaging.

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For example, it is well known that epidemiologic studies have suggested that individuals who are engaged in regular cognitive activity and physical exercise have a lesser risk for MCI and dementia than their peers who are not so engaged (Yaffe et al., 2001; Wilson et al., 2002). A well-controlled clinical trial of physical exercise and cognitive function among elderly normal subjects and those with MCI suggests that exercise may enhance cognition among these subjects (Lautenschlager et al., 2008). With regard to cognitive rehabilitation, procedures such as face–name association enhanced by spaced retrieval and fading cues techniques can improve cognitive function. Moreover, functional skills, such as making change for a purchase, can be facilitated by using motor and procedural learning techniques and paradigms that enhance the speed of cognitive processing. All these techniques make use of the family member as a therapy extender and also employ memory notebooks as compensatory strategies (Loewenstein et al., 2004). Reviews of nonpharmacologic interventions in MCI and early AD by Acevedo and Loewenstein (2007) and Middleton and Yaffe (2009) suggest that further studies of cognitive and physical interventions are necessary because of their potential to improve cognition or decrease cognitive decline through either mechanisms of neuroplasticity, increased oxygenation, or their effect on inflammatory markers.

Treatment of MCI Medications currently available for the cognitive treatment of AD and other dementias, such as donepezil, rivastigmine, and galantamine, have evidenced limited or no effectiveness in their ability to improve cognitive status in MCI or to decrease the rate of progression from MCI to dementia (Farlow, 2009). The most rigorous of these studies compared the use of donepezil, vitamin E (2000 IU daily), and a placebo among more than 750 older adults with aMCI over a 3-year period. Vitamin E showed no benefit at all, but the subjects receiving donepezil had a reduced risk of progressing to AD during the first year of the trial. However, by the end of the 3-year study, their risk was not statistically different from the risk of those taking vitamin E or the placebo, although among APOE e4 carriers, a statistically significant benefit was found. However, these results were not considered strong enough to support a clear recommendation to treat MCI with donepezil (Petersen et al., 2005). It is unclear whether the use of biomarkers such as apolipoprotein E (APOE4), CSF Aβ1-42 and tau levels, and PIB positivity on brain PET scans will identify subgroups of MCI subjects who may respond more favorably to these medications. Nevertheless, most physicians are likely to use cholinesterase inhibitors for the treatment of patients with aMCI. Nonpharmacologic approaches to MCI and early dementia may have a useful and perhaps more effective role in preventing progression of aMCI to dementia.

Impact on society/ethical issues An earlier diagnosis of AD allows the patient and family members to address important medical, social, and financial management decisions sooner. However, although there are obvious advantages to obtaining a diagnosis of MCI, the potential negative consequences deserve serious consideration. Earlier diagnosis could be associated with a higher error rate and mislabeling of individuals who are disease free, especially because milder cases are more likely to be misclassified as cognitively normal or to have other potentially reversible or self-limiting disorders. Among those who are correctly classified, a certain proportion of patients and their families may regard the diagnosis as threatening, intrusive, and unwelcome, regardless of any potential benefits of early intervention. Cultural and individual attitudes toward conveying the diagnosis of an incurable condition that afflicts the elderly need to be assessed and balanced with the possible advantages to be obtained by imparting a diagnosis of MCI to a patient. A diagnosis of very early AD may result in substantial and unnecessary curtailment of the patient’s activities, freedom to make choices, social interactions; loss of employment; inappropriate denial of health care, long-term care, and life insurance; and social isolation. The relatively modest attendant benefits of currently available treatments may not be considered worth the

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cost of the evaluations and treatments. When these potential negative consequences are balanced against the anticipated individual and societal benefits of making an earlier diagnosis, the ultimate decision to proceed with an earlier diagnosis of AD will most likely be influenced by the patient, the physician, societal priorities, the setting and culture in which care is delivered, and governmental healthcare policies. Acceptance of MCI as a diagnostic entity requiring intervention will likely have an economic impact on the healthcare systems of different countries. The negative economic, ethical, social, and other effects of revising AD criteria deserve serious consideration and study.

Future directions The progress being made in diagnosing AD and other forms of dementing diseases in the earliest possible stages will likely continue because it is generally agreed that earlier identification and intervention in any of these diseases will improve outcomes. The criteria for an earlier form of MCI (early MCI or eMCI) have been outlined for ADNI-2, and definitions for a pre-MCI entity have also been proposed (Duara et al., 2011). Studies are currently underway to define the rates of progression and reversal, as well as the biomarker status for these diagnostic entities. The two independent groups (Dubois et al., and the NIA/ Alzheimer’s Association Workgroups) that have proposed new criteria for diagnosing prodromal (e.g., MCI) and preclinical forms of AD in 2010 will likely be continuing studies to support or validate their proposed criteria. Further optimization of information obtained from a variety of biomarkers, such as amyloid load in the brain, CSF proteins and specific patterns of brain atrophy in medial temporal and other brain regions, glucose metabolism, and blood flow, combined with neuropsychological measures will allow these criteria to be refined. A growing database of studies on the natural history of aMCI and the predictive accuracy of individual biomarkers and combinations of biomarker tests for identifying individuals with aMCI who will progress to AD is now becoming available. The ADNI-1 has already provided a host of evidence in this regard (Jack et al., 2010). It is likely that ADNI-2 as well as similar studies in Europe, Japan, and Australia, which are currently in the planning or early execution stages, will provide a wealth of data supporting the use of particular combinations of tests or procedures. This will be a valuable resource for developing practice guidelines for the diagnosis of early AD in different settings. The progression to dementia from preclinical and prodromal stages of AD is a continuous process that may be best predicted by multivariate algorithms, including both neuropsychological variables and biomarkers. However, factors that are predictive of the earliest mani-

festations of disease are not necessarily the same variables that are sensitive to more rapid progression. In devising treatments to be introduced in the earlier stages of AD, these considerations are important. The welfare of the patient is best served by focusing on how to prevent progression toward dementia from an early preclinical or prodromal phase of AD.

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Chapter 9.2 Alzheimer’s Disease Martin R. Farlow

Introduction Alzheimer’s disease (AD) is by far the most common form of dementia in the United States. It currently affects 5.4 million people, the vast majority of whom are over the age of 65 (Alzheimer Association, 2011). The prevalence of this disease is 1–2% at age 65, doubling every 5 years and reaching as high as 50% by age 85 (Alzheimer Association, 2011). It is estimated that the number of patients affected will more than triple, from 16 to 80 million patients worldwide, by 2050 (Alzheimer Association, 2011). The incidence rate for AD in the United States was 454,000 in 2010. The cost of care in 2009 in the United States was estimated to be $150 billion (Alzheimer Association, 2011). Although 90% or more of clinically diagnosed patients with dementia have AD, 50% or more of cases have mixed etiologies for their dementia. The most frequent contributing causes are cerebrovascular disease and, almost as common, diffuse Lewy body disease. This chapter briefly reviews clinical features, evaluation, diagnostic criteria, risk factors, and genetics for AD.

Clinical features and diagnostic evaluation of AD A detailed medical history and mental status examination in a patient with suspected AD is necessary to document symptoms and their progression, including changes in functioning in ADLs and behavior. New criteria allow biomarkers to aid the diagnosis and separate AD from reversible causes. Environmental risk factors can also be assessed, including those for vascular disease, as well as history for head trauma and family history of dementia.

Symptoms of AD History taken from the patient with AD may be helpful or misleading. Subjects often minimize or deny symptoms either, from anosognosia (lack of cognitive awareness of symptoms) or related to fear of the diagnosis, social stigma, or loss of independence. It is almost always necessary to obtain history from a spouse or other family member, a knowledgeable friend, or a caregiver to confirm details of this history, particularly regarding nature and history of onset of cognitive symptoms, functioning in ADLs, or other illness potentially affecting cognitive functioning.

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Certainly, reliable history obtained confirming the decline in episodic memory over time is essential to evaluating and diagnosing AD in a cognitively impaired patient. Also important is documenting deficits in some other aspects of cognitive functioning such as language, visuospatial functions, or executive function. Individuals with the illness in early stages typically repeat themselves in conversation with family and become less reliable in scheduling activities such as appointments and/or daily medication. Patients may have poor recall of the day’s events as seen on television or read in the newspaper. Typical clinical features beyond memory impairment in an early stage of the illness might include language difficulties, starting with trouble remembering first names of acquaintances and then names of family and close friends. They may have difficulty coming up with the right word in conversation and might use more general phrasing or substitute similar but incorrect words. Fluency continuously decreases as the illness progresses to simple phrases in the severe stage; most individuals eventually become mute. Visuospatial difficulties are common in AD, and many patients get lost while driving or misplace personal objects around the house. Difficulties with mathematical calculations are such that an AD patient seen in the mild stages of the illness no longer can balance a checkbook or figure tips. Executive functioning deficits also occur early in the illness, typically contributed to by short-term memory and attention deficits. Patients may no longer keep track of finances, be able to cook a meal from a recipe, or work easily with a personal computer. As the AD dementing process progresses, patients may also exhibit dyspraxia; they may exhibit clumsiness in dressing and using utensils, operate home appliances inappropriately, and even have difficulty opening and closing doors. Behavioral symptoms are common in AD and are part of the core clinical criteria for dementia. In early stages of dementia, patients exhibit apathy, with loss of drive or interest in pursuing activities that previously were important to them. This may be as disabling as short-term memory problems. Significant depressive symptoms are found in as many as 30% of mild-stage patients; typical symptoms include loss of energy, appetite, and insomnia. The differential for causes of insomnia in patients with AD is much broader than depression. Apnea, sleep

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myoclonus, and adverse effects of drugs (often cholinesterase inhibitors) are frequent instigators. Anxiety also often occurs in mild to moderate stages of the illness and is a particular problem when patients leave the home environment, travel outside the home, and/or are in large groups of people. Disinhibition also may be present in AD. Dementia patients may be inappropriately familiar with strangers or, more disturbingly, may make inappropriate advances toward family members, strangers, or even children. As AD progresses to moderate to severe stages of the illness, most instrumental ADLs are lost and patients begin having difficulties with more basic activity, such as dressing, hygiene, eating, and toileting. They may fail to recognize family members and, for example, may think a daughter is a wife. Patients may be irritable and resist participating in activities, particularly bathing and, in the late stages, taking pills. Visual hallucinations and paranoia also may occur. AD subjects commonly believe strangers are in their house or room, when none are present. Verbal or physical aggression occurs commonly, with agitation eventually arising at some point in as many as 75% of AD patients (Farlow, 2007). Regarding medical history, the patient and/or informant should be questioned about risk factors for AD, such as family history of the illness, head trauma, hypertension, hyperlipidemia, diabetes, or insulin resistance. Other causes of dementia, such as vascular dementia, should be excluded by asking questions regarding a previous stroke or TIAs and any associated cognitive deterioration. Fluctuations in alertness and cognitive functions, early onset visual hallucinations, and Parkinson’s disease symptoms all suggest Lewy body dementia. Personality change, executive dysfunction, and language abnormalities suggest possible frontotemporal dementia (FTD). History of hypothyroidemia, B12 or folate deficiency, and especially past medications that might alter cognitive functioning—such as anticholinergics (typically used for bladder incontinence), pain medications (narcotics such as oxycontin or fentanyl patch), anticonvulsants, sedatives, and psychotropics—suggest potential reversible etiologies. Certainly, the patient’s history should rule out depression or a pseudodementia. Typically patients with pseudodementia complain of memory loss and various other cognitive symptoms but do not exhibit them, whereas dementia patients show signs of dementia on examination but are less likely to complain. In summary, the history in a patient with suspected AD should document symptoms and their progression, including changes in functioning in ADLs and behavior. Environmental risk factors should be assessed, including those for vascular disease, as well as history for head trauma and family history of dementia.

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Neurologic examination In evaluating the dementia patient with possible AD, the physical and neurologic examinations assist diagnosis by first looking for signs that suggest or support other types of dementia. The examinations then document cognitive and behavioral abnormalities that directly support the clinical criteria for the illness. The examinations also determine whether more extensive neuropsychological testing is needed to clarify ambiguous results upon clinical evaluation regarding mild cognitive impairment (MCI) or AD. If dementia is clearly present, evaluation results can begin staging the illness to guide recommendations regarding prognosis, drug therapy, and supportive care. The physical examination provides a brief screen for organ system failure contributing to or causing cognitive impairment (such as hepatic or renal encephalopathy). The neurologic examination (aside from cognitive impairment) in the early or middle stage of AD is often normal. The presence of focal findings such as visual field defects, spasticity, and weakness in an arm or leg suggests a potential vascular etiology for the cause of cognitive impairment. Signs of Parkinson’s disease (bradykinesia, rigidity, tremor, stooped and shuffling gait) suggest dementia with Lewy bodies or dementia with Parkinson’s disease in the cognitively impaired patient. Gait imbalance or falling might be seen in early stages of dementia with either Parkinson’s dementia or subcortical vascular dementia. If there is limited vertical eye movement or dysphasia, the diagnosis of progressive supranuclear palsy should be considered. If the gait instability is accompanied by a history of urinary incontinence, normal pressure hydrocephalus needs to be excluded as a cause. However, in the latter stages of AD, gait difficulties become quite common and are less helpful in differential diagnosis: Myoclonic jerks in early stages of dementia are uncommon in AD, and their presence instead suggests an underlying metabolic abnormality or, more rarely, a prion disease such as Creutzfeldt-Jakob disease. However, in the later, more severe stages of AD, myoclonus may be seen in 5–10% of patients, so this symptom again is less helpful in diagnosis. In general, specific neurologic signs, taken in the context of dementia disease stage, may help guide additional laboratory or imaging evaluations directed toward other causes of cognitive impairment that may be acting in a mixed fashion in a patient also afflicted with AD. Mental status and brief clinical cognitive examinations are valuable in both supporting the diagnosis of MCI or AD and defining the disease stage with individual testing assessments and tests. Chapter 4.1 describes commonly used mental status tests and their role in aiding diagnosis. Typical tests used to evaluate the dementia patient include Clock Drawing, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and St. Louis University Mental Status (SLUMS) test.

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In general, ethnicity, education, and familiarity with the English language must be taken into consideration when judging performance on the tests. Finally, questions should be asked of accompanying family members or caregivers regarding function in activities of daily living. This can assist in documenting impairments that are secondary to the cognitive impairment, to support the diagnosis, stage the disease, and guide both supportive care and therapeutic recommendation.

Laboratory studies Laboratory studies in general clinical practice over the last three decades have generally excluded other potentially reversible and nonreversible causes of dementia. Refer to Chapter 8 for more details. A basic evaluation includes these components: • Complete blood count (CBC) • Metabolic panel, including electrolytes, creatinine, glucose, and SGOT • Thyroid function studies (TSH) • B12 and folate levels • Urinalysis • Computerized tomography (CT) or magnetic resonance imaging (MRI), to exclude structural concerns for dementia, particularly normal pressure hydrocephalus and vascular dementia With the recent revision of AD criteria detailed in the next section, structural MRI, positron emission tomography (PET) amyloid imaging, and lumbar puncture with analysis for amyloid β1–42, tau and/or pTau may be more widely used in the future to increase specificity or certainty of diagnosis. Diagnostic criteria for AD Historically, two sets of clinical criteria have been widely used in both general practice and the research communities to define AD over the last three decades. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association, 1994) is the broader of the two sets of criteria. The DSM-IV criteria for AD require gradual and continuing decline in memory, and another aspect of cognitive functioning, that impair function in daily activities, and that other potential causes have been excluded. The consensus criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) (McKhann et al., 1984) were originally developed in 1984 and have defined diagnosis of this illness (particularly for research purposes) without revision until 2011. The original NINCDS-ADRDA criteria for probable AD required deficits in two or more areas of cognitive functioning, with one of them being memory; progressive deterioration was confirmed by clinical and

neuropsychological evaluations, and no other central nervous system or systemic illnesses could be identified as potential causes for the dementia. The diagnosis is supported by impaired functioning in activities of daily living and behavioral symptoms. Both the original DSM-IV and NINCDS-ADRDA sets of criteria relied heavily on clinical history and neurologic evaluations, limiting their diagnostic specificity, and both excluded broad populations of patients in earlier stages of the illness, where disease mechanisms arguably may be less well established and the potential to respond to disease-modifying therapies may be greater. These limitations were initially addressed by the proposed Dubois Consensus Criteria (Dubois et al., 2007), which modified the original NINCDS-ADRDA criteria and effectively introduced an earlier predementia stage for AD. This stage was defined by the following core features: 1 Gradual and progressive decline in memory function reported by patients or informants for more than six months 2 Objective evidence of significantly impaired episodic memory on testing, generally consisting of a recall deficit that does not improve significantly or does not recover with cues 3 Episodic memory problems that may be isolated or associated with other cognitive changes at onset or as the disease process advances These clinical criteria are supported by one or more of the following objective assessments: medial temporal lobe atrophy with volume loss of hippocampus, entorhinal cortex, or amygdala on MRI; decreased amyloid β1–42 levels in cerebrospinal fluid; tau or phosphotau levels in CSF; a specific pattern of altered glucose metabolism on FDGPET known to be associated with AD; and the presence of increased levels of cortical amyloid demonstrated by PIB and or other amyloid binding ligands on Amyloid-PET. The Dubois criteria define a more homogenous prodromal stage for AD out of the broader previously defined MCI population and have been employed in a limited number of recent drug trials. They have not been otherwise broadly adopted in general clinical practice. By 2009, it was recognized that the original NINCDSADRDA criteria of 1984 often were not holding true. These criteria assumed clinical–pathologic association between amnesia progressing to dementia associated with cortical amyloid plaques and neurofibrillary tangles. Amyloid plaques and neurofibrillary tangles were acknowledged to be present in cognitively normal individuals in 20–40% of the elderly population. Furthermore, neuropathologic studies demonstrated that many dementia patients who had language or visual spatial deficits as predominant clinical features at onset rather than episodic memory loss displayed typical plaque and tangle AD pathology at autopsy. Considerable advancement also was made in general knowledge about the biologic processes underlying and associated with AD since the original clinical

Alzheimer’s Disease

criteria were previously established 25 years ago. For these reasons, a broad consensus developed that the AD diagnostic construct needed to be updated. The National Institute of Aging and the Alzheimer’s Association assembled three working groups to revise and extend the original diagnostic criteria (Jack et al., 2011). In 2011, new diagnostic criteria agreed to by these three working groups greatly revised and broadened the original NINCDS-ADRDA 1984 criteria (Albert et al., 2011; McKhann et al., 2011; Sperling et al., 2011). New consensus criteria were with the following changes: 1 New specific research criteria 2 A new prodromal stage, encompassing patients who are biomarker positive and clinically asymptomatic, but at risk for AD 3 Revised MCI criteria that employ biomarker changes 4 Better-defined Alzheimer’s dementia stage that recognizes the spectrum of clinical symptom variation and employs biomarker criteria

STAGE 1 Asymptomatic amyloidosis High PET amyloid tracer retention Low CSF Aβ1–42

STAGE 2 Amyloidosis–neurodegeneration Neuronal dysfunction on FDG-PET/fMRI High CSF tau/p-tau Cortical thinning/hippocampal atrophy on sMRI

STAGE 3 Amyloidosis–neurodegeneration and subtle cognitive decline Evidence of subtle change from baseline level of cognition Poor performance on more challenging cognitive tests Does not yet meet criteria for MCI

MCI

Preclinical stage of AD criteria The operational research criteria for the preclinical stage of AD were proposed to better support longitudinal natural history studies to better determine the roles of various biomarkers in developing various preclinical aspects of the ongoing pathophysiologic disease process and to support potential future disease-modifying therapeutics at a time when such agents may be more effective. It has been recognized that an underlying pathophysiologic cascade of processes may begin decades before the onset of clinical symptoms and the later onset of dementia in the spectrum of AD. Risk for the disease appears likely to be determined by biomarkers that are still being validated regarding specificity and sensitivity and eventual clinical utility. In various populations of cognitively normal elderly patients studied, β-amyloid deposits were detected in 20–40% of patients by determining low levels of amyloid β1–42 protein in CSF or by PET amyloid imaging. This amyloid appears to be a risk factor for future deterioration in cognitive functioning and MCI or eventual dementia. Nonetheless, many individuals with decreased CSF amyloid β1–42 levels or positive amyloid imaging may never develop cognitive symptoms. The biologic correlations and clinical meaningfulness for these biomarkers are still being determined. Figure 9.1 lists the proposed criteria for preclinical AD. Three stages for preclinical AD are proposed. In Stage 1, biomarker abnormalities are present related to amyloid deposition and likely factor directly into an underlying risk for the illness or disease process itself (Sperling et al., 2011). In Stage 2, in addition to biomarker indications of amyloid deposition, there is evidence of neuronal dysfunction or neurodegeneration. Finally, in Stage 3, amyloid plus neuronal loss progresses to subtle cognitive decline, insufficient to meet the criteria for MCI or dementia. Clearly, these are research criteria meant to facilitate further investigation and

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AD dementia

Figure 9.1 The 2011 criteria for preclinical AD.

are likely to be modified in the future to reflect future gains in knowledge regarding biomarkers, pathophysiology, and relevant associations and relationships between these factors and the development of future clinical symptoms.

Dementia due to AD diagnostic criteria The revised guidelines retained the general framework of the original NINCDS-ADRDA criteria for AD (1984). However, the working group for AD recognized that much has been learned about the pathophysiologic processes underlying AD, the breadth of potential clinical symptoms at onset, and the place of AD in the spectrum of other neurodegenerative illnesses that also cause dementia in adults. Knowledge gained over the last 27 years includes: 1 Recognition that AD pathophysiologic process may be found in MCI and even cognitively normal individuals 2 Broader characterization of the other dementias, such as dementia with Lewy bodies and the various subtypes of FTD 3 Recognition that the primary cognitive deficits for AD at onset may be visuospatial or aphasic rather than deficits in episodic memory 4 Recognition of autosomal-dominant causative genes, including primarily mutations in the genes for the amyloid precursor protein, presenilin 1 and 2 protein 5 Recognition of associated biomarkers (MRI, PET, CSF analyses) that may aid diagnosis 6 Recognition that AD pathology and clinical symptoms may occur in patients younger than 40 and older than 90 (McKhann et al., 2011)

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Table 9.1 Core clinical criteria for dementia

Table 9.2 Clinical criteria for probable AD

Criteria for dementia Interferes with function at work or daily activities Decline in functional ability Not delirium or major psychiatric disease Cognitive impairment documented by informant and objective clinical bedside assessment or neuropsychological testing

Clinical criteria for probable AD Meets criteria for dementia Insidious onset with worsening cognition by report or observation Most prominent clinical symptoms at onset include either: Amnestic presentation, impaired learning, particularly of recently learned information Nonamnestic presentation with language dysfunction often word finding or visuospatial deficits in spatial cognition such as object agnosia, impaired face recognition, simultanagnosia and alexia or executive function deficits such as impaired learning judgment, problem solving For both amnestic and nonamnestic presenters, other cognitive deficits should be present AD should not be diagnosed when there is evidence of stroke temporally related to the cognitive deficit, multiple infarcts, dementia with Lewy bodies or FTD or other neurologic or nonneurologic illnesses that could impact cognitive function

Cognitive and or behavioral impairments must include two or more of the following Impaired learning and short term memory deficits Impaired reasoning, judgment, and handling of complex tasks Impaired visual spatial abilities Impaired language which may include speaking, reading, or writing Change in personality, behavior—typical symptoms would include apathy, obsessive compulsive behavior, agitation, socially inappropriate behavior

With these facts in mind, the working group proposed new core clinical criteria for all causes of dementia (Table 9.1). These are similar to those previously described in the original 1984 criteria. The revised criteria for AD include core clinical criteria for probable AD and for possible AD, and new categories for probable and possible AD (Table 9.2). New to the core clinical criteria are explicit recognition of onset with symptoms other than amnesia, including language dysfunction, visual spatial dysfunction, and executive functioning deficits. Also explicitly recognized under the probable AD category are core clinical dementia criteria associated with autosomal dominant causative mutations (Table 9.3). Criteria for probable AD dementia with evidence of AD pathophysiologic process incorporate in a manner similar to MCI criteria two classes of biomarkers: (1) indicators of amyloid-β protein deposition in the brain (PET amyloid imaging and low CSF amyloid β1–42 levels) and (2) indicators of neuronal dysfunction or degeneration with

Probable AD with increased certainty of diagnosis Meets core clinical criteria for probable AD Evidence of increasing progression in cognitive decline from informant or by formal neuropsychological testing Carries dementia-associated genetic mutations in APP, PSEN1, or PSEN2

decreased FDG uptake in temporal lobes on PET; atrophy in medial, basal, and lateral temporal lobes and medial parietal cortex on structural MRI sequences; and high total tau and phosphorylated-Tau (pTau) levels in CSF (Table 9.2) (McKhann et al., 2011). The major advantage of incorporating these biomarkers is that they increase the certainty of diagnosis, which may aid research studies, particularly clinical trials. Major limitations for these biomarkers are that the methods of imaging, collecting, and analyzing cerebrospinal fluid and interpretation of the data are not fully standardized, and access of these services may be limited at many healthcare sites. In addition, cut points and practical clinical utility in realworld settings remain to be demonstrated.

Table 9.3 AD dementia criteria incorporating biomarkers Diagnostic category Probable AD dementia Based on clinical criteria With three levels of evidence of AD pathophysiologic process

Possible AD dementia Atypical clinical presentation Based on clinical criteria With evidence of AD pathophysiologic Dementia unlikely due to AD

Aβ (PET or CSF)

Neuronal injury (CSF tau, FDG-Pet, sMRI)

Biomarker probability of AD etiology

Unavailable, conflicting, or indeterminate Unavailable or indeterminate

Unavailable, conflicting, or indeterminate Positive

Uninformative Intermediate

Positive Positive

Unavailable or indeterminate Positive

Intermediate High

Unavailable, conflicting, or indeterminate Positive

Unavailable, conflicting, or indeterminate Positive

Uninformative

Negative

Negative

High but does not rule out second etiology Lowest

Alzheimer’s Disease

Probable and possible AD dementia; core clinical criteria In the possible AD core clinical criteria, patients with dementia who are atypical for meeting criteria for dementia with Lewy bodies or FTD but who are positive for both a biomarker associated with the amyloid B pathophysiologic process and a biomarker associated with neuronal degeneration would need criteria for possible AD. Again, as more data and experience with these biomarkers in association with clinical diagnoses become available, there will likely be further modification in the use of these criteria in aiding the diagnostic process, further improving their validity and future diagnostic utility. Table 9.3 lists levels of certainty in the research diagnosis of AD incorporating various biomarkers (McKhann et al., 2011).

Epidemiology The major risk factors for AD are increased age and the apolipoprotein E ε4 genotype (Farlow, 2007). Other potential clinical and demographic risk factors for developing AD at an earlier age of onset identified over the last three decades include depression, female gender, low levels of education, smaller head circumference, and family history of Down’s syndrome. History of head trauma, previous exposure to anesthesia, and low levels of physical activity have also been associated with increased risk for developing AD (Geldmacher, 2011). Over the last two decades, increasing evidence suggests that vascular disease, such as myocardial or cerebrovascular infarction, also is associated with increased risk for developing AD at an earlier age (Dodge et al., 2011). Vascular risk factors in general that are associated with the metabolic syndrome, including increased body weight (particularly abdominal adiposity), hypertension, diabetes mellitus, insulin resistance or prediabetes, hypercholesteremia (high LDL levels, low HDL levels), and hypertriglyceridemia (Martins et al., 2006), are all associated with increased risk for AD. In addition, increased plasma levels of homocysteine associated with increased risk for vascular disease have been associated with increased risk for AD (Shumaker et al., 2003, 2004). Epidemiologic studies have suggested that several types of drugs may be protective or reduce risk for AD, including estrogens, nonsteroidal anti-inflammatories, and statins. However, none of these drugs have proven to reduce risk in prospective double-blind, placebocontrolled trials (Aisen et al., 2003; Espeland et al., 2004; Maillard and Burnier, 2006). Estrogens, in particular, have proven to increase rather than decrease risk for AD in women over the age of 60 years (Craig et al., 2005).

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Genetics Family history of dementia affecting two or more firstdegree relatives is obtained in approximately 20% of individuals with AD, with the other 80% being of sporadic occurrence (Alzheimer Association, 2011). In families with early-onset AD under the age of 65, mutations in a handful of genes have been identified that are associated with autosomal-dominant inheritance with high prevalence for dementia typically in the fourth to seventh decades. The first causative mutation described was in the amyloid precursor protein gene on chromosome 21 in the region of the gene that codes for the β-amyloid proteins that are deposited forming the cores of amyloid plaques. More than a dozen mutations in this region have now been associated with either dementia or cerebral amyloid vasculopathy in two dozen families. These mutations are thought to alter β-amyloid metabolism and have been associated with chronically higher levels of β-amyloid, potentially a key factor leading to AD in these families. Duplication of the APP gene and missense mutations (black box) in the APP gene cause inherited forms of AD and cerebral amyloid angiopathy (Goedert and Spillantini, 2006). Other families with early-onset forms of the disease have been found to have different mutations in the presenilin 1 gene on chromosome 1 (a handful of mutations in a few dozen families) and presenilin 2 gene on chromosome 14 (several hundred different mutations) (Goedert and Spillantini, 2006; www.molgen.ua.ac.be/ADMutations/). Presenilin 2 mutations are by far the most commonly identified cause of presenile familial AD, but they still are the cause for dementia in less than 10% of these families and less than 0.5% of AD patients overall. The presenilin proteins coded for by these genes operate in a complex with other proteins functionally acting as gamma secretase, a key enzyme in one of the major degradative pathways for the amyloid precursor protein that potentially is involved in the disease process (De Strooper, 2003). Increased β-amyloid1–42 levels have been found in association with almost all of the reported presenilin 1 and 2 mutations (Citron et al., 1997). Clinically, in addition to causing early onset of dementia, these mutations have been associated with a variety of other neurologic signs and pathologies, including spasticity, seizures, extrapyramidal signs, and cortical hemorrhages (Menendez, 2004). Identifying mutations in at-risk members of families with known genetically associated presenile forms of the illness allows for potential genetic counseling by facilitating the identification of the at-risk gene carrier. In the future, it may enable investigations of presymptomatic therapeutic interventions. However, the most significant impact of these genes has been to speed clinical drug research by enabling the

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development of animal models for AD. Hopefully this will hasten preclinical testing of promising therapies. The most significant genetic risk factor identified for AD is inheritance of the apolipoprotein E ε4 genotype located on chromosome 19. ApoE is one of the major lipid- and cholesterol-carrying proteins in peripheral blood, and it plays a similar role in the central nervous system, where it is the major lipid transport protein and the predominant transport protein for the soluble form of the β-amyloid protein (Mayeux et al., 1998). Ninety-nine percent of the general population carry three major genotypes—ε2, ε3, and ε4—in different combinations. Approximately 1–2% of people are homozygous for the ε4 genotype, and these individuals have a 50% risk of developing AD by their midto late 60s (Saunders et al., 1993). Approximately 15–20% of the population carry one copy of the ε4 genotype and have a 50% risk of developing AD by their mid- to late 70s. Individuals with ε3 (the predominant genotype) are more likely to develop AD later in their 80s or not at all. Interestingly, evidence indicates that the ε2 genotype may be protective, reducing overall risk for AD (Rebek et al., 2002) while simultaneously conveying some increased risk for cardiovascular disease. However, if an individual with one or more copies of ε4 has remained cognitively normal into the age range of significant dementia risk, there is evidence that their future risk of dementia is no greater than that of a non-ε4-carrying individual of the same age going forward. Patients clinically diagnosed with AD in some series, followed to autopsy, will be found in 20% of cases to have other primary dementing illnesses and pathologies. ApoE ε4 genotyping has been suggested to be potentially useful as a diagnostic tool improving specificity for diagnosis of AD in elderly patients with dementia. If ApoE ε4 genotyping is performed as a diagnostic adjuvant, the strong association particularly for homozygotes to AD has in some series strengthened post-mortem clinical pathologic diagnostic correlations to 93% (Mayeux et al., 1998). However, given the great overlap of AD with vascular dementia and the Lewy body dementias, and given the absence of differential therapies to be more directly targeted by more accurate diagnosis, the clinical utility of ApoE4 genotyping in the broad elderly dementia population is questionable; however, it may be helpful in patients with atypical clinical features such as rapid or slow course or unusual clinical symptoms at onset. ApoE genotyping in patients with MCI has demonstrated that 40–50% of patients carry one or two copies of  ε4. When followed for 3–4 years, these subjects are much more likely to convert to AD than ε2 or ε3 genotypes (Petersen et al., 1995). MCI subjects carrying ε4 are also more likely to be responsive to cholinesterase inhibitor therapy (Galasko et al., 2005; Feldman et al., 2007). However, once AD is diagnosed, the ApoE genotype through the different disease stages has not been demonstrated to differentially affect rates of disease progression.

These data suggest that underlying disease mechanisms at the MCI stage may be differentially affected by ApoE proteins of different phenotype, but once the various pathogenetic mechanisms underlying more fullblown dementia become widespread, the difference in ApoE genotype effects becomes less significant. In the last 5 years, genome-wide association studies (GWAS) of progressively increasing size and power have been undertaken in Europe and the United States in elderly affected and unaffected members of families with late-onset AD. These studies have employed gene chips that screen for 100,000s of single nucleotide polymorphisms (SNPs) spanning the chromosomes. Using this technology, new genetic polymorphisms associated with late-onset AD have been identified and both confirmed and reconfirmed; these include CLU, PICALM, and BIN-1 (Harold et al., 2009; Lambert et al., 2009; Seshadri et al., 2010). Recently, a large GWA study combining multiple large population data sets established ABCA7, MS4A/ MS4A6E, CD2UAP, CD33, and EPHA1 as additional genes associated with AD (Schellenberg et al., 2011). It is important to note that the magnitudes of increased risk associated with the inheritance of one or more of these polymorphisms are small and that the frequencies of some of these associated polymorphisms are very low compared to the much larger risk associated with inheritance of the ApoE ε4 genotype. Nonetheless, they provide further valuable clues regarding the complex disease mechanisms that underlie AD and the factors that may influence risk for and age of onset for dementia. Known general actions for the proteins coded for by these genes include lipid metabolism, amyloid metabolism, chaperone proteins enhancing amyloid deposition, inflammation, and cellular maintenance mechanisms. Fuller understanding of how these genes and their proteins interact with the environment is the goal of ongoing active research and should aid future diagnosis and therapy.

References Aisen, P.S., Schafer, K.A., Grundman, M., et al. (2003) Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression: a randomized controlled trial. J Am Med Assoc, 289: 2819–2826. Albert, M.S., DeKosky, S.T., Dickson, D., et al. (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging– Alzheimer’s Association workgroups on diagnostic guideless for Alzheimer’s disease. Alzheimers Dement, 7: 270–279. Alzheimer Association (2011) Facts and Figures (Available from www.alz.org/downloads/Facts_Figures_2011.pdf). American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Citron, M., Westaway, D., Xia, W., et al. (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid

Alzheimer’s Disease

beta-protein in both transfected cells and transgenic mice. Nat Med, 3 (1): 67–72. Craig, M.C., Maki, P.M., and Murphy, D.G.M. (2005) The women’s health initiative memory study: findings and implications for treatment. Lancet Neurol, 4 (3): 190–194. De Strooper, B. (2003) Aph-1, Pen-2 and nicastrin with presenilin generate an activity gamma secretase complex. Neuron, 38 (1): 9–12. Dodge, H.H., Chang, C.C., Kamboh, I.M., et al. (2011) Risk of Alzheimer’s disease incidence attributable to vascular disease in the population. Alzheimers Dement, 7 (3): 356–360. Dubois, B., Feldman, H.H., Jacova, C., et al. (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDSADRDA criteria. Lancet Neurol, 6: 734–746. Espeland, M.A., Rapp, S.R., Shumaker, S.A., et al. (2004) Conjugated equine estrogens and global cognitive function in postmenopausal women: women’s health initiative memory study. J Am Med Assoc, 291: 2959–2968. Farlow, M. (2007) Alzheimer’s disease. Continuum, 13 (2): 39–68. Feldman, H., Ferris, S, Winblad, B., et al. (2007) Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment: the InDDEx study. Lancet Neurol, 6 (6): 501–512. Galasko, D.R., Gauthier, S., Bennett, D., et al. (2005) Impairment in activities of daily living in patients with amnestic mild cognitive impairment in an ADCS randomized clinical trial. Neurology, 64 (Suppl. 1): A144. Geldmacher, D.S. (2011) Alzheimer disease. MedLink (Available from www.medlink.com/cip.asp?UID=mlt000ou&src=Search& ref=32573591). Goedert, M. and Spillantini, M.G.. (2006) A century of Alzheimer’s disease. Science, 314: 777–781. Harold, D, et al. (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet, 41 (10): 1088–1093 [Erratum in: Nat Genet 2009; 41 (10): 1156]. Jack, C.R. Jr, Albert, M.S., Knopman, D.S., et al. (2011) Introduction to the recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement, 7 (3): 257–262. Lambert, J.C., Heath, S., Even, G., et al. (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet, 41 (10): 1094–1099. Maillard, M. and Burnier, M. (2006) Comparative cardiovascular safety of traditional nonsteroidal anti-inflammatory drugs. Expert Opin Drug Saf, 5: 83–94. Martins, I.J., Hone, E., Foster, J.K., et al. (2006) Apolipoprotein E, cholesterol metabolism, diabetes and the convergence of risk

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factors for Alzheimer’s disease and cardiovascular disease. Mol Psychiatry, 11: 721–736. Mayeux, R., Saunders, A.M., Shea, S., et al. (1998) Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. N Engl J Med, 338 (8): 1325. McKhann, G., Drachman, D., Folstein, M., et al. (1984) Clinical diagnosis of Alzheimer disease report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer Disease. Neurology, 34: 939–944. McKhann, G.M., Knopman, D.S., Chertkow, H., et al. (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guideless for Alzheimer’s disease. Alzheimers Dement, 7: 263–269. Menendez, M. (2004) Pathological and clinical heterogeneity of presenilin 1 gene mutations. J Alzheimers Dis, 6: 475–482. Petersen, R.C., Smith, G.E., Ivnik, R.J., et al. (1995) Apolipoprotein E status as a predictor of the development of Alzheimer’s disease in memory-impaired individuals. J Am Med Assoc, 273: 1274–1278. Rebek, G.W., Kindy, M., and LaDu, M.J. (2002) Apolipoprotein E and Alzheimer’s disease: the protective effects of ApoE2 and E3. J Alzheimers Dis, 4: 145–154. Saunders, A.M., Strittmatter, W.J., Schmechel, D., et al. (1993) Association of apolipoprotein E allele epsilon 4 with lateonset familial and sporadic Alzheimer’s disease. Neurology, 43: 1467–1472. Schellenberg, G.D., et al. (2011) Alzheimer Disease Genetics Consortium. Common variants in MS4A4/MS4A6E CD2AP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet, 43 (5): 436–441. Seshadri, S., et al. (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. J Am Med Assoc, 303: 1832–1840. Shumaker, S.A., Legault, C., Rapp, S.R., et al. (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the women’s health initiative memory study: a randomized controlled trial. J Am Med Assoc, 289 (20): 2651–2652. Shumaker, S.A., Legault, C., Kuller, L., et al. (2004) Conjugated equine estrogens and incidence of probably dementia and mild cognitive impairment in postmenopausal women: women’s health initiative memory study. J Am Med Assoc, 291: 2947–2958. Sperling, R.A., Aisen, P.S., Beckett, L.A., et al. (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guideless for Alzheimer’s disease. Alzheimers Dement, 7: 280–292.

Chapter 9.3 Dementia with Lewy Bodies Clive Ballard

Overview Dementia with Lewy bodies (DLB) is a synucleinopathy characterized by a progressive dementia syndrome that is usually associated with parkinsonism and typically dominated by attentional, visuospatial, and executive dysfunction and relatively preserved memory. Additional key symptoms are visual hallucinations, cognitive fluctuations, and sleep disturbances such as excessive daytime sleepiness and REM-sleep behavioral disorder (McKeith et al., 2005).

has a higher frequency in DLB (Klatka et al., 1996; Ballard et al., 1999) than in AD. From 60–80% of DLB patients experience parkinsonian symptoms. These are generally similar to the symptoms of Parkinson’s disease (PD), but the tremor is often qualitatively different from that seen in patients with PD, and the presentation is more likely to be symmetrical. In addition, postural instability and gait difficulties, predominantly mediated by nondopaminergic lesions, may be more pronounced in DLB patients (Gnanalingham et al., 1997).

Clinical profile

Neuropathology

Similar to Alzheimer’s disease (AD), DLB results in a dementia syndrome with progressive loss of cognition and function. However, it is apparent that significant components of functional disability in DLB derive from associated motor and autonomic impairments and the impairments of cognition. The profile of cognitive impairment in DLB reflects a combination of cortical and subcortical neuropsychological impairments with substantial attentional deficits and prominent executive and visuospatial dysfunction (Calderon et al., 2001; Collerton et al., 2003). This profile may be harder to recognize later in the disease when global cognitive difficulties obscure the picture. It has been suggested that a “double discrimination” can help differentiate DLB from AD, with relative preservation of short- and medium-term recall and recognition, and greater impairment on visual perception and performance tasks (Walker et al., 1997). Composite global cognitive assessment tools, such as MMSE or CAMCOG, do not distinguish DLB from other common dementia syndromes. DLB patients with additional neocortical tangle Alzheimer pathology often lack the typical DLB cognitive profile (Ballard et al., 2004), showing pronounced memory deficits and a clinical presentation more characteristic of AD. Fluctuating attention, a key feature of DLB, is not evident in patients with AD and is less pronounced in DLB patients without parkinsonism (Ballard et al., 2002). Visual hallucinations and delusions are much more common in DLB than in AD, occurring in 60–70% of patients with DLB (Klatka et al., 1996; Ballard et al., 1999). REM-sleep behavior disorders are also substantially more common in DLB than in AD and may actually precede the dementia syndrome in many patients (Boeve et al., 2004). Depression is common in most dementias, but it probably

Limbic and cortical Lewy bodies (LB) are the main substrate of the clinical dementia syndrome in DLB (Harding and Halliday, 2001; Aarsland et al., 2005a, 2005b; Tsuboi and Dixon, 2005). The density of temporal lobe LB also correlates with the early occurrence of the characteristic well-formed visual hallucinations, and the overall severity of cortical LB pathology correlates with psychosis and fluctuating cognition (Harding et al., 2002). In addition, increasing LB densities in limbic and frontal cortices correlates with the presence and severity of dementia in the related condition of Parkinson’s disease dementia (PDD; Samuel et al., 1996; Kovari et al., 2003). The majority of DLB patients also have concurrent amyloid pathology, with a density of Aβ-positive plaques in many DLB patients equivalent to that found in AD, and 90% of DLB patients meet CERAD criteria for probable AD (Hansen et al., 1990). The amount of Aβ deposition also correlates with dementia severity in DLB (Harding and Halliday, 2001). Although typically the density of neocortical plaques is similar to AD (Hansen et al., 1990), the burden of tangles is less than in “pure” AD (Hansen et al., 1990). For example, when LBs occur in conjunction with Alzheimer’s pathology sufficient to meet CERAD criteria for probable or definite AD, neocortical neurofibrillary tangles are usually rare or absent, and tangles in the entorhinal cortex and hippocampus are intermediate between age-matched controls and AD patients (Hansen et al., 1990). Fewer than 40% of DLB patients meet criteria for a Braak stage IV or higher, although several recent studies indicate that these patients are less likely to present with a “typical” DLB profile and are less likely to meet consensus criteria for probable DLB (Ballard et al., 2004).

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α-Synuclein is the key constitutive protein of LB and is also widely found in more diffuse cortical aggregates, usually referred to as Lewy neurites, in DLB patients. α-Synuclein is a cytosolic protein, enriched in presynaptic terminals associated with synaptic vesicles. Three known alternatively spliced isoforms of α-syn exist, fulllength, consisting of 140 amino acids and shorter isoforms of 112 and 126 amino acids, respectively. In addition to α-synuclein, β- and γ-synuclein are members of the protein family of synucleins. α- and β-synuclein proteins are primarily found in brain tissue, and γ-synuclein predominantly is a protein of the peripheral nervous system. Recent work has also begun to indicate that β-synuclein may play an important pathological role as well (Fujita et al., 2009). Findings of missense mutations in the gene encoding for α-synuclein (Polymeropoulos, 1998) and multiplications of the gene of α-synuclein SNCA in families with PD (Singleton et al., 2003) suggest that the conversion of α-synuclein from soluble monomers to aggregated, insoluble forms in the brain is an important event in the pathogenesis synucleinopathies (Koprich et al., 2010). Truncated forms of α-synuclein have been isolated from LBs, and several studies have also shown that specific truncated forms of α-synuclein have an increased tendency to form aggregates (Murray et al., 2003). This tendency of truncated α-synuclein species to rapidly aggregate suggests that they may play a role in inducing LB formation. In addition to the α-synuclein and concurrent AD pathology, there is clear evidence of a loss of cortical synapses, as observed by a loss of dendritic spines, drebrin, and synaptophysin in DLB (Kramer and SchulzSchaeffer, 2007).

Neurochemistry The majority of neurochemical studies of DLB have explored the dopamine and acetylcholine systems in neuropathologic studies. One of the characteristic features is the presence of marked cortical cholinergic deficits, which are probably secondary to cell loss of forebrain nuclei. These deficits are even more severe than in AD (Bohnen et al., 2003) and are associated with decreased performance on tests of attentional and executive functioning (Bohnen et al., 2006). In DLB patients, there is also a correlation between visual hallucinations and cholinergic deficits in the temporal cortex (Ballard et al., 2000). These studies have also suggested an association between delusions and up-regulation of muscarinic M1 receptors in DLB patients (Ballard et al., 2000). In addition, there is evidence linking cholinergic changes, particularly nicotinic modulation of thalamo-cortical circuitry, with the disturbed consciousness in patients with DLB (Pimlott et al., 2006). Neuroimaging studies using SPECT ligands have also reported cholinergic receptor changes

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in DLB, with increased muscarinic (Colloby et al., 2006) and reduced nicotinergic binding in comparison to AD (O’Brien et al., 2007). Nigrostriatal dopamine changes are evident in DLB, although there appears to be no associated post-synaptic dopaminergic up-regulation in DLB patients, which may partly explain the increased risk for neuroleptic sensitivity reactions in these individuals (Piggott et al., 1999). Preliminary data from our group show a significant increase in frontal 5-HT1A receptor-binding density in DLB patients, which may be associated with mood disorders (Sharp et al., 2008). A preliminary post-mortem study has also reported glutamatergic alterations in DLB, suggesting that group I mGluR dysfunction may be implicated in the pathogenesis of cognitive impairment and dementia in the common form of DLB (Dalfo et al., 2004).

Frequency Dementia with Lewy bodies was first reported in the 1960s (Woodard, 1962). Several small case series also emerged from Japan in the 1960s, 1970s, and early 1980s (Okazaki et al., 1962; Kosaka et al., 1984), before reports describing larger groups of patients in the late 1980s and the early 1990s (Byrne et al., 1989; Gibb et al., 1989; Hansen et al., 1990; Perry et al., 1990; McKeith et al., 1992) began to highlight the frequency of the syndrome and the characteristic clinical features. However, not until the emergence of ubiquitin staining and the later identification of α-synuclein as the fundamental core pathologic hallmark, was the true extent of the pathology and importance of the syndrome acknowledged. A recent systematic review concluded that the proportion of dementia patients fulfilling the clinical diagnostic criteria for DLB in hospital-based single-center cohorts varied from 0% to 26% (Aarsland et al., 2008a, 2008b). Even among the few community-based studies, the proportion varies markedly from 0% to 30.5% (Aarsland et al., 2008a, 2008b). In two more recent community-based studies with a specific focus on DLB, the proportion of subjects with dementia with clinical probable DLB was reported to be 10.9% in those 65 years and older and 14.6% in those 75 years and older (Aarsland et al., 2008a, 2008b). However, there has been some concern that the limited sensitivity of the 1996 consensus diagnostic criteria, upon which most clinical studies of prevalence are based, may have led to an underestimation of frequency (see the next section on diagnosis).

Diagnosis Based initially on clinicopathologic studies, diagnostic criteria were proposed by Byrne et al. (1991), and McKeith et al. (1992), and were superseded by international

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Table 9.4 Sensitivity, specificity, positive predictive value, and negative predictive value of the consensus criteria for probable DLB: diagnostic validation studies No. of cases

Diagnosis

Sensitivity

Specificity

PPV

NPV

0.4 0.18

1.0 0.99

1.0 0.75

0.93 0.89

0.57 0.34 0.61

0.9 0.94 0.84

0.91 – 0.48

0.56 – 0.96

0.80 0.22 0.83 0.38

0.80 1.0 0.91 1.0

0.80 1.0 0.96 –

0.80 0.91 0.80 –

Retrospective Mega et al. (1996) Litvan et al. (1998)

24

Luis et al. (1999) Lopez et al. (1999) Verghese et al. (1999)

56 40 18

Hohl et al. (2000) Holmes et al. (1999) McKeith et al. (2000) Lopez et al. (2002)

Prospective

10 75 50 26

AD, PD, PSP DLB, PS, PSP, CBD, MSA, FTD, AD, CJD, VP DLB, AD, mixed DLB/AD AD, PSP, FTD, DLB DLB AD, DLB, PSP AD, VaD, DLB, mixed DLB, AD, VaD DLB, AD, mixed AD/VaD, PSP, CJD, FTD

AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; VaD, vascular dementia; PSP, progressive supranuclear palsy; CBD, cortico-basal degeneration; MSA, multisystem atrophy; CJD, Creutzfeldt–Jakob disease; VP, vascular parkinsonism; PPV, positive predictive value; NPV, negative predictive value.

consensus criteria (McKeith et al., 1996). In addition to the presence of a progressive dementia, the core diagnostic criteria were described as fluctuating cognition, persistent or recurrent visual hallucinations, and spontaneous motor features of PD. Two of these three core features were required for a diagnosis of probable DLB. A number of validation studies of these criteria have been reported (Table 9.4). Although probable DLB was diagnosed with a specificity of more than 80%, sensitivity was an issue, and the diagnosis of DLB in patients with a concurrent cerebrovascular disease was problematic (McKeith et al., 2000). Importantly, diagnostic accuracy may also vary with dementia severity; for example, Lopez et al. (2002) compared 180 patients with AD alone to 60 patients with AD and concurrent DLB. In patients with mild dementia, no specific clinical syndrome was associated with concurrent LBs. Overall, the McKeith et al. (1996) consensus criteria for DLB worked reasonably well in clinical practice and in research studies, and this was an important first step. However, refinement of the criteria to improve sensitivity was clearly a priority.

Approaches to improving diagnostic accuracy Although a great starting point, applying the consensus criteria for DLB in clinical practice may not be sufficient. In order to improve diagnostic accuracy, refinement of the criteria may be needed to improve sensitivity. Additional clinical markers and biomarkers such as dopamine transporter SPECT may help make the diagnosis in selected cases.

Fluctuating cognition Fluctuating cognition was identified as one of the three core diagnostic features of DLB, but accurately identifying fluctuating cognition can be a major clinical challenge. For example, two inter-rater reliability studies suggested poor agreement between different expert raters regarding the presence of fluctuating cognition in individual patients (Mega et al., 1996; Litvan et al., 1998). Subsequently, several validated clinical ratings scales have been shown to substantially improve the recognition of fluctuating cognition. The Clinician Assessment of Fluctuation Scale (Walker et al., 2000a, 2000b) uses two screening questions about the presence of “fluctuating confusion” or “impaired consciousness” and requires an experienced clinician to judge its severity during the previous month. The semi-structured One Day Fluctuation Assessment Scale (Walker et al., 2000a, 2000b), which can be administered by less experienced health professionals or research staff, generates a cut-off score that reportedly distinguishes DLB from AD or VaD. The Mayo Fluctuations Composite Scale (Ferman et al., 2004) requires three or more “yes” responses from caregivers to structured questions about the presence of daytime drowsiness and lethargy, daytime sleep greater than two hours, long periods of staring into space, or episodes of disorganized speech, as suggestive of DLB rather than AD. Finally, recording variation in attentional performance using a computer-based test system offers an independent method of measuring fluctuation that is also sensitive to drug treatment effects (Walker et al., 2000a, 2000b). REM sleep behavior disorder RBD is manifested by vivid and frightening dreams during REM sleep but without the muscle atonia that normally occurs. Patients therefore “act out their dreams,”

Dementia with Lewy Bodies

vocalizing and moving around the bed sometimes violently. Vivid visual images are often reported, although the patient may have little recall of these episodes. The history is obtained from the bed partner, who may report many years of this sleep disorder before the onset of dementia and parkinsonism (Boeve et al., 2004). Of particular importance, several cross-sectional studies have identified RBD in 60% or more of people with DLB or related synucleinopathies, and further reports indicate that the clinical symptoms of idiopathic RBD precede the onset of neurologic disease PD (Olson et al., 2000) and DLB (Boeve, 1998) by 1–7 years in more than 60% of individuals (Olson et al., 2000). In a more recent prospective study, Iranzo and coworkers (2006) assessed survivors of 44 patients with idiopathic RBD who had been diagnosed 5 years earlier. About 45% had developed a neurologic disorder, usually of the α-synuclein type—such as PD, DLB, or MSA—based on clinical evaluation. The findings are also consistent with the current autopsy literature, which indicates that idiopathic RBD is underpinned by α-synuclein pathology in all the cases reported (as reviewed in Boeve et al., 2007). Screening questions about the presence of daytime and nighttime sleep disturbance should always be included and may be facilitated by the use of sleep questionnaires. A history of RBD can be confirmed by polysomnography, when available.

Severe neuroleptic sensitivity Approximately 25–50% of DLB patients receiving typical or atypical antipsychotic agents experience severe neuroleptic sensitivity reactions (McKeith et al., 1992; Ballard et al., 1998; Aarsland et al., 2005a, 2005b). Conversely, at least 50% of individuals with DLB do not react adversely to antipsychotics; therefore, a history of neuroleptic tolerance does not exclude a diagnosis of DLB. However, a positive history of severe neuroleptic sensitivity is strongly suggestive of DLB. Deliberate pharmacologic challenge with D2 receptor-blocking agents should not be used as a diagnostic strategy for DLB because of the high morbidity and increased mortality associated with neuroleptic sensitivity reactions (McKeith et al., 1992); this is why severe neuroleptic sensitivity reactions were omitted from the original 1996 consensus criteria for DLB. Dopamine transporter SPECT imaging Imaging with specific single positron emission computerized tomography ligands for DAT (FP-CIT, beta-CIT, IPT, and TRODAT) provides a marker for presynaptic neuronal degeneration. DAT imaging is abnormal in idiopathic PD, MSA, and PSP and does not distinguish among these disorders. Low striatal uptake has also been reported in DLB and is normal in AD, making DAT scanning particularly useful in this common clinical distinction (Walker et al., 2002; O’Brien, 2004). Notably, a recent phase III multicenter study demonstrated a sensitivity and specificity

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of abnormal DAT scans in diagnosing probable DLB from AD of 75% and 90%, respectively (McKeith et al., 2007). A similar degree of discrimination is evident between DLB patients without parkinsonism and patients with AD. The impact of concurrent vascular pathology striatal DAT binding has not been determined (Brooks and Piccini, 2006). Despite this minor caveat and the limited diagnostic potential to distinguish different synucleinopathies, DAT scans clearly play a key role in the differential diagnosis of DLB and AD.

Revised consensus diagnostic criteria To address some of the issues raised from validation studies of the McKeith et al. (1996) criteria and to enable new developments to be incorporated, the consensus criteria have subsequently been updated The core diagnostic criteria remain the same—fluctuating cognition, recurrent visual hallucinations, and spontaneous motor features of PD—but the operationalization of these symptoms has been refined. In addition, although the presence of two of these features is still sufficient for a diagnosis of probable DLB, probable DLB can also now be diagnosed if one of these symptoms is present in combination with REM sleep behavior disorder, severe neuroleptic sensitivity (Aarsland et al., 2005a, 2005b), or low dopamine uptake in the basal ganglia (as indicated by dopamine transporters SPECT or PET scanning).

Do the revised criteria improve case identification? A Norwegian study examined whether the proportion of patients diagnosed as having probable DLB is increased by using the 2005 consensus criteria in comparison to the 1996 criteria. Only 25 (12.8%, CI 8.1–17.4) patients fulfilled criteria for probable DLB using the 1996 criteria compared to 31 (15.8%, CI 10.7–20.9) using the revised criteria, a 24% (CI 18.0–30.0) increase in the frequency of probable DLB. The transition from possible to probable DLB using the revised criteria was due to RBD in four and a positive CIT SPECT in two (Aarsland et al., 2008a, 2008b; Rongve et al., 2010). Table 9.5 shows this information in more detail. Although this study does suggest that the new criteria improve case identification, more robust prospective validation against post-mortem diagnosis is needed. Applying the operationalized consensus criteria in clinical practice Some useful clinical common-sense steps can be adopted to try to improve the accuracy in everyday practice. For example, visual hallucinations are much more indicative of DLB if they initially arise in the relatively early stages of the dementia and become more frequent in AD patients during the moderate stages of the disease (Ballard et al.,

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Table 9.5 Number of patients fulfilling the criteria of the old 1996 and the revised 2005 criteria for a clinical diagnosis of DLB Diagnosis

Criteria N VH Parkinsonism Fluctuations RBD DATSCAN Neuroleptic sensitivity

Probable DLB

Possible DLB

Old/ McKeith 96

New/ McKeith 05

Old/ McKeith 96

New/ McKeith 05

25 24 11 17 – – –

31 25 14 18 10 3 0

13 3 8 3 – – –

8 2 5 2 0 0 0

1999). Similarly, parkinsonian symptoms are a less useful discriminator in the more severe stages of the disease, when they become more frequent in the context of AD (Lopez et al., 2002). In addition, we strongly recommend using one of the standardized tools for assessing cognitive fluctuation (see the previous section).

Other potential investigations that may contribute to improved diagnosis Additional biomarkers such as myocardial scintigraphy, 99mTc-HMPAO SPECT, structural MRI, and CSF biomarkers are being investigated and eventually may contribute in cases where diagnostic accuracy is low after using the established criteria.

Myocardial scintigraphy It is important to note that LB pathology is also present in the autonomic peripheral nervous system, affecting postganglionic sympathetic nerves (Orimo et al., 2005). For example, cardiovascular autonomic dysfunction is particularly common in DLB (Allan et al., 2007). Myocardial scintigraphy with 123I-MIBG is a common technique for the quantification of post-ganglionic cardiac sympathetic innervation (Orimo et al., 2005). A number of studies using 123I-MIBG scintigraphy have shown reduced cardiac versus mediastinal uptake in DLB, compared to AD and healthy controls (Watanabe et al., 2001; Yoshita et  al., 2001, 2006). Indeed, cardiac MIBG imaging was able to distinguish between clinically diagnosed DLB and AD with high sensitivity and specificity in these studies (Yoshita et al., 2006). Importantly, similar findings have been reported in DLB patients with no overt parkinsonism (Yoshita et al., 2006). Therefore, if these findings were to be replicated in multicenter studies with large patient groups, it could be suggested that MIBG scintigraphy may be a useful tool for the early discrimination of DLB from AD (Aarsland et al., 2008a, 2008b). However, it should be cautioned that pathologic MIBG scans are difficult to interpret (Aarsland et al., 2008a, 2008b). Moreover, other

non-neurologic diseases—such as diabetes, myocardial infarction, ischemic heart disease, and cardiomyopathy— that are common in older patients may damage the postganglionic sympathetic neurons. More information is needed about the impact of concurrent cardiac pathology on the interpretation of the results. An abnormal profile on MIBG scintigraphy is already highlighted in the consensus criteria as supportive of DLB, and it is likely to be adopted as a more important aspect of the criteria with further studies. 99mTc-HMPAO

SPECT

Loss of the 99mTc-HMPAO SPECT signal is observed in the parietotemporal and frontal cortical regions in AD (Colloby et al., 2002). By contrast in DLB, there are greater parieto-occipital deficits, but temporal hypoperfusion is absent (Colloby et al., 2002). Differences in regional cerebral blood flow (rCBF) visualized by 99mtechnetiumhexamethylpropylene amine oxime (99mTc-HMPAO) SPECT may therefore assist discrimination between DLB and AD (Colloby et al., 2002, 2004) in patients with characteristic patterns, but the overall sensitivity and specificity of this approach is much less impressive than for DAT scans.

PET/SPECT imaging to monitor changes in nondopaminergic neurotransmitter systems Dementia with Lewy bodies can potentially be distinguished from other forms of dementia by measuring changes in cortical cholinergic function (Perry et al., 1994; Lippa et al., 1999). For example, several studies have shown alterations in uptake of SPECT tracers directed toward nicotinic and muscarinic acetylcholine (ACh) receptors (AChR) in DLB and AD patients (Colloby et al., 2006, 2008; O’Brien et al., 2008). Analysis of nicotinic AChR (nAChR) using (123)I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380)-SPECT indicates decreased uptake in the frontal, temporal, and cingulate cortex, as well as the striatum in DLB patients, compared to healthy controls (O’Brien et al., 2008); in contrast, the study showed decreased uptake in medial temporal lobe, frontal cortex, striatum, and pons, respectively, in AD patients (O’Brien et al., 2007). In addition, investigations of differences in the distribution of muscarinic AChR (mAChRs) using (R,R)-123I-iodo-quinuclidinyl-benzilate (QNB) suggest elevated binding in the occipital lobe of DLB patients (Colloby et al., 2006) but decreased tracer uptake in the hippocampus, temporal lobe, and frontal rectal gyrus in patients with AD (Pakrasi et al., 2007). Although potentially interesting, further work is needed to determine the diagnostic potential of these approaches. In addition, PD, DLB, and PDD patients have been studied using objective measures of acetylcholinesterase (AChE) activity by N-[11C]-methyl-4-piperidyl acetate PET (Shimada et al., 2009). In these studies, AChE activity was clearly reduced in all patient groups and could

Dementia with Lewy Bodies

not reliably separate or distinguish among PD, DLB, and PDD (Shimada et al., 2009). Whether there are differences between DLB and AD patients and whether this technique can be used to objectively measure disease progression remain important questions. A number of studies focusing on AD have now imaged amyloid load using N-methyl-[11C]2-(4′methylaminophenyl)-6-hydroxybenzothiazole (Pittsburgh compound B, PIB) PET, which binds β-amyloid plaques in cortical association areas and diffuse amyloid deposits in the striatum, with a twofold increase in uptake compared to healthy controls (Klunk et al., 2003, 2004). Several studies utilizing 11C-PIB PET have now been undertaken in DLB patients, suggesting that the majority of individuals have raised amyloid load (Edison et al., 2008; Gomperts et al., 2008; Maetzler et al., 2008). Further work is needed to determine whether different magnitude of amyloid binding can be used to distinguish DLB and AD patients, and whether this can be used as a reliable method of tracking disease progression or treatment response.

Structural MRI Building upon previous clinical studies (such as Barber et al., 2000; Burton et al., 2002; Beyer et al., 2007), recent data from a series of neuropathologically confirmed cases with antemortem MRI indicated significantly greater medial temporal lobe atrophy (MTA) in AD patients, compared to those with DLB (Burton et al., 2009). However, it is still debatable whether the overall sensitivity and specificity of these differences is sufficient to make this useful as part of a diagnostic assessment. Functional MRI (fMRI)—which measures alterations in patterns of brain activation in response to a stimulus or task— has also been compared between DLB and AD patients, highlighting potential differences in the occipitotemporal activation and default network deactivation in response to visual color, face, or motion stimuli in the two conditions (Sauer et al., 2006). However, further work is needed to understand the potential significance of this finding.

Cerebrospinal fluid Studies of CSF have consistently shown characteristic changes of amyloid-beta and tau peptides in AD, but

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the initial studies focusing on DLB have shown conflicting results (reviewed by Aarsland et al., 2008a, 2008b). α-Synculein is the pathologic hallmark of DLB and PDD and appears to be the pathologic substrate most closely related to progressive cognitive decline in these individuals. α-Synculein is therefore a potentially attractive biomarker, and although recent progress has been made on the measurement of α-synculein in the CSF, the results are highly conflicting (El Agnaf et al., 2003; Mollenhauer et al., 2008; Ballard and Jones, 2010; Ballard et al., 2010). Recent work does suggest that an increase in α-synculein dimers in the CSF (Tokuda et al., 2010) may be more indicative of DLB/PDD than alterations in total α-synculein. The small number of studies and the absence of longitudinal studies directly comparing CSF markers in DLB and AD across the spectrum of disease severity make it difficult to develop firm conclusions.

Spectrum of Lewy body dementias: relationship of PDD to DLB The distinction and overlap between DLB and PDD has been controversial. There is a substantial overlap in symptoms between the two conditions (reviewed by Aarsland et al., 2004a, 2004b), probably reflecting a common underlying cortical molecular pathology, with cortical LBs and more diffuse α-synuclein pathology as common diagnostic features of both conditions at autopsy. More specifically, several studies have suggested that, in many cortical regions, the amount of LB pathology does not differentiate DLB from PDD or PD (Harding and Halliday, 2001; Tsuboi and Dixon, 2005). In contrast, data from the Newcastle brain bank (see Table 9.6) indicate more pronounced cortical LB pathology in DLB compared to PDD in a range of cortical areas, although the prolonged duration of PD prior to dementia in this cohort may explain the magnitude of disparity in cortical LB pathology. Other work has suggested a more specific regional pattern of differences in LB density, with higher LB densities in parahippocampal and inferior temporal cortices in DLB compared to PDD (Harding et al., 2002). In both DLB and PDD, cortical LB pathology impacts phenotype. For example, the density of temporal lobe LB in DLB correlates with the early occurrence

Table 9.6 Lewy body pathology: a comparison of DLB and PDD

Age F gender MMSE closest to death Duration of dementia Duration of parkinsonism Frontal LB density Transentorhinal LB density Anterior cingulate LB density

DLB (N = 29)

PDD (N = 11)

Evaluations

79.9 ± 4.8 17

74.2 ± 4.3 5

9.6 ± 9.1 2.6 ± 1.8 1.2 ± 1.4 1.2 ± 1.5 3.8 ± 2.9 2.5 ± 2.4

12.2 ± 9.4 2.1 ± 1.3 9.9 ± 6.9 0.4 ± 0.3 1.8 ± 1.0 1.4 ± 1.1

t = 3.3; p = 0.002 χ2 = 0.6; p = 0.46 t = 0.7; p = 0.47 t = 0.9; p = 0.35 t = 6.5; p < 0.0001 t = 2.5; p = 0.02 t = 3.1; p = 0.004 t = 2.0; p = 0.049

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of the characteristic well-formed visual hallucinations, and increasing LB densities in limbic and frontal cortices in PDD correlate with the severity of dementia (Samuel et al., 1996). The density of amyloid plaques has generally been reported to be higher in DLB than in PDD, with the density of Aβ-positive plaques in many DLB patients equivalent to that found in AD. Although the amount of Aβ deposition and cortical LBs correlates with dementia severity in DLB, this does not seem to be the case in PDD (Harding and Halliday, 2001). Neurofibrillary tangles are typically substantially less pronounced than in AD, but they may influence the clinical phenotype, particularly in DLB (Merdes et al., 2003; Ballard et al., 2004). One study reported a marked LB neurodegeneration in the striatum in DLB but not PD. PDD patients had striatal neurodegeneration intermediate between PD and DLB (Duda et al., 2002). In contrast, an important preliminary report focusing on striatal pathology in 28  brains—including 7 PD, 7 PDD, and 14 DLB— indicated that striatal α-synuclein pathology is similar in PDD and DLB. Amyloid plaques were also similar in severity in the striatum in the two conditions (Tsuboi and Dickson, 2005). Overall, studies consistently indicate higher amyloid pathology in DLB than in PDD, but the literature is highly variable, with marked discrepancies related to cortical LB pathology and striatal pathology. One study from our group, examining the relationship between LB pathology and the number of years of PD prior to dementia as a spectrum, demonstrated substantially less cortical LB pathology in patients with long-standing PD prior to dementia than in DLB patients, but the differences were less pronounced in patients with 1–5 years of PD before dementia developed (Ballard et al., 2006). Importantly, this suggests pronounced clinical heterogeneity within the two syndromes and indicates that the differences within the PDD group may be even more substantial than between PDD and DLB. For example, some PD patients may develop dementia early in the course of the disease, whereas others remain cognitively intact or develop dementia late in course (Aarsland et al., 2007a, 2007b). Studying the relationship between the time from onset of PD to dementia, we found that those with early dementia (less than 10 years after onset of PD) had similar morphologic and neurochemical changes as those with DLB, whereas PD patients with late-onset dementia had less morphologic cortical pathology (LBs, amyloid plaques, and neurofibrillary tangles) but more severe cholinergic deficit in temporal cortex (Ballard et al., 2006). This study supports the concept of a continuum of LB disease instead of two distinct diseases, and the different duration of PDD in different studies may explain some of the discrepancies in results.

Comparative studies of clinical features in PDD and DLB The overall profile of cognitive deficits is similar in the two syndromes, with both PDD and DLB patients exhibiting significantly more marked executive and attention deficit, fluctuating attention, and less severe memory deficits than those with AD (Aarsland et al., 2004a, 2004b). Some studies have reported more pronounced executive dysfunction in DLB than in PDD, particularly in patients with mild dementia (Downes et al., 1998; Aarsland et al., 2003). Although studies based on group means provide important information, comparison of group means may disguise heterogeneity within the groups. Indeed, recent evidence has demonstrated that in PD and PDD, subgroups with different cognitive profiles exist: The majority of patients have an executive-visuospatial-dominant profile, whereas others have a memory-dominant profile (Foltynie et al., 2004; Janvin et al., 2006). Similarly, some DLB patients, probably those with more abundant Alzheimer-type changes, may lack the characteristic pattern of neuropsychological deficits usually associated with LB diseases. The profile of neuropsychiatric symptoms is also similar in DLB and PDD. Persistent visual hallucinations are the most frequent psychiatric symptoms and are characteristic of both dementias (Ballard et al., 1999; Aarsland and Cummings, 2004). Although misidentification syndromes and delusions are also frequent and have a similar phenomenology in both DLB and PDD patients (Mosimann et al., 2006), they may be more frequent in DLB than in PDD, possibly due to morphologic or neurochemical differences reported earlier. A modest proportion of DLB patients do not have parkinsonism, but in those who do have it, severity and profile of parkinsonism is similar to the findings in PDD, and parkinsonism is a key factor explaining the functional impairment in DLB (McKeith et al., 2006). In the most detailed comparative study of parkinsonism to date, Burn et al. (2003) reported that DLB patients had less severe parkinsonism than PDD but had a similar severity of motor deficits compared to PD patients without dementia. Postural instability and gait difficulties, predominantly mediated by nondopaminergic lesions, were more pronounced in DLB and PDD than in PD patients without dementia, whereas the opposite was found for tremor.

Genetic studies In a systematic review of the available literature about familial occurrence and genetics of dementia plus parkinsonism to explore the genetic evidence of PDD and DLB, we found substantial coincidental familial occurrence of

Dementia with Lewy Bodies

dementia and parkinsonism in 24 families (Kurz et al., 2006). In 12 families, the presentation of dementia and parkinsonism fulfilled current criteria for DLB and PDD, implying that the same mutation in different members of the same family caused different clinical entities. This demonstrates a substantial overlap between the entities in at least a proportion of the cases, suggesting a shared underlying pathophysiology of PDD and DLB. Furthermore, it implies that the arbitrary distinction between PDD and DLB according to the relative timing of parkinsonism and dementia does not reflect the molecular biology of the disease process. As this overlap is clearly evident in familial cases of PDD or DLB, the same will likely be true in sporadic presentations. Interestingly, patients with familial co-occurrence of dementia and parkinsonism either displayed mutations in the synuclein gene or showed positive correlations with the APOE3/4 and E4/4  allele. Consistent with these observations, a threegenerational Belgian family with different phenotypes involving dementia and/or parkinsonism (Bogaerts et al., 2007) was described, with significant linkage to 2q35-q36. Together these reports support the hypothesis of a common genetic underpinning of DLB and PDD.

Treatment of DLB and PDD Because there are relatively few treatment studies, a number of the studies have included patients with DLB and those with PDD. As presented earlier, the literature strongly indicates that DLB and PDD are on a spectrum instead of being completely distinct conditions. This section focuses on the treatment of both DLB and PDD. Given the complex combination of symptoms in people with DLB and PDD, it is helpful to think about the different treatment targets. Ultimately, the goal is to identify therapies that fundamentally impact the disease process. Some emerging evidence indicates that cholinesterase inhibitors (CHEIs) may reduce the accumulation or impact of concurrent amyloid pathology (Ballard et al., 2007) and points to a number of other potentially exciting avenues of exploration, such as the relationship between proteosome function and α-synuclein pathology (MacInnes et al., 2008), the role of β-synuclein (Fujita et al., 2009) and the impact of altered forms of α-synuclein on the propensity to aggregate (Ballard and Jones, 2010). However, these remain research questions, and clinical management needs to focus on key symptoms. DLB and PDD are both progressive neurodegenerative dementias associated with global cognitive deterioration and impairment of self-care and other activities of daily living. As with all dementias, improving cognition and stabilizing self-care skills are major treatment goals. However, in DLB and PDD, prominent neuropsychiatric symptoms, parkinsonism, falls, autonomic dysfunction,

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or sleep disorders may be the most important symptoms for a particular individual. It is therefore helpful to document the symptoms that require assessment and treatment in a therapeutic plan, based on a problem list of key symptoms, prioritized in order of importance to the patient. Caregiver opinion about the impact of particular symptoms should also be inquired about, particularly because some symptoms—such as sleep or behavioral disturbances—may have the most impact upon them. Before any pharmacologic intervention, it is helpful to explain that improvements in one symptom domain may lead to deterioration in others, and slow and careful titration of drug dose may help reduce this. Frequent monitoring for response to treatment and adverse effects of medications is recommended.

Pharmacologic treatments for cognition and function in DLB and PDD The main evidence base for treating cognitive symptoms pertains to the use of acetyl CHEIs. The first trial was a small open-label study of seven patients with PDD treated with tacrine. They experienced improvement in cognition (MMSE score) and visual hallucinations and suggested that, contrary to previous concerns, parkinsonian symptoms actually improved. Although the potential utility of tacrine is limited by the high risk of hepatotoxicity, the trial was extremely important in highlighting the potential value of CHEI therapy (Hutchinson and Fazzini, 1996). Aarsland et al. (2004a, 2004b) summarized the literature and highlighted 14 small studies focusing on CHEI treatment in patients with PD with an open or randomized crossover design, including a total of 144  patients and trials with tacrine, donepezil, rivastigmine, and galantamine between 1996 and 2003. Overall MMSE scores improved by approximately two points, and more than 90% of patients had an improvement in their visual hallucinations. Although the overall balance of the literature did not support Hutchinson and Fazzini (1996) in suggesting an improvement in motor symptoms, only a modest proportion of individuals experienced a worsening of parkinsonism. The only large parallel group, randomized, controlled trial of a CHEI in PDD, published in 2004 (Emre et al., 2004), confirmed the impression from the previous preliminary studies and demonstrated that rivastigmine was significantly better than a placebo during 24 weeks of treatment for 541 patients with PDD (allocated 2:1 rivastigmine : placebo). During the treatment period, the rivastigmine-treated patients had a one-point advantage on the MMSE, an almost three-point advantage on the ADAS-COG, and significant benefits on more specialized assessment of attention and executive function. There were also significant two-point advantages for rivastigmine-treated patients on the ADCS activity of daily living scale and the neuropsychiatric inventory. Although there was no

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overall significant worsening of parkinsonism, there was a significant increase of tremor as a reported adverse event in the rivastigmine-treated patients. As expected, the participants receiving rivastigmine were more likely to experience nausea (29% vs. 11%) and vomiting (16.5% vs. 2%), but there was no difference in falls, with 75% of participants able to tolerate rivastigmine for the duration of the study. Mortality rates were significantly lower in the rivastigmine-treated patients (1.1% vs. 3.9%). A similar evolution of studies was seen for DLB, with initial small case series (such as Kaufer et al., 1998; Shea et al., 1998; Aarsland et al., 1999) indicating that about two-thirds of patients experienced benefit from CHEI treatment, especially with respect to neuropsychiatric symptoms. Several reports (such as Kaufer et al., 1998) highlighted improvements in fluctuating confusion. In general, this literature supports the conclusions of the treatment studies in PDD, indicating that parkinsonian symptoms worsened in only a minority of individuals; however, in one of the reports (Shea et al., 1998), three of the nine patients experienced a worsening of parkinsonism. Again, this literature emphasizes the need for a randomized, controlled clinical trial, culminating in a multicenter, placebo-controlled trial (McKeith et al., 2000) of 120 DLB patients treated with rivastigmine (mean dose 7 mg) or placebo for 2 weeks. The primary outcome measure was 30% improvement in a four-item subscore (delusions, hallucinations, apathy, and depression), which was attained by 63% of people treated with rivastigmine and 30% of people treated with placebo—a significant difference on the observed case analysis. On the total NPI, there was a nonsignificant three-point advantage to the rivastigmine-treated patients. However, it should be emphasized that this difference was not evident at the 12-week assessment point, and the benefit appeared to emerge between 12 and 20 weeks. The impact on specific psychiatric symptoms and fluctuating cognition has been studied less. Significant improvements were also seen in attentional performance, with a nonsignificant one-point advantage to the rivastigmine-treated patients on the MMSE. The reports of adverse events were similar to those in the subsequent PDD trial. The literature overall is extremely encouraging, with evidence from two large RCTs supported by extensive case series literature, indicating that rivastigmine is significantly better than placebo for the treatment of cognitive deficits and neuropsychiatric symptoms. Evidence from the PDD study (Emre et al., 2004) also showed significant advantages for activities of daily living. Rivastigmine is well tolerated, with no significant exacerbation of parkinsonism, although nausea and vomiting can be a problem. In addition, detrusor instability is common in DLB patients, can occur early in the course of the illness (Del-Ser et al., 1996), and may be exacerbated by CHEIs. The RCTs in DLB and PDD were undertaken with the rivastigmine capsule. More recently, a successful RCT in

AD has been completed with a rivastigmine transdermal patch (REF), which appears to have a favorable side effect profile compared to the capsule and is now widely licensed for the treatment of AD. There have not yet been any RCTs in PDD or DLB using the transdermal formulation. The case series literature suggests that donepezil is also an effective treatment for DLB and PDD (Aarsland et al., 2004a, 2004b). More recent RCTs show more mixed results. In a recent large placebo-controlled RCT showed only limited benefits in comparison to a placebo (Dubois, 2009). In contrast, an RCT from Mori et al. (2012) indicated significant advantages in comparison to placebo, with a similar magnitude of benefit to that reported with rivastigmine. One large 2-year RCT comparing rivastigmine and donepezil for the treatment of AD did suggest a modest advantage for rivastigmine in the subgroup of patients who met criteria for possible DLB, but the diagnostic status of these patients is unclear (Bullock et al., 2005). One small crossover study with donepezil in a combined cohort of DLB and AD patients indicated a significant exacerbation of syncope and carotid sinus hypersensitivity (CSH) and related falls in donepezil-treated patients (McLaren et al., 2003). This is a real clinical concern, given the high frequency of CSH and other aspects of autonomic dysfunction in DLB and PDD patients, but it is unclear whether the propensity to exacerbate these problems differs between the different CHEI. An ECG, assessment of autonomic function and postural hypotension, and a good clinical history to evaluate syncope should probably be completed before instigating treatment. Any emergent symptoms or features of autonomic dysfunction should also be monitored carefully during therapy. Studies of CHEI other than rivastigmine and donepezil are limited.

Predictors of treatment response to CHEI The presence of visual hallucinations or more severe attentional impairments, probably both markers of more severe cholinergic deficits, are both associated with preferential treatment response (McKeith et al., 2004).

Memantine Memantine is an N-methyl d-aspartate (NMDA) receptor antagonist that affects glutamatergic neuronal transmission and prevents the toxic effects of raised concentrations of the excitatory neurotransmitter glutamate. Memantine has established efficacy as a treatment for AD. Of note, altered glutamatergic markers have been identified in patients with DLB (Dalfo et al., 2004). Three RCTS have now been reported. Leroi and colleagues (2009) reported a 22-week placebo-controlled RCT of 25 participants with PDD. Memantine was well tolerated by participants at 20 mg/day dosing, and no participants were withdrawn due to memantine-related adverse events. The power of the study to detect clinical benefits

Dementia with Lewy Bodies

was limited, but the results suggested a benefit in global clinical outcome. In another RCT, 72 patients (40  with PDD and 32 with DLB) were randomized to memantine or placebo for 24 weeks. Again, memantine conferred significant benefit compared to placebo in global clinical outcome, with a mean CGIC score in the memantine group of 3.5 (SD 1.5; median 3.0), compared with 4.2 (1.2; 4.0) in the placebo group. In the intention-to-treat analysis with LOCF, the mean difference was 0.70 (95% CI 0.04–1.39; p = 0.03), with an effect size of 0._52. A moderate or substantial clinical improvement was noted in eight (27%) patients in the memantine group, compared with none in the placebo group. There were also significant benefits in cognition (as measured by the MMSE) but not in neuropsychiatric symptoms (Aarsland et al., 2009). A further paper based on secondary outcomes indicated additional benefits with respect to sleep symptoms (Larsson et al., 2010). Although the numbers are too small to permit a detailed subanalysis, there was some suggestion that the main benefits were evident in the PDD patients. In the largest RCT, 195 patients (75 DLB and 120 PDD) were randomly assigned to memantine or placebo treatment (Emre et al., 2010). At week 24, patients with DLB who received memantine showed greater improvement in global clinical outcome (Clinical Global Impression of Change) than did those who received placebo (mean change from baseline 3.3 vs. 3.9, respectively, difference −0.6 [95% CI −1.2 to −0.1]; p = 0.023). There was also a significant improvement in neuropsychiatric symptoms but not in cognition. The incidence of adverse events and number of discontinuations due to adverse events was similar in the two groups. In contrast to the Aarsland et al. study, the benefits were mainly evident in the DLB patients. Overall, global clinical benefits and good tolerability were reported in all three studies, indicating the potential value of memantine as a treatment for PDD and DLB patients. However, the specific benefits with respect to neuropsychiatric symptoms and cognition and the relative benefits conferred to DLB and PDD patients, respectively, all require further clarification.

Neuropsychiatric symptoms When assessing the treatment of these symptoms, it is critical to determine whether there is any medical comorbidity, review potentially contributing medications, assess relevant visual impairments, and determine the severity of the symptoms and the level of distress caused to the person and the caregiver. Particular attention should be paid to the potential contributing role of antiparkinsonian medications, and dose reduction or even discontinuation of some antiparkinsonian medications may be indicated. Nonpharmacologic interventions have been shown to effectively ameliorate neuropsychiatric symptoms in people with dementia, but they have not yet been systematically evaluated in DLB. Approaches vary in complexity,

217

from optimizing the care and support package and promoting good communication and person-centered care, to tailoring specific interventions involving the patient, caregiver, or environment. If symptoms are not causing enormous distress, nonpharmacologic treatments should probably be the intervention of first choice, although CHEIs prescribed as a more generic pharmacotherapy may confer additional benefit. When specific pharmacologic intervention is required to treat neuropsychiatric symptoms in DLB or PDD, the main options are CHEIs or atypical antipsychotic medications. Open-label and placebo-controlled studies have suggested possible benefit with all three generally available CHEIs on visual hallucinations, delusions, and associated agitation in DLB and PDD (Aarsland  et  al., 2004a, 2004b), although this question has not been specifically addressed in RCTs. The RCTs in DLB and PDD have compared rivastigmine to placebo and show a general improvement in neuropsychiatric symptoms (McKeith  et  al., 2000; Emre et al., 2004), but the specific impact on visual hallucinations has not been reported and the time to improvement appears to be 3–6 months. Although there is some disparity between the case series and the RCT data, a trial of a CHEI will give general benefits, is well tolerated, and is the pharmacologic treatment of first choice. No comparative data exists between the CHEIs in PDD or DLB, although given the higher level of evidence, rivastigmine is probably the treatment of choice. Beneficial effects of CHEIs may be sustained for at least 2 years of treatment (Grace et al., 2001), and sudden withdrawal may precipitate marked deterioration in neuropsychiatric symptoms (Minett et al., 2003). If symptoms are particularly severe and distressing, the time frame of response to CHEI therapy may be too slow. The use of atypical neuroleptics creates a more difficult clinical dilemma because of the general potential for adverse events and the specific risk of severe neuroleptic sensitivity reactions in DLB and PDD patients. Widely reported general side effects of neuroleptics include parkinsonism, drowsiness, dystonia, and abnormal involuntary movements (tardive dyskinesia) associated with longterm treatment (with many agents also causing anticholinergic side effects, including delirium). In people with AD, evolving evidence has also highlighted serious risks, including cerebrovascular adverse events and increased mortality (Ballard and Howard, 2006). In DLB and PDD, there is the additional specific problem of severe neuroleptic sensitivity reactions (McKeith  et  al., 1992; Ballard et al., 1998; Sadek and Rockwood, 2003; Aarsland et al., 2005a, 2005b). McKeith et al. (1992) reported that 50% of neuroleptic-treated patients with DLB experienced severe drug sensitivity, with symptoms that included marked extrapyramidal features, confusion, autonomic instability, falls, and accelerated mortality. An accumulating literature of case reports and case series, as well as subsequent

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larger and more systematic series, shows that severe sensitivity reactions occur with a wide range of typical and atypical antipsychotics, including clozapine, in DLB and PDD patients (such as Aarsland et al., 2005a, 2005b). Failure of neuroleptic prescriptions to up-regulate dopamine D2 receptors has been highlighted as a major contributing factor to severe neuroleptic sensitivity (Piggott et al., 1998, 1999). However, the largest and most systematic study suggested that the highest frequency of severe neuroleptic sensitivity reactions occurred in olanzapine-treated patients (Aarsland et al., 2005a, 2005b), raising the possibility that antimuscarinic properties may also be important. Clinically, severe neuroleptic sensitivity reactions are a major concern, as they can occur after only a few doses (Ballard et al., 1998) or even single doses (Sadek and Rockwood, 2003) of neuroleptic. Clear evidence from RCT in AD patients with behavioral and psychiatric symptoms indicates that atypical neuroleptics are an effective treatment for the short-term (6–12 weeks) treatment of aggression but with more marginal benefits for psychosis and other symptoms of agitation (Ballard and Howard, 2006; Schneider et al., 2006). There is only one RCT of an antipsychotic in DLB/PDD, which indicated that quetiapine did not confer any benefit in the treatment of neuropsychiatric symptoms in these individuals (Kurlan et al., 2007). Balancing the risks of therapy with atypical antipsychotics and the limited specific evidence of benefit in DLB and PDD, atypical antipsychotics should be used for only extremely severe neuropsychiatric symptoms in which there is extreme distress or risk to the patient or others. If therapy is instigated, it should be undertaken with extremely close monitoring during the first 2 weeks, especially the first 2–3 days, so that any early indications of severe neuroleptic sensitivity reactions or other major adverse events can be identified and treatment can be discontinued as soon as possible. In AD, some evidence from crossover studies and RCT indicates that anticonvulsants, such as carbamazepine and sodium valproate, and antidepressants, such as citalopram, may improve some neuropsychiatric symptoms (Ballard and Howard, 2006; Ballard et al., 2009). However, the evidence is limited and mainly indicates potential benefit for symptoms of agitation rather than psychotic symptoms. There are no studies of these agents in people with DLB or PDD, and the safety of these treatment approaches has not been established in these individuals. Emerging data from AD trials also suggests that memantine may confer benefit in the treatment of neuropsychiatric symptoms, although the evidence from the RCTs so far conducted with memantine in DLB/PDD patients is contradictory between studies (see the previous section regarding treatment of cognition and function). A recent placebo-controlled RCT of the 5HT2C inverse agonist pimavanserin has indicated significant benefit in the treatment of psychosis in people with Parkinson’s disease, including the subgroup with

significant cognitive impairment. Tolerability was also favorable (Cummings et al., 2013).

Mood disorders Depression is common in both DLB and PDD, and there have been no systematic studies of its management. Currently, SSRI and SNRIs are probably preferred pharmacologic treatment, although studies of SSRIs in PD without dementia have been disappointing (Zahodne and Fernandez, 2008). Tricylic antidepressants and those with anticholinergic properties should be avoided. Nonpharmacologic interventions, such as activity programs and exercise, have been shown to be effective for the treatment of depression in AD (Teri et al., 1997, 2003) but have not been evaluated in DLB. Anxiety is also frequent and may be secondary to fluctuating confusion, psychotic features, or depression. Treating the underlying neuropsychiatric condition often results in resolution. However, there is no specific evidence base to inform the treatment of more severe or persistent symptoms. In studies of CHEIs in AD, anxiety is often one of the symptoms that show a preferential response (Gauthier et al., 2002). Nonpharmacologic interventions, similar to those utilized for depression, can be helpful and SSRIs may be worth considering. Benzodiazepines should probably be avoided because of the risks of worsening amnesia, decreased alertness, impairment of motor function, and increased risk of falls. Sleep disorders are also frequently seen in LB disease and may be an early feature. RBD can be treated with clonazepam (0.25 mg at bedtime), titrating slowly and monitoring for both efficacy and side effects (Boeve et al., 2004). CHEIs (Reading et al., 2001) and memantine (Larsson et al., 2010) may also be helpful for disturbed sleep. Apathy, often associated with attentional and executive impairments, is a common feature that often adds to social and functional disability and generally responds well to CHEIs (McKeith et al., 2000). Fluctuating cognition is often a prominent and distressing symptom, which adds to impairment on everyday activities and can create major practical problems for planning an appropriate care package. Several case series include patients whose fluctuating cognition improved with CHEI therapy, but the data are less clear-cut from the RCTs. In the McKeith et al. (2000) study, after adjusting for overall improvement in attentional performance, there was no specific improvement of fluctuation. Fluctuating cognition is an important treatment target meriting further research, but it may be improved by using CHEI treatment. Parkinsonism Motor symptoms contribute to the disability experienced by DLB and PDD patients and are associated with an increased risk of falls. l-Dopa can be used for the motor disorder of both DLB and PDD, but doses should be titrated more carefully. l-Dopa is generally well tolerated but may

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increase confusion in a small proportion of patients (Molloy et al., 2005). Responsiveness to l-dopa is more limited in both DLB and PDD patients, with significant improvement of parkinsonism seen in approximately half of PDD patients and a smaller proportion of individuals with DLB, although falls may be reduced even in some patients without optimal motor response (Molloy et al., 2005). Caution should be exercised in adding other parkinsonian medications— including selegeline, amantadine, COMT inhibitors, and dopamine agonists—because of concerns about exacerbating confusion and psychosis (visual illusions, hallucinations, and delusions). Anticholinergics should also be avoided in both DLB and PDD. Cognition and psychosis should be monitored with standardized evaluations. Motor disability, including parkinsonism and postural instability, may also be improved by physiotherapy and occupational therapy approaches. The unpredictable and fluctuating nature of cognitive and motor impairments can prove particularly frustrating to patients and caregivers. Education, discussion, and reassurance on dealing with variable performance can help both parties adopt a flexible approach, depending upon the patient’s functional level.

Falls and dysautonomia There is a high prevalence of falls in DLB and PDD, with a considerable risk of related injuries. There is little direct evidence from specific RCTs to inform clinical practice; therefore, recommendations are based upon best practice recommendations for the management of falls in older people without dementia and some anecdotal clinical experience in the management of these problems in people with DLB and PDD. Falls prevention is therefore an important management consideration. Falls are multifactorial in dementia patients, with a number of factors including parkinsonism (with or without postural instability), postural hypotension, muscle weakness, posture, confidence/ anxiety, medication, and the environment all contributing. Therefore, a broad approach is needed that should include an evaluation of the patient’s environment, the need for walking devices, physiotherapy for gait training, and other rehabilitation efforts. Blood pressure should be checked for orthostatic BP, and minimization of cardiac medications and benzodiazepines is recommended. Management of postural hypotension includes removing medications that may be causative or additive. If postural hypotension persists following medication adjustment, potential additional pharmacologic treatments could include fludrocortisone and midodrine. Syncope may be an important attributable cause of falls. If suggestive symptoms are apparent, a detailed cardiovascular assessment is recommended, including head-up tilt and carotid sinus massage in a specialist facility. From anecdotal experience, cardiac pacing may be beneficial in some of these patients. Protective underwear and careful attention to flooring may reduce the risk of serious injury in patients at high risk of falling.

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Chapter 9.4 Vascular Cognitive Impairment Helena C. Chui and Freddi Segal-Gidan

In the United States, the second leading cause of dementia is cerebrovascular disease (CVD), either alone or in combination with Alzheimer’s disease (AD). In the Framingham study, the lifetime risk for stroke was comparable to that of AD (Seshadri et al., 2006). Because approximately one-third of persons meet criteria for dementia following stroke, these two statistics alone underscore the adverse consequences of CVD for cognitive health. Stroke, however, is only the tip of the iceberg of vascular brain injury (VBI; Sacco, 2007). VBI contributes additively to cognitive impairment, and a surge in obesity and metabolic syndrome portend increasing risk of VBI. Although vascular

cognitive impairment (VCI) is potentially preventable, recent increases in vascular risk factors warn that the frequency of VCI may rise instead. Vascular cognitive impairment is the nomenclature currently employed to encompass all degrees of cognitive impairment greater than expected for age caused by CVD. In this chapter, the terms subclinical vascular brain injury (subclinical VBI), vascular cognitive impairment not demented (vascular CIND), and vascular dementia (VaD) are used to denote the spectrum of cognitive impairment encompassed by VCI. For a summary of terms and abbreviations used in this chapter, see Table 9.7.

Table 9.7 Glossary of terms and abbreviations SYNDROMES CIND MCI MCI subtypes Memory impairment Amnestic memory impairment VCI VaD

Cognitive impairment not demented Mild cognitive impairment (cognitive impairment without significant compromise of instrumental or personal activities of daily living) Amnestic, amnestic plus other cognitive domain, non-amnestic single domain, non-amnestic plus other cognitive domains Free recall is below expectations Free recall is below expectations and is not attributed to diminished attention or retrieval (i.e., is not improved significantly with cueing) Vascular cognitive impairment (cognitive impairment ascribed to vascular disease or vascular brain injury) Vascular dementia (dementia ascribed to vascular disease or vascular brain injury)

ALZHEIMER’S DISEASE AD Alzheimer’s disease (refers to progressive cognitive decline associated with widespread neurofibrillary tangles and neuritic amyloid plaques) Clinically diagnosed AD Mild cognitive impairment or dementia ascribed to AD, without pathological data CEREBROVASCULAR DISEASE CAA Cerebral amyloid angiopathy CVD Cerebrovascular disease (disease of blood vessels; e.g., atherosclerosis, arteriolosclerosis) Atherosclerosis Disorder affecting endothelial and elastic lamina of larger arteries Arteriolosclerosis Disorder affecting smooth muscle cell layer of arterioles Arteriosclerosis Includes atherosclerosis and arteriolosclerosis VASCULAR RISK FACTORS VRF Vascular risk factors (refers to known risk factors for stroke; e.g., hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation) Vascular factors Includes VRF and CVD VASCULAR BRAIN INJURY Stroke Sudden onset neurological deficit ascribed to CVD Subclinical VBI Evidence of vascular brain injury (e.g., WMH and SBI) in non-symptomatic individual VBI Vascular brain injury (parenchymal brain injury ascribed to vascular disease) MRI LESIONS WMH SBI SI SL

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White matter hyperintensity on MRI (synonyms include WML = white matter lesion, WMSH = white matter signal hyperintensity, leukoaraiosis = rarefaction of white matter on CT) Silent brain infarct on MRI Silent infarct on MRI Silent lacune (may include infarcts and perivascular spaces)

Vascular Cognitive Impairment

History

Subcortical ischemic vascular disease (SIVD, SVD)

During the past century, the relative gravitas assigned to CVD and AD has swung back and forth like a pendulum. As new knowledge accrues, the AD–CVD model is adjusted and refined. It is now clear that CVD and AD are both highly prevalent disorders in the elderly that have additive but differential effects on cognitive health (Figure 9.2). In the early to mid-twentieth century, “hardening of the arteries” (arteriosclerosis) was thought to be the primary cause of progressive loss of intellectual function in late life. Later, widespread neurofibrillary tangles and senile plaques (as in AD) were recognized as the predominant cause of dementia (Tomlinson et al., 1970). Multi-infarct dementia fell to a more distant second, requiring diagnosis of frank cerebral infarction, usually symptomatic stroke, not merely the presence of CVD (Hachinski et al., 1974). Today the pendulum has turned again, as neuroimaging and neuropathology frequently reveal subclinical evidence of VBI (such as white matter hyperintensities (WMH) and silent brain infarcts (SBI)) alone or in combination with AD. In the 1990s, the incorporation of structural imaging techniques (CT and MRI) in large community-based studies revealed evidence of widespread subclinical vascular pathology in many elderly, asymptomatic individuals, leading to the resurgence of interest in CVD and VCI. Asymptomatic WMH and SBI were identified by MRI in 20–30% of nondemented, community-dwelling elderly (Longstreth et al., 1996, 1998; Vermeer et al., 2003a, 2003b; see Figure 9.3). The term vascular cognitive impairment was adopted to emphasize recognition and treatment of early, subclinical VBI, as well as mild cognitive changes not severe enough to be classified as dementia. Later epidemiologic studies called out associations between risk factors for stroke (hypertension, diabetes, hyperlipidemia) and clinically diagnosed AD (cognitive impairment without frank stroke). During the past 5 years, community-based autopsy studies have shown that mixed pathologies are common in older CVD

Brain injury

225

WMH SBI

AD

Stroke

Beta-amyloid VCI Phosph-tau

Impact on cognition Subclinical

CIND

Dementia

Spectrum of cognitive impairment Figure 9.2 Evolving model: relative contributions of CVD and AD

to cognitive impairment.

Figure 9.3 Silent infarcts and white matter changes are found in

20–30% elderly persons.

persons with either dementia or mild cognitive impairment (Schneider et al., 2007, 2009a, 2009b; White, 2009). Various combinations of amyloid plaques/neurofibrillary tangles, cerebral infarcts, and Lewy bodies are found in more than half of dementia cases (Schneider et al., 2007). Moreover, converging evidence from clinical–pathologic correlations illustrate that infarcts and AD pathology contribute additively to the risk of dementia (Schneider et al., 2004). Although the mechanistic link between vascular factors and type of neuropathology and the functional link between VBI and cognition are still subject to debate, the importance of vascular disease to brain health is incontrovertible.

Conceptual framework VCI is not a disease, but a syndrome or phenotype, based on cognitive impairment due to underlying VBI. The model used in organizing this chapter identifies the blood vessel pathology or CVD as the primary disease process. It follows logically that primary prevention should be directed at reducing CVD. This conceptual model of VCI can be summarized as VRF ➡ CVD ➡ VBI ➡ VCI. Underlying CVD results in VBI (such as cerebral ischemia, oxidative stress, infarcts, hemorrhage, and inflammation), which, in turn, leads to VCI. Many types of CVD exist, including arteriosclerosis (atherosclerosis and arteriolosclerosis) and cerebral amyloid angiopathy (Table 9.8) (Grinberg and Thal, 2010). Many types of risk factors are at work. Well-known vascular risk factors for arteriosclerosis include hypertension, diabetes mellitus, hyperlipidemia, and smoking. The apolipoprotein E ε4 allele is a genetic risk factor for cerebral amyloid angiopathy, increasing the accumulation of β-amyloid in blood vessels as well as in the brain parenchyma as amyloid plaques. Genetic mutations give rise to Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts

Cardiac Atrial fibrillation Endocarditis Myopathy Mural thrombus

Nonmodifiable Age Gender Race Heredity CADASIL CARASIL HCHWA-D HCHWA-I Vein

Hemorrhage Leaky BBB Anoxia

Chronic Hypoperfusion

Acute Thrombosis Embolism

Ischemia

Mechanism of brain injury Complete infarction (symptomatic or silent) Incomplete infarction (demyelination, selective neuronal loss) Hematoma Microbleed Neuronal loss with gliosis

Brain pathology phenotype: VBI

Limbic-diencephalic memory system Multimodal association areas Cortico-basal ganglia-thalamocortical loops Deep white matter connections (cingulum, superior frontal occipital fasciculus, superior longitudinal fasciculus)

Location/neural network

Multi-infarct dementia Strategic infarct dementia Lacunar state SVD Binswanger syndrome

Clinical phenotype or syndrome: “Stroke” VCI

BBB, blood–brain barrier; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; HCHWA-D, hereditary cerebral hemorrhage with amyloidosis, Dutch type; HCHWA-I, hereditary cerebral hemorrhage with amyloidosis, Icelandic type.

Blood content Hypoglycemia Hypoxemia Hemoglobinopathy Coagulopathy

Single artery (large artery, small arteriole, capillary)

Cerebrovascular Atherosclerosis Arteriolosclerosis Amyloid angiopathy Vasculitis Tortuosity Anomaly

Modifiable Hypertension Hyperglycemia Hyperlipidemia (apolipoproteins) Smoking Obesity Border zone (large arteries, small arterioles, capillaries)

Vascular distribution

Vascular phenotype: “CVD”

Risk factors

Table 9.8 The pathogenetic spectrum of vascular cognitive impairment: RF → CVD → VBI → VCI

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Vascular Cognitive Impairment

and leukoencephalopathy (CARASIL), and hereditary cerebral hemorrhage with amyloidosis (HCHWA). A variety of pathways can lead to the development of VBI and the subsequent development of VCI. This results from complex interactions between lesions that vary depending on site, size, and number (Tomlinson et al., 1970). It may involve a large number of lesions in various locations throughout the cerebral cortex, or one or more lesions strategically located within cognitive networks. The relative impact of VBI on cognitive function ranges widely, from mild effects on executive function or processing speed to devastating hemispheric neurobehavioral syndromes (refer to Figure 9.2). Ergo, no singular behavioral phenotype or temporal course for VCI exists. The major determinant of clinical symptoms (such as aphasia, neglect, visual–spatial impairment, and executive dysfunction) is the anatomic location of VBI (e.g., dominant perisylvian cortex, nondominant parietal lobe, deep white matter). One of the subtypes of VCI, namely subcortical vacular dementia due to small vessel arteriolosclerosis is associated with greater impairment of executive compared to memory function. The pathophysiologic mechanism of VBI is a major determinant of temporal course and clinical progression. For example, embolization, thrombosis, and hemorrhage are associated with abrupt onset or stepwise decline. In contrast, widespread small vessel disease may be associated with slowly progressive decline (such as Binswanger syndrome). Mixed CVD/AD may be associated with a combination of stepwise and slowly progressive decline.

Epidemiology VCI is a syndrome, not a disease, so there are many ways of operationalizing the definition of vascular CIND and VaD (see the upcoming section “Diagnostic criteria”). Differences in severity and pattern of cognitive impairment, evidence of vascular etiology, and inclusion or exclusion of mixed AD/ VCI cases affect epidemiologic estimates. In this section, we review various estimates of VaD, vascular CIND, poststroke cognitive impairment, and preclinical VBI. VCI is considered to be the second most common cause of cognitive impairment in late life, after AD. Most epidemiologic data relate to VaD, with rates approximating half those of AD. As with AD, the incidence of VaD increases exponentially after 65 years of age. For persons older than age 65, the overall rate is estimated to be 11 per 1000 person-years (about 1% per year; Fitzpatrick et al., 2004; Ravaglia et al., 2005). At age 80, the incident rates for VaD vary from 0.3% to 1.9% (Rocca and Kokmen, 1999; Knopman et al., 2002). A higher incidence rate for VaD in men than women has been reported in some studies (Ruitenberg et al., 2001; Fitzpatrick et al., 2004), but pooled analyses showed no significant differences (Andersen et al., 1999). The Cardiovascular Health Study reported twice as many African Americans with

227

incident VaD, compared to European Americans (Fitzpatrick et al., 2004). Several factors may contribute to apparent differences in rates of VaD, including differences in definition, methodology, education, and socioeconomic status. Far less data is available for vascular CIND. In the Canadian Health & Aging Study, there were twice as many prevalent cases with CIND (16%) as dementia (8%) or stroke (8%) (Jin et al., 2006). Although the etiology of CIND was not differentiated, CIND was associated with increased risk of not only incident dementia, but also incident stroke. In the Religious Orders and Rush Memory and Aging autopsies studies, macroscopic infarcts were commonly found in subjects with MCI (both amnestic (18.6%) and nonamnestic (13.3%)) and dementia (Schneider et al., 2009). The epidemiologic and pathologic data suggest that CVD is an important contributing factor to CIND or MCI. CIND and dementia are frequent sequelae of stroke. Following a first stroke, one in three survivors experiences cognitive impairment that meets criteria for dementia (Tatemichi et al., 1992b; Henon et al., 2001). Stroke survivors who are not affected by dementia after their first stroke are twice as likely to develop dementia in the following decade, compared to normal controls (Ivan et al., 2004). The latter finding is consistent with the notion that underlying CVD poses ongoing risk to cognitive health. Silent brain infarcts are five times as common as symptomatic infarcts. Estimates of the prevalence of SBI on MRI in community-based samples have varied between 5.8% and 17.7%, depending on age, ethnicity, presence of comorbidities, and imaging techniques (Das et al., 2008). On average, SBI is present in approximately 11% of individuals in middle or late life. Most have a single lesion, and the infarcts are most often located in the basal ganglia (52%), followed by other subcortical (35%) and cortical areas (11%) (Das et al., 2008). Risk factors for SBI are generally the same as those for clinical stroke (Das et al., 2008; Prabhakaran et al., 2008). WMH are often present in most individuals over 30 years of age ( Decarli et al., 2005), and increase steadily in extent with advancing age. WMH also shares risk factors with stroke, especially with hypertension and smoking (Jeerakathil et al., 2004). Importantly, a semi-quantitative rating of WMH has been developed (Longstreth et al., 1996), with age-specific definitions of extensive WMH (Massaro et al., 2004); this proves useful in defining risk for VCI in a community cohort (Debette et al., 2010). The data confirm the common prevalence of subclinical SBI and WMH in older community samples.

Evaluation In 2006, the National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to

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recommend minimum, common, clinical, and research standards for the description and study of VCI (Hachinski et al., 2006). As a clinical phenotype, VCI is inherently heterogeneous. Collection of common variables in a standardized manner (harmonization) is greatly needed to reduce extraneous noise and improve understanding of brain-behavior correlations, diagnosis, prognosis, and outcome. The clinical evaluation for VCI, or VaD, follows the established approach to the evaluation of cognitive impairment: a thorough history (from both the patient and a reliable informant); physical examination, including a screening mental state examination, with emphasis on complete neurologic (focal neurologic signs, gait disturbance) and cardiovascular components (funduscopic examination of retinal vessels, carotid bruit, and cardiac arrhythmia); laboratory testing (left ventricular hypertrophy and renal insufficiency); and neuroimaging (brain CT or MRI). Additional testing (such as comprehensive neuropsychological, diffusion weighted MRI, and genetic testing) should be done as indicated by the history and presentation. Emphasis is placed on identification by history of vascular risk factors (hypertension, hyperlipidemia, diabetes, and heart disease), medical history, and family history (stroke, TIA, MI) for risk reduction, and on the pattern of cognitive and affective disturbance and functional decline for symptomatic treatment, management, and support.

Mental status examination Mental status screening tests commonly employed for dementia screening may underestimate VCI, especially vascular CIND. The Folstein Mini-Mental State Examination (MMSE; Folstein et al., 1975) does not include any measures of speed or executive function, which are affected by WMH and SBI. The Modified MMSE (3MS; Teng and Chui, 1987) and the Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005) contain elements of verbal fluency (semantic and phonemic list generation), similarities, and cued recall that add to their utility in cases of VaD, as well as other non-AD dementias. Neuropsychological testing Comprehensive neuropsychological testing may be utilized in VCI to identify areas of cognitive decline, particularly in the early stages of CIND. On neuropsychological testing, the executive domain often shows the earliest impacts of small vessel VBI. In particular, inclusion of Trails B, phonemic and semantic fluency, clock drawing, and digit symbol substitution are recommended, along with tests sensitive to episodic memory, language, and visual–spatial domains. The cognitive deficits in VaD and VCI are characterized by the disturbance of frontal functions, with less verbal memory impairment (Sachdev et al., 2004a, 2004b). In contrast to AD, in which category fluency is usually more impaired than verbal fluency, both types of fluency are affected to a comparable degree in VCI (Tierney et al., 2001). Recommendations for 5, 30, and

60 minutes of neuropsychological assessment have been proposed (Hachinski et al., 2006).

Structural imaging Brain imaging (preferably MRI) is an essential tool for the clinical evaluation of VCI. Many types of VBI are visible on structural neuroimaging studies, including infarcts, hemorrhages, SBI, dilated perivascular spaces, white matter changes, and microbleeds. Semi-quantitative rating scales are useful in describing the severity of white matter lesions (Longstreth et al., 2005) and have been correlated with volumetric measures (Gottesman et al., 2010). Microbleeds appear as rounded hypointense foci, larger than 5 mm, on T-2* weighted MRI and are associated with hypertension, cerebral amyloid angiopathy, and CADASIL (Viswanathan et al., 2007). At the present time, microinfarcts are too small to be reliably detected by MRI and are found only upon autopsy. Hippocampal volume is usually preserved in pure VCI, in contrast to AD and hippocampal sclerosis (Zarow et al., 2005). Diffuse cerebral cortical atrophy is a nonspecific finding in many dementias, including VaD (Jagust et al., 2008). Harmonization standards for MRI have been proposed and include measures of brain atrophy, WMH, infarction, and hemorrhage (Hachinski et al., 2006). Neuropathology Neuropathologic examination post-mortem provides information about the underlying nature and severity of CVD (atherosclerosis, arteriosclerosis, and cerebral amyloid angiopathy). Pathologic examination provides a measurement of VBI that can confirm lesions identified by in vivo neuroimaging; identify lesions not detectable by current imaging techniques (microinfarcts and hippocampal sclerosis; Vinters et al., 2000; White et al., 2002); and determine the presence, distribution, and severity of other brain pathology, such as neuritic plaques and neurofibrillary tangles associated with AD. A number of recent studies have shown that VBI and AD exert additive effects on risk of dementia (Snowdon et al., 1997; Schneider et al., 2004; White, 2009). An autopsy study of SIVD/AD suggested that although silent VBI contributes to CIND, its effects are comparatively dwarfed by those of AD and hippocampal sclerosis in cases with dementia (Chui, 2007). Important elements in the assessment of CVD (such as atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy), VBI, leukoencephalopathy, hippocampal lesions, and associated neurodegenerative lesions are outlined by the NINDS– CSN Harmonization standards (Hachinski et al., 2006).

Diagnostic criteria No well-established consensus guidelines exist for the clinical diagnosis of vascular CIND or for the diagnosis of mixed AD/VCI. On the other hand, numerous criteria cover the clinical diagnosis of VaD (Table 9.9). In addition, there are published criteria for two subtypes of VaD,

Unequal distribution of deficits in higher cognitive functions, with some affected and others relatively spared Multifaceted cognitive impairment sufficient to interfere with customary affairs of life

ICD-10 (WHO, 1993)

ADDTC (Chui et al., 1992)

Possible

Probable

Possible

Memory loss plus impairment in two other cognitive domains

Memory loss Sufficient to interfere No clouding of consciousness

DSM-IV (APA, 1994)

NINDS-AIREN (Roman et al., 1993)

No specific criteria

Hachinski ischemic score (0–17 points; Hachinski et al., 1974) HIS ≥7 suggests MID HIS 5–6 suggests MIX HIS ≤4 suggests AD

Probable

Dementia

Diagnostic criteria

Table 9.9 Clinical criteria for VaD

Abrupt onset Stepwise progression Temporal relationship to onset of cognitive impairment

Either imaging findings, abrupt onset, or stepwise OR temporal relationship

Focal neuro signs Imaging findings

Not required

Two infarcts, or one infarct with temporal relationship to onset of cognitive impairment

Infarct outside cerebellum by imaging

One infarct outside cerebellum by imaging OR confluent white matter change

From the history, examination, or test, evidence of significant CVD, which may reasonably be judged to be etiologically related to the dementia (history of stroke, evidence of cerebral infarction)

Evidence from the history, physical examination, or laboratory tests of significant CVD that is judged to be etiologically related to the disturbance

Not specifically required

Evidence of causal relationship

Evidence of focal brain damage, which manifests as at least one of the following: unilateral spastic weakness of the limbs, unilaterally increased tendon reflexes, an extensor plantar response, or pseudobulbar palsy

Stepwise deteriorating course, and “patchy” distribution of deficits, focal neurologic signs, and symptoms

CVD risk factors (HTN, ASCVD) Sudden onset Stepwise progression Focal neurologic signs and symptoms

CVBI

Vascular Cognitive Impairment 229

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namely subcortical vascular dementia (SVD) (Erkinjuntti et al., 2000) and Binswanger syndrome (Bennett et al., 1990). In general, these criteria address three basic issues: (1) evidence of cognitive impairment, (2) evidence of VBI (by neurologic examination or neuroimaging study), and (3) likelihood that cognitive impairment results from VBI. Memory impairment, while included in several of the criteria, need not be prominent and is generally not considered essential. The Hachinski Ischemic score (Hachinski et al., 1975), developed four decades ago, is still useful (Table 9.9). Under this framework, 1 or 2 points are assigned to a list of risk factors, signs, and symptoms associated with stroke (for example, sudden onset, stepwise progression, and focal neurologic symptoms and signs). A score of >7 is associated with a high likelihood, and a score of <4 is associated with a low likelihood of vascular contribution to cognitive decline. The Diagnostic and Statistical Manual IV (APA, 1994) and ICD-10 (WHO, 1993) leave the clinician to determine whether there exists “significant CVD that is judged to be etiologically related to the disturbance.” Criteria developed by the Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC; Chui et al., 1992) require neuroimaging evidence of an infarct with a temporal relationship to the onset of cognitive impairment or two infarcts outside the cerebellum, with no requirement for prominent memory disturbance or focal neurologic signs. The National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINCDS–AIREN) criteria require (1) impairment in memory plus two other cognitive domains, (2) focal neurologic signs and infarcts or white matter changes on neuroimaging, and (3) onset of dementia within 3 months of stroke or stepwise progression (Roman et al., 1993). The NINCDS–AIREN criteria are most conservative and have been the most widely adopted for research studies, particularly for pharmacologic drug trials. Each of the diagnostic criteria provides a similar but not identical or interchangeable approach to the clinical diagnosis of VCI/VaD. A patient who meets criteria for probable or possible ischemic vascular dementia (IVD) under ADDTC may not meet criteria for NINCDS–AIREN VaD or DSM or ICD-10 criteria, and vice versa. The Cardiovascular Health Study Cognition Study compared cases classified as probable VaD by ADDTC, NINDS–AIREN, and DSM-IV and found significant differences, with almost three times meeting ADDTC criteria (n = 117), compared to NINDS–AIREN (n = 42; Lopez et al., 2005). Pathologic examination remains the gold standard for determining the underlying etiology of dementing disorders, although biomarkers and amyloid imaging are improving etiologic specificity for AD. Unlike AD, presently there are no established criteria for the pathologic diagnosis of VCI/VaD. The current standard is based on the identification of VBI in the neocortex, without requiring specific linkage to clinical symptoms or presentation.

Gold et al. (2002) compared the sensitivity and specificity of these clinical criteria for VaD against a pathologic reference standard (evidence of cortical ischemic brain injury). They demonstrated that overall current clinical criteria for VaD are highly specific (0.78–0.94), but lacked sensitivity (0.20–0.70), suggesting that clinical criteria may underestimate the extent of ischemic brain injury. The accuracy of various criteria for VaD has been reviewed (Chui, 2005). Positive likelihood ratios generally fall in the range of 2–5, which is associated with small but sometimes important changes between pre- and post-test probability.

VCI subtypes At present, no agreed-upon classification system addresses the various presentations and underlying neuropathologic changes in VCI. Several subgroups of VCI commonly encountered in the literature are post-stroke dementia (PSD), SVD, Binswanger syndrome, CADASIL, and preclinical silent VBI. Post-stroke dementia refers to the onset of cognitive and functional impairment in a temporal association with an acute stroke. Cross-sectional studies post-hospitalization have reported that approximately one-third of first-stroke survivors (26–32%) meet criteria for dementia 3 months post-stroke (Tatemichi et al., 1993; Pohjasvaara et al., 1999; Desmond et al., 2000; Henon et al., 2006). In up to one-third of these cases, a history of cognitive decline prior to the stroke suggests that underlying VCI or neuropathologic changes of AD may play a contributing role (Henon et al., 2001). A history of stroke has been reported to increase risk of dementia over 10 years (Ivan et al., 2004), and at 5 years post-stroke, the incident of PSD has been reported as high as 48% (Kokmen et al., 1996). Even after adjusting for other risk factors (demographics, cardiac disease, stroke severity, and stroke reoccurrence), the long-term mortality has been reported to be two to six times higher in patients with PSD (Leys et al., 2005). Among neuroimaging findings, silent cerebral infarcts, white matter changes, and global and medial temporal lobe atrophy are associated with increased risk of PSD (Leys et al., 2005). Left hemisphere, anterior and posterior cerebral artery distribution, multiple infarcts, and strategic infarcts have been associated with PSD in at least two studies. Based on small case studies, locations considered to be “strategic” have traditionally included the left angular gyrus, inferomesial temporal, mesial frontal, anterior and dorsomedial thalamus, left capsular genu, and caudate nuclei. The concept of strategic infarction, however, needs to be re-examined in larger prospective MRI studies, with the extent and location of VBI defined in relation to cognitive networks (Mayda and DeCarli, 2009). It is difficult to determine the extent to which cognitive impairment may be due to stroke vs. concomitant AD.

Vascular Cognitive Impairment

Estimates of the proportion of PSD patients with presumed AD vary widely between 19% and 61% (Leys et al., 2005). About 15–30% of persons with PSD have a history of dementia before stroke (Pohjasvaara et al., 1999; CordolianiMackowiak et al., 2003), and approximately one-third to one-half have significant medial temporal atrophy (Henon et al., 1998; Bastos-Leite et al., 2007). In the Lille study, the incidence of dementia 3 years after stroke was significantly greater in those patients with vs. without medial temporal atrophy (81% vs. 58%; Cordoliani-Mackowiak et al., 2003). It is plausible that the likelihood of AD is higher among patients with cognitive impairment preceding stroke or with MTA atrophy, but this remains conjectural in the absence of neuropathologic confirmation. Subcortical dementia refers to the accumulation of small infarcts in the deep white and gray matter. SVD includes lacunar state, strategic infarct dementia, and Binswanger’s syndrome. Small vessel infarcts comprise approximately 25% of subjects hospitalized for strokes, but nearly 60% of asymptomatic strokes in community-based studies (Vermeer et al., 2002). A single infarct in a strategic location, such as the anterior or dorso-medial nuclei of the thalamus, or the genu of the internal capsule that disrupt frontal–subcortical loops, can produce a dementia syndrome (see Figure 9.4; Tatemichi et al., 1992a, 1992b, 1995; Carrera and Bogousslavsky, 2006). Binswanger’s syndrome can be considered an extreme phenotype of SVD, which is clinically characterized by a slowly progressive decline in cognition, gait apraxia, and urinary incontinence (Roman, 1987; Bennett et al., 1990). This triad presentation may be confused with normal pressure hydrocephalus (NPH) clinically, but on structural brain imaging, there is diffuse cerebral atrophy and confluent deep white matter changes. The SVD subtype of VCI has been proposed, emphasizing slowing of cognition, executive

Prefrontal cortex

Anterior gentrum semiovale Anterior limb internal capsule

Capsular genu

Head of caudate

Globus pallidus

Anterior and dorsomedial thalamus Figure 9.4 Subcortical vascular dementia prefrontal–subcortical

circuits.

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dysfunction (impairment in select attention, abstract reasoning, and mental flexibility), depression, extrapyramidal signs, and gait disturbance (Erkinjuntti et al., 2000). In an autopsy-confirmed study, a “low executive” profile was 67% sensitive and 86% specific in distinguishing SVD from AD (positive likelihood ratio = 4.7; Reed, et al., 2007). Although the sample size was relatively small, categorization based on neuropathologic finding avoids circularity inherent in purely clinical studies and suggests modest clinical utility of the executive dysfunction profile for SVD. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered representative of “pure” SIVD. The disorder is caused by a defect in the Notch3 gene on chromosome 19 and causes progressive degeneration of vascular smooth muscle cells (Tournier-Lasserve et al., 1993). It is estimated to be present in 500 families worldwide, making this entity more common than familial AD (FAD). Diagnosis can be confirmed by skin biopsy or genetic testing, but no specific treatment is currently available. The MRI in CADASIL is characterized by subcortical infarcts, severe confluent white matter changes, and microbleeds (Lesnik Oberstein et al., 2001; O’Sullivan et al., 2001). The involvement of frontal, parietal, and temporal white matter, along with claustrum and corpus callosum, distinguishes CADASIL from the frontoparietal white matter changes associated with chronic hypertension. Associated with CADASIL are recurrent migraine attacks, ischemic events, and progressive subcortical dementia associated with premature death (mean age 65 years; Dichgans et al., 1998). The neuropsychological profile of CADASIL is characterized by pronounced deficits in executive function and processing speed (Peters et al., 2005). The recognition of WMH and SBI as harbingers of future cognitive impairment emerged from prospective, longitudinal, community-based studies. In the Rotterdam Scan Study, the presence of SBI at baseline more than doubled the risk of dementia at 3.6 years and tripled the risk of stroke at 4.2 years, even after adjustment for WMH and atrophy (Vermeer et al., 2003a, 2003b). Progression of WMH and incident SBI were associated with decline in overall cognitive function, especially information processing speed, but not with change in memory function (van Dijk et al., 2008). With more than 5 years’ follow-up in the Cardiovascular Health Study, incident SBI and worsening of WMH grade predicted greater decline in the modified MMSE and the digit symbol substitution test (Longstreth et al., 2002, 2005). In the Framingham Offspring Study of middle-aged adults where AD pathology is likely to be low, SBI predicted increased risk of stroke and dementia, independent of vascular risk factors (Debette et al., 2010). WMH also portended increased risk of stroke, mild cognitive impairment, dementia, and death, independent of vascular risk factors and interim vascular events (Debette et al., 2010). The data indicate the importance of SBI and WMH as preclinical signs of VCI and important targets for risk reduction.

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Treatment The best approach to the treatment of VCI is prevention through early identification and management of vascular risk factors and CVD. The Framingham Stroke Risk Profile is useful for estimating the 10-year risk for stroke in men and women 55–80 years old. The risk profile weighs age, systolic BP, diabetes, smoking, cardiovascular disease, atrial fibrillation, and left ventricular hypertrophy to predict the future 10 years’ risk of stroke (Wolf et al., 1991; D’Agostino et al., 1994). The benefit of treating vascular risk factors for stroke prevention has been well established by randomized clinical trials, and evidence-based guidelines that incorporate these have been disseminated for use in clinical practice (Goldstein et al., 2009). On the other hand, there is still relatively little clinical trial data demonstrating the effectiveness of vascular risk factor reduction on cognitive outcome measures. Lack of evidence, however, is not the same as negative evidence. To demonstrate protective effects for cognition, clinical trials may need to be started earlier in life, last much longer, and use more sensitive cognitive measures.

Primary prevention: identification and reduction of stroke risk factors Primary or secondary prevention trials that include cognitive outcome measures are more limited. Hypertension control for the prevention of stroke is well-established and accepted medical practice (see Table 9.10). By extension, it is believed that hypertension control will reduce VCI, but studies supporting this are limited. A follow-up of the Systolic Hypertension in Europe Trial (Syst-Eur trial)

demonstrated that long-term antihypertensive therapy (3.9 years) reduced the risk of dementia by 55% (43  vs. 21 cases, p < 0.001; Forette et al., 2002). Using this outcome data, it is estimated that treating 1000 patients for hypertension for 5 years can prevent 20 cases of dementia. In the Systolic Hypertension in the Elderly (SHEP) trial, hypertensive treatment was associated with a significant reduction in stroke (36%; p = 0.0003) and a 16% reduction in dementia (nonsignificant; SHEP 1991). Initiating hypertensive treatment early and maintaining optimal blood pressure control over the years is believed not only beneficial for reducing stroke and heart disease, but also necessary to preserve cognitive function. Diabetes is another well-recognized risk factor for cardiovascular disease, due to accelerated atherosclerosis and arteriosclerosis. Thus, it is also thought to play a role in the development of VCI. The Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial focuses on a randomized subset (2977) of the 10,251 individuals with established type 2 diabetes whose screening A1C was ≥7.5%, to specifically address whether interventions reduce cognitive decline and structural brain changes. Baseline data from ACCORD–MIND showed that higher A1C levels were associated with lower MMSE scores and slowing on the digit symbol substitution test (Cukierman-Yaffe et al., 2009). With the growing epidemic of metabolic syndrome, research is greatly needed to improve understanding and treatment of diabetes and cognitive impairment. The use of statins for primary prevention cognitive impairment remains unproven. In the PROSPER study (n = 5804; mean age = 75.3 ± 3.4 years), no difference in

Table 9.10 Primary and secondary prevention antihypertensive trials with cognition outcome measure Duration of follow-up (years)

Main results for dementia

Significance

Diuretic (chlorthalidone) and/or beta blocker (atenolol) or reserpine

4.5

16% reduction in dementia

n.s.

Forette et al. (1998) N = 2418

Ca-channel blocker (dihydropyridine) with or without beta blocker (enalapril maleate) and/or diuretic (hydrochlorothiazide)

2.0

50% (0–76%) reduction in dementia

p = 0.05

Lithell et al. (2003) N = 4937

ARB (candesartan cilexetil) and/or diuretics

3.7

7% increased risk in active arm (but only 3.2/1.6 mmHg reduction in BP in treatment vs. control arm)

p > 0.20

Peters et al. (2008) N = 3336

Diuretic (indapamide) with or without ACEI (perindopril)

2.2

14% (–9% to 23%) reduction in dementia Trial stopped early because of significant reduction in stroke and mortality

p = 0.2

Secondary prevention Tzourio et al. (2003) N = 6104

ACEI (perindopril) with or without diuretic (indapamide)

4.0

12% (–8% to 28%) reduction in dementia

p = 0.2

ARB (telmisartan)

2.4

No reduction of risk of dementia

p = 0.48

Antihypertensive medication Primary prevention SHEP (1991) N = 4736

Diener et al. (2008) N = 20,332

Vascular Cognitive Impairment

cognitive decline was found in subjects treated with pravastatin, compared to placebo (all p > 0.05; Trompet et al., 2010). The MRC/MRC/BHF Heart Protection randomized, controlled study of 20,536 high-risk individuals given 40 mg simvastatin daily demonstrated reduced rates of myocardial infarction, stroke, and revascularization by about one-quarter over 5 years (2002) but did not include cognitive outcome measures. The size of the benefit was related to the participants’ overall risk of major vascular events rather than on their blood lipid concentrations alone. The use of antioxidants to preserve cognitive function has been the subject of great public interest, leading researchers to investigate whether these claims have any validity. In individuals with cardiovascular risk factors or disease, there is no evidence that antioxidants preserve cognitive function or reduce mortality. The Women’s Antioxidant Cardiovascular Study (n = 2824), a trial of vitamin E, beta carotene, and vitamin C, for the secondary prevention of cardiovascular disease reported no slowing of cognitive change among women with pre-existing cardiovascular disease or cardiovascular disease risk factors (Kang et al., 2009). In the MRC/BHF Heart Protection Study, antioxidant treatment was not associated with any significant differences in all-cause mortality, deaths due to vascular or nonvascular causes, nonfatal myocardial infarction or coronary death, nonfatal or fatal stroke, or coronary or noncoronary revascularization (MRC/BHF, 2002).

Secondary prevention: recurrent stroke and cognitive decline The risk for subsequent stroke is known to increase after an individual has had one or more TIAs or a stroke. Whether the prevention of additional ischemic injury and another stroke can prevent further cognitive decline has not been proven. In the secondary prevention PROGRESS trial (Tzourio et al., 2003), 6105 subjects with previous stroke or TIA were randomized to perindopril plus or minus indapamide vs. placebo and followed for 3.9 years. Using the MMSE as an outcome measure, the treatment group showed a 19% relative risk reduction vs. placebo in cognitive decline and a 43% reduction in new WMH on MRI imaging (Dufouil et al., 2005). In the secondary prevention PRoFess trial, 20,332 subjects were randomized to two antiplatelet regimens, with one arm combined with telmisartan vs. placebo. After 2.4 years of follow-up, no differences were found in disability due to recurrent stroke and cognitive decline (Diener et al., 2008). Treatment of VaD The basic principles and approach to dementia care, emphasizing supportive care to optimize quality of life and advance care planning, are similar and of equal importance for patients and families with VCI and VaD as they are for those with AD and other dementias.

233

Presently, there are no specific treatments for the cognitive impairment associated with VCI or VaD, once developed. Although they do not have Food and Drug Administration (FDA) approval in the United States for VaD (or other non-AD dementia), during the past decade, three cholinesterase inhibitors have been studied in randomized, controlled trials of VaD. A vascular rationale for cholinesterase inhibitors in VaD has been proposed based on a study that showed galantamine increases cerebral vascular reactivity in subjects with both AD and VaD (Bar et al., 2007). Mild benefits in the Alzheimer’s Disease Assessment Scale, cognitive subscale (ADAS–-cog) have been reported with use of galantamine and donepezil in subjects with probable VaD (Erkinjuntti et al., 2002; Wilkinson  et al., 2003; Auchus et al., 2007). Among subjects meeting NINDS–AIREN criteria for probable or possible VaD, over 24-week clinical trial periods, donepezil (5–10 mg) was associated with an approximately 1- to 2-point difference in the ADAS-cog subscale, compared to placebo (Black et al., 2003; Wilkinson et al., 2003; Roman et al., 2010). Some caution is warranted, however, as increased mortality has been noted in a meta-analysis of donepezil in VaD (Kavirajan and Schneider, 2007) of unclear significance (Figure 9.5). A small, randomized study of rivastigmine among patients with stroke and cognitive impairment without dementia showed statistically significant improvement in animal fluency in the treatment group (n = 25), compared to controls (n = 25) (Narasimhalu et  al., 2010). In a study of CADASIL, a relatively pure example of VaD, no significant differences were noted in the ADAS-cog between the treatment (n = 86) and placebo (n = 82) groups (Dichgans et al., 2008). However, in this relatively small study, treatment effects favoring donepezil were observed for secondary executive outcome measures (Trails B time, Trails A time, and EXIT25). Memantine has also been studied for the treatment of VaD in randomized, clinical trials, with modest benefits shown (Orgogozo et al., 2002; Wilcock et al., 2002; Narasimhalu et al., 2010). A meta-analysis of randomized clinical trials in VaD found favorable effects of cholinesterase inhibitors and memantine on cognition but not global outcomes (Kavirajan and Schneider, 2007). VaD has significant heterogeneity, such that subjects with VaD enrolled across trials may have variable underlying pathology (large vs. small vessel, mixed VaD/AD) and severity of cognitive impairment. This confounds the results, raising the possibility that certain VaD subgroups may be more or less likely to benefit. Treatment must also address the affective and behavioral symptoms of VaD. Depressive symptomatology, both dysphoria and depression meeting DSM criteria, and apathy frequently accompany VCI and VaD. Treatment with antidepressants is effective. Selective serotonin reuptake inhibitors (SSRI) are the first choice in

234

Neurologic Conditions in the Elderly

Drug n

Mean (SD)

Placebo n Mean (SD)

WMD (fixed; 95% CL)

Weight (%)

Donepezil 5 mg vs placebo 370 196 –0.96 (5.49) 194 0.72 (5.64) 308 199 –1.75 (4.70) 180 –0.10 (5.36) 319 648 –0.71 (5.18) 326 0.00 (5.18) Subtotal 1043 700 Test for heterogeneity: χ2=3.37; df2 (p=0.19); P=40.70% Test for overall effect; p<0.00001 Donepezil 10 mg vs placebo 307 195 –1.52 (5.74) 194 308 194 –2.19 (6.27) 180 Subtotal 389 374 Test for heterogeneity: χ2=0.03; df1 (p=0.86); P=0% Test for overall effect: p<0.00001 Galantamine 24 mg vs placebo GAL-INT-6 149 –2.00 (6.10) 77 GAL-INT-26 367 –1.80 (5.94) 373 Subtotal 516 450 2 Test for heterogeneity: χ =0.24; df1 (p=0.63); P=0% Test for overall effect: p<0.0001 Rivastigmine 12 mg vs placebo VantagE 360 –0.70 (7.21) Test for overall effect: p=0.04

338

Memantine 20 mg vs placebo MMM300 147 –0.40 (5.70) 141 MMM500 277 0.53 (7.02) 261 Subtotal 424 402 Test for heterogeneity: χ2=0.07; df1 (p=0.79); P=0% Test for overall effect: p<0.0001

WMD (fixed; 95% CL) –1.68 (–2.78 to –0.58) –1.65 (–2.67 to –0.63) –0.71 (–1.40 to –0.02) –1.15 (–1.65 to –0.64)

0.72 (5.64) –0.10 (5.36)

–2.24 (–3.37 to –1.11) –2.09 (–3.27 to –0.91) –2.17 (–2.98 to –1.35)

0.00 (6.76) –0.30 (6.32)

–2.00 (–3.80 to –0.20) –1.50 (–2.38 to –0.62) (–2.39 to –0.80)

0.40 (6.99)

–1.10 (–2.15 to –0.05) –1.10 (–2.15 to –0.25)

1.60 (6.10) 2.28 (7.77)

–2.00 (–3.36 to –0.64) –1.75 (–3.00 to –0.50) 1.86 (–2.79 to –0.94)

Favors drug

Favors placebo

Figure 9.5 Meta-analysis of controlled trials of AchEI and memantine in VaD. Source: Kavirajan and Schneider (2007). Reproduced with

permission from Elsevier.

VaD. They are activating, helping to overcome the slowness and apathy that is often associated with VaD, and are well tolerated. The older tricyclic antidepressants can be sedating and are less well tolerated due to their significant anticholinergic side effects. Disruptive behaviors, agitation, delusions, and other psychotic symptoms are much less common in VaD than AD. Antipsychotic medications for behavior management in VaD should be used cautiously, particularly in VaD patients with extrapyramidal signs, as they may increase imbalance and the risk of falls. If required, atypical antipsychotics (risperdone, quetiapine, and olanzapine) have fewer side effects and should be used for only a limited period of time; they should be closely monitored and their ongoing need reassessed frequently. These medications each carry a “black box” warning due to the increased risk of sudden death in older individuals. Benzodiazepines are sedating, increase confusion and the risk of fall, and should be avoided in all older individuals, especially those with dementia. VaD patients often have one or more vascular risk factors (e.g., hypertension, diabetes, atrial fibrillation, and hyperlipidemia) that require ongoing management. The optimal control of these chronic medical conditions to

minimize vascular ischemia requires addressing the need for supervision or assistance with medication management early on. To be successful, a proactive, multidisciplinary approach that is patient–family-centered and addresses risk reduction, patient safety, advanced care planning, and quality of life is required.

Prognosis/outcome The two outcomes that have received the most attention have been cognitive decline and mortality in VaD. The prognosis and outcome for silent VBI—namely SBI and WMH—have been discussed under subtypes of VCI. In general, the rate of cognitive decline in VaD is believed to be slower and more variable than AD. In placebocontrolled drug trials for VaD, there was no significant change in cognitive decline, as measured by ADAScog, over 6–12  months (Erkinjuntti et al., 2002; Wilkinson et al., 2003). A 7-year study of elderly persons with dementia in Sweden found that the average annual rate of cognitive decline over 3 years was greater for those with AD than VaD (Aguero-Torres et al., 1998a, 1998b). In longitudinal studies of stroke survivors, the presence

Vascular Cognitive Impairment

of dementia or additional stroke was associated with greater cognitive decline (Nyenhuis et al., 2002; Sachdev et al., 2004a, 2004b). Multivariate analyses in a prospective, longitudinal MRI study of normal aging, subcortical ischemic vascular disease, and AD showed higher mortality rates in association with cognitive impairment, age, male gender, depressed mood, and presence of lacunes (Lavretsky et al., 2010). Participants with both lacunes and depressed mood had the shortest survival among all cognitive groups. Not unexpected, given the close association with known cardiovascular risk factors (hypertension, diabetes, and hyperlipidemia), mortality is greater in VaD than AD. A community-based study of people over age 75 in Sweden reported a mean survival of 2.8 years for VaD, compared to 3.1 years for AD (Aguero-Torres et al., 1998a, 1998b). A retrospective study in Rochester, Minnesota, found twice the mortality risk for VaD, compared to AD (Knopman et al., 2003). On the other hand, a more recent cohort study reported no difference in the 7-year survival rate among African Americans with AD, VaD, or stroke without dementia (Freels et al., 2002). Current clinical practice focused on earlier identification and better control of vascular risk factors is based on the belief that this will preserve cognitive function longer and delay mortality.

Conclusion The role of CVD in cognitive decline, especially in late life, has received increased attention during the past half-century. VCI is not a single entity, but a heterogeneous phenotype with differences in severity, underlying pathophysiology, and symptomatology, depending upon site(s), size, and sum of the underlying VBI. Emerging evidence from neuropathologic studies indicates that cerebral infarcts contribute additively with AD pathology to cognitive impairment. No agreed-upon clinical or pathologic diagnostic criteria currently exist for vascular CIND, mixed AD/VCI, or even VaD. Structural MRI currently provides the most sensitive and specific measure of VBI. Many of the risk factors associated with VBI (e.g., hypertension, diabetes mellitus, and dyslipidemia) are known, clinically identifiable, and modifiable with treatment. Clinical trials to date, focusing primarily on stroke, have often started too late, been too short in duration, or lacked sufficiently sensitive cognitive outcome measures to demonstrate an impact on cognitive function. Currently, no specific FDA-approved symptomatic treatments address VCI. In the meantime, clinical care focusing on reducing risk factors through early identification, aggressive treatment, and close monitoring are essential to minimize cognitive decline, impairment, and dementia from underlying CVD.

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Vascular Cognitive Impairment

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Chapter 9.5 Frontotemporal Dementia David Perry and Howard Rosen Introduction and definition of terms In 1892, Arnold Pick described a patient with progressive behavior and language deterioration and left temporal lobe atrophy. Based upon subsequent cases described by Pick and pathologic findings described by Alois Alzheimer, the entity of Pick’s disease was recognized (Pick, 1892, 1904; Alzheimer, 1911). Although the terminology has changed over the subsequent decades and the term frontotemporal dementia (FTD) has gained favor, the hallmark features of these disorders remain a progressive deterioration in personality and behavior and/or language impairment. Instead of being one homogeneous disorder, FTD is now understood as including multiple distinct clinical subtypes that can be caused by several pathologic processes. The nomenclature in the field has been inconsistent and confusing. In this chapter, the term frontotemporal dementia is used as an overarching term to refer to any of the three core clinical syndromes of FTD. These include the behavioral variant of FTD (bvFTD), which presents primarily with changes in personality and socioemotional function, and two variants of primary progressive aphasia (PPA), including the semantic variant (svPPA) and the nonfluent/agrammatic variant (nfvPPA). The term frontotemporal lobar degeneration (FTLD) is used to describe the associated pathologic entities. Chapter 9.6 describes the clinical, imaging, and pathologic features of PPA; this chapter focuses on the clinical features of bvFTD and on FTLD as a whole, along with its diverse clinical, pathologic, and genetic features. Research in FTD has also identified links between FTD and other neurologic syndromes, including corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and motor neuron disease (MND), which are associated with FTLD pathology and are often considered as part of the FTLD spectrum. PSP and CBS are discussed in detail in other chapters of this volume, but the disorders are reviewed here to highlight their relationships with FTD.

Epidemiology Frontotemporal dementia was previously felt to be a rare entity, but current data indicate that it is the third most common cause of dementia (Ratnavalli et al., 2002; Ikeda et al., 2004a; Brunnstrom et al., 2009). Prevalence estimates have varied, but in one study in the Netherlands, it was estimated at 2.7/100,000 (Rosso et al., 2003). A study conducted

in Rochester, Minnesota, indicated that, in patients whose dementia begins prior to age 60, FTD is as common as Alzheimer’s disease (Knopman et al., 2004). Onset is most commonly in the sixth decade but has been described as early as the third decade and as late as the ninth (Rosso et al., 2003; Mercy et al., 2008). Survival from disease onset is shorter than in Alzheimer’s disease. The longest survival is in svPPA, at 11.9 years from onset; the shortest is in patients with FTD and coexisting MND (approximately 2 years). BvFTD and nfvPPA are intermediate, at 8.7 years and 9.4 years, respectively (Roberson et al., 2005).

Core FTD clinical syndromes

Behavioral variant of FTD (bvFTD) Case 1 A 58-year-old right-handed accountant began to change his performance at work 4 years before presentation. He began to delay submission of his clients’ tax returns, saying he was too busy to submit them and instead getting extensions without their permission. He also began to skip meetings with his partners. Because of his experience and proficiency, he managed to keep his job. Two years before presentation, however, he developed a gradual change in personality. He began to swear at his clients and colleagues and say inappropriate things to strangers, including commenting on their weight and other physical characteristics and telling them dirty jokes or telling them about personal problems he was experiencing with his wife. He became less engaged in group activities and was thought to be depressed. Over time, he started to develop new habits, including monitoring the duration of visits with family and friends, insisting that they leave at exactly at the time they had planned. He began craving sweet foods, eating whole bags of cookies in a sitting and gaining 20 pounds, causing his wife to begin locking the pantry. At a baseball game, he might eat food found on the bleachers. One afternoon 6 months before presentation, his daughter called from a hospital to tell him that she had been in a car accident; his wife was shocked when he told their daughter to call when she needed a lift home and then left the house to play his weekly round of golf. He developed repetitive behaviors, involving pacing and rubbing his arms and hair. He began to compulsively arrange water bottles or papers to make certain they were aligned with the edge of the desk.

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On presentation to the clinic, he was asked why he was visiting the clinic. He said, “I have some problems” but could not elaborate. He recognized that he had lost his job but said it was because the partners at work were jealous of his success. On examination, he had increased speech output and asked repetitive questions, but his speech was fluent and sensible, and he followed complex commands quickly and accurately. He did not persist in following commands—for instance, he would close his eyes when asked by the examiner but repeatedly opened them immediately before the examiner asked him to (motor impersistence). He stared at the examiner for long periods of time, and he interrupted the examination twice to tell off-color jokes. The rest of the physical neurologic examination was unremarkable. On neuropsychological testing, he scored 26/30 on the Mini–Mental State Examination (MMSE), had a flat learning curve on a test of verbal memory, and had particular difficulty with the Stroop interference task and impaired fluency, particularly phonemic fluency, as he named three words beginning with the letter D in 1 minute. His MRI scan (Figure 9.6) showed right greater than left frontotemporal atrophy, with particular orbitofrontal and caudate atrophy.

Symptoms in bvFTD Sometimes referred to as frontal variant or simply as FTD, bvFTD is the most common presentation of FTD, comprising about 50% of cases, with svPPA and nfvPPA making up the other 50% (Johnson et al., 2005). The symptoms begin with insidious changes in behavior and

personality. Frequently, these are felt either to be psychiatric in nature or to represent a “midlife crisis” (Woolley et al., 2011). Typical early symptoms include disinhibition, apathy, loss of empathy, changes in eating behaviors, and compulsive behaviors. Patients with bvFTD often have a lack of insight into their own symptoms. Disinhibited acts can include socially inappropriate behaviors, involving touching strangers, displaying a lack of manners or response to social cues, or carrying out impulsive or anti-social actions such as stealing. Symptoms of apathy include a loss of interest or motivation, as well as decreased initiation of behavior. A distinction between a disinhibited subtype and an apathetic subtype has been proposed (Neary et al., 1988), although they tend to be coexistent. Affected patients are often described as cold, unfeeling, and indifferent to the emotions of others, which can be illustrated by dramatic examples such as the one detailed in Case 1, in which the patient was inappropriately casual about his daughter’s accident. Typical eating behaviors include both overeating and displaying a change in food preference, with more consumption of sweet or high-carbohydrate foods, and sometimes developing food fads, such as insisting on foods from certain establishments or foods of a certain color. Repetitive motor behaviors can be observed, including simple stereotypic behaviors such as tapping or rubbing, or compulsive behaviors such as hoarding, checking, cleaning, and arranging.

Imaging Both structural and functional brain imaging reveals abnormalities that can help support a diagnosis. Structural

Figure 9.6 MRI axial, coronal, and sagittal T1 showing bifrontal atrophy, more on the right.

Frontotemporal Dementia

imaging with CT or MRI typically shows a pattern of atrophy that corresponds with the affected systems. Atrophy is generally most prominent in the frontal and/or the anterior temporal lobes. If there is asymmetry, the right hemisphere is often more affected (Fukui, 2000). The earliest structures affected include the anterior insula, anterior cingulate, and orbitofrontal cortices (Seeley et al., 2008), which are much less severely affected in Alzheimer’s disease (Liu et al., 2004). The reason for the selective vulnerability of these regions in FTD is not known, but it has been noted that these regions are the only location of large bipolar projection cells, called von Economo neurons (Seeley et al., 2006). These neurons are found only in humans, great apes, certain whales, dolphins, and elephants, and are particularly targeted in FTD. It has been suggested that the introduction of these phylogenetically new cells into these brain regions may have induced some vulnerability (Seeley, 2008). The prominent involvement of these paralimbic structures that are known to be involved in emotional processing (Lane et al., 1998; Craig, 2003) explains the prominence of socioemotional dysfunction in FTD, as specific symptoms such as apathy, disinhibition, and loss of empathy have been correlated with structural atrophy in particular portions of this network (Rosen et al., 2005; Rankin et al., 2006). Even some of the bizarre changes in eating behavior, compulsions, and lack of self-awareness have been linked to specific portions of this network (Tonkonogy et al., 1994; Rosso et al., 2001; Snowden et al., 2001; McMurtray et al., 2006; Whitwell et al., 2007; Woolley et al., 2007; Josephs et al., 2008; Piguet et al., 2011). While structural imaging usually demonstrates specific patterns of regional atrophy in bvFTD, functional brain imaging such as positron emission tomography using flourodeoxyglucose (FDG–PET) and single photon emission computed tomography using Tc-hexamethylpropyleneamine oxime (HMPAO–SPECT), which images cerebral perfusion, has been frequently used to identify frontotemporal abnormalities in FTD (Ishii et al., 1998; Foster et al., 2007).

Neuropsychological testing Early in the course of the disease, patients may perform well on traditional neuropsychiatric measures (Gregory et al., 1999), because most neuropsychological tasks assess executive functions mediated by dorsolateral prefrontal cortex rather than the medial and orbital portions of the frontal lobe (Krueger et al., 2011). Degeneration of the regions affected in FTD results in deficits in social cognition. Accordingly, research studies have demonstrated that FTD patients are impaired at recognizing emotion (Lough et al., 2006), recognizing sarcasm (Kosmidis et al., 2008), and appreciating another’s point of view (Theory of Mind) (Gregory et al., 2002). Efforts are currently being made to develop tasks that examine these abilities into assessment tools that can be used in a clinic, with appropriate norms. As FTD progresses to involve the

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more dorsal and lateral frontal regions, patients develop deficits in many traditional tests of frontal executive functions. These include tests such as the Trails B task, which assesses the ability to flexibly switch between two different types of responses (Strauss et al., 2006); the Stroop task, which assesses the ability to inhibit automatic or “prepotent” responses (Strauss et al., 2006); and phonemic fluency, which assess the ability to continually generate novel responses (Henry and Crawford, 2004). While everyday memory is often relatively spared in FTD, performance on tests of verbal and visual memory can be variable (Pasquier et al., 2001; Hornberger et al., 2010). Similarly, visuospatial function is relatively spared, although performance on tasks may be affected by poor planning or organization (Kramer et al., 2003).

Primary progressive aphasia The term primary progressive aphasia (PPA) refers to progressive disorders in which language deterioration is the most prominent symptom and the primary cause of a patient’s impairment for the initial period of the illness (Weintraub et al., 1990; Mesulam, 2001). This category includes three syndromes: semantic variant PPA (previously referred to as semantic dementia), nonfluent or agrammatic PPA (also referred to as progressive nonfluent aphasia), and logopenic progressive aphasia. The details of all these syndromes are discussed in Chapter 9.6, so they are briefly reviewed here. SvPPA is characterized by progressive deterioration in knowledge about words and objects. It begins with word finding and sometimes subtle word recognition difficulties, and progresses to involve loss of knowledge about objects and what they do. The disease appears to begin in the left temporal pole, and often dramatic, asymmetric medial temporal atrophy can easily be appreciated on MRI (Seeley et al., 2005). When the disease begins on the right side, knowledge about faces can be an early deficit, such as not recognizing famous faces of politicians or entertainers (Snowden et al., 2004). In addition, patients with right temporal disease often present mainly because of behavioral problems such as loss of empathy, but at least some evidence of word finding and word recognition difficulties is often evident (Thompson et al., 2003). Whether the disease begins on the right or left, svPPA patients usually develop behavioral symptoms typical of bvFTD within 3 or 4 years of onset, presumably because of spread of the disease from temporal to frontal structures (Seeley et al., 2005). NfvPPA is characterized by slow, hesitant speech and difficulty with articulation and agrammatism (decreased use of grammatical function words) and is anatomically associated with atrophy and hypometabolism in the left inferior frontal region (GornoTempini et al., 2004a; Josephs et al., 2006). Although behavioral problems can develop over time in nfvPPA, they have less of the dramatic change in socioemotional function seen in bvFTD and svPPA (Rosen  et  al., 2006).

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Logopenic aphasia is characterized by hesitant speech and profound difficulty with word finding but relatively preserved word comprehension. Imaging usually shows left posterior temporal and parietal abnormalities. While svPPA and nfvPPA are usually associated with FTLD pathology, logopenic aphasia is usually associated with underlying Alzheimer’s disease

Other clinical syndromes associated with FTD Although bvFTD, svPPA, and nfvPPA represent the core clinical syndromes of FTD, emerging research has demonstrated that several other neurodegenerative syndromes are associated with FTLD pathology at autopsy and have overlapping clinical features. These syndromes are now often included in discussions of FTD as “FTD-spectrum” or “FTLD-spectrum.” Frontotemporal dementia with motor neuron disease (FTD-MND) About 10–15% of patients with FTD also develop MND, similar to what is seen in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) (LomenHoerth et al., 2002). This combination is associated with the most rapid progression and shortest survival (Roberson et al., 2005). MND may occur with any of the three core FTD syndromes, but it is most likely to occur with bvFTD. MND is characterized by muscular weakness, atrophy, and fasciculations (twitching) due to degeneration of anterior horn cells in the spinal cord, as well as pyramidal signs such as spastic tone and hyperreflexia due to degeneration of neurons in the primary motor cortex. The symptoms frequently involve the bulbar muscles (tongue, face, those associated with swallowing), and this is more common when MND is associated with FTD. Either cognitive or motor symptoms may present first. When FTD is associated with MND, patients may have strong, uncontrollable bursts of laughing or crying, referred to as pseudobulbar affect (PBA) (Chang et al., 2005), and symptoms of PBA in the setting of FTD should prompt investigations for MND. The behavioral symptoms in FTD-MND are similar to those occurring in FTD without MND, although psychotic symptoms are more common in FTD-MND (Lillo et al., 2010). Imaging in FTD–MND can sometimes be less dramatic than in FTD without MND. Although ALS was traditionally thought to be associated with dementia very rarely, the occurrence of MND in the setting of FTD prompted researchers to examine patients with ALS more closely. These studies revealed that a small percentage of patients presenting to neuromuscular clinics with only motor complaints actually have substantial cognitive and behavioral problems consistent with FTD (Murphy et al., 2007), and that up to 50% of ALS patients have more subtle cognitive deficits detectable using psychometric or quantitative assessment. These

findings further cemented the link between FTD and ALS (Lomen-Hoerth et al., 2003; Murphy et al., 2007).

Progressive supranuclear palsy Progressive supranuclear palsy has traditionally been included in neurologic texts as an atypical form of parkinsonism. The disorder is characterized by progressive difficulty with balance, resulting in falls; progressive stiffness of the body and neck (called axial rigidity); and an inability to voluntarily move the eyes (supranuclear gaze palsy). In addition, many patients develop cognitive difficulties suggesting frontal lobe dysfunction, and they frequently develop behavioral and or language symptoms seen in bvFTD and nfvFTD. PSP patients can also initially suffer from these cognitive or behavioral symptoms, with minimal or very subtle motor difficulties, and only then progress to develop the typical motor features of PSP. This symptomatic overlap, along with the fact that PSP is associated with the pathologic features of FTLD, has led to its inclusion with FTD-spectrum disorders. Corticobasal syndrome Corticobasal syndrome is another atypical parkinsonian disorder that shows symptomatic and pathologic overlap with FTD and is also a disorder in which the true spectrum of clinical presentation is in flux. Traditionally, CBS (often called corticobasal degeneration, or CBD) was described as a cognitive and motor disorder with markedly asymmetric movement difficulties, including tremor and myoclonus (jerking), rigidity and dystonia, alien limb (tendency for the limb to move on its own and sometimes interfere with movements of other limbs), and asymmetric sensory problems, suggesting dysfunction in the somatosensory cortex. Studies have also described language difficulties similar to nfvPPA or, less commonly, lvPPA, as well as profound visuospatial disturbances and neglect of the left side of space (Rebeiz et al., 1968; Gorno-Tempini et al., 2004b). Recent studies have suggested that many CBS patients, even with asymmetric motor symptoms, have Alzheimer’s pathology (Boeve et al., 1999; Hu et al., 2009) and those with AD pathology have more temporoparietal atrophy (Whitwell et al., 2010). When CBD is found pathologically, patients can present with the asymmetrical motor symptoms or with cognitive and behavioral deficits typical of frontal lobe dysfunction similar to those seen in FTD, and they may not have significant motor deficits (Lee et al., 2011). Pathology One of the challenges clinicians who see patients with neurodegenerative disorders, face is translating the clinical syndrome that a patient presents with into a prediction of the underlying molecular and histopathology. These correlations will be more relevant as treatments are developed that target the molecular basis of disease.

Frontotemporal Dementia

Unfortunately, this prediction is made more complicated by the fact that FTLD is associated with more than one type of pathology. All subtypes of FTLD pathology show gross frontal and temporal lobe atrophy, as well as neuronal loss, variable gliosis, and microvacuolation (Brun, 1987). Subtypes are differentiated from each other by the types of neuronal inclusions and other morphologic features. The earliest reports of FTLD described Pick bodies (Alzheimer, 1911), which were later recognized to contain hyperphosphorylated tau proteins. Subsequently, many cases of FTLD were described with tau inclusions but not necessarily Pick bodies; however, this still accounted for only about half of cases of FTLD. The pathologic descriptions for the other half have evolved over time, having been described for many years as dementia lacking distinctive pathology (Knopman et al., 1990). Subsequently, more careful staining demonstrated that many patients who would have been described in this way actually show tau-negative ubiquitinated inclusions, termed FTLD-U. In 2006, it was discovered that the ubiquitinated protein in these cases is the 43 kD TAR DNA binding protein (TDP-43) (Neumann et al., 2006). Now it is recognized that these two pathologies, tau inclusions or TDP-43 inclusions, are approximately found in equal frequencies in bvFTD and account for the majority of cases (Snowden et al., 2007). Recently, it was discovered that patients showing inclusions with the fused in sarcoma (FUS) protein explain most of rest of the cases.

Tau The tau protein, which is also called microtubule associated protein tau (MAPT), is coded on chromosome 17 and is important for stabilizing microtubules; it supports molecular transport within neurons (Weingarten et al., 1975). The protein exists in two forms created by alternative splicing, which leads to a three amino acid sequence repeat form (3R) and a four-repeat form (4R). Both forms are present in normal cells, but some pathologies are associated predominantly with one form. Pick bodies, the classic histopathology in FTLD, contain the 3R form of tau (Figure 9.8). Pick cells, or achromatic ballooned neurons, are associated with Pick bodies, and many patients have Pick cells without Pick bodies. Other pathologic settings dominated by tau pathology include FTD with parkinsonism linked to chromosome 17, a genetic form associated with mutations in the MAPT gene; this is a mixture of 3R and 4R tau. The rarer tangledominant dementia (TDD) and the Guam ALS Parkinson’s dementia complex are also 3R+4R mixtures. CBD and PSP are both 4R tau forms. CBD is associated with tau immunoreactive astrocytic plaques and glial threads and coils. PSP is characterized by globose neurofibrillary tangles and tufted astrocytes (Cairns et al., 2007). Argyrophilic grain disease (AGD) and multiple system

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tauopathy with dementia are rarer 4R tau pathologies (Cairns et al., 2007).

TDP-43 The functions of the TDP-43 protein are not completely understood, but it is a normal constituent of neurons. In these circumstances, staining is limited to the nuclei, which is consistent with data indicating that TDP-43 is a regulator of DNA transcription (Buratti and Baralle, 2008). In FTLD, TDP-43 inclusions are found in the cytoplasm, and various patterns of staining have been recognized based on whether the TDP-43 appears to be collecting mostly in the cytoplasm of the neuronal bodies, the dendrites, or both. This classification is important because certain pathologic subtypes are associated with specific clinical presentations. The Sampathu classification (Sampathu et al., 2006) recognizes four types of TDP-43 pathology. Type I has long dystrophic neurites in superficial layers and few neuronal cytoplasmic inclusions. Type II has numerous neuronal cytoplasmic inclusions in superficial and deep cortical layers with infrequent neurites. Type III includes frequent small dystrophic neurites and neuronal cytoplasmic inclusions and may have neuronal intranuclear inclusions. Type IV is relatively rare and includes dystrophic neurites and intranuclear inclusions. At the time that the link between TDP-43 and FTLD was discovered, it was also found to be present in the majority of patients with ALS, which provides a pathologic basis for the clinical links between ALS and FTD noted earlier (Neumann et al., 2006; Mackenzie et al., 2007). FUS Fused in sarcoma (FUS) pathology was initially discovered in patients with familial ALS. Soon thereafter, it was discovered in patients with FTD (Neumann et al., 2009a). Basophilic inclusion body disease (BIBD) (Munoz et al., 2009), neuronal intermediate filament disease (NIFID) (Neumann et al., 2009b), and atypical FTLD-U (aFTLD-U) are rare pathologies in the FTLD spectrum that are now attributed to FUS pathology as well. Other Some cases still have no inclusions and thus “lack distinctive histopathology.” Other cases, termed FTD-3, are discussed shortly with the corresponding genetic mutation.

Clinical–pathologic correlation Overall, the relationship between the specific clinical presentation and the molecular and histopathology is far from a 1:1 correlation (Figures 9.7), but some clinical presentations are fairly predictive of specific pathologies. SvPPA is usually caused by TDP-43 pathology, specifically Sampathu Type I (Gorno-Tempini et al., 2004a), although it can also be caused by Alzheimer’s disease

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PPA

PSP

CBS

FTLD-TAU

bvFTD

svPPA

FTLD-FUS

nfvPPA

lvPPA

FTLD-TDP

and very rarely by tau pathology (Davies et al., 2005). Nonfluent PPA is often caused by tau pathology, usually PSP or CBD (Josephs et al., 2006), although it can be the result of other pathologies as well (Kertesz et al., 2005). ALS, with or without FTD, is caused by Sympathu Type II pathology. Type III pathology is seen in patients with familial FTD associated with Progranulin mutations and can cause multiple other sporadic FTD syndromes. Type IV pathology is also associated with familial cases of FTD, inclusion body myositis, and Paget’s disease of bone due to mutations in Valosin-containing protein (VCP). Clinically, patients with FUS pathology have a young age of onset and often have a psychiatric presentation

FTD-MND

Figure 9.7 Clinical and pathologic correlates

between FTD spectrum syndromes and FTLD pathologies. PSP, progressive supranuclear palsy; CBS, corticobasal syndrome; bvFTD, behavioral variant frontotemporal dementia; PPA, primary progressive aphasia; svPPA, semantic variant primary progressive aphasia; nfvPPA, nonfluent variant primary progressive aphasia; lvPPA, logopenic variant primary progressive aphasia; FTD-MND, frontotemporal dementia with motor neuron disease; FTLD-tau, frontotemporal lobar degeneration with tau pathology; FTLD-TDP, FTLD with TAR DNAbinding protein 43 (TDP-43) pathology; FTLD-FUS, FTLD with fused in sarcoma (FUS) pathology; AD, Alzheimer’s disease.

AD

(Urwin et al., 2010). Their imaging is associated with more caudate atrophy than other pathologies (Josephs et  al., 2010). While svPPA and nfvPPA are strongly associated with specific pathologies, bvFTD is associated about equally with tau or TDP-43 pathology, and no clinical features are currently recognized as predicting the subtype. Some patients with bvFTD show Alzheimer’s pathology. In some cases, this is seen in addition to FTLD pathology, but in many cases, Alzheimer’s pathology appears to be the only cause. When the supranuclear gaze difficulties characteristic of PSP are present, PSP pathology is highly likely (Litvan et al., 1996). As noted earlier, the clinical features of CBS can be associated with various pathologies, including Alzheimer’s disease, and the features predicting CBD pathology are still being resolved.

Genetics The majority of cases of FTD are sporadic and there is no clear pattern of inheritance. About 10% are associated with an autosomal dominant inheritance pattern. About 40% of patients have a family history of dementia or psychiatric conditions but do not necessarily have a clear inheritance pattern (Goldman et al., 2005). There are two haplotypes of tau, H1 and H2, and the H1/H1 genotype has been associated with an increased risk of developing 4R tau disorders, PSP or CBD (Baker et al., 1999; Houlden et al., 2001).

MAPT Figure 9.8 Pick’s bodies detected in a 74-year-old woman with

progressive nonfluent aphasia due to Pick’s disease. A 3-repeat tau antibody was applied to the dentate gyrus, where Pick bodies can easily be detected due to the neuronal packing density of the structure. Hematoxylin counterstain. Courtesy of W.W. Seeley, University of California, San Francisco.

The MAPT gene, found on chromosome 17, contains more than 40 different currently recognized disease-causing mutations. Carriers of this gene develop symptoms at a younger age than sporadic cases, and imaging reveals a more symmetric pattern of atrophy, with more temporal lobe atrophy than other cases (Whitwell et al., 2009b).

Frontotemporal Dementia

There is also some suggestion that different mutations may be associated with different patterns of atrophy (Whitwell et al., 2009a).

PGRN Mutations in the progranulin gene (also on chromosome  17) can cause a wide variety of clinical presentations, including not only symptoms of bvFTD, but also parkinsonism, memory impairment, hallucinations or delusions, and a nonfluent aphasia, often without apraxia of speech. The atrophy pattern tends to be more asymmetric and more posterior than other forms of FTLD. The mechanism by which PGRN mutations lead to TDP43 pathology is currently unclear. In contrast to MAPT, mutations in PGRN lead to haploinsufficiency rather than a toxic gain of function.

CHMP-2B The gene CHMP-2B (charged multivesicular body protein 2B, also referred to as chromatin-modifying protein 2B) is found on chromosome 3. It encodes a component of the endosomal sorting complex required for transport III and causes the type of FTLD known as FTD-3. It is not associated with tau, TDP-43, or FUS pathology. It is extremely rare and described in only a few families, with the original one being Danish (Gydesen et al., 2002).

VCP

patients meet the major criteria, and many of the minor criteria in these publications occur too inconsistently to be clinically useful (Rascovsky et al., 2007). New, simpler criteria have been proposed by an international consensus panel and are being validated (Table 9.11). Whereas prior criteria depended only on clinical features for diagnosis, the new criteria make use of newer knowledge about biomarkers to increase the certainty of diagnosis. Thus, while clinical features can be used to make a diagnosis of possible bvFTD, imaging findings consistent with FTD— such as PET hypometabolism or atrophy in the frontal lobes, or mutations associated with FTD—are necessary to increase the certainty to a probable diagnosis. The use of imaging is supported by studies showing that imaging enhances the accuracy of diagnosis (Foster et al., 2007). In fact, a subset of patients has been identified who meet Table 9.11 Proposed international consensus criteria for bvFTD I. Required criterion: Progressive deterioration of behavior and/or cognition by observation or history II. Possible bvFTD (three of six required) A. Early behavioral disinhibition—socially inappropriate behavior, loss of manners or decorum, or impulsive actions B. Early apathy or inertia C. Early loss of sympathy or empathy D. Early perseverative, stereotyped, or compulsive/ritualistic behavior E. Hyperorality and dietary changes F. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions

Valosin-containing protein mutations on chromosome 9 are associated most commonly with an inclusion body myositis and, in some affected, individuals also with symptoms of Paget’s disease of bone and FTD. VCP mutations have also been associated with familial ALS.

III. Probable bvFTD (all of the following required) A. Meets criteria for possible bvFTD B. Significant functional decline C. Imaging results consistent with bvFTD (frontal and/or anterior temporal atrophy on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET)

Other

IV. bvFTD with definite FTLD pathology (one and either two or three required) A. Meets criteria for possible or probable bvFTD B. Histopathologic evidence of FTLD on biopsy or at postmortem C. Presence of a known pathogenic mutation

Some families show an autosomal dominant pattern of inheritance of FTD without a known gene. It is considered likely that a gene resides on chromosome 9 that is associated with FTD and MND (Morita et al., 2006; Vance et al., 2006), but the gene itself has not yet been discovered. Genome-wide association studies (GWAS) have been performed to look for additional genes that may confer risk. While variants in several genes have been found to increase risk in single studies, none of these results have yet been replicated. Mutations in the TDP-43 and FUS genes have been found and linked mostly to familial ALS, with rare associations with an FTD presentation.

Diagnosis Criteria published in 1994 (The Lund and Manchester Groups, 1994) and 1998 (Neary et al., 1998) have been used most commonly for diagnosis. These criteria have proven difficult to use in clinical practice because not all

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V. Exclusion criteria for bvFTD (criteria A and B must both be answered negatively; criterion C can be positive for possible bvFTD but must be negative for probable bvFTD) A. Pattern of deficits is better accounted for by other nervous system or medical disorders B. Behavioral disturbance is better accounted for by a psychiatric diagnosis C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process Additional features A. Onset before age 65 B. Presence of MND C. Motor symptoms and signs similar to CBS and PSP D. Impaired word and object knowledge E. Motor speech deficits F. Significant grammatical deficits

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clinical criteria for bvFTD but either do not progress in time or progress very slowly (Kipps et al., 2007). Imaging and neuropsychological performance in this group is normal. This group has been referred to as FTD phenocopy, implying that the etiology in these cases is not FTD, although this has yet to be established, and the etiology of clinical symptoms in these cases is not known. The reason for lack of progression is unclear. Imaging studies tend to be normal (Davies et al., 2006). Similarly, new knowledge about the clinical and imaging features and of PPA has led to new criteria for these disorders (Gorno-Tempini et al., 2011). The development of additional biomarkers to identify the molecular subtype in each case of FTD is currently of great interest. Some patients with clinical features of FTD show AD pathology at autopsy, and spinal fluid levels of tau and amyloid have shown promise for discriminating between FTLD and AD (Bian et al., 2008). PET ligands are also available for detecting amyloid plaques in vivo, providing another approach for making this distinction. Recent work has suggested that it may be possible to distinguish FTLD-tau from FTLD-TDP based on assaying multiple specific CSF analytes (Hu et al., 2010). Low progranulin levels measured in serum, plasma, and CSF have been found in patients with progranulin mutations (Coppola et al., 2008; Ghidoni et al., 2008; Finch et al., 2009; Sleegers et al., 2009). One study suggested that elevated serum TDP-43 levels might be useful (Foulds et al., 2008). All these findings, however, must still be considered preliminary.

worsening of behavior (Mendez et al., 2007). An openlabel study of rivastigmine showed improvement in neuropsychiatric symptoms but not cognition (Moretti et al., 2004), and another study of galantamine showed a nonsignificant trend toward language improvement in a cohort of PPA patients that may have included some with lvPPA (Kertesz et al., 2008). Weak evidence supports the use of memantine. Two open-label studies have shown that the medication is well tolerated (DiehlSchmid et al., 2008; Boxer et al., 2009). A double-blind, placebo-controlled trial in France recently showed no improvement with memantine after 1 year (Vercelletto et al., 2011). Another study in the United States is currently underway. Behavioral symptoms can be treated with antidepressants, particularly serotonergic agents. Open-label studies of fluoxetine, fluvoxemine, sertraline, and paroxetine have shown efficacy in controlling behaviors (Swartz  et  al., 1997; Ikeda et al., 2004b). Paroxetine was effective in a placebo-controlled study (Moretti et al., 2003a), although a separate, very brief randomized study of this drug showed no effect (Deakin et al., 2004). Trazodone has also been shown effective in one study (Lebert et al., 2004). No evidence supports the use of mood-stabilizing agents. Antipsychotic medications should be used with caution, given the unfavorable side effect profile, and the US FDA has advised extra caution in using these agents. Seroquel has less D2 receptor antagonism, making it a more appealing choice for avoiding extrapyramidal side effects. Data show benefit only for olanzapine (Moretti et  al., 2003b) (one open-label study), ariprazole (Fellgiebel et al., 2007), and risperidone (single-case reports) (Curtis and Resch, 2000).

Treatment No medications are approved by the US FDA for the treatment of FTD. Limited evidence exists regarding symptomatic treatment. Treatments directed at specific molecular targets are currently being developed.

Symptomatic Nonpharmacologic methods of dealing with behavioral symptoms are important, particularly given the lack of proven pharmacologic treatments. Caregiver education regarding the effects of the disease and an approach of ensuring safety while otherwise avoiding confrontation may be helpful. It is important for caregivers to realize that rational debate or argument may not be helpful in modifying the patient’s behavior. The pharmacologic agents used in AD are not necessarily useful in FTD, which affects different neural networks. FTD is not associated with a cholinergic deficit, and there is no strong evidence for the use of cholinesterase inhibitors in FTD. In one open-label trial, donepezil showed no beneficial cognitive effect and resulted in

Disease modifying The ultimate goal of treatment is not to ameliorate symptoms but to cure disease. Current efforts are underway to develop medications to target tau and TDP-43 pathology. Tau-active drugs in development include those that prevent tau kinase activity to block phosphorylation and those that clear tau aggregates, microtubule stabilizers, and aggregation inhibitors. A pilot study of one such drug has recently been completed in PSP, and a Phase III study is underway. Progranulin mutations result in their deleterious effect through haploinsufficiency, so treatments aimed at this molecular pathology are intended to increase progranulin levels.

Conclusion The term frontotemporal dementia encompasses multiple distinct clinical phenotypes with personality, behavior, and language changes, as well as extrapyramidal

Frontotemporal Dementia

syndromes and MNDs. It is caused by multiple distinct pathologies and, in some cases, genetic mutations. Treatments are currently symptomatic, but molecular-based treatments are in development.

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Frontotemporal Dementia

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Chapter 9.6 Primary Progressive Aphasia Maya L. Henry, Stephen M. Wilson, and Steven Z. Rapcsak

Introduction The term aphasia refers to impairments of spoken and written language caused by neurologic disease or damage. The fact that aphasia can be the initial and most salient behavioral manifestation of a neurodegenerative disorder has been known for more than 100 years (Pick, 1892; Serieux, 1893). In the modern era, interest in primary progressive aphasia (PPA) was reignited by Mesulam’s (1982) seminal report of six patients who presented with slowly declining language function in the absence of general cognitive impairment. Neuroimaging studies showed focal left-hemisphere atrophy involving the perisylvian language areas. For the past three decades, PPA has been the focus of intense study, leading to the rapid accumulation of scientific information regarding the clinical features and neurobiologic correlates of this unique syndrome. In the course of these investigations, it has become apparent that PPA is not a single, homogeneous entity. Patients may present with distinct language profiles that, in turn, can provide important clues regarding the anatomic distribution and possible etiology of the underlying neuropathologic process. In particular, the three PPA subtypes currently recognized (nonfluent/ agrammatic, semantic, and logopenic variants) demonstrate a predilection for involving different functional components of the left-hemisphere language network and have different probabilities of association with pathologies related to frontotemporal lobar degeneration (FTLD) or Alzheimer’s disease (AD). In this chapter, we review the clinical, neuroimaging, genetic, and neuropathologic correlates of PPA, with the primary goal of outlining a practical approach to diagnostic assessment. Accuracy in predicting the underlying pathology based on in vivo cognitive and neurologic evaluation is critical for identifying individuals with PPA who might benefit from emerging disease-modifying therapies.

Diagnosis of PPA A diagnosis of PPA should be suspected in individuals who present with gradual speech-language deterioration with early sparing of episodic memory, perceptual/ visuospatial processing, executive function, and social behavior (Mesulam, 1982, 2001). It should be emphasized, however, that the sparing of nonverbal cognitive

functions is relative rather than absolute, and detailed neuropsychological assessment may demonstrate mild to moderate impairments outside the language domain. In fact, certain nonverbal cognitive deficits are regularly associated with specific PPA subtypes and thus may have differential diagnostic value (such as impaired knowledge of objects and people in the semantic variant of PPA). At the same time, it is important to keep in mind that language dysfunction can interfere with performance on a variety of neuropsychological tests (due to a failure to understand instructions or because of the requirement for a verbal response) and, therefore, can artificially lower scores on tests ostensibly measuring nonverbal cognitive abilities. Despite these complexities, the diagnosis of PPA is appropriate when language impairment is the dominant behavioral abnormality at presentation and constitutes the main functional impediment for the patient with respect to activities of daily living (Mesulam, 1982, 2001). Furthermore, even though other cognitive domains may become increasingly compromised with disease progression, language function usually remains disproportionately affected throughout the course of the illness. The frequency of PPA is difficult to estimate, but it has been suggested that approximately 20–40% of patients with FTLD present with predominant language impairment (Grossman, 2010). It is currently unknown what percentage of patients with AD have aphasia as their initial symptom, compared to the much more common amnestic presentation of the disorder. However, some autopsy series have reported that AD is the underlying pathology in about 30% of patients with the clinical diagnosis of PPA (Knibb et al., 2006; Alladi et al., 2007). As a general rule, patients with PPA are younger (often 55–65 years of age) than the characteristic age of onset for typical AD (>65). Although most cases appear to be sporadic, familial PPA has been described in association with FTLD spectrum pathology. The majority of these patients had mutations of the progranulin (PGRN) gene on chromosome 17 (Snowden et al., 2006; Mesulam et al., 2007; Beck et al., 2008). Although mutations of the microtubuleassociated protein-tau (MAPT) gene on chromosome 17 can also be associated with progressive language impairment, these patients typically present with a behavioral/ social disorder (Snowden et al., 2006; Pickering-Brown et al., 2008). When the clinical diagnosis of PPA is established and nondegenerative etiologies (such as stroke, tumor, and

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Table 9.12 Consensus criteria for diagnosis of PPA variants Speech–language core characteristics Nonfluent variant

Semantic variant

Logopenic variant

One of the following must be present: 1) Agrammatic production 2) Effortful, halting speech with speech sound errors, including distortions, deletions, insertions, substitutions, transpositions (consistent with apraxia of speech) Both of the following must be present: 1) Impaired confrontation naming 2) Impaired single word comprehension

Both of the following must be present: 1) Impaired word retrieval in spontaneous speech and confrontation naming 2) Poor repetition of sentences and phrases

Speech–language-associated characteristics

Typical imaging findings

Predicted neuropathology

Two of the following must be present: 1) Agrammatic comprehension 2) Spared single-word comprehension 3) Spared object knowledge

Left anterior perisylvian/ fronto-insular atrophy and/or hypometabolism

FTLD-tau (Pick’s, CBD, PSP) FTLD-TDP-43

Three of the following must be present: 1) Poor object knowledge 2) Surface dyslexia/dysgraphia 3) Spared repetition 4) Spared grammar and motor speech Three of the following must be present: 1) Phonologic errors in speech 2) Spared single-word comprehension and object knowledge 3) Spared motor speech 4) Absence of agrammatism

Asymmetrical (L>R) anterior temporal lobe atrophy and/ or hypometabolism

FTLD-TDP-43

Left posterior perisylvian/ temporoparietal atrophy and/or hypometabolism

Alzheimer’s disease

Source: Adapted from Gorno-Tempini et al. (2011) with permission from Lippincott Williams & Wilkins.

subdural hematoma) for the language disorder have been successfully ruled out by routine imaging studies (CT/ MRI), an attempt should be made to determine the specific PPA phenotype (Gorno-Tempini et al., 2011). As noted earlier, PPA is a heterogeneous syndrome comprising distinct variants that are associated with different underlying pathologic processes. In clinical practice, the identification of PPA subtypes is based primarily on precise characterization of the language phenotype supported by neuroimaging evidence of signature patterns of localized cortical atrophy/hypometabolism within the left-hemisphere language network. Additional diagnostic information can be obtained from neuropsychological evaluation, molecular imaging with Pittsburgh Compound B (PIB) that tags beta amyloid deposits in the brain, genetic testing, and the use of cerebrospinal fluid (CSF)/blood biomarkers. The highest accuracy in predicting the underlying brain pathology will likely be achieved by combining information from multiple sources (Wilson et al., 2009b; Hu et al., 2010).

Clinical features and neurobiologic correlates of PPA subtypes Behavioral profiles of individuals with PPA are often categorized broadly into three subtypes or variants: nonfluent/agrammatic, semantic, and logopenic. The clinical classification of patients into one of these PPA subgroups is based on identifying the unique combination of impaired and preserved language and cognitive abilities that characterizes each phenotype. It should be noted, however, that subtyping patients is not always a straightforward exercise, as symptoms may overlap and

linguistic profiles may change as the disease evolves. For instance, a number of researchers have commented that the binary assignment of patients into nonfluent vs. fluent subgroups can be problematic (Rogers and Alarcon, 1999; McNeil and Duffy, 2001), and Kertesz and colleagues (2003) suggested that fluency status in PPA may be a function of disease progression rather than an indicator of distinct syndromes. Nonetheless, diagnosis by variant is viewed as an increasingly feasible and important endeavor, as specific language phenotypes are predictive of patterns of brain atrophy/hypometabolism and also provide clues about the underlying neuropathology. An international group of experts recently put forth a set of consensus criteria for identifying PPA variants (Gorno-Tempini et al., 2011; Table 9.12), including both core and supportive features, as well as criteria for imaging- and pathology-supported diagnosis. This effort was intended to streamline and standardize the diagnostic process, in hopes of facilitating scientific exchange across clinics and laboratories and furthering efforts to develop appropriate selection criteria for entering patients into therapeutic trials. It is acknowledged, however, that these diagnostic criteria are most clearly applicable in the early stages of the disease and that certain patients will not easily fit into any taxonomic category.

The nonfluent/agrammatic variant of PPA The nonfluent variant is clinically identified by agrammatic language and halting, effortful speech production with speech-sound errors as core features.

Primary Progressive Aphasia

Variable pathologies may underlie nonfluent PPA such as FTLD spectrum disorders, including tauopathies (Pick’s disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD)) and TDP-43 proteinopathies.

Speech–language profile The current consensus criteria identify agrammatic language and halting, effortful speech production with speech-sound errors as core features in nonfluent PPA. Either must be present for diagnosis (Gorno-Tempini et al., 2011; Table 9.12). Speech is slow in rate (approximately 70% reduction in the number of words produced per minute, compared to healthy controls; Ash et al., 2010; Wilson et al., 2010b) and consists mostly of content words (nouns > verbs), with omission of function words (articles, prepositions, and pronouns) and bound grammatical morphemes (such as the past tense). Syntactic structure is simplified, and grammatical errors include noun–verb agreement violations (as in “The girl are running”) and tense errors (as in “Tomorrow I ate lunch”) (Grossman et al., 1996; Turner et al., 1996; Wilson et al., 2010b). Although frankly telegraphic speech output is rare (Knibb et al., 2009), it may emerge with disease progression. In general, however, agrammatism in production is not as severe as that observed in patients with Broca’s aphasia due to vascular pathology (Graham et al., 2004). (See Box 1 for a sample of connected speech from an individual with nonfluent PPA.) Comprehension deficits, particularly for complex syntactic structures, are also noted in nonfluent PPA, consistent with a central syntactic deficit (Hodges and Patterson, 1996; Gorno-Tempini et al., 2004a; Grossman and Moore, 2005; Peelle et al., 2008). Whereas initial characterizations of nonfluent PPA emphasized agrammatism, motor speech impairment is now viewed as an important feature of the syndrome and, in some cases, may be the presenting sign (Ogar et  al., 2007). In these patients, speech production is effortful, with prominent impairment of motor planning or apraxia of speech (AOS); dysarthria may also be present (Gorno-Tempini et al., 2004a; Josephs et al., 2006a; Ogar et al., 2007; Rohrer et al., 2010b). In severe cases, motor speech production deficits can progress to complete mutism (Gorno-Tempini et al., 2006). Ogar et al. (2007) examined speech errors in 18 individuals with nonfluent PPA and found that 7 patients demonstrated AOS without dysarthria, with the remainder exhibiting both types of motor speech deficits. Features of AOS included slow, halting speech and effortful “groping” of the articulators, with inconsistent distortions, deletions, substitutions, insertions, and transpositions of speech sounds. Dysarthria was described as spastic, hypokinetic, or mixed spastic– hypokinetic. Disturbances of speech prosody (melody and intonation) were also common.

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Box 1. Connected speech samples from each PPA variant. Patients are asked to describe the “picnic scene” picture from the Western Aphasia Battery Nonfluent variant Um the dinner the parents have the /tıknık/ and um the car is the driving the driveway. The um the kid um boy is crying (flying) it the. . . it’s the /klaıt/ flying. The dog is the um. . . someone is fishing on the dock. It’s the. . . another kid is um it’s the water . . . it’s the lake. And two things um two things is uh sailboat on the water and um flag is flying. The um parents have um all um /radi/ (radio) and it’s the um tree is shade and um it’s the home and the back of the tree and the um father is um /bεlf t/ (barefoot) in the uh sand and uh he was reading and the wife is um um trying to um drink. It’s the um coffee or so and um. . . the um ball is the lake is the um it’s the um sand is the /pll/ um pail . . . and sail boat. Semantic variant Well there’s a man and a lady that uh are close by . . .I don’t know if they’re close by their house but they’re close by the . . .water. Now, I say the water but I can’t remember . . . I don’t remember what this (lake) is. There’s a . . .there’s some people in the water that are using their. . . I don’t remember that word. And um there’s a person in the water and this is a . . . I don’t remember. . . what’s the name (sailboat)? And this man or boy has something up on the top (kite). There’s a car in the house and there’s a tree. And these people. . . this boy is reading something and she is eating. . . she is drinking. And they probably have a . . . phone? No not a phone. . .music (radio) here and probably some food in there. Logopenic variant Ok looks. . .a. . . looks like a. . . a family having a picnic. Dad is /dri/ uh. . .um. . . reading a book. He took his foot. . .uh. . .shoes off and the uh. . . food is in that basket. His. . .uh. . .wife is pouring a. . . drink for the. . .picnic. And the r. . .radio is on. There’s a truck (car) over here behind this tree. There’s a boy with a. . . kite. . . across the water. There’s a dog. . .just one dog. There’s a man. . . off of the dock. . .fishing. There’s a boy. . . playing in the sand. And then there’s. . .a. . .uh. . .what is that? Oh a /t∫^k/ . . .no not a /t∫^k/ . . .a shovel. . . and a. . .is that a. . . . . .pail? There’s a. . .flag. . .on the pole.

Although the presence of speech-sound errors is a generally accepted feature of nonfluent PPA, the nature of these errors is a matter of some debate. Some researchers assert that speech-sound errors originate at a phonologic rather than motoric or articulatory level (Mendez et al., 2003). In particular, Ash et al. (2010), examined 16 individuals with nonfluent PPA and concluded that the majority

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of errors were phonemic (substitution of one well-formed speech sound for another) rather than phonetic (a distorted production of a speech sound, such as slurring a consonant) and, thus, more consistent with a phonologic than a motor speech deficit. This is in contrast to other recent studies, which report that the majority of speech production errors in nonfluent PPA are sound distortions and, therefore, indicative of AOS (Wilson et al., 2010b). Precise determination of the nature and origin of speechsound errors can be difficult, and errors should be evaluated in the broader context of the language profile. In general, the presence of speech-sound errors (phonemic or phonetic) in conjunction with agrammatism, reduced utterance length, and a slow speech rate is strongly suggestive of the diagnosis of nonfluent PPA. Whereas syntax and speech production are typically impaired in nonfluent PPA, single-word lexical comprehension and object knowledge are generally spared (Gorno-Tempini et al., 2004a), even in patients with severely reduced spontaneous language output. These features, along with syntactic comprehension deficits, are considered to be supportive of the clinical diagnosis (Gorno-Tempini et al., 2011; also refer to Table 9.12) and are important for distinguishing nonfluent PPA from other variants (Mesulam et al., 2009), as in Figure 9.9. In addition, some degree of anomia is typically observed on tests of confrontation naming, and letter fluency may be more impaired than category fluency (GornoTempini et al., 2004a). Although reading and spelling impairments have been documented in nonfluent PPA, the characteristic alexia/agraphia profile has not been fully defined (Watt et al., 1997; Croot et al., 1998; Graham et al., 2004). In summary, the linguistic profile of nonfluent PPA is characterized by prominent impairments in the domains of syntax, motor speech, and, by some accounts, phonology, in the context of relatively preserved lexical-semantic processing and object knowledge.

Associated cognitive, behavioral, and neurologic deficits Impairment of frontal executive functions, specifically working memory, has been noted in nonfluent PPA (Libon et al., 2007). Buccofacial apraxia for nonverbal oral movements may be present (Gorno-Tempini et al., 2004a; Josephs et al., 2006a). Episodic memory for day-to-day events is generally intact, but patients may experience difficulty on formal memory tests using verbal materials. Visuospatial processing is characteristically preserved. Concomitant behavioral features may include apathy, agitation, and depression (Rohrer and Warren, 2010). Neurologic examination in patients with the language profile of nonfluent PPA may reveal the presence of extrapyramidal signs, including an asymmetric akinetic-rigid syndrome, limb apraxia, alien hand, dystonia, or myoclonus suggestive of CBD. Other patients demonstrate typical clinical findings associated with PSP, including eye movement abnormalities (vertical gaze paralysis, especially affecting downward gaze), axial/nuchal rigidity, and severe postural instability, leading to frequent falls. Finally, some individuals with nonfluent PPA show neurologic signs consistent with motor neuron disease (MND), including bulbar and limb weakness, muscle wasting, and fasciculations. Neuroimaging Brain imaging can provide important diagnostic information about the topographic distribution of the underlying pathology in PPA. On structural imaging studies (CT/ MRI), nonfluent PPA is associated with anterior perisylvian atrophy. There is prominent involvement of left inferior frontal cortex (Gorno-Tempini et al., 2004a), with posterior inferior frontal gyrus/operculum and the anterior insula most severely affected (Figures 9.10 and 9.11). As the disease progresses, atrophy is seen in the middle/superior frontal cortex and the left superior temporal gyrus (Rohrer et al., 2009). There is reduced volume of white matter underlying

+naming impairment =SV =LV =NFV

+single word comprehension impairment = SV -single word comprehension impairment =LV =NFV

+agrammatism OR effortful, halting production, motor speech errors =NFV -agrammatism AND effortful, halting production, motor speech errors

+phrase/sentence repetition impairment =LV Figure 9.9 Decision tree for PPA diagnosis by variant: core features. SV, semantic variant; LV, logopenic variant; NFV, nonfluent variant.

Primary Progressive Aphasia

(a) Nonfluent variant

(b) Semantic variant

(c) Logopenic variant

(d) Normal control

Figure 9.10 MRI scans showing distinct patterns of focal left-

hemisphere cortical atrophy in patients with different PPA subtypes. Atrophy predominantly involves left inferior frontal cortex and insula in the nonfluent variant, left anterior temporal cortex in the semantic variant, and temporoparietal cortex in the logopenic variant (arrows). Source: Wilson et al. (2009b). Reproduced with permission from Oxford University Press.

Figure 9.11 Voxel-based morphometry (VBM) demonstrating the

topographic distribution of left-hemisphere cortical atrophy in three PPA cohorts (red = nonfluent/agrammatic, blue = semantic, and green = logopenic). Courtesy of S.M. Wilson and M.L. GornoTempini. (For a color version, see the color plate section.)

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the frontal lobe (Wilson et al., 2010a), and diffusion tensor imaging (DTI) has revealed abnormalities in the superior longitudinal fasciculus (SLF; Whitwell et al., 2010). Damage to this important white matter tract, which connects anterior and posterior perisylvian language areas, may contribute to the syntactic and motor speech impairments seen in nonfluent PPA. Atrophy of distinct left frontal lobe regions has been linked to specific speech/language deficits in nonfluent PPA. In general, reduced fluency and syntactic production/ comprehension impairment (agrammatism) correlate with volume loss in posterior inferior frontal cortex (Amici et al., 2007a; Peelle et al., 2008; Ash et al., 2009; Gunawardena et al., 2010; Wilson et al., 2010b), whereas motor speech deficits (AOS, dysarthria) are associated with atrophy involving premotor cortex/supplementary motor area (SMA), primary motor cortex, insula, and basal ganglia (Gorno-Tempini et al., 2006; Josephs et al., 2006a; Ogar et al., 2007). Consistent with the pattern of atrophy observed on structural imaging studies, [18F] fluorodeoxyglucose(FDG)PET in nonfluent PPA shows left frontal lobe hypometabolism particularly severe in inferior frontal gyrus/operculum and the anterior insula (Nestor et al., 2003; Josephs et al., 2010). Patients with AOS may show evidence of more superior frontal hypometabolism, including premotor cortex/SMA, whereas in patients with nonfluent PPA characterized by agrammatism and reduced speech rate but no AOS, the most significantly affected region is posterior inferior frontal gyrus/operculum (Josephs et al., 2010). The left posterior inferior frontal cortex is also functionally abnormal: the blood oxygen level-dependent (BOLD) signal measured by fMRI is not modulated by syntactic complexity as it typically is in healthy subjects (Cooke et al., 2003; Wilson et al., 2010a). To summarize, the distribution of the atrophy/hypometabolism within the language network in nonfluent PPA indicates a predilection of the pathologic process for left frontal lobe regions implicated in syntactic processing, phonology, motor speech control, and articulation.

Neuropathology The most common pathologies underlying nonfluent PPA are FTLD spectrum disorders, including tauopathies (Pick’s disease, PSP, CBD) and TDP-43 proteinopathies (Kertesz et al., 2005; Knopman et al., 2005; Josephs et al., 2006b; Knibb et al., 2006; Snowden et al., 2007; Josephs, 2008; Mesulam et al., 2008; Deramecourt et al., 2010). AD has been reported much less frequently (Kertesz et al., 2005; Knibb et al., 2006; Alladi et al., 2007) and may sometimes reflect the inclusion of patients who might have been diagnosed by other groups as logopenic PPA using current consensus criteria. Consistent with the notion that nonfluent PPA is predominantly associated with FTLD rather than AD histopathology, patients with this variant typically do not demonstrate increased PET uptake of the

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Pittsburgh Compound B (PIB) that tags amyloid-β (Aβ) (Rabinovici et al., 2008), and there is no evidence of an increased frequency of the APOE-e4 genotype in this population (Gorno-Tempini et al., 2004a). There is some indication that tauopathies, especially PSP and CBD, are the most likely pathologies in patients with nonfluent PPA characterized by prominent AOS or motor speech impairment (Josephs et al., 2006a; Josephs 2008; Deramecourt et al., 2010). By contrast, in patients with nonfluent agrammatic language but no AOS/motor speech deficits, TDP-43 pathology is more common (Josephs et al., 2006a; Snowden et al., 2007; Josephs 2008; Deramecourt et al., 2010). TDP-43 is also the underlying histopathology in patients with nonfluent PPA and evidence of MND (FTLD/MND overlap syndrome; Snowden et al., 2007; Josephs, 2008; Lillo and Hodges, 2009). TDP-43 pathology in nonfluent PPA is almost always Sampathu type 3 (dystrophic neurites, neuronal cytoplasmic, and intranuclear inclusions; Sampathu et al., 2006; Snowden et al., 2007; Deramecourt et al., 2010). Many nonfluent patients with type 3 TDP-43 pathology have mutations of the progranulin (PGRN) gene; (Snowden et al., 2006; Deramecourt et al., 2010). However, PGRN mutations more commonly result in an initial behavioral presentation (Beck et al., 2008), and nonfluent patients with PGRN mutations often have concomitant behavioral symptoms (Deramecourt et al., 2010). Nonfluent PPA in the setting of FTLD/MND has been associated primarily with Sampathu type 2 TDP-43 pathology (dystrophic neurites and neuronal cytoplasmic inclusions; Snowden et al., 2007; Josephs 2008; Lillo and Hodges, 2009). Biofluid biomarkers may have some utility for antemortem prediction of the underlying pathology in nonfluent PPA. Although tau levels can be assayed in CSF, these results must be interpreted cautiously because both reduced and increased levels have been reported in patients with FTLD (Arai et al., 1997; Grossman et al., 2005). However, the CSF tau/Aβ42 ratio is significantly lower in patients with FTLD, compared to patients with AD, suggesting that this biomarker may be useful for discriminating between these disorders (Bian et al., 2008). TDP-43 can be detected in plasma (Foulds et al., 2008), and CSF (Steinacker et al., 2008) and elevated levels may indicate TDP-43-related pathology. Individuals with PGRN mutations have been shown to have reduced PGRN levels in plasma (Ghidoni et al., 2008). Biomarkers such as these may greatly aid PPA diagnosis in the future, but much research is needed to establish the sensitivity and specificity of these measures.

The semantic variant of PPA In the semantic variant of PPA, the characteristic language impairment reflects the gradual erosion of semantic memory (Hodges and Patterson, 2007). Unlike episodic

memory, which stores information about personally experienced events, semantic memory refers to general knowledge of facts, objects, people, and the meanings of words (Tulving, 1995). Selective impairment of semantic memory was first documented by Warrington (1975), and the term semantic dementia was later adopted or patients with degradation of conceptual knowledge caused by neurodegenerative disease affecting the anterior temporal lobes (Hodges et al., 1992).

Speech–language profile In semantic variant PPA, speech output is fluent with preserved phonology, syntax, and articulation, but there is evidence of a reduction in expressive and receptive vocabulary (Hodges and Patterson, 2007). (See Box 1 for a sample of connected speech from an individual with the semantic variant of PPA.) Early in the course of the disease, anomia is the most prominent feature and may be the only obvious clinical sign. Word-finding difficulty is usually apparent in conversational speech but tends to be particularly severe on more constrained tests of confrontation or generative naming. During confrontation naming tasks, patients frequently produce coordinate semantic errors (such as “chair” for sofa), superordinate errors (such as “animal” for lion), or outright omissions (Hodges et al., 1995; Hodges and Patterson, 2007). Phonemic cueing is rarely of any benefit (Hodges et al., 1992). On generative naming tasks, category fluency is typically more impaired than letter fluency, a pattern opposite to that observed in patients with nonfluent PPA. Due to progressive anomia, conversational language becomes increasingly devoid of content, with patients using generic terms such as thing in instances of lexical retrieval failure for specific items. Whereas anomia is the most salient early feature in semantic variant PPA, lexical comprehension deficits also become increasingly apparent, with patients often questioning the meanings of words: “What is a thermometer? I don’t know that one” (Kertesz et al., 2010). These two features (impaired naming and single-word comprehension deficits) represent the core diagnostic characteristics according to consensus criteria (GornoTempini et al., 2011; Table 9.12). Both naming and word comprehension deficits are frequency and familiarity dependent, with worse performance on low-frequency items that are less familiar to the patient (Bird et al., 2000; Adlam et al., 2006). Other important variables include typicality, with less accurate performance on items that are atypical members of their class (such as penguin vs. duck), and level of specificity, with disproportionate difficulty on tasks probing subordinate rather than basic category or superordinate knowledge (Adlam et al., 2006; Hodges and Patterson, 2007). In particular, with increasing disease severity, one often observes a specific-to-general deterioration of semantic memory in

Primary Progressive Aphasia

which knowledge about the distinctive semantic properties of objects is lost before information about shared attributes of category members (Rogers and McClelland, 2004). Accordingly, patients may initially identify the picture of a “beagle” as a “dog” and, later in the course of their illness, as an “animal.” It is important to emphasize that the degradation of conceptual representations in semantic variant PPA gives rise to multimodal deficits that are apparent on both verbal and nonverbal tests of semantic knowledge. Thus, patients not only fail to produce and comprehend the names of objects, but they also exhibit parallel, though typically less severe, impairments on nonverbal tests of object knowledge (such as picture semantic association tests or tests requiring matching of pictures of objects with their characteristic colors, sounds, or functions; Bozeat et al., 2000; Adlam et al., 2006; Hodges and Patterson, 2007). The multimodal semantic deficit also extends to knowledge of familiar persons, manifested by a difficulty in recognizing famous individuals from face, voice, or name cues (Gainotti, 2007). Defective object and person knowledge is an important diagnostic feature of semantic variant PPA (Gorno-Tempini et al., 2011; see Table 9.12), and appropriate tests for identifying impairments in these domains should be incorporated into the cognitive assessment battery. In semantic variant PPA, performance on language tasks that do not depend on semantic memory is characteristically preserved. For instance, patients can often correctly repeat low-frequency lexical items made up of complex sound sequences (such as stethoscope) without being able to comprehend these words, a pattern that is the opposite of what is observed in individuals with nonfluent PPA (Hodges et al., 2008). Sentence repetition is also usually spared. Furthermore, patients may retain the ability to produce and comprehend sentences containing complex grammatical structures, attesting to the relative preservation of syntactic processing (Hodges and Patterson, 2007). Patients with semantic variant PPA demonstrate a characteristic pattern of reading and spelling deficits, referred to as surface dyslexia and dysgraphia (Patterson and Hodges, 1992; Graham et al., 2000; Woollams et al., 2007; Table 9.12). The hallmark of this syndrome is the disproportionate difficulty in reading/spelling irregular words that contain exceptional or atypical spelling-sound correspondences (such as choir). By contrast, reading/ spelling of regular words (such as start) and nonwords (such as boke) that contain predictable phoneme–grapheme mappings is preserved. It has been proposed that accurate reading/spelling of irregular words requires semantic mediation, particularly when these items are of low frequency (Woollams et al., 2007). With reduced input from the semantic system, patients with semantic variant PPA produce “regularization” errors on irregular words,

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reflecting an over-reliance on sublexical sound–letter conversion rules (reading yacht as /jæt∫t/ or spelling tomb as t-o-o-m). In summary, semantic variant PPA is a distinct syndrome characterized by poor performance across a variety of language and nonverbal tasks tapping conceptual knowledge/semantic memory. Distinguishing individuals with semantic variant from other PPA variants can be accomplished based on the presence of a fluent language profile with marked anomia and poor single-word comprehension. Supporting features, at least three of which must be present to satisfy current diagnostic criteria, include poor object knowledge, surface dyslexia/dysgraphia, spared repetition, and preserved grammar and motor speech (Gorno-Tempini et al., 2011).

Associated cognitive, behavioral, and neurologic deficits Patients with semantic variant PPA may remain oriented and demonstrate preserved day-to-day episodic memory for personal events. On formal testing, memory for verbal materials is impaired, but nonverbal memory can be relatively intact. Basic visuoperceptual and visuospatial skills are unaffected, and patients may perform reasonably well on tests of executive function and working memory. Individuals with semantic variant PPA are more likely than patients with other PPA variants to show abnormal behavioral patterns, including apathy, emotional coldness, disinhibition, irritability, obsessive–compulsive rituals, rigidity, and eating disorders (Rosen et al., 2006; Rohrer and Warren, 2010). Features reminiscent of the Kluver–Bucy syndrome (hyperorality, hypersexuality) have been observed (Hodges et al., 1992). These behaviors can be particularly striking and are early features in individuals, with greater right than left temporal lobe involvement (Gorno-Tempini et al., 2004b; Seeley et al., 2005). Neuroimaging In semantic variant of PPA, the neurodegenerative process has a predilection for anterior and inferior temporal lobe regions, including temporal pole, middle/inferior temporal gyri, and anterior fusiform gyrus. Atrophy is typically bilateral but more extensive in the left hemisphere. Medial temporal lobe regions are also affected, including amygdala, hippocampus, and entorhinal/perirhinal cortices (Mummery et al., 2000; Chan et al., 2001; Galton et al., 2001; Rosen et al., 2002; Gorno-Tempini et  al., 2004a). Temporal lobe atrophy can be extreme, and it is not uncommon to see volume loss greater than 50%. Although hippocampal atrophy is often as marked as it is in AD, semantic variant PPA differs from AD, in that anterior parts are more affected than posterior areas (Chan et al., 2002; Davies et al., 2004). As the disease progresses, atrophy extends to the contralateral hemisphere,

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to ventromedial, insular, and to anterior cingulate regions within the frontal lobes and caudally within the temporal lobe (Brambati et al., 2007; Rohrer et al., 2009). In semantic variant PPA, white matter abnormalities are most striking in the inferior longitudinal fasciculus (ILF) and the uncinate fasciculus (UF), as revealed by DTI (Agosta et al., 2010; Whitwell et al., 2010). The ILF connects occipital and temporal lobe regions, and damage to this tract may contribute to the object/person recognition, picture naming, and reading impairments documented in these patients. It has been suggested that damage to the UF that connects frontal and temporal lobe regions may play a role in the prominent behavioral abnormalities observed in semantic variant PPA (Agosta et al., 2010; Whitwell et al., 2010). The same anterior temporal and ventromedial frontal lobe regions that are atrophic on structural imaging studies in semantic variant PPA are also hypometabolic on FDG-PET (Diehl et al., 2004; Drzezga et al., 2008; Josephs et al., 2010). Functional imaging studies (PET/fMRI) have shown reduced activation in inferior temporal lobe regions but preserved functionality of dorsolateral frontoparietal cortical networks on semantic and reading tasks (Mummery et al., 1999; Wilson et al., 2009a). Specific linguistic and cognitive impairments in semantic variant PPA have been shown to correlate with left anterior temporal lobe atrophy, including anomia and verbal/ nonverbal semantic deficits (Mummery et al., 2000; Galton et al., 2001; Davies et al., 2004; Grossman et al., 2004; Williams et al., 2005; Adlam et al., 2006; Amici et al., 2007b), poor reading of irregular words (Brambati et al., 2009), and reduced use of low-frequency content words in connected speech (Wilson et al., 2010b). Atrophy of the right anterior temporal lobe has been linked to defective recognition of faces (Josephs et al., 2008b). Taken together, these findings are consistent with the proposal that anterior temporal cortex plays a critical role in semantic memory and may function as an amodal “semantic hub” that binds and integrates information about the attributes of objects, people, and words represented in sensory, motor, and language-specific cortical regions (Patterson et al., 2007).

Neuropathology Semantic variant PPA is usually associated with TDP-43 FTLD pathology (Davies et al., 2005; Snowden et al., 2007). TDP-43 histopathology is almost always Sampathu type 1, characterized by a predominance of dystrophic neurites with few or no neuronal inclusions. A minority of patients have been found at autopsy to have Pick’s disease or AD (Knibb et al., 2006; Alladi et al., 2007). Consistent with the predominance of FTLD pathology, PET Aβ molecular imaging with PIB is usually negative in semantic variant PPA (Drzezga et  al., 2008; Rabinovici et al., 2008), and the frequency of the APOE-e4 genotype is not significantly increased in this patient population (Gorno-Tempini et al., 2004a).

No genetic biomarkers for semantic variant PPA are known, as aphasias due to PGRN mutations are typically nonfluent (Snowden et al., 2006). Some patients with mutations of the MAPT gene, which encodes tau, have semantic loss but always in the context of a behavioral disorder (Snowden et al., 2006; Pickering-Brown et al., 2008). TDP-43 can be detected in plasma and CSF (Foulds et al., 2008; Steinacker et al., 2008), and this biomarker may turn out to have diagnostic utility.

The logopenic variant of PPA For more than two decades, individuals with PPA were dichotomized broadly into two subgroups based on fluency status (fluent vs. nonfluent). Ultimately, however, it became apparent that not all patients fit neatly into a binary classification scheme (Grossman and Ash, 2004). A third variant of PPA was occasionally mentioned in the literature (Kertesz et al., 2003) and, once fully characterized, was referred to as logopenic progressive aphasia (LPA; Gorno-Tempini et al., 2004a, 2008) or, more recently, the logopenic variant of PPA (Gorno-Tempini et al., 2011; Henry and Gorno-Tempini, 2010).

Speech–language profile Initial characterizations of the logopenic (from Greek, meaning “lack of words”) variant of PPA described a paucity of verbal output, with relative sparing of syntactic, semantic, and articulatory aspects of speech and language (Kertesz et al., 2003). Subsequent work has refined this clinical picture, identifying a fluency profile intermediate between patients with nonfluent and semantic variants. Spoken language is slow in rate, with frequent word-finding pauses but spared grammatical form (Gorno-Tempini et al., 2004a, 2008; see Box 1 for a sample of connected speech from an individual with logopenic variant PPA). Confrontation naming is impaired; however, single-word comprehension and object knowledge are preserved. As a rule, the confrontation naming deficit in logopenic PPA is less severe than in the semantic variant, and patients tend to produce phonologic rather than semantic errors. An important diagnostic feature of logopenic PPA is poor repetition of sentences and phrases with relatively spared reproduction of short, single words, consistent with an impairment of phonologic working memory (Gorno-Tempini et al., 2004a, 2008). Careful evaluation of the functionality of the “phonological loop” component of working memory has confirmed that this is a characteristic area of deficit (patients have difficulty holding and rehearsing verbal information in short-term memory). In particular, span performance for digits and short words is limited to approximately three items, and patients are often unable to repeat more than a single long word (word length

Primary Progressive Aphasia

effect; Gorno-Tempini et al., 2008). Attempts at sentence repetition, particularly for low probability/uncommon sentences may reveal a semantically appropriate yet incorrect rendition, such as “The baker was happy” for “The pastry cook was elated,” suggesting a semantic rather than phonologic approach to the task. Phonologic short-term memory impairment may also play a central role in the sentence comprehension deficits documented in this group of patients. Consistent with this hypothesis, performance on sentence comprehension tasks in logopenic variant PPA is influenced more by the length and probability of sentences than by their grammatical complexity, a pattern opposite to that observed in patients with nonfluent PPA (Gorno-Tempini et al., 2004a; Grossman and Moore 2005; Gorno-Tempini et al., 2008; Peelle et al., 2008). A central phonologic deficit is also likely to be responsible for the disproportionate impairment of nonword reading in individuals with logopenic PPA, a profile referred to as phonologic alexia (Brambati et al., 2009; Rohrer et al., 2010a, 2010b, 2012). Unlike real words, nonwords contain unfamiliar combinations of phonologic elements, and correct performance on these items relies critically on the ability to identify, maintain, and manipulate sublexical phonologic information (Rapcsak et al., 2009). Spelling deficits have also been observed in logopenic PPA (Sepelyak et al., 2011), but their precise nature awaits further clarification. Individuals with logopenic PPA can be distinguished from semantic variant patients by spared performance on lexical-semantic measures, such as single-word comprehension (Mesulam et al., 2009) and, in spontaneous speech, by a slower overall speech rate, the presence of phonologic paraphasias, and less severe impairment of lexical retrieval (Wilson et al., 2010b). Logopenic patients can be distinguished from nonfluent PPA patients based on spared syntactic abilities on formal testing (Mesulam et al., 2009) and, in spontaneous speech, by the absence of frankly agrammatic productions (Wilson et al., 2010b) and the lack of motor speech errors (AOS, dysarthria). In conclusion, recent studies have provided compelling support for the existence of a logopenic variant of PPA with a language phenotype that is distinct from both the nonfluent and semantic variants identified earlier. Core diagnostic features include impaired single-word retrieval in spontaneous speech and confrontation naming, and poor repetition of sentences and phrases. Additional supporting features, at least three of which must be present for diagnosis, include phonologic errors in speech, spared single-word comprehension and object knowledge, preservation of motor speech, and lack of agrammatic utterances (Gorno-Tempini et al., 2011). Current evidence suggests that the characteristic language profile in logopenic PPA is attributable to an underlying deficit of phonologic short-term memory.

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Associated cognitive, behavioral, and neurologic deficits In addition to the characteristic language impairment, several associated cognitive and behavioral deficits have been identified in individuals with logopenic PPA. Relative to the other PPA variants, they often show difficulty on tests of calculation (Gorno-Tempini et al., 2004a; Amici et al., 2006; Rohrer et al., 2010a, 2012) and may demonstrate worse performance on episodic memory tasks (Mesulam et al., 2008; Rohrer et al., 2012). Limb apraxia has also been noted in some individuals with logopenic PPA (Rohrer et al., 2010a, 2010b, 2012), and apathy, irritability, anxiety, and agitation may be associated behavioral features (Rosen et al., 2006; Rohrer and Warren, 2010). Neuroimaging Structural imaging studies in logopenic PPA indicate preferential involvement of left posterior perisylvian cortex by the neurodegenerative process. Atrophy is most prominent in the left temporoparietal region, specifically in the posterior portions of the superior and middle temporal gyri, and in the inferior parietal lobule (GornoTempini et  al., 2004a, 2008; Rohrer et al., 2010a, 2010b, 2012). This pattern is similar to that observed in patients with AD, particularly the early age of onset form (Frisoni et al., 2007; Migliaccio et al., 2009) but with greater lefthemisphere lateralization. In some logopenic patients, atrophy extends into anterior temporal lobe regions, but in comparison to semantic variant PPA, there is always a more posterior temporoparietal predominance of the gray matter volume loss. As the disease progresses, other brain regions typically involved in AD are also impacted, such as medial temporal lobe areas and posterior cingulate cortex (Rohrer et  al., 2012). DTI studies of logopenic patients suggest that the only abnormal tract is the posterior indirect segment of the arcuate fasciculus (AF) that connects the inferior parietal lobule to the posterior temporal lobe (Galantucci et al., 2011). The temporoparietal atrophy, as well as the structural abnormalities in this important white matter tract that is part of the indirect pathway connecting anterior and posterior perisylvian language regions (Catani et al., 2005), is consistent with the phonologic short-term memory and repetition impairments documented in logopenic PPA. Vascular patients with conduction aphasia, who exhibit a similar profile of linguistic deficits, also have damage to posterior temporoparietal cortex and/or underlying white matter tracts (Hickok and Poeppel, 2004; Catani and Mesulam, 2008). The left temporoparietal regions that are atrophic on structural imaging studies in patients with logopenic PPA are also hypometabolic on FDG-PET (Rabinovici et al., 2008; Josephs et al., 2010). There have been no published functional MRI studies on specifically diagnosed

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logopenic PPA patients, but a study on nonfluent patients who appear to have been mostly of the logopenic variant revealed reduced network connectivity between anterior and posterior perisylvian language areas (Sonty et al., 2007).

Neuropathology The most common pathology underlying logopenic PPA is AD (Gorno-Tempini et al., 2004a, 2008; Josephs et al., 2008a; Mesulam et al., 2008; Grossman 2010; Rohrer et al., 2012). A few logopenic patients had TDP-43 pathology at autopsy (Mesulam et al., 2008; Grossman 2010). Consistent with the prevalence of AD pathology, Rabinovici et al. (2008) reported that four of four logopenic patients had evidence of increased cortical amyloid binding on PIB-PET, in contrast to only one of six nonfluent variant patients and one of five semantic variant patients. The regional distribution of PIB uptake in logopenic PPA does not mirror the focal leftlateralized temporoparietal atrophy/hypometabolism seen on structural imaging and FDG-PET studies, but is diffuse, with greatest uptake in the frontal lobes, posterior cingulate gyrus, parietal and anterolateral temporal cortex, and striatum, similar to the pattern seen in typical AD. In patients with logopenic PPA, CSF biomarkers may show a profile consistent with AD (increased tau, reduced Aβ42, and an elevated tau/Aβ42 ratio), and there is evidence of a higher-than-expected frequency of the APOE-e4 genotype in this population (Gorno-Tempini et al., 2004a, 2008; Migliaccio et  al., 2009; Henry and Gorno-Tempini 2010; Rohrer et al., 2010a, 2010b, 2012).

Assessment of speech–language function in PPA Although bedside testing may be sufficient for establishing the clinical diagnosis of aphasia, we recommend formal assessment of linguistic function in PPA. A thorough evaluation can substantially improve diagnostic accuracy by allowing a more detailed characterization of impaired and preserved speech–language abilities, and it can also provide a quantitative measure of aphasia severity that can be used to chart the progression of the disease and document potential treatment benefits. Standard aphasia batteries such as the Western Aphasia Battery (WAB; Kertesz, 1982) and Boston Diagnostic Aphasia Examination (BDAE; Goodglass et al., 2001) may be used to characterize overall language profile and to provide a gross measure of aphasia severity in PPA. However, it is likely that these language assessment batteries, which were designed for use in individuals with vascular aphasias, may not be sensitive to the subtle deficits observed in early PPA, and the

classification of aphasia by subtype (such as Broca’s or Wernicke’s) is not relevant in this patient population. Therefore, in addition to such general measures, specific tasks designed to assess spontaneous speech production, confrontation and generative naming, motor speech, repetition, single-word and sentence comprehension, nonverbal semantic processing, and written language should be administered. A simple picture description task (such as the “Cookie Theft” picture from the BDAE or the “Picnic Scene” from the WAB) can be used to assess fluency (speech rate/length of utterance), grammatical competence, lexical retrieval ability, and motor speech. In fact, recent work has indicated that measures of speech and language derived from such a sample can be helpful in discriminating among the PPA variants (Wilson et al., 2010b). Confrontation naming may be assessed using the Boston Naming Test (Kaplan et al., 2001). Of particular interest is not only the severity of the naming deficit, but the nature of naming errors, which are likely to differ among the three PPA variants. Individuals with the semantic variant are likely to fail to name all but the highest frequency items and may make superordinate or coordinate semantic errors. They are unlikely to be aided by phonemic cues and may also do poorly when given multiple-choice options. Individuals with nonfluent PPA generally demonstrate less severe impairment of lexical retrieval and are likely to show spared semantic knowledge for pictured items (i.e., are able to describe sensory/functional attributes or typical locations of the objects they fail to name and correctly select the word from a field of written choices). Naming errors may be phonetic or phonemic in nature, and phonologic cues may be beneficial. Finally, individuals with the logopenic variant are likely to have naming impairment less severe than semantic variant patients but more severe than nonfluent patients. Similar to nonfluent cases, patients with logopenic PPA may demonstrate spared semantic knowledge for items they cannot name and may be aided by phonologic cues and multiple-choice options. Phonemic errors on naming tasks are frequently observed. Motor speech may be evaluated using test batteries such as those designed by Wertz and colleagues (1984) or Duffy (1995). These batteries of tasks include diadochokinetic measures (rapid repetition of alternating speech sounds such as “puh-tuh-kuh”) and repetition of utterances of increasing articulatory complexity, from single sounds to long sentences, as well as multiple repetitions of words containing difficult articulatory sequences, such as artillery or catastrophe. Such an evaluation can reveal the presence of subtle dysarthria or AOS, which may not be apparent in conversational speech. Particular factors to attend to are rate and ease of articulation, voice

Primary Progressive Aphasia

quality, and presence and nature of speech errors, as motor speech deficits are characteristic features of nonfluent PPA. Oral repetition of nonwords, words, phrases, and sentences can also be used to identify impairments of phonologic processing. Factors that influence repetition accuracy include lexical status/familiarity (worse performance on nonwords compared to real words), predictability of the phrase, and sentence length. Poor repetition of sentences may indicate phonologic working memory deficits, which can be an important diagnostic feature in identifying logopenic PPA patients. Single-word comprehension can be assessed by spoken/written word–picture matching tasks (PALPA subtests 47 and 48; Kay et al., 1992). Impaired single-word comprehension is a characteristic finding in patients with semantic variant PPA. Sentence comprehension tasks from standardized aphasia tests such as the WAB, BDAE, or Curtiss–Yamada Comprehensive Language Evaluation (CYCLE; Curtiss and Yamada, 1988) can be used to identify impairments of receptive syntax. Individuals with nonfluent PPA often show deficits in comprehension of syntactically complex sentences, such as constructions featuring a subject-relative or object-relative embedded clause (such as “The brown horse that the dog chased was fast”), whereas individuals with logopenic PPA may be impaired for sentences of increasing length and decreasing familiarity/probability, regardless of syntactic complexity. Nonverbal semantic processing may be evaluated with picture tests of object knowledge. Picture association tests (such as the Pyramids and Palm Trees Test; Howard and Patterson, 1992) and picture–sound or object–function matching tests can be used. Knowledge of people can be assessed by asking patients to identify photographs of famous individuals and celebrities. Impairments on tests of object/person knowledge are particularly sensitive for identifying patients with semantic variant PPA. Finally, assessments of written language at the singleword and text level should be incorporated into the PPA evaluation. Single-word assessments of reading and spelling should examine the effects of word frequency, regularity (with regular words, such as stop and irregular words, such as tomb), and lexical status (i.e., both real words and phonologically plausible nonwords such as flig should be included). Individuals with semantic impairment are likely to have particular difficulty with reading/spelling irregular words (profile of surface dyslexia/dysgraphia), whereas those with phonologic impairment, particularly logopenic patients, may show disproportionate deficits in processing nonwords (profile of phonologic dyslexia/dysgraphia). Text-level writing, such as picture description, can reveal agrammatism that is not yet apparent in spoken discourse in individuals with nonfluent PPA.

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Treatment approaches in PPA There are currently no proven pharmacologic treatments for PPA caused by AD or FTLD. Behavioral speechlanguage treatments, however, have been shown to result in improved communication in domains such as naming, sentence production, and written language.

Pharmacologic treatment Successful pharmacologic treatment for PPA ultimately depends on accurate antemortem prediction of the underlying pathologic substrate, given that the syndrome can be caused both by FTLD spectrum disorders and by AD. There has been a great deal of research examining pharmacologic treatment of AD, and the FDA has approved several drugs, including cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) and an NMDA receptor agonist (memantine), to treat cognitive symptoms associated with this disorder. However, no studies to date have addressed the efficacy of these drugs in treatment of atypical variants of AD, including logopenic PPA. No FDA-approved treatments currently exist for FTLD and its associated syndromes, including the nonfluent and semantic variants of PPA. Acetylcholinesterase inhibitors and memantine have been administered in small trials with mixed groups of PPA patients, with minimal effects (Kertesz et al., 2008; Boxer et al., 2009; Johnson et al., 2010); however, larger, randomized, controlled clinical trials are warranted. Additional small studies have examined effects of bromocriptine, a dopamine agonist, in PPA. Treatment with bromocriptine had little effect on cognitive-linguistic deficits in PPA patients (Reed et al., 2004) and failed to provide enhanced benefit when combined with language treatment (relative to behavioral treatment alone) (McNeil et al., 1995). Behavioral treatment for speech and language deficits Compared to individuals with vascular aphasia, patients with PPA are under-referred for speech–language pathology services (Taylor et al., 2009) and are far less likely to be offered behavioral treatment, in part because referring and treating clinicians lack knowledge about the disorder and also because of negative assumptions with regard to the feasibility and utility of treatment in patients with neurodegenerative disease. The body of research literature examining treatment in PPA continues to grow, including restitutive treatments designed to rehabilitate impaired language processes (McNeil et al., 1995; Schneider et al., 1996; Murray, 1998; Graham et al., 1999; Graham, 2001; Snowden and Neary, 2002; Frattali, 2004; Rapp et al., 2005; Jokel et al., 2006, 2007; Dewar et al., 2008; Henry et al., 2008; in press; Bier et al., 2009; Heredia et al., 2009; Newhart et al., 2009; Rapp and Glucroft, 2009), augmentative/alternative approaches to treatment (Murray, 1998;

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Cress and King, 1999; Pattee et al., 2006), and interventions designed to address activity and participation limitations (Croot et al., 2008). Restitutive treatments have addressed word-finding deficits as well as sentence production (Schneider et al., 1996) and written language impairments (Rapp and Glucroft, 2009). At present, there is cause for cautious optimism with regard to the utility of speech– language treatment in PPA. Studies have reported gains on language measures, which were largely restricted to treated language domains, but which appeared to slow the progression of language deficits for specifically trained behaviors. Nonetheless, much remains to be learned with regard to the nature of the behavioral impairments in PPA and the types of treatment that may be beneficial for its clinical variants and stages.

Conclusions PPA has emerged as a unique syndrome of isolated and gradual language deterioration caused by a neurodegenerative disorder. PPA is a clinically and pathologically heterogeneous entity, and current classification systems have distinguished three major variants or subtypes: nonfluent/agrammatic, semantic, and logopenic. The behavioral manifestations of these PPA variants are determined primarily by the neuroanatomic distribution rather than by the nature of the underlying pathologic process, and the distinctive language profiles reflect the preferential involvement of specific left-hemisphere cortical regions dedicated to syntax, phonology, semantics, and motor speech. In clinical practice, the identification of PPA subtypes is based on detailed language assessment and neurologic/neuropsychological examination, supported by structural/functional imaging studies demonstrating characteristic patterns of focal cortical atrophy/hypometabolism. Molecular imaging (PIBPET), genetic testing, and CSF/blood biomarkers have excellent potential for identifying the pathologic basis of PPA during the patient’s lifetime, but these techniques are not generally available or recommended for routine clinical use at this time. Most patients with PPA harbor pathology related to FTLD spectrum disorders (tauopathies, TDP-43 proteinopathies) or AD. Probabilistic inferences about the underlying pathology are possible based on demonstrated associations between PPA subtypes and specific disease etiologies. However, it is important to keep in mind that the clinical diagnosis of a PPA variant does not reliably indicate the presence of a specific pathology in an individual patient; therefore, the language phenotype cannot be considered diagnostic of the underlying disease process (Grossman, 2010). Despite these caveats, we expect that progress in clinical, imaging and biomarker research will further improve antemortem diagnostic accuracy in PPA and facilitate

the selection of appropriate patients for participation in emerging etiology-specific therapeutic trials.

Acknowledgments This work was supported by grants R01DC008286, P30AG19610, F32DC010945, R03010878, R01NS050915, P01AG019724, and P50AG023501.

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Chapter 9.7 Prion Diseases Michael D. Geschwind and Katherine Wong

Introduction The most common causes of dementia in the elderly (over age 65) are, in decreasing order, Alzheimer’s disease (AD), vascular dementia (VaD), and, far behind, other dementias. For earlier-onset dementia (under the age of 65), AD and VaD are still the most common, but other dementias have higher prevalence. These include frontotemporal dementia (FTD), Lewy body dementias (LBDs), metabolic dementias, Huntington’s disease (HD), and assorted other etiologies, including prion diseases. Prion (pronounced pree-ahn) diseases are a group of uniformly fatal neurodegenerative diseases caused by the transformation of an endogenous protein, PrP (prion-related protein), into an abnormal conformation, called the prion. Dr Stanley Prusiner and colleagues identified prions as the cause of a family of diseases called transmissible spongiform encephalopathies. The term prion is derived from proteinaceous infectious particle (Prusiner, 1998). The transmissibility of the diseases and the long incubation period between exposure and symptom onset (Gajdusek et al., 1977; Brown et al., 1986b) puzzled researchers for some time and supported the erroneous theory that these diseases were caused by a slow virus or other exogenous infectious agents. Research by Prusiner and others, however, determined that the infectious agent did not contain DNA or RNA, a component of viruses. In 1997, Stanley B. Prusiner received the Nobel Prize in Physiology and Medicine for this work (Prusiner, 1998). It is now well established that prions are necessary and sufficient for causing these diseases, although other proteins might also play a role in the disease process. This has been proven resolutely by animal models, identification of prion gene mutations causing prion disease in humans, and in vitro production of prions with transmissibility (Mead, 2006; Kim et al., 2010; Makarava et al., 2010). Although prion diseases occur in animals and humans, this chapter focuses on human prion diseases and discusses prion diseases in animals only when relevant to humans.

Overview of human prion diseases Prion diseases can develop in three different ways in humans: spontaneously (sporadic), genetically, and through transmission (acquired) (Prusiner, 1998).

Approximately 85% of cases are sporadic, 15% are genetic, and fewer than 1% are acquired (iatrogenic or variant). Sporadic prion disease, or sporadic Jakob–Creutzfeldt disease (sCJD), is thought to occur due to the spontaneous transformation of the normal cellular prion protein (PrPC, in which C stands for cellular) into the abnormally shaped, disease-causing form, called the prion (PrPSc, in which Sc stands for scrapie, the prion disease of sheep and goats). Genetic prion diseases (gPrD) are caused by a mutation in the prion protein gene, PRNP, which codes for the prion protein, PrPC (Figure 9.12). Familial CJD (fCJD), Gerstmann–Sträussler–Scheinker (GSS), and fatal familial insomnia (FFI) are the three major forms of gPrDs. Acquired prion diseases are the least common form of human prion disease, but they are perhaps the most notorious, in part due to their occurrence through inadvertent transmission of prions, such as by iatrogenic means or from animals to humans, as in the case of BSE and human vCJD epidemic in the United Kingdom. Genetic and acquired forms of human prion disease are even less common in the geriatric population; therefore, the majority of this chapter focuses on sporadic CJD (sCJD).

Epidemiology The incidence of human prion diseases is about 1–1.5 per million per year in most developed countries, with some variability from year to year and between countries. This incidence translates to approximately 6000 human prion cases worldwide and 250–400 in the United States annually. The peak age of onset of sCJD occurs around a unimodal relatively narrow peak of about 68 years (Brown et al., 1986a). Because sCJD tends to occur within a relatively narrow age range, a person’s lifetime risk of dying from sCJD is much higher than the prevalence and is probably about one in tens of thousands.

History of CJD nomenclature In 1921 and 1923, Alfons Jakob published four papers describing five unusual cases of rapidly progressive dementia (RPD). Dr Jakob felt his cases were nearly identical to a case described in 1920 by his professor, Hans Creutzfeldt. This disease was referred to for many decades as Jakob’s or Jakob–Creutzfeldt disease until

267

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refers to all human prion diseases, whereas sCJD refers only to sCJD. As mentioned, prion diseases historically have been referred to as transmissible spongiform encephalopathies (TSEs) due to two distinguishing characteristics of prion disease. Yet some gPrDs might not be transmissible, and not all human prion diseases have spongiform changes (now called vacuolation, due to fluid-filled vesicles in the dendrites) on pathology.

(a) “Refolding” model PrPC

PrPSc

(b) “Seeding” model PrPC

PrPSc

What are prions?

Very, very slow

Rapid

Rapid

Figure 9.12 Models for the conformational conversion of PrPC to

PrPSc. (a) The “refolding” model. The conformational change is kinetically controlled, a high-activation energy barrier preventing spontaneous conversion at detectable rates. Interaction with exogenously introduced PrPSc causes PrPC to undergo an induced conformational change to yield PrPSc. This reaction could be facilitated by an enzyme or chaperone. In the case of certain mutations in PrPC, spontaneous conversion to PrPSc may occur as a rare event, explaining why familial CJD or GSS arises spontaneously, albeit late in life. Sporadic CJD may come about when an extremely rare event (occurring in about one in a million individuals per year) leads to spontaneous conversion of PrPC to PrPSc. (b) The “seeding” model. PrPC and PrPSc (or a PrPSc-like molecule, light) are in equilibrium, with PrPC strongly favored. PrPSc is stabilized only when it adds onto a crystal-like seed or aggregate of PrPSc (dark). Seed formation is rare; however, once a seed is present, monomer addition ensues rapidly. To explain exponential conversion rates, aggregates must be continuously fragmented, generating increasing surfaces for accretion. (For a color version, see the color plate section.) Reproduced from Weissmann C et al. (2002).

Clarence J. Gibbs, a prominent researcher in the field, started using the term Creutzfeldt–Jakob disease because the acronym was closer to his own initials (Gibbs, 1992). We now know from the pathology and records that Creutzfeldt’s case not only was very different clinically than Jakob’s cases but also did not have what we today refer to as prion disease. The disease probably should be called Jakob’s, or at least Jakob–Creutzfeldt, disease, certainly not Creutzfeldt–Jakob disease. Unfortunately, the term JCD might confuse some with the JC virus. Therefore, we use the term Jakob–Creutzfeldt disease, with the acronym CJD. The term CJD is used sometimes to refer to all human prion diseases and sometimes to refer to just the classic or sporadic form, sCJD. In this chapter, CJD

The normal prion protein (PrP or PrPC) is not pathogenic, but it can change shape into an abnormal, infectious form of PrP called PrPSc. PrPC and PrPSc have identical primary structures (amino acid sequence) but have different tertiary structures (3-D shape). Prions are characterized by their infectious properties and by the intrinsic ability of their structures to act as a template and convert the normal physiologic PrPC into the pathologic, disease-causing form, PrPSc. It is thought that the accumulation of prions, PrPSc, in the brain leads to nerve cell injury and death (Prusiner, 1998; Prusiner and Bosque, 2001), although the specific pathologic mechanism is debated (Mallucci et al., 2007). Prions are thought to spread in the brain via either a refolding mechanism or a seeding model, which are not mutually exclusive (Figure 9.12). The complete function of PrP is still not known (Geschwind and Legname, 2008). It is coded for by the PRNP gene located on the short arm of chromosome 20 (Oesch et al., 1985; Basler et al., 1986) and is a primarily membrane-bound protein on nerve and other cells (Figure 9.13). It is highly conserved evolutionarily, so it presumably plays an important role in neuronal development and/or function (Kanaani et al., 2005). Mice that have had both copies of the open reading frame (ORF) of their PrP gene, PRNP, deleted (PrP-/-) have a normal lifespan and appearance (Bueler et al., 1992; Manson et al., 1994). Conditional knockout mice, in which the gene is not removed until after the mouse has already developed, also appear normal and unaffected by gene removal. Both mice have some subclinical deficits found later on postmortem examination (Legname et al., 2005). PrPC interacts with many proteins and cellular constituents. Animal and cell models have generated a variety of possible functions of PrPC. Cell signaling, adhesion, proliferation, differentiation, and growth have all been identified as possible PrPC functions through animal and cell models. Importantly, mice devoid of PrPC cannot be infected with prions—nor can they replicate them— providing strong evidence that PrPC is necessary for prion disease (Bueler et al., 1993; Prusiner, 1993; Katamine et al., 1998).

Prion Diseases

(a)

Codons 1

PrPC

–8

23

–M 129V

50

100

150

Cu2+ β1

(b)

PrPSC

E219K

PrPSC

Type Type 1 2 82

97

(c)

αA

200

Y αB β1

231 254

Protein X Y

αc

GPI

S-S

Y αB

Protein X Y

αc

S-S

GPI

Cell membrane

PRNP

269

P1 D2L

(d) Figure 9.13 The prion protein. (a) The prion protein gene (PRNP) is located on the short arm of the human chromosome 20. The

nonpathogenic polymorphism includes deletion of one of the octarepeat segments, methionine–valine polymorphism at the 129 position, and glutamine–lysine polymorphism at position 219. (b) Post-translational modification truncates the cellular prion protein (PrPC) at positions 23 and 231 and glycosylates (Y) at positions 181 and 197. The phosphatidylinositol glycolipid (GPI) attached to serine at position 231 anchors the C-terminus to the cellular membrane. The intracellular N-terminus contains five octarepeat segments, P(Q/H)GGG(G/-) WGQ (blue blocks), that can bind copper ions. The central part of the protein contains one short α-helical segment (α-helix A encompassing residues 144–157 [green block]), flanked by two short β-strands (red blocks): β1(129–131) and β2(161–163). The secondary structure of the C-terminus is dominated by two long α-helical domains: α-helix B (residues 172–193) and α-helix C (residues 200–227), which are connected by a disulfide bond. The blue arrows indicate binding sites of the protein X within α-helices B and C. The dashed frame marks a segment between positions 90 and 150, which is crucial for the binding of PrPC to PrPSc. (c) PrPSc has increased β-sheet content (red dashed block). (d) Unlike PrPSc, which is anchored to the membrane, GSS amyloidogenic peptides are truncated and excreted into the cellular space, where they aggregate and fibrillize into GSS amyloid deposits. This example is an 8-kDa PrP fragment associated with the most common GSS/P102L mutation. A synthetic form of this peptide (90–150 residues), exposed to acetonitrile treatment to increase β-sheet content, is the only synthetically generated peptide that, when injected intracerebrally into P102L-transgenic mice, is able to induce the GSS disease. Source: Geschwind (2011). Reproduced with permission from Elsevier. (For a color version, see the color plate section.)

Clinical aspects of human prion diseases Sporadic prion disease Sporadic CJD is thought to occur spontaneously in the brain either through random transformation of PrPC into PrPSc or possibly through somatic mutations that accumulate in the body (see Watts et al., 2006, for a discussion on possible origins of sCJD). The course typically constitutes a rapid disease with a median survival of about 7–8 months and mean survival of 4 months. More than 90% of patients die within 1 year of onset of symptoms (Brown et al., 1986a, 2006) The mean age of onset is 68, and the median age is in the early 60s, although the range is from the 20s to the 80s (Table 9.13). Occurrence of sCJD at young (from 20s to 40s) or old (>75) ages is uncommon (Will, 2003).

A broad range of symptoms is associated with sCJD, typically including cognitive changes (dementia), behavioral and personality changes, difficulties with movement and coordination, visual symptoms, and constitutional symptoms (Brown et al., 1986a; Rabinovici et al., 2006). sCJD usually progresses rapidly over weeks to months from the first obvious symptoms to death, although some patients live for more than 1.5 years. Most patients die from aspiration pneumonia preceded by a state of akinetic mutism. Cognitive problems in sCJD typically include confusion, memory loss, and difficulty concentrating, organizing, or planning. Motor manifestations of CJD include extrapyramidal symptoms (bradykinesia, dystonia, tremor), cerebellar symptoms (gait or limb ataxia), and, later in the disease, myoclonus (sudden jerking movements). Although myoclonus has traditionally been considered

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Table 9.13 Clinical characteristics of most common types of human prion diseases Characteristic

sCJD

vCJD

fCJD

iCJD

FFI

GSS

Kuru

Average age at onset 67 (yr)

28

Variable among kindreds 23–55

All ages

50

40

All ages

Average duration of disease (mo.)

7

14

Variable among kindreds 8–96

12

18

60; variable among kindreds 60–240

11

Average incubation periods (range)

N/A

17 yr (12–23 yr); blood transfusion 7 yr

—

Neurosurgical 18 mo. (12–28); dura graft 6 yr (1.5–23 yr); hGH 5 yr (4–36 yr)

N/A

N/A

12 yr (5–50 yr)

Most prominent early Cognitive signs and/or behavioral dysfunction

Psychiatric abnormalities, sensory symptoms (later dementia, ataxia, and other motor symptoms)

Cognitive and/ or behavioral dysfunction

Cognitive dysfunction, ataxia

Insomnia, autonomic instability

Ataxia, tremor, extrapyramidal symptoms

Ataxia, tremor

Cerebellar dysfunction (%)

>40

97

>40

>40

No

100 in P102L mutation; much less common in other mutations

100

DWI/FLAIR MRI positive

Yes, >92%

Yes, pulvinar sign

Yes for most mutations

Variable; some positive in deep nuclei or cerebellum

Unclear

Variable; most negative

N/A

PSW on EEG

Yes, 65%

No (rarely at end stage)

Yes

Yes

No

No

N/A

Amyloidosis

Sparse plaques Severe in all in 5–10% cases

Sporadically seen

Sporadically seen

No

Very severe

75% of cases

Presence of PrPSc in the lymphoreticular system

No

No

Yes

No

No

Unlikely

Yes

Source: Geschwind (2011). Reproduced with permission from Elsevier. Parchi et al. (1999), Brown et al. (2000, 2006), Valleron et al. (2001), Huillard d’Aignaux et al. (2002), Collie et al. (2003), Will (2003), Kong et al. (2004), Collinge et al. (2006), Collins et al. (2006), Lewis et al. (2006), Brandner et al. (2008), Vitali et al. (2008), and Heath et al. (2010). CJD, Creutzfeldt–Jakob disease; EEG, electroencephalogram; FFI, familial fatal insomnia; GSS, Gerstmann–Sträussler–Scheinker syndrome; mo., months; N/A, not available or not applicable; PSW, paroxysmal sharp waves; yr, years.

a classical sign in CJD, this abnormality may also be found in dementia with Lewy bodies, AD, and corticobasal degeneration. Subtle behavioral and psychiatric changes and constitutional symptoms (e.g., fatigue, malaise, headache, dry cough, lightheadedness, vertigo) can also be seen early, very subtle symptoms (irritability, anxiety, depression, or other changes in personality) in the disease course. Preliminary research at our center shows that sCJD presents as prominently with behavioral symptoms as behavioral variant FTD. These symptoms are often overlooked and should be given more weight in the diagnosis of sCJD. Problems processing visual information lead to visual symptoms such as blurred or double vision,

cortical blindness, or other perceptual problems. Such patients often are referred to ophthalmologists. As the age of onset in sCJD is also the common age for cataracts, many sCJD patients with visual symptoms have cataract operations, which, of course, do not improve the visual symptoms that have brain origin. Less frequently, other symptoms, such as aphasia, neglect, or apraxia (inability to do learned movements) due to parietal dysfunction occur and can be presenting features. Sensory symptoms such as numbness, tingling, and/or pain are less well-recognized symptoms and are probably under-reported, given the magnitude of the other symptoms in sCJD (Geschwind and Jay, 2003; Will,

Prion Diseases

271

2004; Lomen-Hoerth et al., 2010; Prusiner and Bosque, 2001).

Diagnosing sCJD A diagnosis of sCJD can be considered definite, probable, or possible based on level of certainty. Definite criteria require pathologic evidence of PrPSc in brain tissue (by biopsy or autopsy; Kretzschmar et al. 1996; Budka, 2003). Several criteria exist for the diagnosis of possible or probable sCJD. Unfortunately, most of these criteria are geared toward the purpose of surveillance and epidemiologic studies for patients who were not definitely diagnosed pathologically and thus are intended to catch most patients at the end of their disease course (Figure 9.14). Most of these criteria, therefore, are not very helpful when evaluating a patient early in the disease course (Table 9.14). The most commonly used “probable” criteria are World Health Organization (WHO) Revised criteria (WHO, 1998). In the criteria, pyramidal symptoms might include hyperreflexia, focal weakness, and a positive Babinski (extensor) response. Extrapyramidal symptoms include rigidity, slowed movement (bradykinesia), tremor, and dystonia, for example. Akinetic mutism describes the state when patients are without purposeful movement and mute. Possible CJD criteria are the same as for probable but do not require the ancillary testing (e.g., EEG or CSF 14-3-3 tests; WHO, 1998). Many patients will not meet revised WHO criteria for probable sCJD until late in the disease course. UCSF criteria, utilizing brain MRI, were proposed in 2007 (Geschwind et al., 2007a); in 2009, Modified European sCJD criteria also allowed inclusion of brain MRI.

Figure 9.14 Neuropathology of prion disease. (a) In sCJD, some

brain areas may have no (hippocampal end plate, left), mild (subiculum, middle), or severe (temporal cortex, right) spongiform change. Haematoxylin and eosin (H&E) stain. (b) Cortical sections immunostained for PrPSc in sCJD: synaptic (left), patchy/perivacuolar (middle), or plaque type (right) patterns of PrPSc deposition. (c) Large Kuru-type plaque, H&E stain. (d) Typical “florid” plaques in vCJD, H&E stain. Source: Budka (2003). Reproduced with permission from Oxford University Press. (For a color version, see the color plate section.)

Table 9.14 Current diagnostic criteria for probable sCJD European criteria 2009a (Zerr et al., 2009)

UCSF 2007 criteria (Geschwind et al., 2007a)

1 1 Progressive dementia 2 2 At least two of these four features: Myoclonus Visual or cerebellar disturbance Pyramidal/extrapyramidal signs Akinetic mutism 3 And one of more of the following: PSWCs on the EEG A positive 14-3-3 CSF assay and a clinical duration to death <2 years 3 High signal abnormalities in caudate nuclear and 4 putamen or at least two cortical regions (temporalparietal-occipital, but not frontal, cingulate, insular, or hippocampal), in either DWI or FLAIR MRI 4 No alternative diagnosis on routine investigations

WHO 1998 revised criteria (WHO, 1998)

RPD 1 At least two of the following: 2 Myoclonus Pyramidal/extrapyramidal Dysfunction Visual disturbance Cerebellar signs 3 Akinetic mutism Other higher focal cortical signb And a typical EEG or MRI 4 No alternative diagnosis suggested by routine investigations

Progressive dementia and/or At least two of the following four features: Myoclonus Visual or cerebellar disturbance Pyramidal/extrapyramidal signs Akinetic mutism PSWCs on the EEG and/or a positive 14-3-3 CSF assay and a clinical duration to death <2 years No alternative diagnosis on routine investigations

PSWCs, periodic sharp wave complexes. aThere were errors in the table summarizing the criteria in the paper; criteria shown here are derived from the text of the paper. bHigher focal cortical signs include such findings or symptoms as apraxia, neglect, acalculia, and aphasia.

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Diagnostic tests for sCJD EEG The classic EEG finding in sCJD consists of sharp, or triphasic, waves (periodic sharp wave complexes, or PSWCs) occurring about once every second (Figure 9.15). This EEG is found in only about two-thirds of sCJD patients, often late in the disease. More commonly, sCJD patients present with focal or diffuse slowing (Steinhoff et al., 2004). Other diseases leading to cortical dysfunction such as AD, Lewy body disease, toxic-metabolic and anoxic encephalopathies, progressive multifocal leukoencephalopathy, and Hashimoto’s encephalopathy, also can have PSWCs on EEG (Seipelt et al., 1999; Tschampa et al., 2001). CSF Due to varying degrees of sensitivity and specificity around the world, the clinical utility of CSF biomarkers is somewhat controversial. The 14-3-3 protein was one of the first CSF proteins touted as a diagnostic marker for CJD, but it has limited sensitivity and specificity (Chapman et al., 2000;

Geschwind et al., 2003), as it is found elevated in many nonprion neurologic conditions (Satoh et al., 1999). When first published, the 14-3-3 was reported to have 100% sensitivity and 96% specificity, but this study was limited by small sample size and poor controls (Hsich et al., 1996). Subsequent larger European studies have found this protein to have a sensitivity and specificity of about 85%, but control patients were not sufficiently characterized in some of these studies (Collins et al., 2006; Sanchez-Juan et al., 2006). A more recent survey of the CSF results collected by the UK CJD Surveillance Unit showed 14-3-3 sensitivity of 86% and specificity of 74% in a pathologically confirmed sample (Chohan et al., 2010). Many feel that the 14-3-3 protein is merely a marker of rapid neuronal injury and has little specificity for sCJD (Satoh et al., 1999; Chapman et al., 2000; Geschwind et al., 2003). Elevated CSF 14-3-3 protein may be found in other neurologic conditions resulting in cortical injury, including AD and stroke (Huang et al., 2003). Total-tau (t-tau), neuron-specific enolase (NSE), and the astrocytic protein S100β are also used as CSF biomarkers. The sensitivity and specificity of these biomarkers

Figure 9.15 A typical EEG in a sCJD patient with diffuse slowing and 1 Hz periodic sharp waves complexes (PSWCs). Source: Geschwind

(2011). Reproduced with permission from Elsevier.

Prion Diseases

for sCJD vary greatly among studies. One large multicenter European study recently examined the sensitivity and specificity of four biomarkers: 14-3-3, t-tau, NSE, and S100β. As not all patients underwent all four tests, nor were they necessarily performed in the same CSF samples, this study did not allow for legitimate comparison between biomarkers. Nevertheless, they found the sensitivity and specificity of the 14-3-3 to be 85% and 84%, t-tau (cut-off >1300 pg/mL) 86% and 88%, NSE 73% and 95%, and S100β 82% and 76%, respectively (Sanchez-Juan et al., 2006). The same methodological problems were also present in a more recent 2010 survey of the UK Surveillance Center data. However, they did a separate analysis of cases in which both 14-3-3 and t-tau protein were tested in the same samples. The sensitivity and specificity for 14-3-3 and t-tau tested in the same samples were 85% and 74% for 14-3-3 and 81% and 85% for tau (Chohan et al., 2010). The sensitivity and specificity of these tests in other

273

forms of prion disease, such as vCJD and gPrD, have consistently been reported to be much lower than for sCJD.

MRI MRI, particularly diffusion sequences, has higher sensitivity for sCJD than either EEG or 14-3-3 protein (Shiga et al., 2004; Young et al., 2005; Zerr et al., 2009; Vitali et al., 2011). Typical MRI abnormalities in CJD include T2-weighted (including fluid attenuated inversion recovery [FLAIR] sequences) and diffusion weighted imaging (DWI) weighted hyperintensities in the deep nuclei (caudate, putamen, and, less often, the thalamus) and cortical gyral hyperintensities (cortical ribboning). DWI has higher sensitivity than FLAIR for sCJD (Vitali et al., 2011). When CJD is suspected, a brain MRI with DWI and FLAIR sequences should be obtained (Vitali et al., 2011). Figure 9.16 shows a typical MRI in sCJD. Even at major medical centers, many radiologists are still not familiar

(a)

(c)

(e)

(g)

(b)

(d)

(f)

(h)

Figure 9.16 DWI and FLAIR MRI in sCJD and vCJD. Three common MRI patterns in sCJD: predominantly subcortical (a, b), both cortical and subcortical (c, d), and predominantly cortical (e, f); also a patient with probable variant CJD (vCJD) (g, h). Note that, in sCJD, the abnormalities are more evident on DWI (a, c, e) than on FLAIR (b, d, f) images. The three sCJD cases (a, b; c, d; e, f) are pathology proven. (a, b) A 52-year-old woman with MRI showing strong hyperintensity in bilateral caudate (solid arrow) and putamen (dashed arrow) and slight hyperintensity in bilateral mesial and posterior thalamus (dotted arrow). (c, d) A 68-year-old man with MRI showing hyperintensity in bilateral caudate and putamen (note anteroposterior gradient in the putamen, which is commonly seen in CJD), thalamus, right insula (dotted arrow), anterior and posterior cingulate gyrus (solid arrow, L>R), and left temporal–parietal–occipital junction (dashed arrow). (e, f) A 76-year-old woman with MRI showing diffuse hyperintense signal mainly in bilateral temporoparietal (solid arrows) and occipital cortex (dotted arrow), right posterior insula (dashed arrow), and left inferior frontal cortex (arrowhead), but no significant subcortical abnormalities. (g, h) A 21-year-old woman with probable vCJD, with MRI showing bilateral thalamic hyperintensity in the mesial pars (mainly dorsomedian nucleus) and posterior pars (pulvinar) of the thalamus, the so-called “double hockey stick sign.” Also note the “pulvinar sign,” with the posterior thalamus (pulvinar; arrow) being more hyperintense than the anterior putamen. CJD, Creutzfeldt–Jakob disease; MRI, magnetic resonance imaging; DWI, diffusionweighted imaging; FLAIR, fluid-attenuated inversion recovery. Source: Geschwind (2011). Reproduced with permission from Elsevier.

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with the MRI findings indicative of CJD, and a majority of sCJD MRIs are misread (Geschwind et al., 2010; Carswell et al., 2012). Diagnostic MRI criteria for sCJD have been proposed. Some allow the use of FLAIR or DWI and do not include abnormalities in the frontal lobes (Zerr et al., 2009); others require diffusion abnormalities and do not exclude frontal lobe involvement (Vitali et al., 2011).

Other laboratory testing Basic laboratory studies, such as CBC, chemistry, liver function tests, ESR, and ANA, are generally unremarkable in sCJD. CSF might show a mildly elevated protein (typically less than 100 mg/dL) with normal glucose level. Red and white blood cell counts usually are normal. Pleiocytosis, an elevated IgG index, or increased oligoclonal bands rarely occur in sCJD and should prompt evaluation for other conditions, particularly infectious or autoimmune disorders. At our center, we frequently rule out reversible causes of RPD that sometimes mimic sCJD, including autoimmune paraneoplastic (such as anti-Hu, anti-CV2, anti-Ma2, anti-Ri, and anti-NMDA antibodies) and nonparaneoplastic diseases (such as Hashimoto’s encephalopathy; antithyroid peroxidase and antithyroglobulin antibodies, and antivoltage gated-associated encephalopathy (anti-VGKC antibodies).

Genetic prion disease Mutations in the prion protein gene, PRNP, are responsible for about 15% of all human prion disease cases. They are always autosomal dominant, and most are 100% penetrant (i.e., almost everyone with a mutation develops the disease if they live a normal lifespan). More than 40  mutations, including point mutations, stop codons, insertions, and deletions, have been identified. Testing and diagnosis can be achieved through DNA testing of blood while a patient is alive or through autopsy tissue (Kong et al., 2004). Despite the high penetrance, more than 60% of patients with gPrD do not have a positive family history of prion disease. In most of these cases, relatives were misdiagnosed with other dementias, families hid their medical history, or there was reduced mutation penetrance (Kovacs et al., 2005). Based on clinical, genetic, and pathologic characteristics, three forms of gPrDs have been identified: fCJD, GSS, and FFI. This classification is not absolute, as some mutations have features that blend fCJD and GSS. Patients with gPrD typically have a younger age of onset (typically from 40s to 60s), a slower progressive course, and a longer lifespan (typically a few years) than sCJD patients. Depending on the PRNP mutation and other genetic and epigenetic factors, gPrDs often present identically (clinically and pathologically) to sCJD with rapid onset of clinical symptoms and short survival of weeks to months (Kong et al., 2004). Common early symptoms include parkinsonism or ataxia with only mild personality or early cognitive changes. Other mutations, such as those causing GSS, bring

about a slower illness, often with behavioral and motor abnormalities early on and dementia later in the disease. Some less common PRNP mutations result in an older age of onset, in the 70s or 80s. There is often great variability in presentation and disease course of the several mutations causing gPrDs; in fact, even within the same family members carrying the same mutation, there might be great clinical variability. Polymorphism within PRNP, such as at codon 129, also alters the presentation of gPrDs (Kong et al., 2004). It is generally thought that the mechanism for gPrDs is that mutations in PRNP make PrPC more susceptible to changing conformation into the abnormally shaped, disease-causing form, PrPSc. It is thought that this conformational change occurs throughout life but that these are cleared by the cell; as one ages, the body’s ability to clear abnormal proteins declines, leading to the accumulation of PrPSc (Kong et al., 2004; van der Kamp and Daggett, 2010).

Familial CJD (fCJD) More than 15 mutations are known to cause fCJD. Most are point (missense) mutations, but some are insertion mutations and a deletion (Kong et al., 2004; Meissner et al., 2009). Most fCJD patients present similarly to sCJD, with overlapping clinical MRI and EEG findings. The most common fCJD mutation worldwide is E200K, found most commonly among Libyan Jews and Slovakians.

Gerstmann–Sträussler–Scheinker (GSS) Gerstmann-Sträussler-Scheinker is caused by at least 10 PRNP mutations, including several missense mutations, a stop mutation, and insertion mutations (Kong et al., 2004). The age of onset for GSS mutations is often under the age of 65, typically in the 50s or younger, so we will not delve into too much detail, as the likelihood of a geriatric presentation is low. GSS often presents as a slowly progressive ataxic and/or parkinsonian disorder. Cognitive impairment often comes only later, although some mutations are present with early dementia and/or behavioral abnormalities. However, considerable phenotypic variability exists within and between mutations and families (Kong et al., 2004; Giovagnoli et al., 2008; Webb et al., 2008). Due to the slow course (up to several years), persons with GSS can be mistaken to have other neurodegenerative conditions, such as multiple-system atrophy, spinocerebellar ataxias, idiopathic Parkinson’s disease, AD, or HD (refer to Table 9.13).

Fatal familial insomnia Fatal familial insomnia is one of the rarest gPrDs and is caused by a single PRNP point mutation, D178N, with codon 129 having methionine (129M) on the same

Prion Diseases

30 MM blood

Number of deaths

25

MV primary

20

Untyped primary MM primary

15 10 5 0

1995

1997

1999

2001 2003

2005

2007

2009

Year Figure 9.17 Times series of observed vCJD cases in the United

Kingdom by genotype and presumed transmission route. Bar graph depicting number of deaths from vCJD per year in the United Kingdom through 2009. Bars refer to codon 129 polymorphism of decedent and their method of infection, primary, through consumption of BSE, or blood, through blood transfusion. Three persons, all codon 129 MM, died from vCJD from blood transfusion (black bars). One probable vCJD subject who died in 2009 (lighter bar) was codon 129MV and had primary infection. The number of deaths from vCJD has been relatively stable over the past five years. but it is not clear whether there will be another rise in the number of cases. Source: Garske and Ghani (2010). Reproduced with permission from Public Library of Science.

chromosome (cis; see Figure 9.17). Patients with D178N but cis valine at codon 129 (129V) usually present with fCJD, clinically more similar to sCJD than FFI. FFI usually at a mean age of 49 (range 20–72) presents with progressive, severe insomnia and dysautonomia (tachycardia, hyperhydrosis, and hyperpyrexia), with motor and cognitive problems appearing later in the course. Most FFI patients survive slightly longer than sCJD patients, about one and a half years. Although brain MRI is usually normal, FDG– PET imaging reveals thalamic and cingulate hypometabolism, often even before disease onset (Kong et al., 2004). Confirming a PRNP mutation by DNA extraction is important in diagnosing a gPrD, as pathology alone often cannot confirm a genetic etiology. As many gPrDs appear similar to sCJD and can have obscured family histories, this testing is important after the appropriate genetic counseling (Huntington’s Disease Society of America, 1994).

Acquired CJD Acquired forms of CJD occur because prions are transmissible and infectious. A relatively large number of prions (estimated several thousand proteins) probably are necessary to transmit prion disease, so they are not highly infectious or contagious.

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Acquired prion diseases include Kuru (now essentially extinct, occurring in the Fore tribe in Papua New Guinea due to endocannibalism); iatrogenic CJD (iCJD); and the highly publicized vCJD, occurring primarily in the United Kingdom and France, caused by consumption of bovine spongiform encephalopathy (BSE or mad cow disease), contaminated beef (Will et al., 2000; Prusiner and Bosque, 2001; Will, 2003; Collinge et al., 2006), and, in a few cases, blood transfusion. As prions are proteins, typical sterilization methods do not render them inactive (Bellinger-Kawahara et al., 1987a, 1987b; Prusiner, 1998); inactivation requires other methods or longer times at higher pressure and temperatures than typically used for standard sterilization (Peretz et al., 2006). This difficulty has led to approximately 400 cases of iCJD, from the use of cadaveric-derived human pituitary hormones, dura mater grafts, corneal transplants, the reuse of cleaned and sterilized EEG depth electrodes implanted directly into the brain and other neurosurgical equipment, and blood transfusion (Brown et al., 2000; Will, 2003). Most of the pituitary-derived (human grown hormone [hGH] and gonadotrophin) cases occurred from contaminated batches in France, the United Kingdom, and the United States. Methods have since been instituted to prevent prion transmission through such hormones (Brown et al., 2006). Thankfully, it appears that the number of iCJD cases is declining. Despite WHO recommended practices, however, for managing potential prion-contamination tissues (WHO, 1999, 2003), this still occurs and leaves patients at risk for iCJD. As most persons treated with these materials were children and incubation period is from one year at the shortest and up to one to two decades, such cases of iCJD do not occur in the geriatric population. The most notorious form of CJD is vCJD, first identified in 1995 (Will et al., 1996). It is caused by inadvertent ingestion of BSE (mad cow disease) or, in a few cases, blood transfusion from asymptomatic patients who were unknowing carriers of vCJD (Zou et al., 2008). Cattle are thought to have contracted BSE from being fed scrapieinfected sheep products used as feed (Bruce et al., 1997; Scott et al., 1999). Differing from sCJD, patients with vCJD are generally younger, with a median age of around 27 (range 12–74), and almost all cases have occurred in persons younger than 50. The mean disease duration is longer, about 14.5 months, versus about 7 months for sCJD. Early psychiatric symptoms are more characteristic in vCJD as compared to sCJD (Wall et al., 2005; Rabinovici et al., 2006) and might occur several months before obvious neurologic symptoms begin. Painful paresthesias, relatively persistent through the disease course, often occur in vCJD, although such pain rarely is seen in other prion diseases. The EEG does not show the classic periodic sharp wave complexes, except in rare cases at the end of the disease (Binelli et al., 2006). The best diagnostic marker currently is the brain MRI that usually shows the “pulvinar sign,” in which the pulvinar (posterior thalamus) is

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brighter than the anterior putamen on T2-weighted or DWI MRI (refer to Figure 9.17; Collie et al., 2003); this MRI pattern is very rare in the other prion diseases (Petzold et al., 2004). More specific tests, including detecting vCJD prions in the CSF, are under development. The younger age of onset, MRI findings, prominent early psychiatric features, persistent painful sensory symptoms, and chorea help differentiate vCJD from sCJD. As with sCJD, definitive diagnosis of vCJD is based on pathologic evidence of PrPSc in brain biopsy or autopsy. As the prions in vCJD are present in high numbers in the lymphoreticular system (unlike other human prion diseases, in which there are high prion numbers only in the central nervous system), tonsils and other lymphoid tissue can also be used for pathologic diagnosis. As of November 2013, approximately 225 cases of probable or definite cases of vCJD have been documented, mostly in the United Kingdom, and no cases of vCJD have been acquired in the Western Hemisphere, including the United States or Canada (three patients in the United States and two in Canada have been diagnosed with vCJD, but those cases are thought to have been acquired elsewhere; CDC, 2006; UK National CJD Surveillance Unit, 2013). Following the United Kingdom, France has the second highest number of vCJD cases, which probably have the same origin as those in the United Kingdom (Brandel et al., 2009). The height of the vCJD epidemic passed in 2000. Experts fear that there may be further peaks due to people with different genetic susceptibility who were infected at the same time or the continuing risk of iatrogenic spread of vCJD (Andrews, 2010). One British study found vCJD prions in three of 11,246 appendix samples collected from 1995 to 2000 by immunostaining. Another similar study, the National Anonymous Tonsil Archive, found one positive sample among a subset of 10,000 tested (Garske and Ghani, 2010). Thus, some people in the population are not sick and carry variant prions, but the risk is unclear. These asymptomatic carriers of vCJD might pose the greatest risk for spread of vCJD, through transfusion of blood products or invasive procedures. Most alarmingly, it seems that infected asymptomatic vCJD donors are capable of transmitting the disease 1.5–6 years before they became symptomatic (Health Protection Agency, 2007). As of December 2010, four patients have acquired vCJD through non-leukodepleted (white blood cells removed) blood transfusions received before 1999 (Health Protection Agency, 2007). Figure 9.18 graphs presumed vCJD cases in the United Kingdom.

Prion decontamination Decontamination of prions requires methods that will denature proteins, as prions resist normal inactivation methods used to kill viruses and bacteria. Some

recommended methods for prion decontamination include very high temperatures with steam and caustic denaturing agents—methods that often damage equipment and instrumentation (WHO, 2003). Due to the risk of transmission to subsequent patients, some medical centers opt for the more secure method of preventing iCJD by destroying neurosurgical equipment (through incineration) rather than attempting to decontaminate and reuse. Research into improved methods of decontamination of prions is ongoing (Peretz et al., 2006).

Animal prion diseases In addition to BSE as a cause of acquired human CJD, a relatively new animal form of prion disease is raising similar concerns in North America: chronic wasting disease (CWD). CWD is a prion disease of mule deer, white-tailed deer, elk, and moose. The first clinical cases were recognized in the late 1960s in North America. The disease primarily has been reported in the United States and Canada, with the highest concentrations occurring in the Central Mountain region of the United States, especially Colorado and Montana, as well as the Canadian provinces of Saskatchewan and Alberta. Figure 9.18 shows the distribution of CWD in North America. A most concerning aspect of CWD is its

Chronic wasting disease in North America

Areas with CWD infected cervid populations States/provinces where CWD has been found incaptive populations Figure 9.18 Map of the distribution of CWD in North America.

Darkest areas denotes areas where wild populations have been infected. Medium dark denotes states and provinces with captive herds contaminated with CWD. Reproduced from Chronic Wasting Disease Alliance (www.cwd-info.org) with permission.

Prion Diseases

ease of horizontal transmission between cervids. This might be in part due to the fact that CWD appears to be transmittable through blood, urine, and saliva (Haley et al., 2009). This feature makes it difficult to prevent spread of the disease in free-ranging cervid populations (Williams, 2005). It still is not clear whether CWD can spread to humans or whether there is a species barrier, but there has been no reported increase in human prion cases in states where CWD rates have been highest (Sigurdson et al., 2009).

Molecular and pathologic findings of human prion diseases The key pathologic features of sCJD are the presence of PrPSc deposition (by either immunohistochemistry or Western blot), neuronal loss, gliosis (proliferation of astrocytes), and vacuolation (spongiform changes; see Figure 9.15). We now know that the spongiform changes are due to fluid-filled vesicles formed in distal dendrites near synapses and are not air-filled holes (as in a sponge), so the term vacuolation probably is more appropriate than spongiform. GSS has a distinct neuropathology from most other prion diseases, with large unicentric or multicentric plaques of PrPSc amyloid the unicentric plaques, however, also are seen in a minority of sCJD cases, whereas the multicentric plaques are more specific for GSS. Neuropathology of FFI includes profound thalamic gliosis and neuronal loss, causing atrophy. Involvement of regions outside the thalamus is greater in FFI with codon 129 MV than MM (Cortelli et al., 1997, 2006; Budka, 2003). Because vCJD is typically acquired peripherally, PrPSc can be found in the lymphoreticular system, including tonsillar tissue (Will, 2004). Brain pathology of vCJD shows abundant PrPSc deposition, particularly multiple fibrillary PrP plaques surrounded by a halo of spongiform vacuoles (“florid” plaques) and other PrP plaques, and amorphous pericellular and perivascular PrP deposits, especially prominent in the cerebellar molecular layer; the pathognomonic plaques in vCJD are called florid because they have the appearance of a flower with a dense center and surrounding ring of vacuoles (refer to Figure 9.15; Budka, 2003). The Western blot characteristics of vCJD PrPSc also are different from those seen in other forms of prion disease (Will et al., 2000; Will, 2003, 2004).

Molecular classification of sCJD Sporadic Jakob–Creutzfeldt disease has been divided into approximately six molecular subtypes based on the genetic polymorphism at codon 129 in the prion gene and the type of protease-resistant prion (type 1

277

Table 9.15 Distribution of PRNP codon 129 polymorphism in normal population and several human prion diseases

Normal population sCJD iCJD vCJDa

MV (%)

MM (%)

VV (%)

51 12–17 20 0

37 ~66 to 72 57 100

12 17 23 0

Source: Reproduced from Geschwind (2011) with permission from Elsevier. sCJD, sporadic Jakob-Creutzfeldt disease; iCJD, iatrogenic CJD; vCJD, variant CJD. a All but one clinical case of vCJD have been MM; one probable vCJD case was codon 129 MV, and some subclinical cases with vCJD prions in the lymphoreticular system have been identified (Parchi et al., 1999; Brown et al., 2000; Collins et al., 2006; Garske and Ghani, 2010; Peden et al., 2010).

or 2). Codon 129 polymorphisms are comprised of different combinations of either methionine (M) or valine (V) at location 129 of PRNP (e.g., MM, MV, or VV; see Table 9.15 and Figure 9.18). Additionally, upon extraction from the brain and partial digestion with proteinase, PrPSc may be cleaved at two possible sites (codon 82 or 97; refer to Figure 9.14), resulting in either a longer, 21 kDa (type 1) or a shorter, 19 kDa (type 2) peptide on a Western blot. To some extent, this classification separates sCJD cases based on their clincopathologic features. MM1 and MV1 are the most common forms (70%) and present as classic sCJD, with RPD and a duration of just a few months. VV2 (16%) starts with ataxia, later-onset dementia, and a short duration. The remaining four types, MV2 (9%), MM2-thalamic (2%), MM2cortical (2%), and VV1 (1%), have a duration of about 1–1.5 years. MV2 presents similarly to VV2 with ataxia, but these cases have focal amyloid kuru plaques in the cerebellum. MM2-thalamic presents often with insomnia, followed later by ataxia and dementia, with most pathology confined to the thalamus and inferior olives with very little vacuolation; some call this form sporadic fatal insomnia (sFI) because it presents similarly to the genetic prion disease, FFI. MM2-cortical patients have progressive dementia with large confluent vacuoles in all cortical layers. sCJD patients with VV1 also present with progressive dementia, but these cases have severe cortical and striatal pathology, with sparing of the brainstem nuclei and cerebellum. Unlike with MM2-cortical, sCJD VV1 patients do not have large confluent vacuoles, but there is faint synaptic PrPSc staining (Parchi et al., 1999). Curiously, as shown in Table 9.15, heterozygosity at codon 129 in the prion gene, PRNP, is somewhat protective against prion disease. Recently, however, it has been found that many sCJD patients have a mix of both type 1 and type 2 prions (Kobayashi et al., 2011), so this classification scheme must be revised.

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Proteinase-sensitive proteinopathy (PSPr): a new form of sCJD Until recently, one marker of prion disease has been the resistance of PrPSc to proteases, enzymes that digest proteins. A new form of sCJD has recently been identified in which the vast majority of patients’ PrPSc is protease sensitive. Thus, standard immunohistochemical techniques that depend on identifying protease-resistant PrPSc for diagnosis are now considered insufficient. These subjects had a different clinical phenotype based on their codon 129 genotype (VV, MV, and MV). These cases presented with psychiatric symptoms and a frontal dementia syndrome (with predominant behavioral symptoms and executive deficits), and most had negative ancillary tests (MRIs, EEGs, and 14-3-3). Although their mean age was commensurate with classic sCJD (late 60s), their mean disease duration was much longer, at 2.5 years (Zou et al., 2010).

Treatments of human prion diseases Human prion diseases have no known cure or diseasemodifying treatment. All cases are uniformly fatal. Some hypothetical mechanisms for treating prion diseases include removing or reducing the endogenous substrate, PrPC; blocking the interaction of PrPC with PrPSc; and removing PrPSc or blocking its toxicity (Korth and Peters, 2006). An immunotherapy approach to treating prion diseases is currently under investigation, and it may be that some antibodies that are effective against prions could be useful in other neurodegenerative diseases as well (Freir et al., 2011). Several medicines have been used to treat human prion disease, but only flupirtine, quinacrine and doxycycline, given orally, have been tested in randomized, double-blinded, placebocontrolled trials. None were effective in prolonging survival (Korth and Peters, 2006; Geschwind et al., 2013). Intraventricular pentosan polysulfate has been used on a compassionate basis in the United Kingdom, Japan, and a few other countries, but observational data suggest that it does not affect survival. The doxycycline treatment trial for human prion disease in Italy and France completed in 2013 and did not show any positive effect in survival or other outcomes. (www.agenziafarmaco.it/en). Other drugs will likely be tested in the near future (Stewart et al., 2008). Several laboratories around the world are screening drug libraries and using medicinal chemistry to identify and develop antiprion therapies. In the absence of any curative treatments, management of prion diseases involves treating symptoms as they arise and providing comfort care.

Differential diagnosis The differential of prion diseases includes RPDs (Geschwind et al., 2007b) and other slower, more common

neurodegenerative diseases, such as AD and Lewy body disease (Tschampa et al., 2001). A useful mnemonic to use when evaluating a patient with an RPD or suspected prion disease is VITAMINS, for vascular, infectious, toxicmetabolic, autoimmune, metastatic-metabolic, iatrogenic, neurodegenerative-neoplastic, and systemic etiologies (Geschwind et al., 2007b, 2008; Vernino et al., 2007).

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Chapter 9.8 Normal Pressure Hydrocephalus Norman R. Relkin

Introduction Normal pressure hydrocephalus (NPH) is a chronic neurologic disorder in older adults characterized by enlargement of the cerebral ventricles and progressive disturbances of gait, urinary continence, and cognition. Hakim and Adams first described the classic symptom triad of shuffling gait, urinary incontinence, and dementia in 1965 and identified NPH as a surgically treatable condition (Hakim and Adams, 1965). NPH is now widely recognized as a potentially reversible cause of physical disability and cognitive impairment in the elderly.

Classification of hydrocephalus The term hydrocephalus is used to describe a number of pathologic conditions in which the size of the cerebral ventricles is increased. NPH is a particular type of hydrocephalus with certain distinguishing features: • NPH is a “communicating” form of hydrocephalus because it develops chronically in the absence of a macroscopic obstruction to the flow of cerebrospinal fluid (CSF). This distinguishes NPH from acute, obstructive forms of hydrocephalus that result from lesions such as brain tumors and intracerebral hematomas. NPH can occur in the aftermath of conditions such as intracranial hemorrhage, meningitis, or head trauma. Such cases are called secondary NPH (sNPH) because hydrocephalus arises as the distal consequences of a brain insult rather than from an obstructive mass lesion. When there is no identifiable antecedent cause for adult hydrocephalus, it is called idiopathic NPH (iNPH). • Enlargement of the ventricles in NPH is not exclusively the result of brain atrophy (so-called hydrocephalus ex vacuo). In practice, differentiating NPH from ex vacuo enlargement of the ventricles can be challenging. The current approach involves subjective judgment of the extent to which ventricular enlargement is disproportionate brain atrophy as assessed from signs such as the degree of sulcal widening on brain imaging. Other potentially distinguishing signs have been identified (see the upcoming section “Neuroimaging”). • NPH is a different disorder than hydrocephalus in neonates and children. However, possible links between certain types of childhood hydrocephalus and NPH have been identified. According to the so-called

“two hit” hypothesis of NPH, benign congenital external hydrocephalus combined with the development of deep white matter ischemia later in life may lead to NPH in older adults (Bradley et al., 2006). Because skull size becomes fixed after the fontanelles close in early childhood, this could help explain why head circumference is significantly increased in a subset of patients with NPH (Krefft et al., 2004). Another NPH-like syndrome related to childhood hydrocephalus is called longstanding overt ventriculomegaly in adults (LOVA) (Kiefer et al., 2002). LOVA is thought to begin with childhood hydrocephalus that is initially compensated but progresses later in life to cause symptoms. Associated findings include an enlarged head circumference and, in some cases, an empty sella turcica. • Aqueductal stenosis (AS) can closely resemble NPH but differs in cause and treatment. In AS, congenital or acquired narrowing of the aqueduct of Silvius leads to ventricular enlargement and symptoms quite similar to those of NPH. Stenosis of the aqueduct can be identified on a midsagittal MRI scan and by flow-sensitive MRI techniques that document diminished CSF flow rates.

Demographics Idiopathic NPH most commonly affects persons over 40  years of age and may occur alone or in combination with Alzheimer’s disease, Parkinson’s disease, and other age-related disorders. NPH occurs in males and females in roughly equal proportions. Familial association has been anecdotally reported but is only rarely encountered in practice. The precise incidence and prevalence of NPH has not been rigorously determined. A Norwegian study in over 200,00 subjects estimated the incidence of NPH at 5.5 per 100,000 population and estimated prevalence at 21.9 per 100,000 population (Brean and Eide, 2008).

Pathophysiology Not surprisingly, the most consistent finding in NPH patients at autopsy is enlargement of the cerebral ventricles. Pathologic studies have failed to identify lesions at

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the gross or molecular levels that are universally diagnostic of NPH or unequivocally explain its etiology. Increased resistance to the clearance of CSF has been documented in some cases, but its cause has yet to be determined. Likewise, it remains unclear how disturbances in the CSF compartment translate into brain dysfunction and clinical symptoms in NPH. Intracranial pressure is only mildly elevated in NPH, typically to 130 mm H2O or slightly higher. Although this pressure is inadequate to cause cerebral dysfunction in normals, it has been argued that the effects are multiplied by the expanded ventricular surface over which it is exerted in NPH. Ventricular expansion, transependymal fluid movement, and age-associated reductions in cerebral compliance may make the brain more susceptible to the repeated impact of the CSF pulsations. A provocative hypothesis has been recently forwarded that implicates disturbances in CSF pulsatility in the pathogenesis of NPH (Bateman, 2008) According to this hypothesis, altered brain compliance and CSF pulsatility leads to cyclical compression of the tributary veins that empty into the sagittal sinus, resulting in increased resistance to CSF outflow (Ro). “Hydrodynamic” interference in CSF clearance could explain the increased Ro documented by CSF infusion studies in many NPH patients, in the absence of an identifiable obstruction of CSF flow. Physical distortion of neurons and their processes caused by ventricular enlargement has been hypothesized to delay or disrupt neuronal transmission in NPH. However, motor-evoked response studies have failed to show alterations in central conduction latencies, as would be expected if physical stretching were the cause of cerebral dysfunction in NPH (Zaaroor et al., 1997). Reduced cerebral blood flow has also been reported in NPH, but brain perfusion is not universally compromised, nor is it consistently improved after treatment. Small-vessel ischemic cerebrovascular disease has been linked to progression of NPH. As the burden of cerebrovascular disease increases, NPH generally becomes more refractory to treatment. In chronically untreated cases, small-vessel infarction occurs throughout the periventricular region, giving rise to a condition that is indistinguishable from Binswanger’s disease.

Neuroimaging A brain imaging study is necessary to identify ventricular enlargement in NPH. However, diagnosis also requires documentation of appropriate clinical findings. X-ray computed tomography (CT) or nuclear medicine scans such as cisternography can be used for this purpose, but MRI is the preferred modality for evaluating NPH. The use of MRI is limited by contraindications such as pacemakers, metallic implants, and claustrophobia, as well as in some venues by cost and availability. A T1-weighted

or other MRI pulse sequence that highlights ventricular and cortical anatomy can readily be used for this purpose. The Evans’ index, a measure of ventricular size calculated from the ratio of the diameter of the skull to the diameter of the lateral ventricle at its widest point, is 0.3 or greater in NPH. Because ventricular enlargement also occurs in aging and neurodegenerative diseases, evaluation of possible NPH requires determining whether the enlargement of the ventricles is disproportionate to cerebral atrophy. This is currently accomplished by visual inspection of brain images to identify widened sulcal markings as proxy measures of brain atrophy. This method is highly subjective and may soon be supplanted by quantitative MRI volumetric techniques that provide more accurate measures of cortical atrophy. Advances in MRI methods and other imaging techniques are likely to contribute to improved differential diagnosis of NPH in the future. Imaging can also be useful for verifying whether there is any obstruction to CSF flow. In some cases, imaging of the spine is useful for identifying obstructive causes for hydrocephalus. Inspection of a midline sagittal T1-weighted image is recommended for examining the patency of the cerebral aqueduct and fourth ventricle. In equivocal cases, a phase contrast CSF flow study can provide useful information about CSF movement. Aqueductal flow rates are low or undetectable in aqueductal stenosis, while in NPH, normal or increased (hyperdynamic) flow is observed. Hyperdynamic flow can sometimes be identified as a fourth ventricular flow void on proton density images or nonwater-suppressed echo planar images. Other structural findings associated with NPH that can be identified on CT scans or MRIs include enlargement of the temporal horns of the lateral ventricles not attributable to hippocampal atrophy, upward doming of the roof of the body of lateral ventricles, enlargement of the Sylvian fissure, and compression of the paramedian sulci of the frontoparietal region near the cranial convexity (see Figure 9.20).

Symptoms Although NPH is associated with gait ataxia, urinary incontinence, and dementia, symptoms fall on a continuum from very mild to severe and are not limited to those of the classic triad. Symptoms are stage dependent and may be minimal early in the disease or confined to just one or two domains. It is therefore important for clinicians to become familiar with the full spectrum of presentations and stages of NPH: • Gait and balance: Impairments of walking and balance are the most readily observed symptoms of NPH and the most reliably reversed by treatment. The characteristic gait disturbance in NPH is often described as

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(a)

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(b)

Figure 9.20 Midsagittal MRIs taken 5 years apart in a patient with Alzheimer’s disease who subsequently developed symptoms of NPH. Note the expansion of ventricles without a commensurate increase in sulcal markings, and the apparent narrowing of sulci at the parietal convexity. (a) Initial presentation of AD. (b) Five years later, coincident with onset of NPH symptoms.

“shuffling” or “magnetic.” Patients with NPH typically show a reduced foot–floor clearance and a widened base, walking in short steps with their toes point outward. There is reduced counter-rotation of the hips and shoulders while walking. Accelerometer studies show an increased tendency to sway while walking and while standing in place. There may be a prolonged latency when starting ambulation or stopping. Tandem gait is frequently disturbed. It takes symptomatic NPH patients longer than normal to rise from a chair and to walk a short distance. The number of steps required to cover a given distance is also increased. Patients with NPH frequently retropulse, either spontaneously or as a consequence of being pulled backward on the “Pull Test.” Turning in place may require multiple small steps, so-called “en-bloc” turning. NPH patients frequently fall directly forward or backward when bending or on uneven terrain but may fall in any direction. Parkinsonism may be present in NPH patients either as a comorbid illness or as a consequence of NPH itself. Parkinsonism secondary to NPH is less responsive to treatment with dopamine precursors or agonists than idiopathic Parkinson’s disease. A timed walking test is an inexpensive and sensitive method for identifying and following the gait disturbances in NPH. Clinical gait scales such as the one published by Boon and colleagues (Boon, 1971) can be useful for rating the full range of associated gait and balance disturbances. • Control of urination: The most common urinary symptoms associated with NPH are urinary frequency, urgency, and nocturia. These early stage symptoms may progress to urinary incontinence as the disease progresses. In most cases, incontinence is confined to micturition, but in advanced stages, defecation may be involved as well. NPH patients are often aware of their urinary symptoms and embarrassed when incontinence develops. With progression of the disease, and particularly with advancing dementia, they may develop indifference to incontinence. Asking subjects or spouses to keep a bladder diary indicating frequency/

urgency of urination and incidents of incontinence can provide useful diagnostic information. Urologic evaluation is recommended to rule out other causes of urinary dysfunction. Urodynamic studies in NPH patients tend to show a neurogenic-type pattern and may reveal an increased post-void residual. Persons with untreated NPH may be at increased risk of urinary tract infections (UTIs), owing to incomplete voiding. Those with recurrent UTIs may benefit from an antimicrobial prophylaxis. • Cognition: The cognitive profile of NPH is typically subcortical with frontally weighted deficits and relative sparing of language function. Not infrequently, NPH occurs in combination with diseases such as Alzheimer’s which may add elements of cortical, limbic, and paralimbic disturbances to the profile of cognitive dysfunction. Cognitive impairments in NPH usually manifest as disturbances of executive function, including difficulties carrying out multistep tasks, multitasking, formulating abstractions, and dividing attention. Memory can fail secondary to impaired information retrieval. Recognition memory is relatively preserved, as evidenced by performance improving with cues or multiple choice. This contrasts with Alzheimer’s disease, in which the information is rapidly lost from memory and may be neither recalled nor recognized. Language ability usually remains intact, although phonemic (letter) fluency and confrontational naming are decreased in conjunction with frontal systems deficits. Ideomotor praxis may be preserved, but some patients with NPH have difficulty transitioning from a standing to recumbent position, such as on an examining table. Screening tests such as the Folstein Minimental State examination may not be sufficiently sensitive to detect subtle frontal systems deficits in NPH. Timed performance-based tasks and tasks with frontal weightings are recommended to assess impairments in suspected cases of NPH. Tests such as Trails A and B, The Digit-Symbol test, tend to be sensitive to NPH-related deficits and improve with treatment. Certain tests of

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upper extremity function (Maze Drawing and Serial Dotting) have recently been found sensitive to impairments in NPH and are responsive to CSF drainage (Tsakanikas et al., 2009). Neuropsychological testing can be useful in documenting subtle cognitive dysfunction in mild stages of NPH and for tracking response to treatment. • Other findings: A variety of psychiatric disturbances ranging from psychosis and agitation to depression and anxiety disorders have been reported in association with NPH, either as exacerbation of pre-existing conditions or arising de novo. In some cases, psychiatric symptoms are responsive to treatment of hydrocephalus. Recent onset of hypertension has been reported in an unexpected fraction of patients with newly diagnosed NPH, leading to the speculation of a possible causal relationship. Decreased hearing and frank deafness have been rarely associated with NPH, but primarily in the aftermath of shunt placement instead of as a presenting symptom. The same is true of epilepsy, which may occur in as many as 10% of shunted NH patients.

Diagnostic criteria International consensus criteria for the diagnosis of iNPH were published in 2005 (Relkin et al., 2005). These evidence-based guidelines divide NPH into probable and possible subcategories, to reflect the level of certainty about the diagnosis. The guidelines also identify shuntresponsive NPH as the subset of cases that have a positive outcome from treatment.

Differential diagnosis The symptoms of NPH overlap those of several conditions that are common in elderly individuals. Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative conditions can manifest similar symptoms and may occur comorbidly with NPH. Spinal stenosis, arthritic conditions, and orthopedic disorders can cause gait and balance disturbances resembling those of NPH. Prostatic enlargement and a number of other urologic conditions can give rise to the urgency, frequency, and incontinence that is also associated with NPH. Differential diagnosis of NPH therefore requires careful exclusion of other conditions, and, in the cases with comorbidities, a determination of the extent to which symptoms are attributable to NPH.

Prognostication Some generalizations can be made about the likelihood of a positive response to shunt treatment based on demographic and medical history, and additional prognostication can be made on the basis of clinical tests:

• Prognosis for a positive response to neurosurgical treatment in NPH is better for patients aged 75 years or less, with duration of symptoms less than 2 years and a lack of serious medical comorbidities. A less favorable prognosis is associated with atypical presentations, advanced dementia, longstanding symptoms, confluent subcortical cerebrovascular changes, and concomitant anticoagulation therapy. • Several tests have been developed to estimate the likelihood that a person with NPH will respond positively to a shunt. These include techniques high volume (30–50 cc) lumbar puncture (LP) “tap tests,” 24- to 72hour external lumbar or ventricular catheter drainage, CSF dynamics studies, MRI CSF flow measurements, B-wave monitoring, radionuclide cisternography, and others. Positive results on these tests can indicate a more favorable prognosis for shunt response, but negative outcomes do not preclude benefit from a shunt. For that reason, these tests tend to be used selectively when the decision about whether to proceed to shunt must be balanced against increased risks. The likelihood of shunt responsiveness can be determined with up to 90% accuracy when prognostic tests are positive (Marmarou et al., 2005).

Treatment A distinctive feature of NPH is that its symptoms can be rapidly reversed by procedures that divert CSF out of the central nervous system. Temporary improvements can occur after LP, external lumbar drainage (ELD), and ventriculostomy. Lasting reversal of symptoms follows neurosurgical implantation of a ventricular shunt. Shunt placement is the standard of care for NPH and fosters excellent recovery in well-selected patients. Shunts are permanent implanted devices that serve as an alternative physical conduit for the outflow of CSF from the central nervous system. Shunts have many different designs and configurations, the full scope of which is beyond the scope of this chapter. The most basic configuration is a tube running from the cerebral ventricles to another location in the body in which drainage occurs by gravity. In most cases, however, a shunt valve is introduced between the two ends to control the rate and volume of drainage of CSF as the position of the head relative to the rest of the body changes. The most common types of shunts in use today are differential pressure valves that open when a certain pressure difference exists between the ventricular side of the shunt and its distal end, which is most often placed intra-abdominally. The shunt valve may be supplemented by an antisiphon device that prevents the valve from remaining open when gravity induces a rapid flow (siphon) effect.

Normal Pressure Hydrocephalus

Until the 1990s, most shunt valves had fixed opening pressures (low, medium, and high). An important innovation that changed the management of NPH was the advent of programmable valves that can be noninvasively adjusted post-operatively. Present-day programmable valves can be adjusted by magnetic or electromagnetic programming devices and can be set noninvasively to a wide range of opening pressures. This provides an opportunity to optimize the shunt function in individual cases and a way to adjust the extent of drainage. The settings of a programmable shunt can be interrogated by various means that are valve dependent, including magnetic compass devices, acoustic devices, and X-rays. The value of programmable shunts relative to reduction of shunt morbidity compared to fixed-pressure shunts has not been conclusively established, but they have given NPH patients and their physicians greater latitude to manage symptoms that would otherwise require repeated surgery. Although shunts can provide relief to well-chosen surgical candidates that persist for several years, the outcome of shunt placement is not uniformly positive. Shunts fail to provide improvement in some cases and are associated with operative and post-operative morbidity rates ranging from 10% to 80% in different case series (Bergsneider et al., 2005). Complications such as subdural hematomas, infections, and shunt blockage take a devastating toll on frail, elderly NPH patients and dramatically increase the costs of NPH care. Maximizing successful treatment of NPH requires accurate diagnosis and skillful clinical management by specifically trained healthcare professionals. LOVA may be treatable by endoscopic third ventriculostomy (ETV), a procedure that creates an alternative conduit for CSF flow through the floor of the third ventricle. ETV may be associated with lower morbidity than using a shunt to treat NPH, but it does not reverse symptoms in all cases. AS can also be treated by ETV instead of a shunt, making it an important condition to recognize and distinguish from NPH. Nonsurgical aspects of management are also extremely important for the care of patients with NPH. In both the pre- and post-surgical periods, vulnerability to falling is increased and appropriate steps should be taken to reduce fall risk. This can be promoted by prescription of a cane, walker, or, when appropriate, wheelchair. Modifications to the household should be considered for safety purposes, including but not limited to installation of grab bars in the bathroom and handrails on ramps and stairwells. Suitable candidates should be referred for physical therapy. A program of scheduled toileting may help those prone to UTIs or daytime incontinence, and prescription of prophylaxis against UTIs should be considered in some cases. Medications such as cholinesterase inhibitors that are approved to treat Alzheimer’s disease and dementia in Parkinson’s disease have not been formally evaluated

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in NPH but may have adjunct therapeutic value in some patients. The same may be said about dopamine precursors such as levodopa. Focal or generalized seizure may emerge after shunt surgery and should be addressed with antiepileptic medication if recurrent. Depression and other behavioral disturbances also occur in the NPH population and may require medication and/or psychotherapy. In patients with advanced symptoms or those who are not candidates for surgery, a home health aide or even institutionalization may become necessary. This is particularly the case for individuals who live alone or are more physically frail or severely demented.

Summary • NPH is a chronic form of adult hydrocephalus that is treatable and sometimes reversible. Idiopathic and secondary forms exist. Pathophysiology is incompletely understood. • Diagnosis of NPH requires evidence of ventricular enlargement disproportionate to cerebral atrophy on a brain imaging study and impairment in gait, balance, continence, and/or cognition. MRI or another brain imaging study is required. Clinical assessment must include appropriate history and physical examination. • The classic triad of gait ataxia, incontinence, and dementia is sometimes, but not always, present in NPH patients and can occur in other disorders. Impairments may be mild and/or in a single domain. Symptoms of NPH may overlap those of Parkinson’s disease, Alzheimer’s disease, and other disorders even when NPH occurs in isolation. • The cognitive profile of NPH is typically subcortical with predominant frontally weighted deficits. Not infrequently, NPH occurs in combination with diseases such as Alzheimer’s, which may add elements of cortical, limbic, and paralimbic disturbances to the cognitive profile. • Gait disturbance tends to be the most responsive to treatment. Balance, control of urination, and cognition follow, respectively, in terms of likelihood and time to improvement. • Invasive examinations such as lumbar drainage, infusion tests, and ICP monitoring may add to diagnostic and prognostic certainty but are not required in every case. • Neurosurgical placement of a shunt that diverts CSF away from the brain in a controlled fashion is the current treatment of choice for NPH. Ventriculoperitoneal shunt is the most common configuration. Shunt valves may be fixed- or adjustable-pressure types. Success rate can be as high as 90% but varies across centers. ETV, devices to alter CSF pulsatility, and medications are under study by are not of proven value in NPH.

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• Although mortality attributable to shunt surgery is generally low, post-operative morbidity from shunts is 10–15% or higher. Subdural hematomas and effusions are common complications. Seizures, infections, and shunt failures are among other serious adverse consequences. Factors such as advanced age, multiple medical comorbidities, extreme frailty, anticoagulation, and severe dementia increase the risk of adverse outcomes from shunt surgery. Accurate diagnosis, skilled surgical intervention, and careful long-term management are required to minimize morbidity and treat NPH successfully.

References Bateman, G. (2008) The pathophysiology of idiopathic normal pressure hydrocephalus: cerebral ischemia or altered venous hemodynamics? Am J Neuroradiol, 29: 198–203. Bergsneider, M., Black, P.M., Klinge, P., et al. (2005) Surgical management of idiopathic normal-pressure hydrocephalus. Neurosurgery, 57 (Suppl. 3): S29–S39. Boon, W. (1971) Steplength measurement for the objective evaluation of the pathological gait. Proc K Ned Akad Wet C, 74 (5): 444–448. Bradley, W., Bahl, G., and Alksne, J. (2006) Idiopathic normal pressure hydrocephalus may be a “two hit” disease: benign external hydrocephalus in infancy followed by deep white matter ischemia in late adulthood. J Magn Reson Imaging, 24 (4): 747–755.

Brean, A. and Eide, P.K. (2008) Prevalence of probable idiopathic normal pressure hydrocephalus in a Norwegian population. Acta Neurol Scand, 118 (1): 48–53. Hakim, S. and Adams, R.D. (1965) The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure: observations on cerebrospinal fluid hydrodynamics. J Neurol Sci, 2 (4): 307–327. Kiefer, M., Eymann, R., and Steudel, W.I. (2002) LOVA hydrocephalus: a new entity of chronic hydrocephalus. Nervenarzt, 73 (10): 972–981. Krefft, T., Graff-Radford, N., Lucas, J., and Mortimer, J. (2004) Normal pressure hydrocephalus and large head size. Alzheimer Dis Assoc Disord, 18 (1): 35–37. Marmarou, A., Bergsneider, M., Klinge, P., et al. (2005) The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus. J Neurosurg, 57 (3): S17–S28. Relkin, N., Marmarou, A., Klinge, P., et al. (2005) Diagnsosing idiopathic normal-pressure hydrocephalus. J Neurosurg, 57 (3): S2-4–S2-16. Tsakanikas, D., Katzen, H., Ravdin, L., and Relkin, N. (2009) Upper extremity motor measures of tap test response in normal pressure hydrocephalus. Clin Neurol Neurosurg, 111 (9): 752–757. Zaaroor, M., Bleich, N., Chistyakov, A., et al. (1997) Motor evoked potentials in the preoperative and postoperative assessment of normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry, 62 (5): 517–521.

Chapter 10 Depression in the Elderly: Interactions with Aging, Stress, Chronic Pain, Inflammation, and Neurodegenerative Disorders Douglas F. Watt Department of Neuropsychology, Cambridge City Hospital, Harvard Medical School and Alzheimer’s Disease Center/Clinic for Cognitive Disorders, Quincy Medical Center, Quincy, MA, USA

Summary • The separation-distress hypothesis of depression suggests that depression reflects a conserved neurobiological mechanism to terminate protracted separation distress. • Evolutionary perspectives also suggest that depressive withdrawal may have been selected to protect organisms from intrinsically unreachable goals, particularly, potentially fatal dominance conflicts and terminating other maladaptive forms of motivation and goal seeking. • Depressive illness may reflect hypertrophy and disinhibition of basic depressive shutdown mechanisms and/or disturbance of mechanisms that normally terminate depression upon social re-immersion. • DSM-IV criteria for depression emphasize a depressed mood (which is a fundamentally circular criterion) along with loss of interest and pleasure. • Chronic stresses of wide varieties but, most particularly, chronic forms of separation distress, chronic pain, or other chronic social stressors are potent depressogenic stimuli. Chronic pain combined with virtually any kind of chronic separation distress results in an extremely high incidence of depression. • The elderly are at elevated risk for depression due to their increased exposure to chronic pain, cognitive decline, loss of social supports, and other prototype stressors for depression. • Although SSRIs and other aminergic pharmacology are regarded as first-line treatments and are often times the only treatment patients receive, they are modestly effective at best, while individual psychotherapy, social support, and reduction of social isolation and other forms of chronic stress are underutilized and underappreciated as antidepressant interventions.

The heart asks pleasure first And then, excuse from pain And then, those little anodynes That deaden suffering; And then, to go to sleep; And then, if it should be The will of its Inquisitor, The liberty to die. Emily Dickenson

Introduction and overview: the problem space of depression Depression is our most common mental health condition, yet its fundamental underpinnings remain mysterious. It is also a condition to which the elderly may be exposed disproportionately, perhaps for many reasons. Factors may include increasing exposure to multiple and

profound social losses, increased psychosocial isolation, the stress of multiple age-related chronic and more acute illnesses, chronic pain syndromes, increased financial stress, and perhaps even just the intrinsic degradations and humiliations of aging itself. The biology of depression also appears to interdigitate with many other comorbidities of aging, including an intrinsic upregulation of inflammation (“inflammaging”)

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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and multiple neurodegenerative disorders, notably Alzheimer’s disease, a major comorbidity of depression in the elderly. A basic organizing hypothesis of this review is that depression reflects an evolutionarily conserved mechanism in mammalian brains, selected as a shutdown mechanism to terminate protracted separation distress, which, if sustained, would be dangerous for infant mammals. This fundamental shutdown mechanism remains available to more mature mammalian and human brains, particularly, those with certain polymorphisms in genetic endowment, early loss/separation trauma, or other predisposing factors, which can promote reactivation in relationship to almost any chronic stressor. Although depression must have an adaptive and evolutionary basis (or else it surely could not be so ubiquitous), depressive shutdown mechanisms can become “hypertrophied” and released from normal control mechanisms in vulnerable individuals to potentially yield the full spectrum of depressive illness, which is not adaptive. The neurobiology of depression remains a challenging puzzle box of correlates, involving changes in many biogenic amine and neuropeptide systems and alterations in neuroendocrine and immune function. We suggest that core factors form an interactive and even synergistic “depressive matrix,” arguing against any “single-factor” theory. We review core contributions to the biology of depression from stress cascades, inflammation, and alterations in multiple neuropeptide and monoamine systems. In contrast to single-factor theories, this review suggests synergisms between core neurobiological factors, as well as a recursive (looping) control architecture regulating both entry to and exit from depression. Such an interactive matrix of factors may help explain why such an enormous multiplicity of potential treatments are antidepressant, ranging from psychotherapy and exercise to multiple drugs, vagal and deep brain stimulation, and electroconvulsive therapy (ECT). Unfortunately, traditional biological psychiatric perspectives are almost totally “bottom up” (neglecting relationships between depression and social isolation and stress) and typically cannot explain why depression is such a pervasive problem or why evolution could have ever selected for such a mechanism. This hypothesis suggests, in practical terms, that a primary reduction of social isolation and increased social support might be a fundamental and highly cost-effective preventative measure in elderly at-risk populations. Exercise and diet may also have protective and preventative effects. Depression in the elderly must be understood in the context of the problem of depression in general. In addition, we must appreciate the unique constellation of factors that might promote depression in late life. Depression is surely an ancient issue for human beings at virtually every stage of the lifecycle, with references to depression appearing in many classical sources onward

from the earliest recorded human history. Depression may be both our most common and our most “mystified” emotional condition bringing patients into clinical contact with a health professional, not just in this country, but in most, if not all, Western technologic societies. Not only is it the most common emotional issue bringing patients to physicians and mental health professionals, but it is also probably substantially underdiagnosed (Lecrubier, 2007), with the true epidemiologic incidence of depression poorly charted, due to significant underreporting bias. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association [APA], 1994), lifetime risk for major depression is roughly 10–25% for women and 5–12% for men; given the many who never seek treatment and have highly motivated underreporting, however, these numbers are probably serious underestimates. If one were to include its milder forms or briefer depressive episodes, the lifetime incidence of some form of depressive-spectrum disorder would likely be much higher, perhaps as high as 80% or more. For unknown reasons, there is perhaps a twofold higher prevalence in females, potentially indicating that their emotional systems are more sensitive or more affected by the abundant stressors that promote depression. From a societal perspective, depression may exact a staggering human and economic cost—recent estimates place major depression as the third leading cause of disability worldwide and, overall, the single most expensive disorder confronting Western societies (including both the costs of treatment and lost productivity; World Psychiatric Association [WPA], 2002). Because depression may worsen many other medical conditions (Kessler et al., 2003), including being a significant risk factor for cardiac disease, immune dysregulation, obesity, and addiction, to name a few, the total human and economic costs associated with depression may be larger than what have yet been estimated. Although the popular media typically conceptualize depression as an “illness caused by a chemical imbalance,” with major pharmaceutical firms highly motivated to advance similar notions, most scientific literature suggests that depression should be treated as a syndrome and not as a distinct illness. Additionally, popular depictions of depression as “a chemical imbalance” are trivial, without a concurrent functional–psychological analysis, as all biologic conditions, including death, are accompanied by “chemical imbalances.” The “illness” categorization also begs the question of why evolution might have permitted, or even selected for, such a common process in the first place, a question rarely asked due to the equation of depression with maladaptive behavior. Equating clinical depression with maladaptation (implying that no selection processes would be involved), while understandable, is scientifically problematic if two core questions are thereby obscured: (1) Why is depression so common?

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(2) What evolutionarily conserved brain mechanisms promote depression? The neglect of such evolutionary perspectives may reflect, in part, psychiatry’s attempt to map psychiatric syndromes directly onto brain mechanisms while simultaneously ignoring the intervening neural systems that generate the core prototype emotional states in mammalian brains. (For a summary of these core affective processes, including fear, rage, playfulness, separation distress, lust, and maternal care, see Panksepp, 1998.) Curiously, this long-standing neglect of potential relationships between depression and mammalian-brain emotional systems exists side-by-side with vigorous ongoing efforts to develop and use multiple animal models in preclinical antidepressant drug discovery and testing. Although it is frequently presented in almost exclusively molecular and reductionist terms in mainstream psychiatry, evidence suggests that depression is a conserved mammalian brain process, with correspondingly ancient origins, possibly emerging concomitant with many other aspects of a highly social brain (Insel and Young, 2001; Baron-Cohen, 1999; Watt, 2007; Watt and Panksepp, 2009). It indeed may reflect an intrinsic and dark vulnerability in all highly social brains. Such considerations suggest a possible logic to the greater incidence of depression in females, as several authors have suggested that the female brain is intrinsically more social. It has already been argued that depression may represent a conserved mechanism to terminate protracted separation distress (Watt and Panksepp, 2009), a potentially fatal state for infant mammals separated from their conspecifics. It may also serve additional adaptive purposes in adult mammals, as a mechanism to withdraw from and terminate potentially fatal dominance conflicts (Neese, 2000). Our lack of an integrated picture of depression is evident in the dozens of neurobiologic correlates for depression presented in a voluminous literature, yet without any clearly defined mechanistic integration that might allow clinicians and researchers to link disparate facts to central generative mechanisms. So far, candidate “driving” mechanisms in depression are envisioned largely in neuromodulatory and biochemical terms, including some form of monoamine deficiency (Schildkraut, 1965), cholinergic overactivity (Janowsky et al., 1972), hypothalamic-pituitary-adrenal (HPA) stress axis alterations (Holsboer, 2000; de Kloet et al., 2005) that promote atrophic change in the hippocampus (Dranovsky and Hen, 2006), potential deficits in neuronal growth factors (Duman and Monteggia, 2006), and associated alterations in corticotropin-releasing factor (CRF), glucocorticoid receptor function, and brainderived neurotrophic factor (BDNF). A recent reappraisal of the role played by stress cascades has emphasized fundamental changes in the hippocampus associated with cortisol, effects countered by BDNF (Holsboer, 2000), coincident with the finding that antidepressants promote

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or restore neuronal proliferation and neuroplasticity in this brain region. Additionally, more recent ideas emphasize multiple alterations in other neuropeptide systems besides CRF, especially substance P, opioids, and oxytocin (Holsboer, 2003), as well as upregulation of dynorphin (the “dysphoric” or “paradoxical” opioid), which modulates the nucleus accumbens (Todtenkopf et al., 2004) and decreases motivation to seek rewards. There is also evidence for significant functional alterations in both glutamate and γ-aminobutyric acid (GABA), with evidence for both GABAergic downregulation and glutamatergic upregulation. However, the basis for these changes in both GABA and glutamate is unclear. Glutamatergic changes may be driven in part by possible upregulation of quinolinic acid, which acts as an N-methylD-aspartate (NMDA) agonist, due to alterations in pathways associated with upregulated pro-inflammatory cytokines (for review, see Muller and Schwartz, 2007). Because of the prolific roles in all brain functions of GABA and glutamate, so far with limited therapeutic implication for depression (Matsumoto, Puia, Dong, and Pinna, 2007) except for the mood-stabilizing ability of certain antiepileptic agents that inhibit excitatory drive/processes (such as affecting sodium channels), we note only the most promising new lines of evidence in this enormous field of research. Because of preclinical reports suggesting that blockade of glutamate might have antidepressant effects, recent clinical reports have now indicated that intravenous administration of ketamine, which blocks one of the glutamatergic receptors (the NMDA receptor), yields robust and rapid (within 2 hours, after a short dissociative effect) antidepressant effects that could last for several days to a week (Zarate et al., 2006). This study is part of a larger body of work suggesting that, in a variety of preclinical models, metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, as well as agonists at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, have antidepressant-like activity. Of course, how this antidepressant effect from NMDA antagonism is transduced in the brain remains uncertain, but it must be noted that glutamatergic stimulation of many subcortical brain sites can produce strong negative emotional arousals (Panksepp, 1998). In short, there is a complex panoply of neuromodulatory changes in depression, with very uncertain leading versus trailing edges, particularly given the enormous (and still incompletely mapped) interactions between many modulatory systems. In contrast with any simplistic notion about a primary “chemical imbalance” in depression, virtually every modulatory system that has been closely studied shows complex alterations in depression. A “prime mover” in this complex symphony of changes remains elusive. In addition to these traditional bottom-up neurochemical/neuromodulatory perspectives, there has been increasing evidence that depression involves fundamental

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changes in large-scale corticolimbic emotional networks (particularly, hyperactivity in Brodmann’s area 25, the subcallosal cingulate, particularly, in severe refractory depressions; Mayberg et al., 2005), along with shifts in baseline activation of a wide variety of corticolimbic systems, some appearing upregulated and some, downregulated. However, any putative functional integration of all these disparate candidate mechanisms is rarely, if ever, evident in the currently available literature. Might a more concerted focus on conserved mammalian emotional systems potentially coordinate many disparate and otherwise fragmented lines of biologic thinking about depression? If so, such approaches may eventually significantly improve biologic treatments of depression and better clarify and refine psychotherapeutic practices as well. It may also help eventually coordinate the growing numbers of putative neurochemical correlates and causes into a more coherent theoretical framework than presently exists.

A multifaceted separation-distress hypothesis of depression The many brain changes in depression may be differential manifestations—different “faces”—of a fundamental shutdown process, reflecting ancient and evolutionarily conserved mammalian brain mechanisms aimed at the termination of separation-distress responses (see Watt and Panksepp, 2009 for a comprehensive review). In Bowlby’s (1980) terms, the shift from a “protest” to a “despair” phase following social losses suggests a conserved psychobehavioral shutdown mechanism that may initiate and promote depression. The evolutionary adaptation (“purpose”) of such a shutdown mechanism may have been the benefits of terminating protracted separation distress, particularly in younger and infant mammals. Sustained separation distress (crying) would likely prove fatal, either by alerting predators to prey availability or by metabolically exhausting small infants if they remained in a protracted panic phase. Analogously, the protest that follows the loss of other rewards, as well as other homeostatic losses (such as illness and chronic pain), may also engender depressive shutdown. Depression is fundamentally connected to social attachment, social status, and comfort and its many vicissitudes. This is not a new idea, but the possibility that the fundamental neuroscience of depression could be better integrated under this affective neuroscience umbrella is a relatively novel idea within biologic psychiatry. One could contrast this potential social biology view of depression with classic molecular reductionism and argue that mere “brute-force” cataloging of dozens of neurochemical changes is not optimally heuristic or integrative. The prevailing radical reductionism in mainstream psychiatry still envisions that one can jump from molecules and similar brain details all the way to highly complex psychiatric

diagnostic categories and organized behavior, with no psychologically meaningful or evolutionarily grounded neuroscience of emotions in between, almost as if the psychological properties of the brain and its adaptive mandates are irrelevant to the predominantly molecular analysis.

Previous evolutionary views of depression Evolutionary perspectives on depression have not been prominently featured in mainline psychiatric journals. The first major volley occurred at the beginning of this new century. Neese (2000) argued that depression might serve several adaptive purposes, including communicating a need for help, as well as signaling submission in social hierarchy conflicts, where one has little chance of winning and considerable chance of losing and being seriously injured or even killed (Malatynska et al., 2005). Thus, depression might provide a mechanism for disengaging from unreachable goals and for regulating patterns of maladaptive emotional investment and motivation. The idea that social loss leads to depression was perhaps first articulated in the 1970s and 1980s (Bowlby, 1980; Reite et al., 1981), but it remained without substantive neuroscientific foundations until fairly recently. Since then, several other contributions, following themes advanced by Nesse, have emphasized that brain mechanisms promoting depressive states must have an evolutionary basis; otherwise, they could not exist. More recently, Keller and Nesse (2006) have argued that not only was there selection for depressive mood, but also that depression may come in subtypes according to the particular type of adaptive challenges for which an organism has no viable solution to cope with, especially when sustained efforts to pursue difficult goals may result in danger, loss, injury, or wasted effort. In such situations, depressive “pessimism” and lack of motivation may provide a fitness advantage by virtue of inhibiting actions when one has inadequate resources or plans, particularly when challenges to dominant figures may be hazardous. Depression could thus confer a significant fitness advantage by terminating risky or damaging dominance conflicts. These arguments are complementary to our main hypothesis, which focuses on the adaptive value of terminating protracted separation distress, especially for young and vulnerable infants. Separation distress is indeed intimately coordinated with the generalized HPA stress response that has been a mainstay of depression research, in humans as well as animal models (Henn and Vollmayr, 2005; Keck et al., 2005; Maier and Watkins, 2005). Shutdown mechanisms activated in early-life separation-distress episodes could be recruited later in life in relation to social losses experienced in dominance–hierarchy conflicts. Indeed, it seems more likely that evolution would select a mechanism if it could “kill several birds with one stone,” so to speak.

Depression in the Elderly

A critical review of DSM-IV criteria for major depressive episode As with every syndrome in DSM-IV (APA, 1994), there are no objective or laboratory diagnostic tests for the presence of depression, even though biomarkers—abundant brain abnormalities—have been demonstrated at both structural and biochemical levels. Indeed, given the lack of bona fide objective tests for depression beyond a compilation of symptoms approach favored in DSM-IV, there is probably no absolutely clear line distinguishing someone with a mild form of clinical depression from those who are simply having a difficult time in the course of day-to-day existence and are simply mildly to moderately dysphoric. This may further underline the ubiquitous nature of depressive-spectrum phenomena. The DSM-IV criteria for a major depressive episode are the following: (a) Five (or more) of the following symptoms have been present during the same 2-week period and represent a change. At least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1 Depressed mood most of the day, nearly every day (NED), as indicated by either subjective report (feels sad or empty) or observation made by others (appears tearful). Note: In children and adolescents, it can be irritable mood. 2 Markedly diminished interest or pleasure in all, or almost all, activities most of the day, NED (as indicated by subjective account or observation). 3 Significant weight loss when not dieting or weight gain (a change of more than 5% of body weight in a month), or decrease or increase in appetite NED. Note: In children, consider failure to make expected weight gains. 4 Insomnia or hypersomnia nearly every day. 5 Psychomotor agitation or retardation NED (observable). 6 Fatigue or loss of energy NED. 7 Feelings of worthlessness or excessive or inappropriate guilt (may be delusional) (not merely self-reproach or guilt about being sick) NED. 8 Diminished ability to think or concentrate, or indecisiveness NED (either by subjective account or as observed by others). 9 Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a plan, or a suicide attempt or a specific plan for committing suicide. (b) The symptoms do not meet criteria for a mixed episode. (c) The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. (d) The symptoms are not due to the direct physiologic effects of a substance (such as a drug of abuse or a medication) or a general medical condition (such as hypothyroidism). (e) The symptoms are not better accounted for by bereavement (APA, 1994).

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Several issues are worth noting in regard to these criteria. First, the criteria cut across the entire hierarchy of functional domains of the brain (cognition, emotion, and homeostasis) and involve cognitive disruption (especially criteria 8 and, to a lesser extent, 9), obvious changes in emotion/mood (criteria 1, 2, 7, and 9), and altered homeostasis (criteria 3–6), with sleep and appetite typically disrupted, but also sexual functioning, endocrine status, and, more recently appreciated, immune status, all altered in depression. Core criteria emphasize either (1) depressed mood or (2) loss of interest or pleasure as required for a diagnosis of major depression. Unfortunately, the notion of a “depressed mood” as a central diagnostic criterion for depression is strikingly circular, a circularity rarely commented on or even acknowledged in psychiatric circles. Also, unfortunately, the criteria fail to make a careful distinction between sadness and depression, using them as rough synonyms, a recurrent problem in the psychiatric literature. We argue instead that these states have to be viewed as quite distinct, albeit potentially related. They are commonly conflated in part because they are found together, in many instances. In other words, patients are simultaneously both sad and depressed, a coincidence of states underlining that depressions are often reactions to losses; many depressions, however, especially retarded and more severe ones, show no sadness whatsoever, suggesting that sadness is actually terminated by deepening depression and supporting our core hypothesis. Additionally, we argue that the core criteria of depressed mood necessarily indexes a fundamental loss of hopefulness—in other words, “depressed mood” means an intrinsically less hopeful mood and orientation. Depression means that we no longer anticipate or expect good things to happen. Indeed, in our judgment, it is a curious omission that hopelessness is not specified at all in the DSM-IV criteria, even though despair and loss of hope probably have a quite fundamental connection to suicidal ideation and wishes to die. Earlier, DSM II and DSM III criteria did reference hopelessness, but for uncertain reasons, this notion has been pulled out of the more recent versions of DSM diagnostic criteria. Although “hopefulness” is not easily defined and operationalized (perhaps leading recent revisers of DSM to drop hopelessness as a criterion), hopefulness is traditionally contrasted with its antonyms, hopelessness and despair. Although depression is, in a sense, more complex than simple despair, these considerations suggest intrinsically close linkages between loss of hope and depression. Perhaps one of the clearest operational indices of hopefulness may be an organism’s willingness to struggle with adversity. Indeed, this ability to struggle with adversity without giving up the pursuit of rewarding activities or abandoning our social connections may directly index a fundamental emotional resilience and resistance to depression. This intrinsic connection between hopefulness and a willingness to struggle is implicit in one of the most important behavioral

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tests frequently used to evaluate potential antidepressants in the animal literature—the “forced swim test.” In this very important sense, depressed individuals lose their fundamental willingness and ability to struggle with challenging circumstances and basically give up. This “giving up” of core organism goals is a fundamental dimension to depression that any candidate theory must at least attempt to explain, and it certainly suggests that depression must have fundamental inhibitory effects on basic motivational systems in the brain, especially the complex brain network “energized” by the ventral tegmental mesolimbic dopamine system (conceptualized in Panksepp, 1998 as a generalized motivational arousal, or “seeking” system). Indeed, if our core hypothesis about depression is correct—namely, that it emerges from an evolutionarily selected mechanism to terminate protracted separation distress—such a putative shutdown mechanism would have to negatively feed back on central motivational arousal mechanisms in the brain and attenuate the ability of those mechanisms to energize behavior. Dynophin appears ideally positioned between chronic stress and VTA modulation to help achieve such a shutdown of motivational machinery. The second core criterion in DSM-IV for major depression (after depressed mood) is anhedonia and loss of interest. Interest in a wide variety of stimuli and pursuits in the world, and the anticipation of reward, may be intrinsically related both to the operation of the ventral tegmental mesolimbic–mesocortical “seeking” system (Panksepp, 1998) and to social rewards garnered in individuals with low activity in separation-distress systems and high activity in maternal care and “play” systems. Taken together, this suggests that depression may fundamentally disrupt both the anticipation and the pursuit of rewards (“interest”), along with a diminished ability to experience pleasure, even when rewards are available and obtained. We argue that this loss of interest and anhedonia are also fundamental phenomena that any heuristic theory must attempt to explain. Although loss of interest and loss of pleasure are treated as one homogeneous entity in this important criterion, evidence suggests that these are probably separate issues, with loss of interest more dopamine-related and loss of pleasure more opioidergic (for a thorough review, see Berridge, 2004). None of the subsequent seven criteria after these first two are necessarily required for the diagnosis of depression, but one must have at least four of the other “subordinate” criteria and either depressed mood or loss of interest/pleasure to meet diagnostic criteria. This approach (“at least one from column A” and “at least four from column B”), with two core criteria and seven secondary criteria, allows the DSM-IV diagnostic criteria to at least partially cover the challenging heterogeneity of depression, without prematurely committing to a subtyping paradigm (when subtypes are still not completely understood or extensively validated in the literature).

A brief neuroscientific overview of depression Due to space considerations, in-depth coverage of neurobiologic work on depression is not feasible. We instead emphasize heuristic (“big picture”) summation, particularly how multiple neurobiologic processes may interdigitate and form recursive and looping control factors that regulate both entry into and exit from depressive states. Aside from the general acceptance that severe life stress is a prominent factor in the genesis of depression (see Holsboer, 2000; Vollmayr and Henn, 2003), the largest “bin” in the neurobiology of depression “box” would clearly be classic neurotransmitter perspectives. Classically, the earliest hypotheses about depression centered on the first three monoamines characterized in the brain—norepinephrine, serotonin, and dopamine—along with the first transmitter discovered in the brain, in the 1920s, acetylcholine. The monoamine deficiency hypothesis, with a focus on norepinephrine deficits, is the oldest neurochemical hypothesis about depression (Schildkraut, 1965; for an update of the classic monoamine hypothesis, see Harro and Oreland, 2001). However, simple aminergic deficiency as an explanatory hypothesis has fallen by the wayside and been largely discredited, in the context of enormous evidence that depression is significantly more complicated than a simple “deficiency” state in any monoaminergic system, singly or even collectively (for a summary of the history, see Healy, 1997). The strongest data points against a simple noradrenergic (NE)/serotonergic (5-HT) deficiency hypothesis are: (1) the failure of norepinephrine or serotonin synthesis inhibition to create depressive symptoms in normal individuals, even though it can diminish mood in recently depressed individuals (Delgado et al., 1990); and (2) the lack of rapid amelioration of depression following the rapid onset of reuptake inhibition of various noradrenergic and serotonergic antidepressant drugs, resulting in significantly more synaptic availability of biogenic amines in forebrain areas within hours of ingestion (Delgado, 2000, 2004). Antidepressant efficacy for these classic amine facilitators occurs weeks later. Although the classical viewpoint has been that the therapeutic effects are associated with an active downregulation of receptors and/or their active pruning in the forebrain, more recent hypotheses have focused on a variety of neuronal growth and neuroplasticity factors modulated by aminergic tone (Stone et al., 2003, 2008). In addition to older hypotheses emphasizing the role of norepinephrine and serotonin, more recently, monoamine perspectives have increasingly focused on dopamine as well, particularly given its superordinate role in motivated behavior (Panksepp, 1998; Ikemoto and Panksepp, 1999; Alcaro, Huber, and Panksepp, 2007; Berridge, 2007). Also, mounting evidence now indicates that multiple other neurotransmitter systems, including GABA,

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glutamate, and multiple neuropeptides (CRF, substance P, cholecystokinin, dynorphin and other opioids, and oxytocin), may also be centrally involved in depression. Many aminergic and peptidergic neurotransmitter systems intimately coregulate each other in ways still incompletely understood, adding layers of complexity to any purely ‘modulator-centric’ neuroscientific understanding and treatment of depression (Wong and Licinio, 2001; Norman and Burrows, 2007; Stone et al., 2008). Additionally, much thinking about depression has been guided by depression’s intimate connection to alterations of the HPA axis (for example, hypercortisolemia promoting hippocampal atrophy; McEwen, 2004; Warner-Schmidt and Duman, 2006; Drew and Hen, 2007). Moreover, increasing evidence argues for an important role for pro-inflammatory cytokines in the modulation of mood and for a primary role in depression, including critical effects on the HPA axis that prevent hypercortisolemia from renormalizing the stress axis by negative feedback on CRF (Leonard, 2006). In addition to these more traditional bottom-up neuromodulatory perspectives, the neuroscientific and clinical literature on depression has increasingly focused on the possibility that depression may reflect some kind of fundamental alteration in corticolimbic networks. Recent work suggests that mood and self-related emotional information processing probably reflect changes and dynamics within highly distributed medial subcortical–cortical networks (Northoff and Panksepp, 2008). Regions of interest in such distributed network formulations would centrally include the prefrontal systems, the hippocampus, the ventral or limbic stratum, and particularly the shell of the nucleus accumbens/olfactory tubercle, along with several other subcortical limbic and paleocortical paralimbic structures, including periaqueductal gray (PAG) (Watt, 2000; Liotti and Panksepp, 2004; Northoff et  al., 2006). Such a distributed network effect is seen when stress reduces reward-seeking through a global reduction of mesolimbic dopamine transmission, partly by the capacity of upregulated dynorphin to make this whole hedonic network less responsive (Nestler and Carlezon, 2006). Considered jointly, these distributed network and neuromodulatory perspectives suggest that depression may reflect global changes in large-scale reticular-limbic– cortical networks critical to “seeking” (basic motivational arousal) and associated exploratory behavior. Therefore, they would also be critical to energizing primary attachment behavior. Attachment behaviors centrally involve the seeking of proximity to objects of attachment and an associated pursuit of multiple rewarding of positive affective states in the context of those social connections, particularly the rewards of playfulness and affection, and the seeking of comfort when distressed. All of these fundamental aspects of social seeking and attachment are shut down, if not profoundly unavailable, to depressed

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individuals (but not to individuals who are merely sad, underlining this distinction). Basic neurobiologic perspectives emerging from our current penchant for molecular reductionism must be integrated with the long-standing intuitive insight that depression is fundamentally related to the brain’s reaction to emotional/social loss. This is particularly noteworthy when the subject feels a keen helplessness to mitigate the loss or when the loss is especially penetrating and hurtful. This is not to suggest that molecular perspectives and a view of depression as related to the vicissitudes of attachment are in any way mutually exclusive. On the contrary, we believe that this more social view of depression, in which depression becomes a dark vulnerability of a highly pro-social brain, dependent on intimate social connection for its fundamental sense of well-being, may eventually better integrate an enormous amount of molecular data.

The challenging multifactorial nature of depression: depression and the social brain Although play, empathy, social bonding, contagion (the social  “infectiousness” of prototype emotions), and separation distress are all largely viewed as discrete processes in neuroscience and investigated quite independent of one another, we argue that these putatively disparate phenomena could be considered interlocking threads, somehow jointly forming the full fabric of a deeply social brain. Therefore, it seems reasonable to us that these processes were selected in an integrated manner by related evolutionary pressures. Each of these phenomena is part and parcel of a truly social brain, in which the pleasures of social connection and the pains of social loss are all first-rank motivators. Consistent with this viewpoint emphasizing the multicomponent nature of a highly social brain, one might suggest that a vulnerability to depression is probably intrinsic within this complex multidimensional fabric of a social brain. Some social brains are clearly more vulnerable to this; some are more resilient and resistant. Individuals with fortunate genetic endowments and supportive and loving upbringings may have intrinsic and robust protection against depression, but even those with more resilient genetic endowments and environmental good fortunes are never totally or permanently protected from the reach of intrinsic depressive mechanisms. At least some degree of depression lies only a major catastrophe away for almost everyone. At present, where radical reductionism and individual neurochemical vectors are receiving primary attention in psychiatry, more integrated (big-picture) psychobiologic views of depression are badly needed. However, typical modes of scientific analysis are obviously not well suited

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for conducting the massive multifactorial studies that such integration would require. Thus, we are left to patch together more holistic levels of understanding from the many factual parts that scientific empirical treatments can spew out in abundance. However, the current tendency to de-emphasize possible primary psychological dimensions in depression within much of molecular psychiatry is, in our estimation, not as likely to lead to a satisfactory integration of all the available pieces of this challenging puzzle. Future work will need to better integrate the many factors that have been identified by existing molecular approaches, summarized earlier and encompassing three monoamine systems: the cholinergic system, multiple neuropeptide systems including multiple opioid systems, the neuroendocrine/stress axes, and immune/cytokine issues. Although it is easy to assume by the current state of the art that these factors constitute all the important pieces of the puzzle, further research may underline that even this impressive collection of factors falls well short of a complete story. This brings us to another touchstone concept. Attempting to delineate unitary “first causes” or “prime movers” in a system as massively recursive and interactive as the brain may be a mostly doomed enterprise. From this perspective, the potential interactions between factors has received overall far less “air time” in the history

of writings on depression than the many proposals promoting single- or primary-factor theories. In general, however, recent work seems more open to multifactorial points of view. Instead, it may be more heuristic and much more practical to think in terms of an interactive matrix of factors that can lead to depression, but where individual variability might map to differential loading of various core factors (suggesting, among other things, that future optimal treatment of depression may require individually tuned multidimensional approaches). As Table 10.1 delineates, these presumed core neurobiologic factors regulate and massively influence one another. This suggests that any individual mind “lurches,” in a sense, sometimes rather unpredictably through a complex trajectory of neurochemical–neurodynamic space as these factors cascade and reverberate in one direction or another, in any particular instance of depression. This multifactorial nature may also help to explain why so many different therapies, ranging from exercise and psychotherapy to ECT and deep brain stimulation, are antidepressant. Although we are a long way from being able to explain why one antidepressant therapy works in one depressed individual and not in another, we suspect that an answer to this also lies somewhere in a deeper understanding of the dynamic relationships between these primary core factors in a depressive matrix. Although it has been long

Table 10.1 Neurobiologic factors: an interactive depressive matrix Depressive factor

Driven by

Producing

Behaviorial and symptomatic correlates

Increased CRF, hypercortisolemia, choleocystokinin, and reduced BDNF

Multifactorial limbic influences on paraventricular nucleus, promoting activation of HPA stress axis

Increased dynorphin, decreased 5-HT, reduced neuroplasticity/HC atrophy, intensification of separation distress, disrupted ventral HC feedback on core affective regions

Dysphoria, sleep and appetite loss, reduced short-term memory, and other cognitive deficits

Increased acetylcholine

Reduction of social and other rewards, opioid withdrawal, and any other social punishment

Facilitation of separation distress circuitry and other negative emotions, effects on other core variables

Negative affect and excess attention to negativistic perceptions and thoughts

Decreased μ-opioids and oxytocin

Separation distress and other stressors, including physical illness and pain

Disinhibition/release of stress cascades, decreased 5-HT and DA, overdriven NE, promotion of cytokine generation

Anhedonia and sadness, reduced positive affect, reduced sense of connection, suicidality

Increased dynorphin in accumbens/VTA

Stress cascades

Downregulation of VTA and mesolimbic DA system

Anhedonia, dysphoria, loss of motivation

Increased cytokines

Acute but probably not chronic stress, acute reduction of opioids

Promotion of stress cascades, decreased serotonergic and increased glutamatergic tone, impairment of HPA axis negative feedback

Fatigue, malaise, and appetitive losses; increased cognitive disruption; anhedonia

Reduced serotonergic drive/vulnerability

Stress, increased corticosteroids, cytokines, decreased μ-opioids

Lowered dopaminergic and increased noradrenergic drive, less functional segregation among brain systems

Poor affective regulation, impulsivity, obsessive thoughts, possible disinhibition of suicidality

Diminished catecholaminergic (DA and NE) tone

Constitutional vulnerability, stress and poor reward availability

Reduced “signal-to-noise” processing in all sensory–perceptual and motor/ executive systems

Fatigue, diminished psychic “energy,” appetitive sluggishness, dysphoria, impaired coordination of cognitive and emotional information processing

HC, hippocampus; 5-HT, serotonin; NE, noradrenergic; DA, dopamine; VTA, ventral tegmental area.

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thought in psychopharmacology that everyone’s chemoarchitecture is different, interactions between these core factors in a depressive matrix may also be differentially “gated” across different individuals. This may eventually allow us to answer the long-standing question of why, in an individual clinical instance, one treatment works and another does not. This review underscores an oft-neglected relevance of opioids and oxytocin for understanding depressive cascades, as critical modulators for social connection and social bonding, and how a strong social connection protects brains against depression-generating chronic stress states. Table 10.1 underlines what we consider to be the handful of core factors constituting this “depressive matrix.” Core factors may consist of (1) diminished tone in opioid and oxytocin systems associated with separation distress; (2) altered and chronic stress neurophysiology promoting upregulation of CRF and hypercortisolemia, leading to hippocampal atrophy and the failure of negative feedback on the stress axis; (3) alterations in numerous amine as well as peptidergic neuromodulatory systems, and choleocystokinin- and dynorphin-induced negative affects, creating inhibitory feedback on the ventral tegmental system dopamine and other catecholamine systems that sustain “energized,” goal-directed bodily and mental activities; (4) a critical role played by the immune system, specifically pro-inflammatory cytokines, which appear synergistic with stress cascades. Cytokines may directly or indirectly promote glutamatergic overdrive and contribute to a hypotonic serotonin system as well (Muller and Schwartz, 2007); they further promote withdrawal, fatigue, and behavioral and affective shutdown, impairing HPA axis regulation by disrupting negative feedback inhibition of CRF (Schiepers et al., 2005). Evidence indicates that social disconnection and separation distress (associated with changes in both μ- and κ-opioid systems) result in potentiated stress cascades and increased cytokine generation (Hennessy et al., 2001). We believe that these interlocking pieces of a puzzle fit together, as differential facets of a basic depressive cascade, although the seams between the pieces cannot be completely stitched together at this time. This view of depression emphasizes the critical importance of social support, in both the long-term protection against depression and its more acute and subacute therapeutic management. Our perspective underlines that social relations have a close relationship to the neurobiology of depression due to their intrinsic connections of social biology to the stress axis, cytokine promotion, modulation of critical growth and neurotrophic factors, and modulation of multiple neuropeptide and amine systems. We believe that the current treatment climate in psychiatry could significantly benefit from such an adjustment in emphasis. Psychotherapy and social support have fallen off the radar in the treatment of many

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patients with depression, due to a largely bottom-up neurochemical view of both etiology and treatment, often to the detriment of basic patient care (Rush, 2007); many patients with depression receive only psychopharmacology, with classic aminergic agents often being modestly effective, at best (see the section “Treatment algorithms in relationship to depression in the elderly”). Opioids and oxytocin, maintained tonically in securely attached creatures, exercise a powerfully inhibitory effect on basic stress cascades. The protracted downregulation of these systems in the context of protracted separation distress may tonically facilitate stress responsivity. The promotion of CRF and the downregulation of opioids and oxytocin may rapidly shift the affective state of the brain from a more euthymic to a more dysthymic one. The older view of stress cascades failed to adequately credit their role in affective changes, viewing changes in the HPA axis as if they were just physiologic changes instead of ones that created psychological change. For a long time, there has been comparative neglect of factors known to regulate separation distress and social attachments, namely opioids and oxytocin systems, in preference for noradrenergic- and serotonergic-centered viewpoints. Also generally neglected until recently within the overall puzzle were peptidergic variables most intimately and directly related to mood (μ- and κ-opioids, cannabinoids, cholecystokinin, CRF, dynorphin, and oxytocin). Protracted stress, the most prototypical being separation distress arising from social loss, may create an altered balance in μ-, δ-, and κ-opioids and oxytocin. Promotion of dynorphin and cholecystokinin tone, especially in the nucleus accumbens and VTA, and the resulting loss of motivation, including centrally the inhibition of attachment-related needs/drives, potentially transform separation distress from an acute (protest) phase to a sustained chronic (despair) phase. This shutdown is assisted by the potential fatigue/sickness-promoting effects of pro-inflammatory cytokines. These parallel changes drive global inhibition of many specific motivations, from food appetite to erotic pursuits, generating a generalized anhedonia (with active dysphoria) and, thereby, loss of a more hopeful orientation toward life opportunities and normal reward seeking. Altered homeostasis, particularly sleep and appetite, may be caused not only by elevated CRF effects on several homeostatic and circadian hypothalamic systems, but also by the diminished influence of prosocial neuropeptides. Such a sustained dysthymic mood may promote negative cognition (which, in turn, may help sustain negative mood via positive feedback effects of sustained ruminations). The hypofunction in prefrontal and hippocampal systems, perhaps associated with several neuromodulatory shifts and the effects of excessive cortisol, results in the characteristic attentional, executive, and mildly amnestic cognitive deficits of depression. Thus, even the most generous allowance

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for the causal role of a single factor may not come close to explaining all the changes that constitute a full-blown depressive episode. The variety of brain–mind factors that can contribute to depressive affect also underscores that surely not every depression is precipitated simply by attachment losses, or even by symbolic (such as social status) losses. Anhedonia and dysphoria can have various causes, including endogenous neurochemical imbalances of the brain and withdrawal from various drugs of abuse. Polymorphisms of multiple genes involved in the neurochemical underpinnings of affective homeostasis can also presumably modify the thresholds for the induction of the various stress and affective cascades. However, it is now also clear that early separation distress can promote lifelong dysregulation of hedonic homeostasis, leading to the disinhibition of negative affective processes and stress cascades. This combination of incompletely mapped genetic and somewhat better understood early environmental factors results in the potentiation of future depressive processes more easily triggered by any severe chronic form of stress, besides the classic precipitation by various forms of separation distress. In fully considering the long-term consequences of early stress, we can envision how the whole system of regulatory controls over intrinsic depressive mechanisms becomes epigenetically more fragile over the entire lifespan (Mann and Courier, 2010). The precise manner in which that happens remains important chapters for both future animal-brain and human developmental research. Of course, due to the challenging heterogeneity of depression (and virtually every other Axis I condition in psychiatry), we must remain open to the possibility of several distinct types of unipolar depression that we cannot yet clearly differentiate unambiguously, either with differential symptom clusters or with biomarkers. Just as the neurobiologic correlates of depression appear very multifactorial, developmental issues contributing to lifetime vulnerability in depression appear equally so. Recent developmental modeling (Kendler et al., 2006) confirms this multifactorial nature of developmental pathways into depression, outlining a host of “outside the skin” factors that presumably interact with multiple “inside the skin” neurobiologic variables in a fashion still poorly plotted. Kendler et al. (2006), found, using a sophisticated statistical algorithm, that roughly half of the variance for major depression in males can be explained by 18 factors and their interactions: genetic risk, low parental warmth, childhood sexual abuse, and parental loss (early childhood factors); neuroticism, low self-esteem, early-onset anxiety, and conduct disorder (early adolescence factors); low educational achievement, lifetime traumas, low social support, and substance misuse/abuse (late adolescence factors); history of divorce and past history of major depression (adult fac-

tors); and factors taking place in the last year (last-year marital problems, other personal difficulties, and stressful life events). How these factors might intersect in the brain remains uncertain. Similar modeling was done for females in an earlier study, with slightly more than 50% of the variance explainable in terms of a similar complex of factors (Kendler et al., 2002). Given that even with such a complex matrix of predisposing variables, they could explain only slightly less than 50% of the variance further underlines the challenging heterogeneity of depression in terms of its multifactorial developmental pathways. In addition to the risk factors outlined in these models, it seems obvious that chronic pain and perhaps numerous other chronic illnesses can be powerfully depressogenic, by virtue of chronic activation of stress and immunologic/cytokine cascades and relative hypoactivation of μ-opioid systems that may require not just social comfort and secure attachment, but also general physical wellness for their maximum tonic promotion (Panksepp, 1998).

Implications for an understanding of common factors promoting late-life depression Such a pleiotropic view of depression suggests several potential bridges to the problem of depression in the elderly. Elderly women again show a greater incidence of depression than elderly men, consistent with the greater penetration of this syndrome in females throughout the entire lifecycle. The elderly who undergo loss of loved ones (especially spouses), increased social isolation due to loss of friends or other social supports, loss of meaningful and rewarding activities (often due to illness or disability), or virtually any major health problem (Kaji et al., 2010) appear most at risk overall. Most obviously and probably most importantly, many elderly are exposed to severe and even catastrophic social losses, in terms of the death of their spouses and friends. In our view, this is a primary and powerful trigger for depressive episodes. Many elderly must deal with primary losses of critical attachment figures, which then leads to significantly increased social isolation, and from there, to significantly increased risk of depression (Cacioppo et al., 2010). Evidence indicates that social isolation also increases the risk for acute medical illness, with acute illness representing an additional pro-depressive stressor to which the elderly are differentially exposed, relative to younger adults (Kaji et al., 2010; Molloy et al., 2010.) An additional major point of intersection between aging and depression may rest in extensive comorbidities between pain and depression. Recent work shows that chronic pain syndromes, recently found to be the most common degrading influence in overall health status and sense of well-being in the elderly over 75 (at

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least in Europe—this has not yet been replicated in the United States), are a powerful pro-depressive influence to which the elderly are differentially exposed (Konig et al., 2010). Comorbidity of depression with chronic pain has been associated with both poorer prognosis and greater functional impairment, compared with those suffering from each illness separately (Arnow et al., 2006). Rates of depression in patients with chronic pain have been reported to range from 30% to 60% (Miller and Cano, 2009), many times higher than incidence in the general population. More severe and persistent pain also increases the incidence of more severe depression and, not surprisingly, is concomitant, with a stronger association toward suicidality (Fishbain et al., 1997). Depressed patients have a four times greater risk of chronic pain, compared with nondepressed patients (Simon et al., 1999). Chronic pain is a risk factor for subsequent development of major depression, while depression is a risk factor for the development of chronic pain (Maletic and Raison, 2009). These fundamental intersections between pain and depression are still incompletely understood but may rest in significant neuromodulatory, stress axis, neural network, and even genetic factors that overlap between the two conditions. Both depression and pain are associated with key alterations in opioid and other neuropeptide systems; increased stress axis activation; changes in dopamine, serotonin, and glutamate systems; and promotion of cytokine/inflammatory processes. Both conditions also recruit functional changes in similar distributed corticolimbic networks (involving prefrontal, medial frontal, insular, and several classic limbic system structures such as hippocampus, amygdala, and nucleus accumbens; see Narasimhan and Campbell, 2010 for a detailed review). In relation to the most immediately relevant neuromodulatory system, that of μ-opioids, both pain and depression might reflect low ebbs in complex subcortical/paleocortical opioidergic systems, signaling basic homeostatic wellness (see de Kloet et al., 2005 for confirmation of primary opioidergic involvement in sadness and separation distress). An intriguing hypothesis about an evolutionary continuity between pain and depression is suggested by the hypothesis that separation distress may have emerged from pain systems (Panksepp, 1998). If our earlier evolutionary hypothesis is correct (that depression was selected as a way of terminating protracted separation distress), pain, as an evolutionary antecedent to separation distress, might constitute a potential primary trigger for depression. Of course, much work remains to clarify (or falsify) such intriguing hypotheses, yet the importance of the common clinical comorbidity of pain and depression cannot be denied, however incompletely we may understand their intersection. An additional nontrivial point of intersection is that both conditions are probably significantly underdiagnosed and all too frequently missed in primary care.

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Additionally, given the relationship between depression and pro-inflammatory signaling cited earlier (also see Pasco et al., 2010), the increased level of inflammatory “tone,” thought to be possibly intrinsic to aging (“inflammaging”; Franceschi et al., 2007), suggests another important potential relationship between aging and increased intrinsic vulnerability to depression. Pro-inflammatory cytokines can function as regulatory signals, with a substantial inhibitory effect on various hormones and neural growth factors, many thought to sustain neuroplasticity and mood. Sustained pro-inflammatory activity has been thought to be a potential pathologic factor in the development of many diseases of aging, including IBS (inflammatory bowel disease), type II diabetes, cardiovascular and cerebrovascular diseases, rheumatoid arthritis and osteoarthritis, major depression, Alzheimer’s disease, and even aging itself (Franceschi et al., 2007). Additionally, recent work shows that classic growth factors (such as Insulin like growth factor [IGF]) and pro-inflammatory cytokines have mutually inhibitory influences on one another and can even induce resistance to the effects of one another (O’Connor et al., 2008). O’Connor et al., hypothesized that a balance between these inflammatory and growth factor processes is essential to optimal aging, with growth factors generally declining and inflammation increasing. This suggests that anti-inflammatory lifestyle variables, such as exercise; a diet rich in polyphenols, fiber, and an adequate ω-3/ω-6 ratio (an “antiinflammatory diet”); adequate sleep; positive social engagement (which has been shown to promote growth factors); and not too much stress especially chronic stress, are all likely to help retain an adaptive balance between pro-inflammatory and growth factor signaling. Additionally, there are potential relationships between dementing disorders and depression, particularly Alzheimer’s disease. Although it has been long known that recurrent major depression is a risk factor for Alzheimer’s disease, recent work suggests a reciprocal relationship, with Alzheimer’s disease also constituting a risk factor for depression (Aznar and Knudsen, 2011). The basis for this association remains to be fully clarified, but evidence indicates that Alzheimer’s disease intrinsically deteriorates affective regulation (Nash et al., 2007), a critical capacity in the resistance to depression in the face of life stresses. Alzheimer’s disease also promotes pro-inflammatory signaling and inhibits neuroplasticity, which has critical links to mood regulation (McEwen, 2004). Comorbidities may also exist between other dementing disorders and depression, although these have been less closely studied. Frontotemporal dementia may predispose to more primary apathy states, frequently misdiagnosed as depression, but also may predispose to depression as well (Chow et al., 2009; Huang et al., 2010). Last, but certainly not least, both acute medical illnesses and more chronic diseases of aging (heart disease, cancer,

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diabetes, arthritis, and all neurodegenerative disorders) have been found to be significant risk factors for depression, perhaps particularly when combined with financial and socioeconomic stress (Almeida et al., 2010; Baldwin, 2010; Kaji et al., 2010).

Treatment algorithms in relationship to depression in the elderly A comprehensive presentation of research into treatment of depression is well beyond the scope of this brief chapter summary. However, outside of paying particular attention to the unique lifestyle and developmental/adaptive challenges facing the elderly, and addressing and mitigating the unique set of stresses that contribute to the risk for depression in the elderly, there is no systematic evidence that either the prevention or the treatment of depression in the elderly is necessarily substantively different from those considerations in a younger adult (although medicine interactions can be significantly more challenging, given that many elderly patients are often on multiple medicines that can interact with psychotropic medicines in a variety of ways). In general, we argue that social support (particularly including reduction of social isolation), both psychodynamically oriented and cognitive behavioral psychotherapy, and careful attention to precipitating stressors (helping patients to generate more adaptive behaviors in response to those stresses) are often neglected in primary care interventions with depressed elderly; often physicians simply hand out a prescription for the latest selective serotonin reuptake inhibitors (SSRI). Current research suggests that psychopharmacology alone is not nearly as effective as a combination of psychopharmacology and psychotherapy (STAR D work—see Rush, 2007). In general, psychopharmacology of depression works best with adopting a flexible empiricism and fitting patient characteristics and symptomatology to drug effect profiles. A detailed review of these issues is well beyond the scope of this chapter, and clinicians looking for a review of specific approaches to the psychopharmacology of depression should consult standard texts (such as APA Publishing Textbook of Psychopharmacology). Recently, published work has suggested that big pharma may have deliberately exaggerated effect sizes for classic aminergic antidepressants. A recent meta-analysis in the New England Journal of Medicine (Turner et al., 2008) suggested widespread exaggeration of effect sizes in relation to many blockbuster (billion-dollar) antidepressant compounds. It further stated that with the inclusion of previously suppressed negative trials, effect sizes for popular antidepressant drugs are significantly less impressive than initially reported. According to the published studies, roughly 94% of the trials conducted on mainline

antidepressant drugs showed positive results. However, if one included unpublished studies in the analysis, only 51% of the trials were positive. Separate meta-analyses of the Federal Drug Administration (FDA) and journal data sets demonstrated an increase in effect size from 11% to 69% for individual drugs, with a 32% overall inflation of effect size across all studies. This recalibration shows that effect sizes for many antidepressant drugs may be relatively modest (0.31 on average, where a 0.5 effect size might be the threshold for a clinically important effectiveness, according to a meta-analysis by Ioannidis (2008). This suggests that the current practice trends, particularly within primary care of an exclusive reliance on popular SSRIs and other related aminergic agents (selective noradrenergic reuptake inhibitors [SNRI] and mixed serotonergic noradrenergic drugs), may have a substantially weaker evidence base than most medical practitioners generally assume. In an insightful study emphasizing a multivariate view of depression and practical ability to predict risk in patient populations, Almeida et al. (2010) showed that a matrix of risk factors predicted a likelihood of minor to major depression. A multivariate logistic regression showed depression was “independently associated with age older than 75 years, childhood adverse experiences, adverse lifestyle practices (smoking, alcohol use, physical inactivity), intermediate health hazards (obesity, diabetes and hypertension), comorbid medical conditions (clinical history of coronary heart disease, stroke, asthma, chronic obstructive pulmonary disease, emphysema, or cancers), as well as social or financial strain.” The authors stratified the risk factors to build a predictive matrix demonstrating a probability of depression increasing progressively with an accumulation of risk factors, from less than 3% for those with no adverse factors to more than 80% for people reporting the maximum number of risk factors. Primary care physicians and other clinicians dealing with the elderly might be able to more accurately gauge the total level of biologic stress, determine the subsequent risk for depression in their patients, and identify the need for early and potentially mitigating, if not completely preventative, interventions. In terms of common lifestyle variables that might prevent depression, fish consumption (Lin et al., 2010), vitamin D levels (Milaneschi et al., 2010; Stewart and Hirani, 2010), and regular aerobic exercise (Cotman et al., 2007; Bots et. al., 2008) appear to have the best empirical support, but conclusive data is still lacking. Unfortunately, systematic studies into preventing late-life depression have been relatively modest, at best (Baldwin, 2010). Hyperhomocysteinemia, an inflammatory marker increasingly viewed as a risk factor for all diseases of aging, and contributing to increased oxidative stress in aging (Wu, 2007), may be a meaningful target for prevention/reduction of systemic inflammation, multiple diseases of aging, and depression as well (Almeida et al.,

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2008). Vitamin D deficiency, sedentary lifestyles, obesity, and sleep deprivation, all risk factors for inflammatory diseases and other diseases of aging, may also be useful prevention targets for delimiting penetration of depressive disorders. Additional prevention targets may include improved management of chronic pain and, of course, reduction of social isolation.

Existential aspects of aging and their impact on mood Although it has not been systematically studied to our knowledge, one might suspect that intrinsic features of aging pose “depressogenic” challenges for many individuals with less than optimal family and social histories. Older individuals face the shrinking sense of any future or substantial time to make up for previous mistakes, disappointments, and lost opportunities, while often struggling with an existential awareness of the inevitability of death and physical decline. In contrast, in individuals who have been most successfully and securely socially connected, and for whom life has presented ample opportunities for both social and work-related rewards, these intrinsic challenges of mortality and aging are substantially buffered by an ongoing affirmation of deep ties to spouses, friends, and other loved ones; devotion to children and grandchildren; and continuing involvement in a cultural and intellectual heritage to which one feels connected and may have substantially contributed in the past. Those without such resources, and lacking successful social and work histories, may inevitably face what Erik Erikson (1950) called, in his eighth stage of life, the crisis of “integrity versus despair.” Instead of having an accumulated wisdom and a reverence for life despite all its many painful limitations, individuals who have not successfully negotiated previous developmental challenges enter the final stage of life with conflicted, traumatic, or simply absent relationships. Instead of affirmation of continuing social, professional, and cultural connections, they may feel a keen sense of despair over their failures and multiple losses, and regret the absence of youthful opportunities for substantially mitigating a negative past. This suggests that, in old age, those who have failed to achieve a secure sense of self-esteem and associated social connection are particularly disadvantaged, as they face their own mortality and, inevitably, declining health and function, intrinsically difficult challenges for even the most resilient elders. Such self-esteem and chronic psychosocial and characterologic deficits in these less fortunate individuals pose enormous burdens on mood and mood regulation in the context of these existential challenges of aging and form a critical and often underappreciated vulnerability to depression in all its forms.

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Chapter 11 Cerebrovascular Diseases in Geriatrics Patrick Lyden, Khalil Amir, and Ilana Tidus Department of Neurology, Cedars-Sinai Medical Centre, Los Angeles, CA, USA

Summary • Aging is influenced by diet, environment, personal habits, and genetic factors. Abrupt decline in any system or function is always due to disease and is not considered “normal aging.” • Symptoms of atypical aging include incontinence, memory disturbance or intellectual impairment, immobility and falls, and instability. • Delirium is defined as an acute decline in attention and cognition and requires the presence of acute onset and fluctuating course, inattention and disorganized thinking, or altered level of consciousness. • Stroke pathology includes cerebral infarction, primary intracerebral hemorrhage, and subarachnoid hemorrhage. National Institutes of Health Stroke Scale (NIHSS) indicates stroke severity with a score more than 24, indicating severe stroke. • In previous studies, carotid endarterectomy (CEA) has been known to reduce the risk of recurrent disabling stroke or death in patients with severe ipsilateral internal carotid artery stenosis. • Biologic therapies, multimodality neuroprotection therapies, therapeutic hypothermia, and sonothrombolysis may possibly help stroke treatment in the future. • Cerebrovascular risk factors (CVRFs) predispose the patient to stroke or heart attack and are more likely to cause depressive symptoms after stroke.

“Care of the elderly” arbitrarily refers to patients older than 65 years of age. The clinical approach to the elderly person is much different than the medical evaluation of a younger adult person. These important differences have many implications for correct diagnoses, appropriate investigations, clinical outcome measures, quality of care, hospital length of stay (LOS), and cost to health care and the general public. Several physiologic and biologic changes take place during aging that have implications for medication-related adverse effects, atypical disease presentations, and the way the aging body responds to stress. Other important factors to consider in the care of the elderly are high prevalence of comorbidities, multiple coexisting and interacting chronic diseases (such as diabetes, ischemic heart disease, heart failure, arthritis, dementia, cerebrovascular and cardiovascular diseases, social isolation, and polypharmacy). As a result of these complex and interactive factors and biologic changes with associated features, the manifestations of diseases are more subtle and present with atypical and nonspecific features. Barriers to physical examinations exist, as do limitations in the correct diagnostic and prognostic tests and therapeutic interventions. The other important variable is the current and future demographic changes that

are more pronounced in the older population, particularly with a significant increase in those 85 years and older. All these changes, whether biologic, iatrogenic, or demographic, have a direct impact on health-related outcomes, quality of life, cost of health care, rate of hospitalizations, the patient, families and caregivers, and medical staff satisfaction. They also impact morbidity and mortality (Warshaw, et al., 1982; Hirsch et al., 1990; Inouye et al., 1993; Brennan et al., 1991).

Biologic changes with aging Physiologically, human aging is characterized by a progressive constriction of the homeostatic reserve of every organ system, called homeostenosis. Evident by the third decade, it is gradual and progressive, but the extent of decline may vary. It is also influenced by diet, environment, personal habits, and genetic factors. Individuals become more dissimilar as they age, belying any stereotype of aging. In addition, it is important to note that an abrupt decline in any system or function is always due to disease, not to “normal aging.” “Normal aging” can be attenuated by modifying risk factors (such as hypertension, smoking, and exercise).

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Generally, as one ages, the relative total body fat increases and the total body water decreases. This has a direct relationship to the volume of distribution (VD) for fat-soluble and water-soluble medications. It increases the VD for fat-soluble medications (such as benzodiazepines and many other cardiac or central nervous system (CNS)-acting drugs), hence increases the half-life and side effects, and decreases the VD for water-soluble medications (such as alcohol, digoxin, and theophylline), with increased concentrations and toxic effects. In terms of cardiac and central nervous systems, several neuroendocrine metabolites are altered such as with a decrease in brain catecholamine synthesis and decreased dopaminergic synthesis, among others, causing stiffer gait, increased body sway, early wakening insomnia, and decreased resting temperatures. In the cardiovascular system, there is decreased arterial compliance, increased systolic blood pressure, decreased β-adrenergic responsiveness, decreased baroreceptor sensitivity, and decreased sinoatrial node automaticity. These, in turn, can cause reduced response to volume depletion, decreased cardiac output and heart rate because of stress, and impaired BP response to standing (Kasper et al., 2005; Evans et al., 2000).

Clinical presentations in the elderly “Healthy old age” is not an oxymoron. In fact, in the absence of diseases, the decline in homeostatic reserve causes no symptoms and imposes few restrictions on activities of daily living (ADL), regardless of age. However, as individuals age, they are more likely to suffer from disease, disability, and the side effects of drugs. When combined with the decrease in physiologic reserves, these compounded factors can make the older person more vulnerable to environmental, pathologic, and pharmacologic challenges. Therefore, managing elder patients involves distinct considerations. In caring for geriatric patients, one typically manages multiple chronic conditions. Similarly, more of an emphasis falls on care versus cure. Coupled with comprehensive geriatric assessment (CGA), dealing with a whole patient rather than disease specifics and using a team approach with coordinated care across multiple sites is essential for continuity of care (Kasper et al., 2005; Evans et al., 2000).

General approach to hospitalized elderly patients Although only 13% of the American population is elderly, they account for 38% of all discharges and 46% of all hospital inpatient days. This means longer hospital stays, greater costs, and more adverse outcomes. Basically, acute

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care is geriatric care (Kozak et al., 2004, 2005; Warshaw et al., 1982; Hirsch et al., 1990).

Atypical presentations in the elderly As mentioned earlier, care of the elderly involves atypical and different clinical presentations. For example, simple and mild hyperthyroidism can present with confusion, atrial fibrillation, depression, syncope, and weakness—all at the same time. In addition, a limited number of symptoms predominates because of the “weakest link” phenomenon. These include confusion, depression, incontinence, falls, and syncope. What constitutes geriatric giants is as follows: • Incontinence (made worse by urinary tract infections, immobility, diuretics, and many other disease processes) • Memory disturbance or intellectual impairment (affected by many disorders such as stroke, Parkinson’s disease (PD), delirium, and medication-related adverse effects) • Immobility and falls (affected by arthritis, postural hypotension, osteoporosis, stroke, PD, Alzheimer’s disease (AD), and medication) • Instability (such as with decreased muscle mass and visual impairment) Other important and complicating factors in terms of the clinical evaluation of an elderly person are that the general rules of clinical approach may not strictly apply. For example, an organ system-related symptom is less likely to be the source of that symptom. Likewise, a clinical depression is not likely strictly due to a psychiatric illness, as would probably be the case for a younger adult with major depression. Similarly, an acute confusional state or delirium would likely not be the result of a new CNS lesion. More likely, the problem is multifactorial, perhaps a contributing risk factor with causative agents playing the major role. Another example of atypical clinical presentation in the elderly is that an older person who presents with syncope or a brief period of loss of consciousness is unlikely to have the illness due to a structural heart disease, unlike a younger adult. It may well be due to postural hypotension, compounded by medication-related adverse effects such as the simple antihistamine, anticholinergic medication diphenhydramine. It is crucial that a clinician’s approach to older patients be proactive and preventative in nature. Because elder persons have decreased physiologic reserves, they can have earlier presentations and manifestations of their illness. An illustration is clinical congestive heart failure exacerbated or caused by mild hyperthyroidism. In addition, a cognitive dysfunction may be related to mild hyperparathyroidism or related to increased drug side effects. For example, diphenhydramine may cause confusion, digoxin may contribute to depression, and

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much-overlooked over-the-counter sympathomimetics can cause urinary retention. Knowing these factors can reduce unnecessary investigations and invasive or risky procedures. Correctly identifying the risk factors and properly diagnosing the clinical condition helps determine appropriate management strategies. All of these are related to improved outcomes, improved quality of life, and decreased morbidity and mortality. In addition, this has cost savings implications and results in improved satisfaction for the patients, their caregivers, and staff. Care of the elderly also involves multiple abnormalities, but small improvements in each may yield dramatic benefits overall. Another aspect of care of the elderly in general involves the theory that there is no anemia, impotence, depression, or confusion of old age. The diagnostic “law of parsimony” often does not apply. As an example, imagine that a patient is admitted to the hospital with a constellation of signs and symptoms consisting of fever, anemia, retinal emboli, and heart murmur. In a young person, this would indicate endocarditis. However, in an elderly person, it could be an aspirin side effect, cholesterol emboli, aortic sclerosis, or simply a viral illness. Even if the correct diagnosis is made, treating a single disease is unlikely to result in a cure or a better outcome. Therefore, the “whole person” approach is much more important than the diseasespecific approach because it addresses other issues related to the care of the elderly (Kasper et al., 2004; Evanse et al., 2000; Kozak et al., 2004, 2005).

Hospitalization of elderly patients We know that hospitalization contributes to a decline in the older patient’s functional status or the ability to function independently in the physical, mental, and social activities of daily life. These include bathing, dressing, toileting, continence, and instrumental activities of daily life (shopping, housekeeping, preparing meals, taking medications, using public transportation, and so on). Therefore, older patients are more likely to depend on ADLs at admission and to suffer functional decline. As we discussed, the elderly have diminished homeostatic reserves and can have multiple comorbid conditions, decreased muscle mass, and strength. This is further compromised by sustained bed rest. Moreover, independent self-care is further threatened in patients with cognitive impairment, stroke, PD, arthritis, and heart and respiratory failure. Studies show that 25–60% of elderly hospitalized patients experience loss of independent function during hospitalization. This increases LOS, nursing home placement, and mortality, with associated high cost.

Table 11.1 Geriatric principles of geriatric medicine Primum non nocere (first, do no harm) Pay attention Avoid causing discomfort or indignity Use meticulous clinical observations and proper technique Actively search for signs and symptoms of dysfunction and disability Evaluate the whole person, including physical, mental, and social functions Emphasize prevention, rehabilitation, and enhanced quality of life Eliminate iatrogenic causes Maintain function and independence at all times Source: Courtesy of Professor Mark E. Williams (with minor modifications).

In summary, the current hospital model can be a restrictive, unfamiliar, and threatening environment, particularly for a patient with mild dementia, poor mobility, decreased hearing, or visual disturbances. In addition, there is significant iatrogenesis, and unnecessary tests and procedures are carried out with related adverse outcomes. The prescription of inappropriate medications in hospitalized elderly is well documented and, again, is related to increased hospital LOS, increased cost, and negative outcomes. To improve all outcomes for elderly hospitalized patients, we can turn to several effective models of care that have been shown to improve morbidity, improve mortality, be cost-effective, reduce LOS, and improve patient and staff satisfaction. These comprehensive models are run with a multidisciplinary team approach and care pathways geared to the care of the elderly. Examples are stroke units, acute care of the elderly (ACE) units, program of all-inclusive care of the elderly (PACE), delirium preventions intervention, and multidisciplinary falls and fracture prevention models (Warshaw et al., 1982; Hirsch et al., 1990; Inouye et al., 1993; Brennan et al., 1991; Landefeld et al., 1995). I want to specifically highlight the geriatric principles in Table 11.1, which I adopted from one of my mentors and role models in the care of the elderly at the University of Virginia in Charlottesville, Virginia.

Specific diseases Several issues need to be addressed while dealing with specific disease, particularly considering the increasing aging population and the high prevalence of delirium in hospitalized elderly patients with associated increased morbidity, mortality, increased LOS, increased cost, patient and caregiver grief, and increased institutionalization.

Delirium or acute confessional state Delirium is defined as an acute decline in attention and cognition. Delirium is often underdiagnosed, has serious implications, and is preventable.

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The key features of delirium are as follows: Acute onset and fluctuating course Inattention Disorganized thinking Altered level of consciousness The Confusion Assessment Method (CAM) has been well validated and is used for rapid assessment and detection of delirium. It has a sensitivity of 94–100% and specificity of 90–95%, and uses the four criteria given below. 1 Acute onset and fluctuating course 2 Inattention 3 Disorganized thinking 4 Altered level of consciousness The diagnosis of delirium requires the presence of criteria 1, 2, and 3, or 4. As we discussed, the prevalence of delirium ranges (on admission) between 10% and 40%, with an incidence (in hospital) of 25–60%. This is associated with significant hospital mortality between 10% and 65% and annual health-care expenditures of more than $8 billion. Clinically, many risk factors predispose older patients to developing delirium. These have been well validated in studies and include the following: • Cognitive impairment • Sleep deprivation • Immobilization • Vision impairment • Hearing impairment • Dehydration Recognizing these risk factors and being alert about them, upon admission, enables health-care professionals to intervene early in each of these steps and potentially prevent delirium. Interventions may include reality orientations, nonpharmacologic sleep protocols, early mobilization protocols, vision aids, amplifying devices (hearing aids), and appropriate hydration. Apart from the previously mentioned risk factors, several etiologies for delirium exist. The pneumonic delirium can be useful. • • • •

Dementia Electrolyte abnormalities Lungs, liver, heart, kidney, brain Infection Rx Injury, pain, stress Unfamiliar environment Metabolic In particular, the list of medications causing delirium is large and important. Some culprits include benzodiazepines, anticholinergics, antihistamines, antidepressants, and many cardiac medications. In terms of management, once risk factors or causative agents are identified, emphasis should be on prevention, risk factor evaluation on admission, and early intervention.

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Generally, treatment is geared toward eliminating these etiologies and treating the underlying condition. A good clinical history including a medication list, a thorough physical examination, a targeted metabolic panel, and a search for occult infection, may be all that is required and will have the greatest yield, as opposed to EEG and CT/MRI–brain. Emphasis is on nonpharmacologic approaches and less invasive investigations. However, low doses of haloperidol (0.5–1.0 mg IM/PO, with a maximum dose of 3–5 mg) or short-acting benzodiazepines (such as lorazepam) can be useful in alleviating symptoms. In summary, delirium should be considered a medical emergency and must be coupled with a thorough history and physical examination. Emphasis should be put on early prevention and risk evaluation and less invasive tests or investigations. Treatment must focus on eliminating the causative agents and using fewer pharmacologic agents (Inouye et al., 1990, 1993,1999a,1999b; Inouye and Charpentier, 1996; Cole et al., 2002; Francis et al., 1990).

Stroke It is suggested and widely believed, though no concrete evidence exists, that Hippocrates may have defined stroke 2400 years ago as apoplexy (struck down by violence), although the term was used for different conditions. Stroke is a clinical syndrome characterized by rapidly developing clinical symptoms or signs of focal—and, at times, global—loss of cerebral function; symptoms last more than 24 hours or lead to death, with no apparent cause other than that of vascular origin. Not long ago, patients with stroke were either treated at home or admitted for compassionate observation. Doctors made an effort to localize lesions and describe vascular syndromes and pathology. An aura of therapeutic hopelessness surrounded stroke care. Fortunately, those days are over and optimism about the benefits of treatment (stroke care units (SCUs) and thrombolysis), coupled with a sense of urgency in dealing quickly with every patient with acute stroke, has swept away that nihilism (Barnett et al., 2000; Lyden 2008, 2009).

Risk factors for stroke The risk factors for stroke are the usual suspects. Such modifiable risks include hypertension, diabetes mellitus, tobacco abuse, hyperlipidemia, atrial fibrillation, transient ischemic attack (TIA), certain medications and recreational drugs, and alcohol. Other risks include nonmodifiable risks such as age, sex, and genetics. Importantly and interestingly, when compared to the risk identification for stroke, only 60% of the time-specific risk factors are identified in stroke versus 90% in ischemic heart disease (Whisnant, 1997; Yusuf et al., 2004).

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Stroke classifications Stroke is classified pathologically, clinically, or by etiology. Pathology/subtypes are as follows: • Cerebral infarction • Primary intracerebral hemorrhage • Subarachnoid hemorrhage (Warlow et al., 2003)

Etiology The etiologic classification of ischemic stroke, which is sometimes referred to as the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, includes the following: • Atherosclerotic • Cardioembolic • Small vessel thrombotic • Other pathology (vasculitis, hypercoagulable state) • Undetermined cause Strokes can be classified into four clinical subtypes according to the (Bamford) Oxfordshire Community Stroke Project (OCSP) classification (Table 11.2). Other causes of stroke and differential diagnosis include the following: • Migraine • Seizure disorder/postictal • GA/TA • Intracranial structural lesions • Tumor • Aneurysm • Arteriovenous malformation • Chronic subdural hematoma • Head injury • Encephalitis • Cerebral abscess • Multiple sclerosis • Labyrinthine disorder • Metabolic disturbance • Hypoglycemia • Hyponatremia • Hypocalcemia • Alcohol and drugs • Myasthenia gravis • Psychological cause • Panic • Hyperventilation • Somatization disorder Another important clinical aspect of stroke is ruling out stroke mimics. This differentiation was illustrated in separate studies that showed an alternative final diagTable 11.2 Stroke clinical subtypes 1 2 3 4

Total anterior circulation syndrome (TACS) Partial anterior circulation syndrome (PACS) Posterior circulation syndrome (POCS) Lacunar syndrome (LACS)

nosis among patients admitted to the hospital with an admission diagnosis of stroke. A retrospective study by Hemmen et al. (2008) reviewed the discharge diagnoses of all patients who presented to the emergency department as a code stroke (411 patients). A patient was considered a stroke mimic, if a code stroke was activated, but none of the first three International Classification of Diseases, Ninth Revision codes on discharge were related to TIA or ischemic stroke. In all, 104 patients (25.3%) were discharged without a diagnosis of stroke or TIA. The diagnoses in this group were intracranial hemorrhage (19 patients), subarachnoid hemorrhage (6), subdural hematoma (3), old deficit (11), hypotension (11), seizure (10), intoxication (8), hypoglycemia (7), mass lesion (6), migraine (5), and others (18). In all, 33 of 307 eligible patients (10.7%) were treated with tissue-type plasminogen activator. None of the patients with a stroke mimic received tissue-type plasminogen activator. In 44 of 104 stroke mimics (42.3%), the acute disease was caused by a severe neurologic condition other than ischemic cerebrovascular disease. Only 60 of 411 code strokes (14.6%) were initiated for patients without a severe and acute neurologic condition. The study concluded that, in their community, 25.5% of all code strokes were initiated for stroke mimics. Most mimic patients had an illness likely to benefit from urgent neurologic evaluation (Adams et al., 1993; Bamford et al., 1991).

Bottom of form Another study by Nor et al. (2005) showed the percentages of final diagnosis of patients admitted with an admission diagnosis of stroke. Seizure disorder (24%) Sepsis (23%) Migraine (10%) Somatization (6%) Labyrinthitis/vestibulitis/vertigo (5%) Metabolic disorder (4%) Brain tumor (4%) Dementia (3%) Encephalopathy (2%) Neuropathy/radiculopathy (1%) Transient global amnesia (1%) Again, similar to the study by Hemmen et al., none of these patients received thrombolysis (Nor et al., 2005; Hemmen et al., 2008).

Stroke care Stroke care is a true interdisciplinary and multidisciplinary approach that has shown to be effective and improve outcomes of stroke, including reducing mortality. It involves

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the patient, the community, the family, general and family practitioners, emergency response services, the emergency department, geriatricians, neurologists, general physicians, psychologists, nurses, and the rehabilitation team. The interdisciplinary team consists of the following: • Physiotherapist • Occupational therapist • Speech and language therapist • Dietician • Pharmacist • Social worker • Bed manager • Coordinator The diagnosis of stroke is clinical and several aids can help with the diagnosis, the severity of stroke, and functional outcomes or prognosis. • Clinical history and examination • Los Angeles Pre Stroke Scale (LAPSS) • Cincinnati Stroke Scale • Face, Arm, Speech Test (FAST) • Recognition of Stroke in the Emergency Room (ROSIER) • Modified Rankin Scale (mRS) • National Institutes of Health Stroke Scale (NIHSS) • Scandinavian Stroke Scale (SSS) • Barthel Index (BI) • Glasgow Coma Scale (GCS) NIHSS, a serial measure of neurologic deficit, is a 42-point scale that quantifies neurologic deficits in 11 categories. Normal function without a neurologic deficit is scored as 0, and the scale is repeated at regular intervals. The NIH designed the NIHSS; the National Institute of Neurological Disorders and Stroke (NINDS), with Dr Patrick D Lyden as one of its leaders, developed the video materials it uses. It is quick (can be done in less than 7 minutes), has good interobserver reliability, and can be administered by non-neurologists. An NIHSS score of more than 24 indicates a severe stroke; a score of less than 4 denotes a mild stroke. Both of these scores are relative contraindications for thrombolysis. The NIHSS has 11 parts as given below. • Level of consciousness (1a, b, c) • Best gaze and vision (2, 3) • Facial palsy (4) • Motor arm and legs (5a, b; 6a, b) • Limb ataxia (7) • Sensory (8) • Language and dysarthria (9, 10) • Extinction/neglect and inattention (11) The mRS is a simplified overall assessment of function that has been widely accepted as an outcome measure in stroke studies. A score of 0 indicates the absence of symptoms, a score of 5 indicates severe disability, and a score of 6 indicates that the patient is dead. Table 11.3 describes the scores for the mRS.

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Table 11.3 Modified rankin scale Score

Measurement

0 1

No symptoms No significant disability, despite symptoms; able to carry out all usual duties and activities Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance Moderate disability; requires some help, but able to walk without assistance Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance Severe disability; bedridden, incontinent, and requires constant nursing care and attention Dead

2 3 4

5 6

The BI is a simple index of independence to score the ability of a patient with a neuromuscular or musculoskeletal disorder to care for him- or herself and, by repeating the test periodically, to assess improvement. A patient scoring 100 BI is continent; eats, dresses, and bathes independently; gets up out of bed and chairs; walks at least a block; and can ascend and descend stairs. This does not mean that the person is able to live alone. He or she may not be able to cook, keep house, or meet the public, although he or she is able to get along without attendant care. As with the mRS, the advantage of the BI is its simplicity. It is useful in evaluating a patient’s state of independence before treatment, progress while undergoing treatment, and status at maximum benefit. It can easily be understood by all who work with the patient and anyone who adheres to the definitions of the items listed, can quickly and accurately score it. The total score is not as significant or meaningful as the breakdown into individual items, because these indicate where the deficiencies are. Management goals for stroke are as follows: • Minimize brain injury • Maximize patient recovery • Improve mortality • Improve functional independence • Increase patient, family, and staff satisfaction • Prevent complications Best practices, recommendations, and full guidelines for stroke care are available from the American Heart Association (AHA)/American Stroke Association (ASA) and many other stroke organizations online (Stroke Unit Trialists’ Collaboration, 2007; Brott, 1989; Bonita and Beaglehole 1988; Van Swieten et al., 1988; Mahoney and Barthel, 1965; Wade and Collin, 1988; Granger et al., 1979; Shah et al., 1989; Sulter et al., 1999).

Stroke outcome data Thrombolysis The original NINDS rt-PA Stroke Study Group study was a randomized controlled trial (RCT) that administered t-PA

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0.9 mg/kg within 3 hours versus placebo, with strict inclusion and exclusion criteria. The primary outcome measures were functional independence as measured by mRS. It showed a 32% relative risk reduction (RRR) and a 12% absolute risk reduction (ARR) at 90 days, with minimal or no disability as per mRS. The number needed to treat (NNT) was 8 to prevent one bad outcome. The odds ratio (OR) for improvement was 2 (95% CI 1.3–3.1). It also showed that at 1 year, 30% were more likely to have a favorable outcome. Mortality was the same, even though the risk of symptomatic intracranial hemorrhage (sICH) was much higher in the intervention group (6.4% vs. 0.6% in placebo). The European Cooperative Acute Stroke Study (ECASS) 3 was a similar, recently published study that increased the timeline from within 3 hours to within 4.5 hours. The RRR was 16% (CI 1.01–1.34); p = 0.04 and 7.2% ARR at 90 days with minimal or no disability as per mRS. The NNT was 14 and OR for improvement was 1.34 (95% CI 1.02–1.76; p = 0.04). Mortality was the same (7.7% vs. 8.4%; p = 0.68), and sICH was 2.4% vs. 0.2% (p = 0.008). For every 100 patients treated, 14 additional patients have a favorable outcome (The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995; Hacke et al., 2004, 2008).

Stroke care units The Cochrane Review under Stroke Unit Trialists’ conducted a meta-analysis of more than 3500 patients in 20 trials. Outcome measures were of patients in stroke units versus general units, with reduction in death OR 0.83 (95% CI 0.71–0.87), reduction in death and dependency OR 0.77 (95% CI 0.65–0.87), ARR 5.6%, and NNT 18. Similarly, other studies showed stroke unit care versus medical ward was associated with reduced mortality at 30 days (39% vs. 63%; p = 0.007) and at 1 year (52% vs. 69%; p = 0.013). Organized inpatient MDT rehabilitation was associated with reduced odds of death OR 0.66 (95% CI 0.49–0.88; p = 0.01) and reduced death of dependency OR 0.65 (95% CI 0.50–0.85; p = 0.001). Patients who were treated in SCU versus general medical wards were discharged home versus NH (47% vs. 19%; p <0.01). The Ottawa Panel showed acute stroke rehabilitation and MDT reduced death and dependency and LOS (OR 0.56). Scientifically, all patients benefited from SCU, regardless of the severity (Stroke Unit Trialists’ Collaboration, 2007; Rønning et al., 2001; Langhorne and Duncan, 2001; Crome and Kalra, 1993; Kalra et al, 1995; Ottawa Panel et al., 2006). Anti-platelet therapy in acute stroke Systematic reviews of aspirin (ASA) in 41,000 patients taking 160–300 mg within 48 hours of stroke and followed up for 6 months showed a decrease in death and dependency OR = 0.94, CI 0.91–0.98. There were two SICH for every 1000 treated, which was offset by seven with less recurrence of ischemia and pulmonary emboli. Furthermore, treatment

increased the odds of making a complete recovery from the stroke (OR 1.06; 95% CI 1.01–1.11): 10 more patients made a complete recovery for every 1,000 patients treated. In absolute terms, 13 more patients were alive and independent at the end of follow-up for every 1,000 patients treated (International-Stroke-Trial-Collaborative-Group, 1997; CAST- Collaborative-Group, 1997).

Hypertension therapy A meta-analysis of seven RCTs showed that antihypertensive drugs reduced stroke recurrence after stroke or TIA (RR 0.76; 95% CI 0.63–0.92), regardless of BP and the type of stroke. Therefore, BP should be lowered and monitored indefinitely after stroke or TIA (Rashid et al., 2003; PATS Collaborating Group, 1995; Yusuf et al., 2000; Bosch et al., 2002; PROGRESS collaborative group, 2001). Hyperlipidemia management In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, statin therapy with atorvastatin reduced stroke recurrence (HR 0.84; 95% CI 0.71–0.99). Similarly, the Heart Protection Study with simvastatin reduced vascular events in patients with prior stroke and reduced stroke in patients with other vascular diseases (RR 0.76). The risk of hemorrhagic stroke was slightly increased in both trials. The ARR achieved with statin therapy was NNT 112–143 for 1 year. Statin withdrawal at the acute stage of stroke may be associated with an increased risk of death or dependency, and no recommendation was made to start statins in the acute stroke setting. Guidelines recommend continuing with the statin therapy if the patient is already on it (Amarenco et al., 2006; Heart Protection Study Collaborative Group, 2002).

Carotid surgery, carotid endarterectomy, and carotid artery stenting after stroke or transient ischemic attack The grading of stenosis should be performed according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Although the European Carotid Surgery Trialists (ECST) and NASCET use different methods of measurement, it is possible to convert the percentage stenosis derived by one method to the other. Carotid endarterectomy (CEA) reduces the risk of recurrent disabling stroke or death (RR 0.52) in patients with severe (70–99%) ipsilateral internal carotid artery stenosis. Patients with less severe ipsilateral carotid stenosis (50–69%) also benefit. CEA should be performed only in centers with a perioperative complication rate (all strokes and death) of less than 6% and should be performed as soon as possible after the last ischemic event (ideally, within 2 weeks). A recent study published by Brott et al., the Carotid Revascularization Endarterectomy Versus Stenting Trial

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(CREST) showed similar outcomes with carotid artery stenting (CAS) and CEA for the treatment of carotid stenosis. CREST is the largest prospective randomized trial to date that compared these two interventions, enrolling 2502 patients from 117 US and Canadian centers. On the composite primary endpoint of any stroke, myocardial infarction (MI), or death during the periprocedural period or ipsilateral stroke on follow-up, stenting was associated with a 7.2% rate of these events versus 6.8% with surgery, a nonsignificant difference. However, individual risks varied. At 30 days, the rate of stroke was significantly higher with stenting, at 4.1% versus 2.3% with surgery, although among those with major stroke, it was no different, at less than 1% in both groups. Conversely, MI was higher with CEA, at 2.3% versus 1.1% with stenting, again, a statistically significant difference. Patients who had an MI, however, reported a better quality of life after recovery than those who had a stroke, the study authors noted. Rates of ipsilateral stroke during a mean follow-up of 2.5 years were equal between groups, at 2% for stenting and 2.4% with surgery. The investigators also reported an effect of age, with younger patients having slightly fewer events with CAS than CEA and older patients having fewer events with surgery. The study was supported by the National Institute of Neurological Disorders and Stroke, with supplemental funding by Abbott (Cina et al., 2000; Inzitari et al., 2000; Rothwell et al., 2003; European Carotid Surgery Trialists’ Collaborative Group, 1996; Brott et al., 2010).

Novel therapies Some novel therapies, such as biologic therapies, multimodality neuroprotection therapies, therapeutic hypothermia, and sonothrombolysis, are currently under investigation and may play a future role in stroke treatment. As clinicians, we need to be aware of important and relevant issues regarding demographics that have direct relation to increasing health-care cost, hospital admission rates, LOS, nursing home placement, and quality of life for older people. The US Census Bureau in 2000 reported that an estimated 35 million (12.4%) people were aged 65 and over and about 25% of these groups were also caregivers for their grandchildren. The demographic data from 2007 showed about 38 million people aged 65 and over, with an average life expectancy of 17 years for men at 65 years and 19.7 years for women at 65 years. Hospital discharges and inpatient care was $13 million for elderly patients 65 years and older; average LOS was 5.5 days. Mortality for this patient population was 1,759,423 and the highest mortality was for 85 years of age and over. The three leading causes of death were heart disease, cancer, and stroke.

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From a cerebrovascular disease point of view, each year 800,000 people experience stroke (either new or recurrent). An estimated 81 million adult Americans have one or more types of cardiovascular and cerebrovascular disease. Of these, 38 million are estimated to be 60 years or older. About 6.5 million people have had a stroke; it is the third most common cause of death in the United States, behind heart disease (with which it is closely linked) and cancer, and it affects more than 700,000 individuals annually in the United States (approximately one person every 45 seconds). About 500,000 of these are first attacks, and 200,000 are recurrent attacks. In other words, someone in the United States dies every 3.3 minutes from stroke, and it is the leading cause of disability among adults in the United States. More than four million people in the United States have survived a stroke or brain attack and are living with the aftereffects. Four out of five families will be somehow affected by stroke over the course of a lifetime. In terms of recovery, 10% of stroke victims recover almost completely, 25% of stroke victims recover with minor impairments, and 40% of stroke victims experience moderate-to-severe impairments requiring special care. Another 10% of stroke victims require care in a nursing home or other long-term care facility, and 15% die shortly after the stroke. Mortality is different in different types of stroke, with 7.6% of ischemic strokes and 37.5% of hemorrhagic strokes resulting in death within 30 days. The outcomes for men and women are roughly the same, with 22% of men and 25% of women dying within a year of their first stroke. TIA should be taken seriously, as 14% of people who have a stroke or TIA will have another within a year and about 25% of stroke victims will have another within 5 years. The ABCD2 score system can be a helpful tool in assessing patients with TIA and a risk of developing future strokes. Cost to health care and the country is another major issue regarding stroke care. The total cost of stroke to the United States is estimated at $43 billion per year, and the direct costs of medical care and therapy are estimated at $28 billion per year. Indirect costs from lost productivity and other factors are estimated at $15 million per year, and average cost of care for a patient up to 90 days after stroke is $15,000. For 10% of patients, the cost of care for the first 90 days after a stroke is $35,000. Table 11.4 gives the percentage breakdown of the direct costs of care for the first 90 days after a stroke.

Table 11.4 Breakdown of costs in first 90 days following stroke Initial hospitalization Rehabilitation Physician costs Hospital readmission Medications and other expenses

43% 16% 14% 14% 13%

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In terms of overall population, especially older persons, the demographics are changing with the rapid growth in older population. The US population is projected to increase to an estimated 403 million by the year 2050, an increase by 47% from the year 2000—and, more importantly, with a significant increase in persons 65 years and older. The number of people 65 years and older will increase from an estimated 35 million to about 80 million (135% change); among these, people 85 years and older will increase from about 4 million to 20 million (a change of 350%). These staggering statistics will have many important implications in our society and for the future medically, socially, financially, and politically, affecting all aspects of our daily lives (CDC). The good news is that, as a result of new interventions (such as stroke units and ACE units), therapeutic advances, and novel models for the care of the elderly and for stroke and other cerebrovascular disease/cardiovascular diseases, the cerebrovascular disease and related outcomes have significantly improved. However, considering the striking statistics, there is a universal consensus that these issues are not being addressed with urgency from a public health or clinical (primary and secondary prevention) point of view. Much more needs to be done to address healthy aging, reduce disparity in health-related outcomes, emphasize rehabilitation and exercise programs, and improve the quality of life for our older population (Rothwell et al., 2005; Centers for Disease Control and Prevention; US census bureau; National Institutes of Health; National Institute of Neurological Disorders and Stroke; American Heart Association; American Stroke Association).

Vascular depression The vascular depression hypothesis states that cerebrovascular diseases may predispose or perpetuate depressive moods in geriatric patients (Alexopoulos et al., 1997). Cerebrovascular risk factors (CVRFs) are pre-existing medical conditions that predispose the patient to stroke or heart attack. These risk factors include diabetes, hypertension, a history of TIA, high cholesterol, obesity or lack of exercise, pregnancy and childbirth, trauma to the brain, alcohol and drug abuse, smoking, and carotid or other arterial diseases. In stroke survivors who suffer from any of those risk factors, a large percentage reported depressive symptoms. In many stroke survivors, structural abnormalities have been discovered in the prefrontal cortex. This includes differences in the bilateral gray matter in separate regions, including the gyrus rectus and anterior cingulated, where differences in the white matter and cerebrospinal fluid (CSF) volume have also been marked in depressed geriatric patients (Alexopoulos et al., 1997). A correlation between CVRFs and these lesions has been reported, which is understandable because the risk factors for subcortical ischemic

diseases are the same as those for stroke (Steffens et al., 2003). Patients who suffer from multiple CVRFs tend to have more severe lesions and are five times more likely to demonstrate depressive symptoms 6–18 months after stroke than those with fewer CVRFs (Mast et al., 2004). What is unknown is whether these lesions were caused by the actual stroke or preceded it and are the result of the CVRFs. It is difficult to determine what the depression, commonly seen in stroke patients, is actually due to. The reasoning behind the depressive symptoms could be simply that the patient is experiencing fear and stress from being at a higher risk of a life-threatening illness, or they could arise because the CVRFs potentially change the actual physical makeup and chemistry of the brain. It has been found that depression can take two paths in the elderly. It can be caused by high-intensity lesions produced by medical comorbidity or through a series of interconnected neurobiologic events that change frontal volumes (Alexopoulos, et al., 1997). Due to this uncertainty of cause, treating the depression in these patients is difficult. Each antidepressant regime must be tailored to the patient, due to the potential differences in cause and the other medications the patient may be taking. A national survey in Sweden found that one in seven stroke victims experienced depressive symptoms after their first stroke. After stroke, 12.4% of male patients, 22.5% of whom used antidepressant medication, and 16.4% of female patients, 28.1% of whom used antidepressant medication, reported depressive symptoms almost every day. Of those using antidepressants, 67.5% reported no appearance of depressive symptoms while on the medication (Eriksson et al., 2004). This, along with other case studies (Steffens et al., 2003), has shown that the use of antidepressants in stroke survivors can be highly beneficial, although drug interactions must be taken into consideration. Because the vascular depression hypothesis has not yet been proven or disproven, the best antidepressants for stroke survivors are believed to also target ischemic lesions and improve neurologic recovery in the region of those lesions (Alexopoulos et al., 1997). According to the Sertraline Antidepressant Heart Attack Trial (SADHART) despite the potential interactions, antidepressants have proven to be helpful in treating major depression in the context of medical illness (Steffens et al., 2003).

Further resources For further information about cerebrovascular disease, refer to the following sources: http://learn.heart.org/ihtml/application/student/ interface.heart2/nihss.html www.NIHSS.com www.strokecenter.org/trials/scales/scales-overview. html http://stroke.ahajournals.org

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Landefeld, C.S., Palmer, R.M., Kresevic, D.M., Fortinsky, R.H., et al. (1995) A randomized trial of care in a hospital medical unit especially designed to improve the functional outcomes of acutely ill older patients. N Engl J Med, 332 (20): 1338–1344. Langhorne, P. and Duncan, P. (2001) Does the organization of postacute stroke care really matter? Stroke, 32 (1): 268–274. Lyden, P.D. (2008) Thrombolytic therapy for acute stroke—not a moment to lose. N Engl J Med, 359 (13): 1393–1395. Lyden, P.D. (2009) Extending the time window for thrombolytic therapy—primum non tardare. Lancet Neurol, 8 (12): 1074–1075. Mahoney, F.I. and Barthel, D.W. (1965) Functional evaluation: the Barthel index. Md State Med J, 14: 61–65. Mast, B.T., Yochim, B., MacNeill, S.E., and Lichtenberg PA. (2004) Risk factors for geriatric depression: the importance of executive functioning within the vascular depression hypothesis. J Gerontol A Biol Sci Med Sci, 59 (12): 1290–1294. doi:10.1093/ gerona/59.12.1290 National Institute of Neurological Disorders and Stroke (NINDS). www.ninds.nih.gov. National Institutes of Health (NIH). www.nih.gov. Nor, A.M., Davis, J., Sen, B., et al. (2005) The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. Lancet Neurol, 4 (11): 727–734. Ottawa Panel, Khadilkar A, Phillips K, et al. (2006) Ottawa panel evidence-based clinical practice guidelines for post-stroke rehabilitation. Top Stroke Rehabil, 13 (2):1–269. PATS Collaborating Group. (1995) Post-stroke antihypertensive treatment study: a preliminary result. Chin Med J, 108 (9): 710–717. PROGRESS Collaborative Group. (2001) Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet, 358 (9287): 1033–1041. Rashid, P., Leonardi-Bee, J., and Bath, P. (2003) Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke, 34 (11): 2741–2748. Rønning, O.M., Guldvog, B., and Stavem, K. (2001) The benefit of an acute stroke unit in patients with intracranial haemorrhage: a controlled trial. J Neurol Neurosurg Psychiatry, 70 (5): 631–634. Rothwell, P.M., Eliasziw, M., Gutnikov, S.A., et al. Carotid Endarterectomy Trialists’ Collaboration (2003) Analysis of pooled data

from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet, 361 (9352): 107–116. Rothwell, P.M., Giles, M.F., Flossmann, E., et al. (2005) A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet, 366 (9479): 29–36. Shah, S., Vanclay, F., and Cooper, B. (1989) Improving the sensitivity of the Barthel Index for stroke rehabilitation. J Clin Epidemiol, 42 (8): 703–709. Steffens, D.C., Taylor, W.D., and Krishnan, K.R. (2003) Progression of subcortical ischemic disease from vascular depression to vascular dementia. Am J Psychiatry, 160 (10): 1751–1756. Stroke Unit Trialists’ Collaboration. (2007) Organised inpatient (stroke unit) care for stroke. Cochrane Database Syst Rev, 17 (4): CD000197. Sulter, G., Steen, C., and De Keyser, J. (1999) Use of the Barthel index and modified Rankin scale in acute stroke trials. Stroke, 30 (8): 1538–1541. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med, 333 (24): 1,581–1,588. U.S. census bureau. www.census.gov/aboutus/citation.html. Van Swieten, J.C., Koudstaal, P.J., Visser, M.C., et al. (1988) Interobserver agreement for the assessment of handicap in stroke patients. Stroke, 19 (5): 604–607. Wade, D.T. and Collin, C. (1988) The Barthel ADL Index: a standard measure of physical disability? Int Disabil Stud, 10 (2): 64–67. Warlow, C., Sudlow, C., Dennis, C., et al. (2003) Stroke. Lancet, 362 (9391): 1211–1224. Warshaw, G.A., Moore, J.T., Friedman, S.W., et al. (1982) Functional disability in the hospitalized elderly. J Am Med Assoc, 248 (7): 847–850. Whisnant, J.P. (1997) Modeling of risk factors for ischemic stroke. The Willis lecture. Stroke, 28 (9): 1840–1844. Yusuf, S., Sleight, P., Pogue, J., et al. (2000) Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med, 342 (3): 145–153. Yusuf, S., Hawken, S., Ounpuu, S., et al. (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet, 364 (9438): 937–952.

Chapter 12 Movement Disorders 12.1 Parkinson’s Disease

Robert Fekete1 and Joseph Jankovic2 12.2 Essential Tremor and Other Tremor Disorders

Holly Shill3 12.3 Progressive Supranuclear Palsy

Virgilio Gerald H. Evidente4 12.4 Corticobasal Degeneration

Katrina Gwinn5 1 Department

of Neurology, New York Medical College, Valhalla, NY, USA Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA 3 Banner Sun Health Research Institute, Sun City, AZ, USA 4 Movement Disorders Center of Arizona, Ironwood Square Drive, Scottsdale, AZ, USA 5 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA 2 Parkinson’s

Summary Parkinson’s Disease • Hallmarks of Parkinson’s disease (PD) pathology include the presence of Lewy bodies with alpha-synuclein aggregates, and a loss of dopamine-producing, melanin-containing neurons in the substantia nigra. This results in dopaminergic deficiency in the striatum. • Resting tremors, rigidity, akinesia/bradykinesia, and postural instability are all common precursors to PD. • PD patients also exhibit neuropsychiatric symptoms such as hallucinations, delusions, agitation, depression, irritability, anxiety, and apathy. • Patients with cognitive dysfunction preceding the development of motor symptoms of PD are said to have diffuse Lewy body disease (DLB), while dementia that develops post motor symptoms is classified as PD dementia (PDD). • Mild symptoms are treated with monoamine oxidase (MAO) inhibitors and dopamine agonists. More severe symptoms require levodopa to treat motor dysfunctions. Dopamine-blocking agents help control hallucinations. Surgical lesioning procedures have been phased out in favor of deep brain stimulation (DBS). DBS helps treat OFF symptoms and is an important therapeutic option for motor fluctuations. Essential Tremor and Other Tremor Disorders • Typical tremors in clinical practice include resting tremor, postural tremor, and kinetic/action tremor. Task-specific tremor and orthostatic tremor are seen in essential tremor (ET) patients. • ET is a monosymptomatic, bilateral, relatively symmetrical postural and kinetic tremor of the hands. • Magnetic resonance spectroscopy and blood flow imaging show abnormalities in cerebellar circuitry with overactivity in the cerebellar-thalamo-cortical loop.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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• Primidone and propranolol are medications most commonly used to treat ET. Gabapentin, topiramate, and pregabalin are also used. No therapy other than thalamic deep brain stimulation (DBS) has been approved for this condition. DBS is especially effective in drug-resistant patients. • Other types of tremors include parkinsonian, primary writing, orthostatic, drug-induced, cerebellar, neuropathic, and psychogenic tremors. Progressive Supranuclear Palsy • Clinical hallmarks of progressive supranuclear palsy (PSP) include supranuclear vertical gaze palsy, pseudobulbar palsy, axial rigidity, and cognitive impairment. • NINDS-SPSP clinical criteria classified cases into three categories: possible, probable, and definite PSP for clinical diagnosis. • Macroscopic pathology includes atrophy in precentral gyrus, midbrain tectum, substantia nigra, pons, superior cerebellar peduncle (SCP), and cerebellar dentate nucleus. Neuronal loss, gliosis, and neurofibrillary tangles (NFTs) affecting the basal ganglia, diencephalon, and brainstem are the typical microscopic findings in PSP. • It is proposed a “penguin silhouette” sign, as observed in all PSP patients on midsagittal magnetic resonance imagings (MRIs) is diagnostic feature. • A poor or absent response to levodopa has been published as one of the diagnostic criteria for PSP. Treatment is largely symptomatic but not very helpful. Corticobasal Degeneration • Initial symptoms of corticobasal degeneration (CBD) usually include asymmetric rigidity, bradykinesis, and dysmetria. Asymmetrical limb dystonia is seen in almost all patients with CBD. Ideomotor apraxia is another abnormality seen in CBD. • The standard for CBD diagnosis is neuropathologic. Magnetic resonance imaging (MRI), SPECT, and DAT scanning are sometimes used. • There is no treatment to slow the course of CBD and symptoms usually resist therapy. • An important part of neuropathology is that CBD results from the pathologic aggregation of tau protein as does frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP).

Chapter 12.1 Parkinson’s Disease Robert Fekete and Joseph Jankovic

Introduction James Parkinson described the disorder that now bears his name in his “Essay on Shaking Palsy” (Parkinson, 2002). He described six cases exhibiting symptoms of the disorder, including fatigue, stooped posture, difficulty initiating ambulation, gait with short steps, hypersalivation, and constipation. He drew attention to rest tremor, “agitation,” which stopped with “sudden” or “violent” action and started over in a crescendo manner up to a minute later. Although Parkinson did not emphasize rigidity, he described manual dexterity leading to difficulty with handwriting and using utensils while eating. He named the disorder paralysis agitans, or shaking palsy. Parkinson predicted success in developing disease-modifying treatment “by which, at least, the progress of the disease may be stopped” but, unfortunately, that promise has not yet been realized (Parkinson, 2002). Prior reports of individual clinical features of the disorder exist, but Parkinson was the first to report the features as a coherent clinical entity. For example, Sauvages de la Croix, Carguet, and Gaubius previously noted scelotyrbe festinans (“hastening” or festinating gait) but did not connect it to other clinical features. Festinare means “to hurry” in Latin, and the authors were referring to “walking with a quick and hastened step, as if hurried along against their will” (Parkinson, 2002). Jean Martin Charcot, professor at the famous Salpêtrière Hospital in Paris, considered by many as the founder of modern neurology, gave Parkinson credit by naming the disorder Parkinson’s disease (PD). In his Leçons sur Les Malades du Système Nerveux of 1877, he further discussed propulsion and retropulsion, with the “individual being apparently forced to follow a particular center of gravity” (Pearce, 1989). He also described rigidity and distinguished rest tremor, which he likened to “spinning wool” or “crumbling bread,” from the action tremor associated with multiple sclerosis (Pearce, 1989).

Epidemiology The frequency of PD varies depending on the diagnostic criteria, study population, and epidemiologic methods used, although the prevalence is generally thought to be about 0.3% in the general population and 1% in people over the age 60 years; the reported incidence figures have ranged from 8 to 18 per 100,000 person-years (deLau and

Breteler, 2006). An estimated 5 million people have PD worldwide. One study showed that the world’s highest prevalence of PD may be among the Amish in the northeastern United States. The prevalence of PD was 5703 per 100,000 (nearly 6%) of people 60 years old or older, more than three times the prevalence for the rest of United States (Racette et al., 2009). One reason for the wide variation in prevalence is difficulties differentiating between PD and essential tremor (ET), a much more common disorder whose clinical (and pathologic) features often overlap with PD (Fekete and Jankovic, 2011). Most studies have demonstrated about 3:2 male preponderance. In one of the largest prospective studies involving 142,902 professionals and nurses, the incidence rate was estimated to be 18.6/100,000 person-years (43.2 for males and 10.7 for females, respectively) (Chen et al., 2003). Furthermore, there appears to be a decreased incidence of PD in black populations, and some have postulated that melanin may have a neuroprotective function. Interestingly, PD patients are more likely to have melanoma, and melanoma patients have a higher risk for PD (Inzelberg and Jankovic, 2007; Pan et al., 2011). Many studies have found that living in rural areas, drinking well water, being exposed to pesticide, and holding certain occupations, such as physicians, dentists, scientists, farmers, teachers, and lawyers, are associated with increased risk of PD (Tanner et al., 2009). In contrast, smoking, caffeine intake, and exercise are associated with reduced risk of PD (Chen et al., 2010).

Pathogenesis PD is classified as a synucleinopathy along with diffuse Lewy body disease (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). The hallmarks of PD pathology are the presence of Lewy bodies with alpha-synuclein aggregates, as well as loss of dopamineproducing, melanin-containing neurons in the part of the midbrain called the substantia nigra pars compacta (Braak, 2002). This results in dopaminergic deficiency in the striatum, particularly the putamen. However, evidence suggests that nondopaminergic and autonomic systems may be involved long before the degeneration of substantia nigra, and some have suggested that PD is

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a developmental disorder with onset as early as in the perinatal period (Le et al., 2009; Mostile and Jankovic, 2009). In contrast to the traditional notion that PD starts in the substantia nigra, Braak et al., provided evidence that Lewy body pathology starts more caudally, in the medullary nuclei (2004). Lesion experiments in cats and other studies have linked locus ceruleus area to rapid eye movement sleep without atonia (RSWA) and other sleep and autonomic disorders, which could explain both the dysautonomic and rapid eye movement sleep behavior disorder (RBD) prodromes (Mostile and Jankovic, 2009). Involvement then progresses to the midbrain, followed by the temporal mesocortex and allocortex and, finally, the neocortex (Braak, 2002; Hawkes et al., 2010). Models of PD, such as the 6-hydroxydopamine lesion, point to an increase in oxidative stress as a possible mechanism of neurodegeneration. In addition, there is a suggestion of changes in 5-hydroxytryptophan metabolism in early disease that may contribute to affective symptoms (Branchi et al., 2010). Functional imaging shows changes of the PD motor-related pattern (PDRP) network that precede the onset of motor symptoms by 2 years (Tang et al., 2010). The majority of the patients in the geriatric age group have idiopathic PD, as opposed to genetic PD, which tends to have an earlier age at onset. Mutation in the gene coding for alpha-synuclein is associated with autosomal dominant inheritance of PD (Polymeropoulos et al., 1997; Irvine et al., 2008), as well as DLB (Zarranz et al., 2004). Mutations in the Parkin gene are an important cause of early-onset autosomal recessive PD (Lücking et al., 2000; Dawson and Dawson, 2003). The E3 ubiquitin ligase function of Parkin specifically targets proteins for degradation via the proteosome (Zhang et al., 2000; Dawson and Dawson, 2003). Loss of this function may potentially allow the accumulation of aggregation-prone proteins. Parkin itself may be subject to post-translational regulation affecting its activity (Yamamoto et al., 2005; Rubio de la Torre et al., 2009), for example, by c-Abl-mediated tyrosine phosphorylation (Imam et al., 2011). In addition to Parkin, DJ-1 as well as PTEN-induced kinase 1 (PINK1) mutations have been recognized as causes of autosomal recessive PD. PINK1 is thought to be a mitochondrial protein kinase (Silvestri et al., 2005). It has been suggested that PINK1 recruits Parkin from the cytoplasm into damaged mitochondria, where the ubiquitin ligase function of wild-type Parkin initiates mitochondrial degradation (Matsuda et al., 2010). Leucine-rich repeat serine/threonine protein kinase 2 (LRRK2) mutations are an important cause of autosomal-dominant PD. Investigation of the mechanism of LRRK2 mutation revealed involvement in cellular signaling pathways (Berwick and Harvey, 2011). Further research is needed to elucidate the pathogenic mechanism underlying genetic forms of PD. Vascular parkinsonism is clinically manifested predominantly by slow, broad-based, shuffling and freezing gait without much involvement of the upper body, hence

the term “lower body parkinsonism” (Winikates and Jankovic, 1999; Kalra, et al., 2010). These patients have risk factors for cerebrovascular disease and have evidence of multiple vascular insults in the basal ganglia or white matter on neuroimaging studies or at autopsy. Although up to half of the patients with vascular parkinsonism improve with levodopa, the response is rarely dramatic; if it is robust, it suggests coexistent PD (Tzen, 2001).

Clinical features Although at least 60% of these neurons are already lost or damaged by the time the patient first develops the cardinal motor features of PD—tremor, rigidity, akinesia (bradykinesia), and postural instability (TRAP)—many nonmotor features of PD may manifest long before the motor symptoms (Jankovic, 2008). For example, depression and anxiety have been noted to precede development of PD (Shiba et al., 2000). Retrospective studies identified certain personality traits that may be associated with PD, but prospective studies are needed to understand this association further (Ishihara, 2006). Rigid, nervous, cautious, conventional, and introverted personality traits were reported (Ishihara, 2006). Constipation has also been reported as preceding the development of PD (Abbott et al., 2001). Other autonomic dysfunction such as orthostatic hypotension (OH), sialorrhea, dysphagia, sexual dysfunction, and respiratory problems (Mostile and Jankovic, 2009; Mehanna and Jankovic, 2010) may also precede the onset of cardinal motor symptoms for several years or decades. RSWA associated with dream enactment behavior not caused by medication or substance use, called RBD, may precede the onset of motor symptoms not just in PD, but also in DLB and MSA, long before other symptoms emerge. In one study, 38% of patients with isolated RBD reportedly developed a parkinsonian disorder after 12.7 years ( Schenck, Bundlie and Mahowald, 1996). Some authors have reported a range of 15–50 years (mean 25 years) between the onset of RBD and PD, DLB, or MSA (Claassen et al., 2010). Two cases of RBD without additional neurologic symptoms were shown to have Lewy body pathology on autopsy, suggesting that this sleep disorder may be viewed as a form of synucleinopathy (Mahowald et al., 2010), although it may also be seen in disorders other than synucleinopathies (Mahowald, 2006). Although a “prodromal phase,” during which these behavioral and autonomic symptoms are present, has been suggested to last an average of 4–6 years, some have suggested that it may last much longer and may even have its onset in the perinatal period (Le et al., 2009; Mahowald et al., 2010; Wu, et al., 2011). The rest tremor is 4–6 Hz, tends to have a pronating/ supinating component, and has classically been described as “pill rolling.” Lip, chin, or jaw tremor may be present

Parkinson’s Disease

as well. PD patients may also have an action tremor (Shahed and Jankovic, 2007). Rest tremor may become more prominent while the patient is walking or performing calculations (Raethjen et al., 2008). As only a few cases of head tremor have been described in PD, the presence of head tremor may signify concurrent ET (Shahed and Jankovic, 2007). Bradykinesia causes impairment of fine motor movements, as initially exhibited by a patient’s difficulty with buttoning a shirt or tying shoelaces. Gait in PD is described as “shuffling” with small steps and reduced arm swing. Difficulty with initiation of gait (start hesitation) and other forms of freezing of gait may be present. Some patients also exhibit involuntary hastening of gait, termed festination (Knuttson, 1972). “Freezing” or arrest of gait may be present especially in tight spaces such as elevators and doorways and when performing turns. Freezing of gait early in the course of the disease is suspicious for vascular parkinsonism or early stages of progressive supranuclear palsy. The various classical features of PD can be objectively assessed by various clinical rating scales, including the Unified Parkinson Disease Rating Scale (UPDRS), which has been recently modified as the Movement Disorder Society (MDS)-UPDRS (Goetz et al., 2007; Jankovic, 2008). In addition to the classic PD symptoms (TRAP), many patients with PD gradually develop flexed posture and other neck, trunk, or joint deformities, so-called striatal deformities, often wrongly attributed to “arthritis” (Ashour and Jankovic, 2006; Jankovic, 2010). These include striatal hand (Figure 12.1) and foot (Figure 12.2) deformities. Other features that may be present include stooped posture, scoliosis, “Pisa syndrome,” and head

Figure 12.1 Striatal hand deformity.

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Figure 12.2 Foot dystonia.

drop (Figure 12.3; Jankovic, 2010). Camptocormia is a severe, involuntary flexion of the trunk (Figure 12.4). The patient with camptocormia is able to straighten the back in the supine position or when performing the “climbing on the wall” maneuver (Jankovic, 2010). PD may be classified into different subtypes, such as young onset versus late onset and familial versus sporadic, and also may be classified according to its clinical presentation; tremor dominant and postural instability gait disorder (PIGD) are major subtypes (Jankovic et al., 1990). The tremor-dominant subtype has been associated with a more favorable prognosis (Jankovic, 2005). Although tremor is the most classic hyperkinetic disorder associated with PD, many PD patients also exhibit abnormal involuntary movements, called dyskinesia, as an adverse effect of levodopa. These dyskinesias may

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Neuropsychiatric manifestations

Figure 12.3 Bent spine deformity.

occur as repetitive, coordinated movements (stereotypies), jerk-like movements that move randomly from one body part to another (chorea), or more sustained, patterned muscle contractions causing abnormal postures (dystonia; Jankovic, 2002). These dyskinesias not only may impair motor functioning and interfere with balance and activities of daily living, but also may impair other functions, including respiration (Mehanna and Jankovic, 2010).

Figure 12.4 Camptocormia.

Patients with PD display a range of neuropsychiatric symptoms, including hallucinations, delusions, agitation, depression, irritability, anxiety, and apathy (Aarsland, 1999). As apathy is associated with executive dysfunction and depression in PD, it may be due to dysfunction of frontal lobe systems (Aarsland, 1999). Visual hallucinations (VH) may affect up to 50% of PD patients and 73% of patients with DLB (Williams and Lees, 2005). They may take the shape of persons, animals, or objects (Meppelink et al., 2009). They are traditionally thought of as effects of dopaminergic treatment, but a challenge with high-dose intravenous levodopa in continuous or pulse infusion did not produce hallucinations, even though dyskinesias worsened (Goetz et al., 1998). On functional MRI, PD patients with VH were found to have impaired processing in occipital and temporal extrastriate visual cortices (Meppelink et al., 2009). Symptoms of depression and anxiety may be present for years preceding the development of motor symptoms of PD (Shiba et al., 2000). A study of consecutive outpatient clinic PD patients found comorbid mood and anxiety disorders in 19.3% of PD patients versus 8.6% of age- and sex-matched controls (Nuti et al., 2004). Another study found current and lifetime prevalence of at least one anxiety disorder diagnosis among PD patients to be 43% and 49%, respectively (Pontone et al., 2009). Dysthymia and depression, possible nonmotor manifestations of dopamine deficiency among PD patients, can lead to mild immediate reward-seeking behavior (Wolters et al., 2008). Impulse-control disorders are thought to be extrinsic and related to dopamine-replacement therapy, especially administration of dopamine agonists (Wolters et al., 2008). These include compulsive gambling, shopping, binge eating, hypersexuality, hoarding, compulsive skin picking, and pathologic Internet use (Wolters et al., 2008; O’Sullivan, et al., 2010). Even impulsive smoking associated with increased dopamine agonist administration has been reported (Bienfait et al., 2010). Treatment consists of lowering the dosage of the offending dopaminergic agent, switching from dopamine agonist to levodopa therapy, and engaging in family or psychiatric counseling. Punding is a stereotypic motor behavior associated with levodopa use that involves repetitive handling, examining, or dismantling of objects (Fernandez et al., 1999). Similar behaviors are observed in patients who abuse amphetamine and cocaine and are associated with a sense of relief in that group; however, no relief or pleasurable sensation is associated with these activities in the PD group (Fernandez and Friedman, 1999). Patients with cognitive dysfunction, particularly if accompanied by hallucinations, preceding the development of motor symptoms of PD are classified as having DLB. Dementia that develops after motor symptoms of

Parkinson’s Disease

PD is called PD dementia (PDD). DLB subjects tend to have more conceptual and attentional errors than PDD subjects, even after controlling for dementia severity (Aarsland et al., 2003). Neuropathologically, DLB has been shown to have widespread alpha-synucleinopathy and Lewy bodies (Lippa et al., 2007). Considerable controversy exists concerning whether PD, DLB, and PDD represent related or independent disease entities.

Nonmotor features of Parkinson’s disease Nocturnal nonmotor symptoms play an important role in affecting the quality of life of PD patients. Sleep fragmentation, vivid dreams, and nightmares may be present (Goetz et al., 2010). Obstructive sleep apnea and hypopnea is common in the PD population (Mahowald and Schenck, 2010). Sleep disruption contributes to excessive daytime somnolence (Ray Chaudhuri, 2006). Rapid transition from wakefulness to stage 2 sleep may cause sudden sleep attacks (Rye and Jankovic, 2002). Dream enactment behavior in RBD may be relatively benign and limited to vocalizations (Ray Chaudhuri, 2006), or it may develop into behaviors that have potentially dangerous consequences. Choking of the bed partner, dives out of the bed, and near defenestration have been reported (Schenck et al., 2009; Mahowald and Schenck, 2010). Gradual weight loss is also commonly present in PD, although other causes should be investigated if the weight loss is abrupt and severe (Jankovic et al., 1992; Bachmann and Trenkwalder, 2006). OH has been reported in 47% of a community-based cohort (Allcock et al., 2004; Mostile and Jankovic, 2009). Cardiac denervation can precede the onset of motor symptoms of PD (Goldstein et al., 2007). Patients with PD–OH have cardiac and extracardiac noradrenergic sympathetic denervation (Sharabi et al., 2008). Even PD patients without OH have cardiac sympathetic denervation (Goldstein et al., 2000) Cardiac sympathetic denervation can precede the onset of motor symptoms of PD (Milazzo et al., 2012). A subset of PD patients present early in the disease course with profound autonomic failure (AF-PD). The symptoms may include OH and postprandial hypotension, in addition to urinary frequency, constipation, and denervation supersensitivity to norepinephrine infusion (Niimi et al., 1999; Mostile and Jankovic, 2009). Sympathetic ganglionic and postganglionic nerves are involved in AF-PD. Olfactory dysfunction is also present almost universally in PD. It includes deficits in odor identification and odor discrimination (Boesveldt et al., 2008). Odor identification deficit is independent of disease progression, but impairment in odor discrimination increases with disease duration (Boesveldt et al., 2008).

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Treatment Treatment of PD depends on the severity of the disease, as well as the subtype. For early, mildly symptomatic disease, monoamine oxidase (MAO) inhibitors such as rasagiline and selegiline may be used. In addition to this mild symptomatic benefit, rasagiline may have a disease-modifying quality and delay the worsening of motor symptoms. Dopamine agonists ropinirole and pramipexole can be initiated once stronger symptomatic relief of loss of manual dexterity, rest tremor, rigidity, or gait disturbance is required. Although early introduction of dopamine agonists may delay the onset of levodopa related motor complications, no diseasemodifying effects have been demonstrated with these drugs (Schapira et al., 2013a). These agents are carefully titrated to a dose providing optimum relief. Extendedrelease versions of both medications are available, which permits simplification of the dosing regimen. Care should be taken to ask the patients about complications of dopamine agonist therapy, which include sudden sleep attacks and extrinsic impulse-control disorders, including pathologic gambling, compulsive shopping, binge eating, and hypersexuality (Wolters et al., 2008). As the disorder progresses, the addition of levodopa is required for treatment of troublesome motor symptoms. This can be done in conjunction with dopamine agonists. Historically, the racemic mixture of dextro- (D) and levorotatory (L) isomers of 3,4-dihydroxyphenylalanine (DOPA) caused more nausea than the current L-DOPA (levodopa) formulation (Pearce, 1989). The enzyme DOPA decarboxylase, discovered in 1938, converts DOPA into dopamine (Hornykiewicz, 2002). Nausea and lightheadedness from peripheral conversion of dopamine is counteracted by peripherally acting DOPA decarboxylase inhibitor such as carbidopa or benserazide, which is not approved in the United States. The medullary vomiting center is not protected by the blood–brain barrier, which allows peripherally acting DOPA decarboxylase inhibitors to exert their effect on this center (Jankovic, 2002). Additional carbidopa (marketed under the trade name Lodosyn) can be utilized for treatment of nausea. Trimethobenzamide has also successfully been used for nausea. The peripheral D2 dopamine receptor blocking agent domperidone is not available in the United States (Jankovic, 2002). Selective 5-HT3 receptor antagonists ondansetron or granisetron may also be useful for this purpose (Jankovic, 2002). Motor fluctuations include OFF phenomena and dyskinesias. Adding entacapone, a catechol-O-methyl transferase (COMT) inhibitor, to the levodopa regimen prolongs the effective duration of each levodopa dosage (Merello et al., 1994). Entacapone’s potential side effects include diarrhea, worsening or dyskinesias, and orange urine discoloration. MAO inhibitors such as selegeline can also be used for this purpose. After prolonged treatment with levodopa,

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dyskinesias that are hyperkinetic, choreiform movements can present. Dyskinesias may occur at the peak of each dose of levodopa therapy or in a diphasic manner (Jankovic, 2002). Avoiding sustained-release formulations of levodopa is recommended in this case, as uneven plasma levodopa levels can contribute to dyskinesias. The total daily dose of levodopa can be divided into smaller and more frequent doses, to avoid the high peak plasma levels involved with peak-dose dyskinesias. Novel delivery strategies, including continuous intestinal infusion of levodopa gel (duodopa) are increasingly utilized to smooth out motor fluctuations (Fernandez et al., 2013). In addition, further analysis of data from the Stalevo Reduction in Dyskinesia Evaluation in Parkinson’s disease (STRIDE-PD) study showed that risk of dyskinesia or wearing off increased with higher levodopa dosages (Olanow et al., 2013). Addition of amantadine may be beneficial for control of dyskinesia (Verhagen Metman et al., 1998; Pereira da Silva-Junior et al., 2005). Anticholinergics such as trihexyphenidyl historically were used for the treatment of PD prior to the development of levodopa, but these drugs are used only rarely today, as they effectively treat only tremor and are associated with a variety of cognitive, urinary, and other side effects (Pearce, 1989). Tremor-dominant subtype of PD may benefit from utilizing additional medications that have been traditionally used to treat ET, including beta-blockers, topiramate, and zonisamide. As mentioned earlier, potential worsening of cognitive status may occur. Higher doses of levodopa may be needed for this subtype as well. See Figure 12.5 for a summary of therapeutic approaches to PD.

PIGD subtype patients need assistive devices earlier in the course of PD. Frequent falls are a source of morbidity, resulting in hospitalizations and associated complications, as well as admission to assisted living facilities. For patients with PD who exhibit AF-PD, treatment of OH is an important consideration. Orthostasis may be improved with pressure support stockings, increased fluid intake, and medications such as midodrine and fludrocortisone. L-threo-dihydroxyphenylserine (droxidopa) is currently being tested for treatment of OH. A potential side effect of these medications is supine hypertension, which may necessitate sleeping in a position with the patient’s head elevated. Hallucinations can be controlled with dopamineblocking agents. The challenge is to select an agent that will least interfere with levodopa therapy. Clozapine, a relatively specific D4 receptor antagonist, can effectively control hallucinations in PD patients without causing worsening of parkinsonian symptoms. Clozapine use is limited by the requirement of weekly blood draws due to risk of agranulocytosis (Jankovic, 2002). Quetiapine, which blocks D1, D2, 5-HT1A, and 5-HT2 receptors, also has a benefit on hallucinations in PD patients (Fernandez and Friedman, 1999). Furthermore, pimavanserin, a selective serotonin 5-HT2A inverse agonist, has been shown in phase 3 clinical trial to provide benefit to PD patients who experience psychosis (Cummings et al., 2013). Treatment of constipation includes typical over-thecounter agents. Lubiprostone and linaclotide also may be helpful for the treatment of constipation in PD patients.

PARKINSON'S DISEASE Therapeutic Strategies

Motor

Behavioral Cognitive

Other Non-Motor Symptoms

Levodopa-Related Complications

MAO inhibitors initially (rasagiline)

Quetiapine for hallucinations and psychosis

Melatonin for RBD

Amantadine for dyskinesias

Dopamine agonists

Clozapine for hallucinations and psychosis

Clonazepam for RBD

Entacapone to reduce OFF time

Levodopa

Acetylcholinesterase inhibitors for cognitive and memory issues

Midodrine or fludrocortisone for orthostatic hypotension

STN or GPi Deep brain stimulation

Figure 12.5 Treatment algorithm in PD.

Parkinson’s Disease

Depression is common with PD and can be treated with selective serotonin reuptake inhibitors (SSRI) or tricyclic antidepressants. SSRI may worsen tremor, which is a consideration in tremor-dominant PD patients. Rapid eye movement (REM) behavior disorder may be treated with melatonin or benzodiazepines if dreamenacting behavior becomes injurious to the patient or bed companion (Aurora et al., 2010). Dihydropyridine L-type calcium channel blockers that traverse the blood–brain barrier have been shown to be potentially neuroprotective (Ritz et al., 2010). Due to this potential effect, their use in PD patients maybe preferred over other classes of antihypertensive medication. Symptomatic treatment for cognitive impairment due to DLB or PDD includes cholinesterase inhibitors. Modest efficacy in randomized, placebo-controlled, doubleblind studies has been demonstrated (Lippa et al., 2007; Karantzoulis and Galvin, 2013).

Lesion surgery The first lesion known to improve symptoms of PD was accidental. Dr. Irving Cooper damaged the anterior choroidal artery while performing aneurysm ligation in a PD patient, leading to startling improvement in PD symptoms (Pearce, 1989). Thalamotomy has been used to treat tremor with PD (Jankovic et al., 1995). Pallidotomy has been found to reduce rigidity (Bravo and Cooper, 1959) and levodopainduced dyskinesias, as well as improve motor function overall in both ON and OFF states (Uitti et al., 1997). Similar to deep brain stimulation (DBS) surgery, pallidotomy has been associated with declines in word generation (Uitti et al., 1997). Due to the ability to make postprocedure adjustments with DBS, lesioning procedures have been phased out in favor of DBS.

Deep brain stimulation Surgical therapy using DBS is an important therapeutic option for patients with motor fluctuations. Treatment with DBS allows for reduced levodopa dosage, resulting in lower expression of dyskinesias. The stable stimulation provided by DBS helps with treatment of OFF symptoms, such as gait freezing. As DBS is a surgical procedure, anesthesia risk and risk of hemorrhage, seizure, and infection exists. Potential complications include worsening of cognitive status, including declines in verbal memory, verbal fluency, timed transcription, and word naming (York et al., 2008); worsening of gait; and dysarthria (Kenney et al., 2007). For these reasons, patients with lower cognitive scores on screening tests such as the Montreal Cognitive Assessment (MOCA) test and patients with significant balance disturbance due to non-PD

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reasons, such as lower extremity neuropathy or clinically significant microvascular disease (especially in the pons), are less likely to have an overall functional benefit from DBS surgery. These effects may be related to the surgical trajectory and electrode placement (York et al., 2009). The primary targets for DBS in PD are the subthalamic nucleus (STN) and pars interna of the globus pallidus (GPi) (Johnson et al., 2008). Bilateral STN or GPi stimulation has been shown to reduce “off” periods and reduce dyskinesia (Obeso et al., 2001). Medication reduction plays a role in reducing levodopa-induced dyskinesia after subthalamic nucleus deep brain stimulation (STN DBS) surgery (Russmann et al., 2004). In a case series of 277 implantation procedures, there were seven cases of intracranial hemorrhage, two infections necessitating removal of electrodes, and four cases of persistent neurologic deficit (Obeso et al., 2001). Bilateral STN DBS surgery leads to symptomatic and functional improvements measured on health-related quality of life questionnaires, including independence from help, energy level, controllability/fluidity of movement, and steadiness when standing or walking (Ferrara et al., 2010). For patients with levodopa-related motor complications, STN DBS leads to improvements in the Unified Parkinson’s Disease Rating Scale, Part III scores above best medical management (Deuschl et al., 2006). The pedunculopontine nucleus has also been considered a possible target (Stefani et al., 2007). Thalamic DBS has been reported to improve tremor in PD, but it is not useful in treating other motor aspects of the disease (Ondo et al., 1998). Hence, it is recommended to reserve thalamic DBS for PD patients whose disability stems from high-amplitude tremor (Ondo et al., 1998).

Future directions James Parkinson had a poignant statement regarding the disorder: “The unhappy sufferer has considered it as an evil, from the domination of which he had no prospect of escape” (Parkinson, 2002). In no less uncertain terms, better disease-modifying therapies for PD are needed. Research into these therapeutic modalities is hampered by the lack of biomarkers both for presymptomatic diagnosis and for the following response to therapy. To this end, the Michael J. Fox Foundation is currently enrolling patients in the Parkinson’s Progression Markers Initiative (PPMI). Patients in this study and controls will receive a functional dopamine transporter imaging scan and will be monitored via serum and spinal fluid studies (Wu, et al., 2011). If successful, the study will allow researchers to monitor biomarker response to emerging therapies. The Longitudinal and Biomarker Study in PD (LABS-PD) is another study designed to prospectively measure the evolution of motor and nonmotor features of PD and sample potential biomarkers (Ravina et al., 2009). Elevated levels of alpha-synuclein oligomers, as well as

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elevation in the oligomer to total alpha-synuclein ratio, have recently been reported in a study with 32 cases and 28 controls (Tokuda et al., 2010). These findings may serve as the basis of a future cerebrospinal fluid (CSF) test if they can be reliably reproduced in larger series (Ballard and Jones, 2010). For a closer target timeframe, a new time-release formulation of carbidopa/levodopa, IPX-066, is being investigated for newly diagnosed PD patients, as well as patients with motor fluctuations. Other agents, including the MAO-B and glutamate inhibitor safinamide, are being tested for these indications. (Schapira et al., 2013b). Adenosine A2A receptor antagonists can control PD symptoms via GABA and glutamate regulation (Pinna et al., 2013). The question of how to best focus research resources remains. Multiple subtypes of PD exist, each with a potentially different response to a particular medication. Most research efforts are dedicated to traditional patients who are “levodopa responders,” but important information might be gleaned from following patients who are poorly levodopa responsive. Patients who are identified as having scans without evidence of dopaminergic deficit (SWEDDs) are an important subgroup (Bajaj, et al., 2010). Although they may be excluded from some trials, it is important to track them on a larger scale, to learn more about the progression of their symptoms as well as pathogenesis.

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Pan, T., Li, X., and Jankovic, J. (2011) The association between Parkinson’s disease and melanoma. International J Cancer (in press). Parkinson, J. (2002) An essay on the Shaking Palsy (reprint). J Neuropsychiatry Clin Neurosci, 14: 223–236. Pearce, J.M.S. (1989) Aspects of the history of Parkinson’s disease. J Neurology, Neurosurgery, and Psychiatry, (Suppl.): 6–10. Pereira da Silva-Junior, F., Braga-Neto, P., Monte, F.S., and Sales de Bruin, V.M. (2005) Amantadine reduces the duration of levodopa-induced dyskinesia: a randomized, double-blind, placebo-controlled study. Park Rel Dis, 11:449–452. Pinna, A., Simola, N., Frau, L., and Morelli M. (2013) Symptomatic and neuroprotective effects of A2A receptor antagonists in Parkinson’s disease. In: S. Masino and D. Boison (eds), pp. 361--384. New York: Adenosine, Springer. Polymeropoulos, M.H., Lavedan, C., Leroy, E., et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 276: 2045–2047. Pontone, G.M., Williams, J.R., Anderson, K.E., et al. (2009) Prevalence of anxiety disorders and anxiety subtypes in patients with Parkinson’s disease. Mov Disord, 24: 1333–1338. Racette, B.A., Good, L.M., Kissel, A.M., et al. (2009) A populationbased study of Parkinsonism in an Amish community. Neuroepidemiology, 33 (3): 225–230. Raethjen, J., Austermann, K., Witt, K., et al. (2008) Provocation of Parkinsonian tremor. Mov Disord, 23: 1019–1023. Ravina, B., Tanner, C., Dieuliis, D., et al. (2009) A longitudinal program for biomarker development in Parkinson’s disease: a feasibility study. Mov Disord, 24: 2081–2090. Ray Chaudhuri, K., Pal, S., Forbes, A., et al. (2001) Does nocturnal sleep disturbance contribute to excessive daytime sleepiness in Parkinson’s disease [abstract]. J Neurol Sci, S395: 1162. Ritz, B., Rhodes, S.L., Qian, L., et al. (2010) L-type calcium channel blockers and Parkinson disease in Denmark. Ann Neurol, 67: 600–606. Rubio de la Torre, E., Luzon-Toro, B., Forte-Lago, I., et al. (2009) Combined kinase inhibition modulates parkin inactivation. Hum Mol Genet, 18: 809–823. Russmann, H., Ghika, J., Combrement, P., et al. (2004) L-Dopa induced dyskinesia improvement after STN-DBS depends upon medication reduction. Neurology, 63: 153–155. Rye, D.B. and Jankovic, J. (2002) Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD. Neurology, 58: 341–346. Schapira, A.H., Barone, P., Hauser, R.A., et al. (2013a) The Pramipexole ER Studies Group. Patient-reported convenience of oncedaily versus three-times-daily dosing during long-term studies of pramipexole in early and advanced Parkinson’s disease. Eur J Neurol, 20: 50–56. Schapira, A., Fox, S., Hauser, R., et al. (2013b) Safinamide Add on to L-Dopa: A Randomized, Placebo-Controlled, 24-Week Global Trial in Patients with Parkinson’s Disease (PD) and Motor Fluctuations (SETTLE) (P01.062). Neurology; 80 (Meeting Abstracts 1). Schenck, C.H., Bundlie, S.R., and Mahowald, M.W. (1996) Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology, 46: 388–393. Schenck, C.H., Lee, S.A., Cramer Bornemann, M., and Mahowald, M.W. . (2009) Potentially lethal behaviors associated with rapid eye movement sleep behavior disorder (RBD): review of the literature and forensic implications. J Forensic Sci, 54: 1475–1484.

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Chapter 12.2 Essential Tremor and Other Tremor Disorders Holly Shill

Introduction Tremor is an involuntary, rhythmic, oscillatory movement of a part or parts of the body. It is produced by alternating or synchronous contractions of antagonist muscles (Figure 12.6). Tremor can be recorded in virtually all normal individuals through use of electromyography (EMG) and accelerometry. The vast majority falls into the category of physiologic tremor and is thought to be necessary for the production of voluntary movement (Elble and Randall, 1976; 1978). Only when the tremor becomes enhanced, either through exaggeration of this physiologic tremor or through a specific disease (such as Parkinson’s disease [PD]) may it become bothersome and warrant treatment. This chapter reviews characterization of tremor and pathologic tremor conditions.

Clinical characterization of tremor The patient should be examined in a variety of postures and movements. Tremor is assessed in the head, neck, limbs, and trunk. The circumstances in which the tremor is more prominently seen and its frequency when combined with the body part affected typically point to the diagnosis. The following classification is useful in discussing tremors typically encountered in clinical practice. • Resting tremor occurs in the absence of voluntary movement and with the body part fully supported.

Resting tremor is most commonly seen in the upper extremity, but its presence or absence should also be noted in the legs and the lip and/or jaw. Essential tremor (ET) in the head/neck may cause a side-to-side (“nono”) head tremor, whereas PD in the head causes a lip quiver or side-to-side jaw tremor. Resting tremor may be brought out by concentration maneuvers such as closing the eyes and counting backward from 100 by 7s. Sometimes Parkinsonian rest tremor may be seen only when the patient is asked to walk down the hallway and the now-relaxed arm is noted to develop tremor at the patient’s side. • Postural tremor is tremor while voluntarily maintaining posture against gravity. Usually this is assessed by asking the patient to hold the arms extended in front. It may also be assessed in the legs in the same manner while sitting. Maintaining posture with the arms flexed and the flattened hands approximating the chin, but not touching, often brings out ET. Rubral tremor, or cerebellar outflow tremor, may also be seen markedly in this position. • Kinetic/action tremor is tremor that is seen during voluntary movement. Classically, it is examined by having the patient do finger-to-nose testing or having the patient run the heel of the foot up and down the opposite shin. More functional assessment can also be done, such as having the patient drink from a cup or use the hand to write. Drawing an Archimedes spiral can bring out the action tremor of ET (Figure 12.7). Electrode: EMG4

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Figure 12.7 Archimedes spiral in a patient with ET.

• Task-specific tremor is kinetic tremor during specific, skilled movement. This term is usually reserved for tremor that is brought out only in specific circumstances and is not seen more generally. Primary writing tremor therefore is a condition in which tremor is seen only with handwriting, but not with posture and finger-to-nose maneuvers. • Orthostatic tremor is tremor of lower extremities or trunk while standing in place. It is brought out by having the patient stand without moving for a reasonable length of time (usually about 1 minute). After a varying latency, a buckling type movement of the legs is seen in place of tremor (Figure 12.8a). If one does an EMG of the muscle during this leg buckling, high-frequency (13–16 Hz) tremor activity underlies this outward movement (Figure 12.8b). Additionally, because this higher frequency may get into the auditory range, the tremor may be appreciated through the use of a stethoscope over the leg muscles. (a)

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Figure 12.8 (a) The variable, mostly low-frequency spectral peaks

seen on accelerometry of the leg during orthostatic tremor. (b) The narrow 17 Hz spectral peak seen on EMG of the anterior tibialis during orthostatic tremor.

Classically, essential tremor (ET) refers to a monosymptomatic tremor condition, most commonly a bilateral, relatively symmetrical postural and kinetic tremor of the hands. The term action tremor is often used, referring to the presence of voluntary muscle activity required to see the tremor. Guidelines for the diagnosis of ET have been proposed (Deuschl et al., 1998) and include primary criteria of bilateral action tremor of the hands and forearms, absence of other neurologic signs (except cogwheel rigidity), and/or head tremor without signs of abnormal posture (dystonia). Secondary criteria include long duration (greater than 3 years), positive family history, and beneficial response to alcohol. Red flags that prompt alternate diagnoses include strictly or strongly unilateral tremor (suggests Parkinsonism), sudden or rapid onset, and/or current use of known tremorogenic drugs. Epidemiologic studies support that ET is a relatively common condition, and the prevalence goes up with aging. Meta-analysis of population studies estimates that it affects about 6.3% of people over 65 and as much as 21% of those over 90 (Louis and Ferreira, 2010). In a movement disorder clinic, 60% reported a positive family history of tremor (Lou and Jankovic, 1991); that percentage is likely quite a bit lower in a population-based study, particularly if older age at onset. There is no gender predominance and no apparent ethnic predisposition. With time, it is accepted that many patients with longstanding ET may have mild cerebellar features, such as gait ataxia (Singer et al., 1994; Hubble et al., 1997). Hearing loss might also be seen with ET, although conclusive data is lacking (Ondo et al., 2003; Benito-Leon et al., 2007). More recently, epidemiologic studies have suggested that late-onset ET (older than 65 years old) may put a patient at increased risk for dementia or cognitive decline (BenitoLeon et al., 2006; Bermejo-Pareja et al., 2007). Whether this is associated with typical ET, as just defined, or with a younger age of onset is unclear. It has been suggested that ET-like tremor in the elderly may be the first symptom of a neurodegenerative disorder such as Alzheimer’s disease (Elble et al., 2007). The overlap of ET and PD is often discussed. Some patients have both conditions in the family, suggesting some underlying genetic predisposition to both in rare cases (Yahr et al., 2003; Spanaki and Plaitakis, 2009). Additionally, tremor-dominant PD may start as ET (Geraghty et al., 1985; Minen and Louis, 2008). In a large Spanish epidemiology study, the elderly with action tremor have a relative risk of 3.47 of developing PD when followed over time (Benito-Leon et al., 2005). Although this risk seems high, it must be tempered by the fact that PD is relatively uncommon, and many of the subjects in the study may not have had typical ET as defined in diagnostic criteria. Specifically, the duration of tremor may have been as

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short as 1 year. This suggests that the elderly with relatively short-duration tremor should be followed closely and not reassured too emphatically as to the benignity of their tremor. This link of ET with PD and dementia has led to a proposal to redefine diagnostic criteria of ET into three categories (Deuschl and Elble, 2009). First, the term hereditary ET would be used for those who fulfill the previous criteria for ET, have at least one affected family member, and have onset before age 65. Sporadic ET would be used for similar patients without a family history. Finally, senile ET would refer to those older than age 65 who may or may not have a family history. This latter group may have more degenerative pathology, such as parkinsonism. At this time, pending widespread acceptance of these categories, it seems prudent to be more cautious with elderly-onset patients monitoring for cognitive decline and parkinsonism.

Pathophysiology of essential tremor The pathophysiology of ET has been extensively studied. Routine brain imaging is generally normal, although magnetic resonance spectroscopy and blood flow imaging have supported abnormalities in cerebellar circuitry with overactivity in the cerebellar-thalamo-cortical loop (Hallett and Dubinsky, 1993; Jenkins et al., 1993; Pagan et al., 2003). Genetic studies have linked ET to certain chromosomal loci in this often hereditary condition (Gulcher et al., 1997; Higgins et al., 1997), but pinning down the genetic abnormality has proved elusive. Polymophphisms in LINGO1 have been linked to ET in genome-wide association studies (Stefansson et al., 2009), although causative mutations have not yet been defined in large ET families. Until recently, there were few neuropathologic studies of patients with ET. Most early studies have emphasized the lack of consistent brain pathology in ET. The largest study done was in 20 patients with ET followed in a movement disorder clinic in Saskatchewan, Canada (Rajput et al., 2004). No consistent pathologic abnormalities were found, unless the patient had additional features of PD (6/20). Another study was done in 11 patients as part of the Honolulu–Asia Aging Study (Ross et al., 2004). Again, researchers found no consistent pathology. Recently, two larger series of autopsied ET patients demonstrated greater cerebellar pathology compared with controls (Louis et al., 2007; Shill et al., 2008). One of these studies also suggested a greater frequency of Lewy body pathology restricted to the locus ceruleus (Louis et al., 2007), but the second study failed to confirm this finding (Shill et al., 2008), leaving the link between PD and ET unclear pathologically. Given the imaging and pathologic studies implicating the cerebellum, it is likely involved in ET. However, whether it is primarily

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involved, indicating a slow neurodegenerative process, or secondarily affected, as a consequence of longstanding oscillation, is debated. Studies suggesting that the cerebellar features such as gait ataxia and reduced eyeblink condition can be improved by alcohol (Klebe et al., 2005) and DBS (Kronenbuerger et al., 2008), respectively, support that the cerebellar abnormalities may be partly a functional consequence of longstanding tremor instead of degenerative.

Treatment of tremor Treatment of tremor disorders is a combination of medical, behavioral, and surgical interventions, guided by persisting symptoms and underlying etiology in many, if not most, patients.

Essential tremor ET is one of the most common neurologic conditions and is disabling for most patients who suffer from it (Busenbark et al., 1991; Koller et al., 1994; Brin and Koller, 1998). Despite the high prevalence and associated impact on quality of life, with the exception of thalamic deep brain stimulation (DBS), no therapy has been developed and approved specifically for this condition. The American Academy of Neurology has developed practice parameters for the treatment of ET (Zesiewicz et al., 2005). The most commonly used medications and the best studied are primidone and propranolol. • Primidone has been studied extensively, and many studies support its efficacy (Koller and Royse, 1986; Sasso et al., 1988). Dosing should start at 25–50 mg at bedtime and increase every several weeks until the desired effect has been reached or the dose reaches 250–350 mg. Patients should be warned of the 25% potential for acute reactions but reassured that this generally improves with time. Long-term tolerability of primidone seems quite good, and in the doses typically used for ET (<500 mg) (Sasso et al., 1991), the incidence of side effects such as sedation, imbalance, and cognitive changes makes it acceptable for use in the elderly. • Propranolol and other beta-blockers have also been well studied, making them appropriate as first-line therapy for ET (Cleeves and Findley, 1984; Cleeves and Findley, 1988). Slow titration is key to achieving the typical effective dose of propranolol in ET, which ranges from 240 mg to 320 mg per day. Patients prefer long-acting preparations (Cleeves and Findley, 1988). Reduction in tremor amplitude is similar to primidone, around 40– 50%. Use of a beta-blocker over primidone should be considered when there is concomitant need to treat both cardiovascular conditions and ET. Relative contraindications for the use of beta-blockers include congestive heart failure, bronchospastic condition, diabetes, and second- and third-degree AV heart

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block. Side effects of beta-blockers include depression, fatigue, and impotence. • Gabapentin has established efficacy in the treatment of epilepsy, as an add-on therapy, and neuropathic pain, particularly postherpetic neuralgia. A total of 61 patients with ET have been studied in double-blind, placebo-controlled studies (Pahwa et al., 1998; Gironell et al., 1999; Ondo et al., 2000). The first study of 20 subjects demonstrated little efficacy but good tolerability of 1800 mg over placebo using a crossover design assessing clinical rating scale (Pahwa et al., 1998). A second 3 month crossover study of 25 subjects compared doses of 1800 mg and 3600 mg with placebo and showed significant improvement (absolute improvement of 3–40% over baseline, p < 0.05) in the subjects’ global impressions and activities of daily living scales (Ondo et al., 2000). No additional benefit was gained in 3600 mg/ day over 1800 mg/day. Again, tolerability was fairly good. A comparator study suggests that gabapentin 400 mg three times daily (TID) may have similar efficacy to propranolol, given 40 mg TID (Gironell et al., 1999). The drug also has some evidence to support its use in neuropathic (Saverino et al., 2001) and orthostatic tremor (Onofrj et al., 1998b; Rodrigues et al., 2005; Rodrigues et al., 2006). Fifty percent of subjects in a much larger postherpetic neuralgia studies were over age 75, and the incidence of these side effects in these studies was only modestly higher than in studies done in the younger epilepsy subjects. This fact, as well as the lack of significant drug interaction or major organ toxicity, has made this drug a particularly appealing consideration in the elderly. The TID dosing regimen may present some problems with patient compliance. • Topiramate is approved for use in epilepsy and migraine. Two of three double-blind, placebo-controlled trials of topiramate in ET in a total of 245 subjects were positive (Onofrj et al., 1998b; Connor, 2002; Rodrigues et al., 2005; Frima and Grunewald, 2006; Ondo et al., 2006; Rodrigues et al., 2006). The largest study, of 208 subjects, showed significant improvement in subjective and objective measurements of tremor at a mean final dose of 292 mg/day (Ondo et al., 2006). Topiramate appears to be efficacious at doses lower than those used to treat approved conditions, with studies suggesting benefit below 100 mg/day (Gatto et al., 2003; Ondo et al., 2006). In the large double-blind study in ET (Ondo et al., 2006), titration was over 12 weeks, and the average age of subjects was 61. Dose-limiting side effects were seen in 31.9% of subjects, with the frequency of cognitive side effects being 13%. Therefore, those ET patients with advanced age and/or baseline cognitive impairment may not be appropriate for topiramate. The 10–22% frequency of appetite suppression and weight loss seen in most topiramate studies and the risk of renal calculi suggest that it should be used cautiously in frail ET patients.

• Pregabalin is indicated for use in painful diabetic neuropathy, fibromyalgia, and postherpetic neuralgia, and as adjunctive therapy for adults with partial complex seizures. Two open-label case reports involve patients with tremor responding to pregabalin (Zesiewicz et al., 2007b; Alonso-Navarro et al., 2008). A double-blind, placebocontrolled study of 22 subjects showed significant benefit in reduction of tremor amplitude at a mean daily dose of 286.8 mg/day (Zesiewicz et al., 2007a). Side effects leading to dropout occurred in a third of ET subjects. Typical side effects with pregabalin across studies include dizziness, sleepiness, dry mouth, and peripheral edema. Less common side effects include weight gain, blurred vision, and decreased visual acuity. Rare reports tell of angioedema occurring. It is reasonable to consider using pregabalin in those refractory patients, although additional data regarding efficacy in ET is needed. • Botulinum toxin, which works by temporarily dennervating the neuromuscular junction, has been studied in ET and, is among the movement disorders that may be amenable to toxin injection (Simpson et al., 2008). An initial small open-label study of 14 subjects with ET demonstrated that five had moderate to marked improvement, supporting the need for additional clinical study (Trosch and Pullman, 1994). An open-label study of 20 refractory limb tremor patients showed improvement over baseline in activities of daily living, tremor rating scores, and acceleometry (Pacchetti et al., 2000). Therapy was tailored to each subject, based on the pattern of muscle activity, with a mean total dose of 95.5 units of botulinum toxin type A (Dysport). Subjects had persistent significant tremor benefit at 3 months, which had worn off by 5 months. A placebo-controlled study of 25 hand tremor subjects reported at least mild to moderate improvement in tremor in 75% with active treatment versus 27% with placebo (Jankovic and Schwartz, 1991). A second study of 133 subjects using fixed doses of 50 or 100 units botulinum toxin (Botox) compared with placebo into forearm wrist flexors and extensors showed significant improvement in postural tremor from 4 to 16 weeks after treatment, as measured by clinical rating scale, but only modestly improved kinetic tremor and ADLs (Brin et al., 2001). This decreased relevant efficacy (kinetic tremor), along with problematic hand weakness as a side effect, makes consideration of botulinum toxin in the limb a consideration only for more refractory and disabled subjects. Botulinum toxin may be particularly useful for subjects with intractable head and/or voice tremor, as these symptoms typically result from fewer overactive muscles and may be appropriate for the very focal therapy that the neurotoxin provides. Forty-three subjects with head tremor underwent open-label injection with botulinum toxin type A (Dysport) into the bilateral splenius capitus muscles (Wissel et al., 1997). All subjects with isolated head tremor without dystonia (N = 14) improved over baseline

Essential Tremor and Other Tremor Disorders

in terms of clinical rating scales and accelerometry. Tolerability is generally good, making this a reasonable option for disabling head tremor. Studies botulinum toxin injection in vocal tremor have shown efficacy (Warrick et al., 2000; Adler et al., 2004). Main adverse effects reported were breathiness (11/13) and dysphagia (3/13). DBS of the Vim nucleus of the thalamus should be considered in drug-refractory ET patients who are appropriate surgical candidates. Significant benefit to tremor is seen in 70–100% of patients (Blond et al., 1992; Benabid et al., 1996; Koller et al., 1997) and is clearly more efficacious than best medical therapy in these more advanced patients. Acute side effects related to surgery primarily include the potential for symptomatic intracranial hemorrhage. Long-term hardware complications are possible, including fracturing of lead, cutaneous erosion, and infection. Side effects related to stimulation itself include imbalance and dysarthria, at times compromising nearperfect tremor control. Battery replacement is necessary for the device and needs to be performed at least every 2 years for those with high stimulation parameters and up to every 9 years for those with rechargeable devices. Unilateral thalamotomy was often done prior to DBS but is rarely done anymore. It may still be considered for patients who might live remotely or who might be at high risk for hardware complications.

Parkinsonian tremor Although this chapter is not meant to provide extensive review of the treatment of PD, the treatment of prominent tremor in the setting of PD is worthy of mention. Tremordominant PD may respond incompletely or not at all to levodopa therapy, leading the clinician to believe that the patient does not have typical PD. Dopamine agonist seem better at suppressing tremor, particularly postural tremor, than levodopa (Koller et al., 1989). However, patients may require higher doses than one might typically use in early PD (Pogarell et al., 2002; Schrag et al., 2002). Anticholinergics can be useful, as it seems that some patients can respond to them rather than typical dopaminergic therapy in early disease (Koller, 1986). Amantadine might be tried, although significant data behind its use in PD tremor is lacking. Clozapine has been studied in PD tremor and can be effective, even in those who have failed other therapies (Jansen, 1994), but its use is limited by the potential side effect of agranulocytosis and the consequent need for periodic blood monitoring. DBS of the subthalamic nucleus is quite effective in treating drug-resistant PD tremor (Krack et al., 1998). Primary writing tremor This is a relatively rare condition, and the term is reserved for tremor that occurs only with writing (type A) or with the posture of writing (type B). Debate surrounds whether it is a variant of ET, dystonia, or its own condition.

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Phyisologic assessment indicates that it is mostly ET like, although some cases have agonist/antagonist muscle contraction typical of dystonia. Treatment can be ET medication, potentially trihexyphenidyl or botulinum toxin (Papapetropoulos and Singer, 2006). Other task-specific tremors such as those seen in skilled professionals (golfers, musicians) would be considered similarly (McDaniel et al., 1989).

Orthostatic tremor Patients with orthostatic tremor disorder often present with a chief complaint of unsteadiness with standing that typically improves with walking (Heilman, 1984). The legs can be noted to give way, with frequent buckling seen despite absence of true weakness on confrontational testing. The unusual appearance can sometimes be misdiagnosed as psychogenic. EMG administered while standing is crucial for the diagnosis, documenting the typical 13–18 Hz frequency not seen in any other tremor condition. The tremor is considered central in origin, as it is highly coherent through the limbs and trunk (Thompson et al., 1986). Primary pathophysiology has not been elucidated. Treatment of orthostatic tremor is clonazepam (Heilman, 1984) or gabapentin (Evidente et al., 1998; Onofrj et al., 1998b). Drug-induced tremor A variety of drugs can cause tremor (Table 12.1). Mostly, these tremors are enhanced physiologic tremor and clinically may look indistinguishable from early ET. This is particularly true with tremor due to adrenergic stimulation, such as bronchodiators and caffeine. Some druginduced tremors are centrally mediated. This includes tremors due to dopamine receptor blocking agents such as neuroleptics or antiemetics. Lithium, cocaine, methamphetamines, and withdrawal state (alcohol, benzodiazepines) are also likely centrally mediated. Valproate is particularly interesting, as it can cause an action tremor that occurs shortly after starting the drug in about 10% of patients (Karas et al., 1982), but it also may rarely cause reversible parkinsonism after some time on the drug (Onofrj et al., 1998a; Shill and Fife, 2000). Amiodarone seems to have a similar clinical spectrum, causing

Table 12.1 Drugs that may cause tremor Caffeine Bronchodilators Valproic acid Amiodarone Lithium Methylxanthines Bronchodilators Corticosteroids

Tamoxifen Antiemetics Neuroleptics Reserpine Tertrabenazine Tocainide Levetiracetam Thyroid hormone

Tricyclic antidepressants Tacrolimus Cyclosporine Mexilitine Cocaine Methamphetamine

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both tremor and parkinsonism, and can also cause neuropathy (Werner and Olanow, 1989; Orr and Ahlskog, 2009). Treatment of disabling drug-induced tremor is mostly aimed at reducing or stopping the offending agent. Sometimes, however, that is not possible when the drug is being used for potentially life-threatening or very disabling conditions like schizophrenia (for example, neuroleptics) or immune suppression after transplant (for example, tacrolimus). The parkinsonian effect of neuroleptics is often partially blocked by anticholinergic agents such as trihexyphenidyl or benztropine but does not respond to beta-blockers (Metzer et al., 1993). Valproate tremors may respond to beta-blockers but not to amantadine or benztropine (Karas et al., 1983). Lithium tremor may respond to beta-blockers (Gelenberg and Jefferson, 1995).

Cerebellar tremor Cerebellar tremor is typically seen in the setting of a structural process involving the cerebellar outflow tracks in the upper brain stem. Vascular, traumatic, and demyelinating processes are the most common. The tremor is generally a slow frequency of 2–3 Hz and is exacerbated with action (intention tremor) and the hand approximating the mouth in the wing-beating position. Tremor in multiple sclerosis is often treated similar to ET (Koch et al., 2007). Studies using serotonergic agents have failed to yield results in double-blind studies (Bier et al., 2003). Thalamic DBS for refractory cerebellar outflow tremor can be considered, but the responses may be less robust than with ET (Koch et al., 2007; Schuurman et al., 2008; Torres et al., 2010). Neuropathic tremor Tremor is not uncommon in both acquired and hereditary neuropathy, particularly demyelinating (Yeung et al., 1991; Cardoso and Jankovic, 1993; Dalakas et al., 1984). They can be clinically indistinguishable from ET. Specific treatments have not been recommended; typically ET treatments are used. Psychogenic tremor Psychogenic tremor is rarely seen in the elderly but is presented here for completeness (Koller et al., 1989; Shill and Gerber, 2006; Kenney et al., 2007). This diagnosis should be considered in a patient, often female, presenting with an abrupt and often dramatic onset of symptoms. Several features allow one to distinguish psychogenic from organic tremor. The tremor often reduces in amplitude or disappears with distraction. The fingers are generally not involved, as they commonly are with ET and PD. The patients may have a “coactivation sign,” which is a tensing of the muscle felt with passive range of motion of the limb. Multiple somatizations and other false neurologic signs often are present (give-way weakness, hemisensory loss, pseudobradykinesia).

Treatment of psychogenic illness is difficult, evidenced by persisting symptoms in many, if not most, patients (Feinstein et al., 2001; Thomas et al., 2006). Informing the patient promptly of the diagnosis is paramount, as a short duration of symptoms seems to be the best prognostic indicator. Treatment is a combination of rehabilitation strategies combined with ongoing psychiatric and psychological therapy (Thomas and Jankovic, 2004).

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Essential Tremor and Other Tremor Disorders

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Pacchetti, C., Mancini, F., Bulgheroni, M., et al. (2000) Botulinum toxin treatment for functional disability induced by essential tremor. Neurol Sci, 21: 349–353. Pagan, F.L., Butman, J.A., Dambrosia, J.M., and Hallett, M. (2003) Evaluation of essential tremor with multi-voxel magnetic resonance spectroscopy. Neurology, 60: 1344–1347. Pahwa, R., Lyons, K., Hubble, J.P., et al. (1998) Double-blind controlled trial of gabapentin in essential tremor. Mov Disord, 13: 465–467. Papapetropoulos, S. and Singer, C. (2006) Treatment of primary writing tremor with botulinum toxin type a injections: report of a case series. Clin Neuropharmacol, 29: 364–367. Pogarell, O., Gasser, T., van Hilten, J.J., et al. (2002) Pramipexole in patients with Parkinson’s disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study. J Neurol Neurosurg Psychiatry, 72: 713–720. Rajput, A., Robinson, C.A., and Rajput, A.H. (2004) Essential tremor course and disability: A clinicopathologic study of 20 cases. Neurology, 62: 932–936. Rodrigues, J.P., Edwards, D.J., Walters, S.E., et al. (2005) Gabapentin can improve postural stability and quality of life in primary orthostatic tremor. Mov Disord, 20: 865–870. Rodrigues, J.P., Edwards, D.J., Walters, S.E., et al. (2006) Blinded placebo crossover study of gabapentin in primary orthostatic tremor. Mov Disord, 21: 900–905. Ross, G.W., Dickson, D., Cersosimo, M., et al. (2004) Pathological investigation of essential tremor. Neurology, 62: A537–A538. Sasso, E., Perucca, E., and Calzetti, S. (1988) Double-blind comparison of primidone and phenobarbital in essential tremor. Neurology, 38: 808–810. Sasso, E., Perucca, E., Fava, R., and Calzetti, S. (1991) Quantitative comparison of barbiturates in essential hand and head tremor. Mov Disord, 6: 65–68. Saverino, A., Solaro, C., Capello, E., et al. (2001) Tremor associated with benign IgM paraproteinaemic neuropathy successfully treated with gabapentin. Mov Disord, 16: 967–968. Schrag, A., Keens, J., and Warner, J. (2002) Ropinirole for the treatment of tremor in early Parkinson’s disease. Eur J Neurol, 9: 253–257. Schuurman, P.R., Bosch, D.A., Merkus, M.P., and Speelman, J.D. (2008) Long-term follow-up of thalamic stimulation versus thalamotomy for tremor suppression. Mov Disord, 23: 1146–1153. Shill, H. and Gerber, P. (2006) Evaluation of clinical diagnostic criteria for psychogenic movement disorders. Mov Disord, 21: 1163–1168. Shill, H.A. and Fife, T.D. (2000) Valproic acid toxicity mimicking multiple system atrophy. Neurology, 55: 1936–1937. Shill, H.A., Adler, C.H., Sabbagh, M.N., et al. (2008) Pathologic findings in prospectively ascertained essential tremor subjects. Neurology, 70: 1452–1455. Simpson, D.M., Blitzer, A., Brashear, A., et al. (2008) Assessment: Botulinum neurotoxin for the treatment of movement disorders

(an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology, 70: 1699–1706. Singer, C., Sanchez-Ramos, J., and Weiner, W.J. (1994) Gait abnormality in essential tremor. Mov Disord, 9: 193–196. Spanaki, C. and Plaitakis, A. (2009) Essential tremor in Parkinson’s disease kindreds from a population of similar genetic background. Mov Disord, 24: 1662–1668. Stefansson, H., Steinberg, S., Petursson, H., et al. (2009) Variant in the sequence of the LINGO1 gene confers risk of essential tremor. Nat Genet, 41: 277–279. Thomas, M. and Jankovic, J. (2004) Psychogenic movement disorders: diagnosis and management. CNS Drugs, 18: 437–452. Thomas, M., Vuong, K.D., and Jankovic, J. (2006) Long-term prognosis of patients with psychogenic movement disorders. Parkinsonism Relat Disord, 12: 382–387. Thompson, P.D., Rothwell, J.C., Day, B.L., et al. (1986) The physiology of orthostatic tremor. Arch Neurol, 43: 584–587. Torres, C.V., Moro, E., Lopez-Rios, A.L. , et al. (2010) Deep brain stimulation of the ventral intermediate nucleus of the thalamus for tremor in patients with multiple sclerosis. Neurosurgery, 67: 646–651. Trosch, R.M. and Pullman, S.L. (1994) Botulinum toxin A injections for the treatment of hand tremors. Mov Disord, 9: 601–609. Warrick, P., Dromey, C., Irish, J.C., et al. (2000) Botulinum toxin for essential tremor of the voice with multiple anatomical sites of tremor: a crossover design study of unilateral versus bilateral injection. Laryngoscope, 110: 1366–1374. Werner, E.G. and Olanow, C.W. (1989) Parkinsonism and amiodarone therapy. Ann Neurol, 25: 630–632. Wissel, J., Masuhr, F., Schelosky, L., et al. (1997) Quantitative assessment of botulinum toxin treatment in 43 patients with head tremor. Mov Disord, 12: 722–726. Yahr, M.D., Orosz, D., and Purohit, D.P. (2003) Co-occurrence of essential tremor and Parkinson’s disease: clinical study of a large kindred with autopsy findings. Parkinsonism Relat Disord, 9: 225–231. Yeung, K.B., Thomas, P.K., King, R.H., et al. (1991) The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. Comparative clinical, immunological and nerve biopsy findings. J Neurol, 238: 383–391. Zesiewicz, T.A., Elble, R., Louis, E.D., et al. (2005) Practice parameter: Therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 64: 2008–2020. Zesiewicz, T.A., Ward, C.L. , Hauser, R.A., et al. (2007a) A pilot, double-blind, placebo-controlled trial of pregabalin (Lyrica) in the treatment of essential tremor. Mov Disord, 22: 1660–1663. Zesiewicz, T.A., Ward, C.L., Hauser, R.A., et al. (2007b) Pregabalin (Lyrica) in the treatment of essential tremor. Mov Disord, 22: 139–141.

Chapter 12.3 Progressive Supranuclear Palsy Virgilio Gerald H. Evidente History In 1955, J. Clifford Richardson, a neurologist at Toronto General Hospital, was consulted by a 52-year-old friend for clumsiness, difficulties with vision, and mild forgetfulness, which progressed to a constellation of signs, including vertical supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria, dystonic neck extension, and mild dementia (Williams et al., 2008). He later observed similar evolution of ocular, motor, and mental symptoms in six more individuals. By early 1960s, seven of them had died and were initially given a neuropathologic diagnosis of postencephalitic parkinsonism (PEP). However, Richardson disagreed with their impression, as none of them had preceding encephalitis. In 1962, Richardson asked neurology resident John Steele and neuropathologist Jerzy Olszewski to assist him in reevaluating the pathology of the seven intriguing cases. Over the next year, Steele and Olzewski described the anatomy and histopathology of the disease in seven cases and the detailed localization of lesions in four of them. Richardson presented the first clinical report of progressive supranuclear palsy (PSP) at the June 1963 meeting of the American Neurological Association in Atlantic City. In the same year, Olszewski presented the neuropathology at the American Association of Neuropathology. In their 1963 reports, Richardson, Olszewski, and Steele initially called the condition heterogeneous system degeneration. Later that year, Richardson proposed calling it PSP. In Europe, however, it was referred to as Steele–Richardson–Olszewski syndrome. In April 1964, the initial publication of PSP reporting nine patients, seven of whom had died, was published in the Archives of Neurology (Steele et al., 1964).

Epidemiology Few studies have looked specifically at establishing the prevalence of PSP. Earlier reports showed a relatively low prevalence, though more recent studies yielded higher estimates. Golbe, et al., conducted a study in New Jersey and reported a crude prevalence of 1.39 per 100,000 in 1988 (Golbe et al., 1988). Schrag et al. conducted a similar study in London and reported an age-adjusted prevalence of 6.4 per 100,000 in 1999 (Schrag et al., 1999). Nath et al. conducted a study in Newcastle-upon-Tyne and reported a crude and age-adjusted prevalence of 6.5 per

100,000 in 2001 (Nath et al., 2001). Bower and colleagues performed an incidence study of PSP and other parkinsonian syndromes in Olmsted County, Minnesota, from 1976 to 1990 and found a crude incidence rate of PSP of 1.1 per 100,000 per year (Bower et al., 1997). This increased exponentially from 1.7 cases per 100,000 per year at ages 50–59, to 14.7 per 100,000 per year at ages 80–99. PSP is estimated to be around 10% of the incidence of Parkinson’s disease (PD) (Bower et al., 1999). Its peak onset is at age 63, and no cases have been reported before the age of 40. In a large autopsy series of the Society for Progressive Supranuclear Palsy brain bank, the average age at death was 75 ± 8 years, and the average duration of disease was around 7 years (usually less than 10 years) (Dickson et al., 2007). There were slightly more men than women with PSP (M:F = 227:195).

Clinical presentation The clinical hallmarks of PSP are supranuclear vertical gaze palsy, pseudobulbar palsy, axial rigidity, and cognitive impairment. In 1996, the National Institute of Neurological Disorders and Stroke (NINDS) and the Society for PSP (SPSP) sponsored an international workshop to improve the specificity and sensitivity of the clinical diagnosis of PSP (Litvan et al., 1996a). The National Institute of Neurological Disorders and Stroke-Society of Progressive Supranuclear Palsy (NINDS-SPSP) clinical criteria classified cases into three categories: possible, probable, and definite PSP (Table 12.2). The NINDS-SPSP criteria for probable PSP are highly specific (100%) but are only 50% sensitive, whereas the criteria for possible PSP are 83% sensitive but only 93% specific. Nath and colleagues described the clinical features and prognostic predictors of PSP in 187 cases (Nath et al., 2003). The most common clinical features were vertical supranuclear gaze palsy (94%), bradykinesia (91%), falls (87%), postural instability (80%), speech problems (74%), dysphagia (60%), increased axial tone/retrocollis (53%), apathy (50%), diplopia/blurred vision (39%), frontal release signs (31%), tremor (21%), photophobia (20%), eyelid apraxia (17%), need for gastrostomy tube (9%), limb dystonia (7%), word-finding difficulty (7%), and slow or hypometric saccades (6%). On examining the symptoms at onset, it was noted that 69% had mobility problems (unsteadiness or slowness/weakness of legs), 15% had cognitive problems (memory impairment, personality

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Table 12.2 NINDS-SPSP clinical criteria for possible, probable, and definite PSP Category of PSP Mandatory inclusion criteria

Mandatory exclusion criteria

Supportive criteria

Possible

Gradually progressive

Recent encephalitis

Onset at 40 years or older

Alien limb syndrome, cortical sensory deficits, focal frontal or temporoparietal atrophy

Symmetric rigidity or bradykinesia, proximal more than distal

Either vertical (upward or downward) supranuclear gaze palsy or both slowing of vertical saccades and prominent postural instability within 1 year of onset Probable

No exclusion criteria Gradually progressive

Hallucinations or delusions (nonmedication-related) Alzheimer’s type of cortical dementia (severe amnesia, aphasia, or agnosia)

Prominent early cerebellar or autonomic Vertical (upward or downward) supranuclear dysfunction (such as severe urinary gaze palsy and prominent postural instability disturbance or orthostastic hypotension) Severe, asymmetric parkinsonian signs within one year of onset (such as bradykinesia) No exclusion criteria Onset at 40 years or older

Definite

Clinically possible or probable PSP with histopathology typical of PSP

Retrocollis or other cervical dystonias Poor or absent response of parkinsonism to levodopa Early onset of dysarthria and dysphagia Early onset of cognitive impairment in at least two of the following domains: apathy, impaired abstract thinking, decreased verbal fluency, utilization or imitation behavior, or frontal release signs

Neuroradiologic structural abnormality Whipple’s disease

change, depression, anxiety, apathy, or word-finding difficulties), 14% had bulbar/language problems (speech or swallowing abnormities, reduced speech output, palilalia/echolalia, or dysphonia), 12% had visual problems (blurred vision or diplopia), and 13% had a tremor. The median latency to development of falls in PSP was less than 1 year from onset, while speech problems developed within a median latency of nearly 2 years and swallowing difficulties developed within a median latency of 4 years. The vertical gaze palsy is one of the most important symptoms of PSP and usually develops early in the course. A preserved vestibulo-ocular reflex supports the “supranuclear” nature of the vertical gaze palsy. Down gaze is usually affected before up gaze, whereas horizontal eye movements are usually preserved except maybe late in the course (Litvan et al., 1996, Verny et al., 1996). Because of the difficulty looking down at their plate while eating, patients often are “messy” eaters. Saccadic velocity is progressively reduced, such that, in the later stages, the eyes tend to follow the head as it turns. PSP patients also exhibit frequent small, paired, horizontal saccadic intrusions during fixation (macro-square wave jerks) (Rivaud-Péchoux et al., 2000). Bilateral internuclear ophthalmoplegia has also been described in PSP (Flint and Williams, 2005). The motor symptoms in PSP include shuffling gait, bradykinesia (usually symmetric), hypertonia (axial more than limb), dystonia (usually retrocollis or truncal extension; see Figure 12.9), and loss of fine and later gross motor skills. Tremor, if present, is fine, bilateral, and postural in the majority. The classic PD medium frequency resting tremor is atypical for PSP (Quinn, 1997). Both limb apraxia (difficulty performing simple motor tasks or fine finger movements) and ideomotor apraxia (difficulty executing familiar tasks, requiring a sequence of steps) are seen in PSP patients. Some exhibit gait apraxia, which can lead to falls. Once they start falling, they are not able to engage

the righting reflexes, thus making them fall en bloc like a toppling tree. When they sit from a standing position, they often “plop” into their chair en bloc, with a tendency for their feet to be above the floor at the moment their buttocks hit the chair. Some patients may develop some ataxia due to pathologic involvement of the cerebellum. Corticospinal tract signs may also be present, including limb weakness, spasticity, hyperreflexia, and Babinski sign. Cranial nerve examination reveals facial hypomimia, reduced blinking (often with a fixed stare), blepharospasm, or apraxia of eyelid opening. Patients may have a “worried look” or the “procerus sign,” with vertical wrinkles in the glabellar region and bridge of the nose, resulting from hypertrophy or dystonia of the procerus, corrugator muscles, and orbicularis oculi (Romano and Colosimo, 2001) (Figure 12.10). Some may have a “startled look” due

Figure 12.9 Patient with PSP with axial hypertonia and retrocollis.

Progressive Supranuclear Palsy

to retraction of the upper eyelids and hypertrophy of the frontalis muscles; rarely, patients may have dystonia of the mimetic muscles, resulting in risus sardonicus. Hypophonia is often observed early, with a pseudobulbar speech developing later. Sialorrhea and swallowing difficulties may develop early, and the gag reflex is often increased. Schmidt and colleagues observed that PSP patients exhibit pathologically decreased pupil diameters in darkness and that a cutoff of 3.99 mm could differentiate PSP patients from other parkinsonian syndromes (Schmidt et al., 2007). Their findings, however, remain to be duplicated. In 103 consecutive pathologically confirmed PSP cases, Williams and colleagues observed two clinical phenotypes of PSP: Richardson’s syndrome (RS) and PSP-parkinsonism (PSP-P) (Williams et al., 2005). RS made up 54% of all cases and was characterized by early onset of postural instability and falls, supranuclear gaze palsy, and cognitive impairment. The PSP-P phenotype comprised 32% of cases and was characterized by asymmetric onset, tremor, and a moderate initial therapeutic response to levodopa. Patients with PSP-P were frequently confused with PD. The rest (14%) could not be separated into the two general phenotypes. One variant, labeled PSP-pure akinesia with gait freezing (PAGF), presents with early gait disturbance, micrographia, hypophonia, and gait freezing (Williams et al., 2007b). Another set of patients presents with progressive asymmetric dystonia, apraxia, and cortical sensory loss very similar to corticobasal degeneration (CBD) and has been termed PSP-corticobasal syndrome (PSP-CBS) (Tsuboi et al., 2005).

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Finally, another rare variant of PSP presents primarily with speech apraxia, the so-called PSP-progressive nonfluent aphasia (PSP-PNFA) (Josephs et al., 2005). Patients with PSP are usually more cognitively impaired than PD patients in numerous cognitive domains, including information processing speed and executive function (Soliveri et al., 2000). Cognitive and behavioral disturbances are more frequent and severe in PSP, often presenting with a frontal type of dementia (Cordato et al., 2006). In the Folstein Mini–Mental Status Examination (MMSE), errors are generally mild and restricted to recall and attention in PD patients, whereas errors are noted in all MMSE items in PSP patients. In addition, PSP patients often present with reduced category fluency, naming, learning, and visuospatial function (Cordato et al., 2006; VanVoorst et al., 2008). Frontal behavioral deficits in PSP become more common as the motor deficits worsen. The “applause sign” (a tendency to initiate an automatic program of applause when one is asked to clap three times) is abnormal in PSP and helps differentiate PSP from frontal or striatofrontal degenerative disease, including frontotemporal dementia (FTD) or PD (Dubois et al., 2005). In the three clap test, the patient is asked to clap three times as quickly as possible after demonstration by the examiner. The performance is normal if he or she claps only three times (score = 3), or abnormal when he or she claps four times (score = 2), claps five to ten times (score = 1), or is unable to stop clapping (score = 0). Polysomnography on PSP patients reveals sleep disturbance with a sleep efficiency of less than 50% in most cases, increased rapid eye movement (REM) without atonia, and REM behavior disorder (RBD) (Sixel-Döring et al., 2009). Clinically significant RBD, however, is about twice more common in synucleinopathies such as PD than in PSP. Despite polysomnographic evidence of sleep disturbance, PSP patients often do not verbalize subjective sleep complaints, possibly due to altered self-perception as part of their neuropsychological disease.

Differential diagnoses and atypical PSP

Figure 12.10 Patient with PSP with the procerus sign, or “worried

look.”

Clinically, PSP can be misdiagnosed as or present like PD, multiple system atrophy (MSA), Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), CBD (Josephs and Dickson, 2003), multi-infarct or vascular disease (Josephs et al., 2002), Whipple’s disease (Averbuch-Heller et al., 1999), neurosyphilis (Murialdo et al., 2000), familial FTD (Miyamoto et al., 2001), progressive subcortical gliosis (Will et al., 1988), progressive multifocal leukoencephalopathy (Alafuzoff et al., 1999), or postencephalitic parkinsonism (Pramstaller et al., 1996). Individuals from the island of Guam may present with clinical manifestations of amyotrophic lateral sclerosis (ALS) or parkinsonism– dementia complex (PDC) (Steele, 2005). The phenotypes of

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Guamanian ALS–PDC include classic ALS (“lytico”), parkinsonism with dementia (“bodig”), parkinsonism without dementia, PSP, CBD, and Marianas dementia. Those that present like PSP have clinical features including parkinsonism, dementia, supranuclear gaze palsy and other oculomotor abnormalities, blepharospasm/apraxia of eyelid opening, and extensor posturing. Guamanian ALS–PDC was initially thought to be due to intake of flour products made from seeds of the false sago palm Cycas micronesica, which contains a neurotoxin rich in beta-N-methylaminoL-alanine (BMAA). Several genetic studies have been negative, including those that examined the tau gene. The steady decline of its annual incidence since 1955 and increasing age at onset implicates an environmental factor that ceased many decades ago, perhaps in relation to events of World War II. In the Caribbean island of Guadeloupe in the French West Indies, cases of atypical parkinsonism similar to PSP were described, presenting with symmetric rigidity and bradykinesia, severe gait and balance problems, frontal lobe syndrome, and supranuclear gaze palsy (Caparros-Lefebvre and Elbaz, 1999). The Guadeloupean parkinsonism was noted to be potentially reversible when the affected individuals stopped eating anonnaceous fruits and drinking herbal teas. In the Kii peninsula of Japan, a clinical syndrome similar to PSP is seen presenting with atypical parkinsonism, dementia, motor neuron disease, or a combination of the three phenotypes (Kuzuhara and Kokubo, 2005). The initial symptom is usually a parkinsonian gait or hypobulia/amnesia, followed by akinesia, rigidity, occasional tremor, bradyphrenia, abulia and amnesia, and, finally akinetic mutism. Familial clustering and continuing morbidity suggest that genetic factors are likely. On neuropathology, Guamanian ALS–PDC, ALS– PDC of the Kii Peninsula, and Guadeloupean parkinsonism are tauopathies with features similar to PSP. Of 180 cases of clinical PSP whose brains were examined in the Society of PSP Brain Bank, only 137 had PSP on neuropathology, with the other 43 having other pathologic diagnoses (Josephs and Dickson, 2003). Of the misdiagnosed cases, 70% had CBD, MSA, and DLB. Tremor, psychosis, early dementia, asymmetric findings, presence of APOE ∈4, and absence of H1 tau haplotype were features that predicted an alternative diagnosis. We retrospectively reviewed the clinical records of all pathologically confirmed cases of PSP in the Sun Health Research Institute Brain and Body Donation Program from 1996 to 2007 (Evidente et al., 2007). Of 990 brain donor subjects, 250 had autopsy by 2007, of which 19 cases fulfilled the NINDS–SPSP criteria for PSP. Of those 19, only 4 (21%) had a premortem diagnosis of PSP, while the other 68% had other clinical diagnoses, including PD (4), PD with dementia (4), parkinsonism with dementia (3), ET (1), ET + PD (1), parkinsonism (1), and normal control (1). Thus, even among specialists, the rate of misdiagnosis is quite high, given the atypical presentations that PSP patients can present with.

A report in 2004 from the Queen Square Brain Bank for Neurological Disorders noted that of 60 cases that were clinically diagnosed as PSP on last assessment in life, only 47 (78%) had a diagnosis of PSP on pathology (Osaki et al., 2004). PD is by far the most commonly confused disorder with PSP. Although PSP-P can be hard to differentiate from PD, one study showed that certain features, such as visual hallucinations, drug-induced dyskinesias, and autonomic dysfunction, had a high positive predictive value and specificity for Lewy body pathology/PD compared to PSP-P (Williams and Lees, 2010). Another synucleinopathy or Lewy body disorder, DLB, can be differentiated clinically from PSP-P by the occurrence of early cognitive decline and visual hallucinations (McKeith et al., 1996). Although autonomic dysfunction is not a prominent feature in PSP (Brefel-Courbon et al., 2000), there are a significant number of patients with pathologic PSP that can be misdiagnosed as MSA premortem. In particular, on autonomic testing and administering semiquantitative anamnesis questionnaires, parasympathetic cardiovascular abnormalities can be prominent in PSP, even to a similar extent as in PD (Schmidt et al., 2008). In contrast, sympathetic dysfunction is more frequent and more severe in PD than in PSP patients. Table 12.3 outlines some of the key clinical features that help differentiate PSP from other parkinsonian syndromes. Table 12.3 Clinical features of PSP that distinguish it from other causes of parkinsonism Differential diagnosis

Distinguishing features

Parkinson’s disease (PD)

Unlike PD, PSP usually presents with early onset of falls within the first year of onset, vertical supranuclear gaze palsy, axial rigidity and dystonia, and poor response to levodopa. Resting tremor is rare in PSP and common in PD. Dysautonomia (especially orthostatic hypotension) usually is absent in PSP and is prominent in MSA. Hallucinations, early onset of dementia, REM behavior disorder (RBD), and dysautonomia are key features of DLB and are uncommon in PSP. Limb apraxia, alien limb phenomenon, and cortical sensory signs are common in CBD and rare in PSP. CBD usually presents with limb dystonia, while PSP often presents with axial dystonia. Vascular parkinsonism usually presents with a stepwise worsening, whereas PSP is slowly progressive. Parkinsonism is usually lower body in distribution in VP and generalized in PSP. Neuroimaging shows strokes/prominent ischemic vascular changes in the brain in VP but not in PSP.

Multiple system atrophy (MSA) Dementia with Lewy bodies (DLB)

Corticobasal degeneration (CBD)

Vascular parkinsonism (VP)

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Neuropathology Macroscopic pathology Although the overall brain weight of PSP patients is within normal limits, gross examination of the PSP brains often shows distinct features (Dickson, 2008). Atrophy may involve the precentral gyrus, midbrain tectum, substantia nigra, pons, superior cerebellar peduncle (SCP), and cerebellar dentate nucleus (Figure 12.11 a–c). There may be dilatation of the third ventricle and aqueduct of Sylvius. The substantia nigra shows loss of pigment, while the subthalamic nucleus and cerebellar dentate nucleus may appear gray due to myelinated fiber loss. Microscopic pathology Neuronal loss, gliosis, and neurofibrillary tangles (NFTs) affecting the basal ganglia, diencephalon, and brainstem are the typical microscopic findings in PSP (Dickson, 2008) (Figure 12.12). The brainstem regions most affected are the globus pallidus, subthalamic nucleus, substantia nigra, superior colliculi, periaqueductal gray matter, oculomotor nuclei, locus ceruleus, pontine nuclei, pontine tegmentum, vestibular nuclei, medullary tegmentum, and inferior olives. The striatum and thalamus also have some neuronal loss and gliosis, as well as the basal nucleus of Meynert. The cerebellar dentate nucleus may show grumose degeneration, and the dentatorubrothalamic pathway consistently shows fiber loss. The spinal cord often shows neuronal inclusions in the anterior horns, posterior horns, and intermediolateral cell column. Silver stains (such as Gallyas staining) or tau immunostaining reveal NFTs in the affected areas. “Tufted

(a)

(c)

(b)

Figure 12.11 Gross neuropathologic findings in a PSP patient showing moderate gyral atrophy of the posterior frontal lobes, paracentral gyrus, and mild to moderate atrophy of the mesial temporal lobes. (a) Left convexity; (b) right convexity; (c) superior view. Courtesy of Dr. Thomas Beach.

Figure 12.12 Gallyas staining of the substantia nigra in a patient with PSP showing neurofibrillary tangles (NFTs). Courtesy of Dr. Thomas Beach.

astrocytes” are a characteristic feature of PSP, most commonly in the motor cortex and striatum (Figure 12.13). Oligodendroglial lesions called “coiled bodies” appear as argyrophilic and tau-positive perinuclear fibers (Figure 12.14). Special stains demonstrate argyrophilic, tau-positive inclusions in both astrocytes and oligodendrocytes. Electron microscopy reveals that the NFTs in PSP are composed of 15-nm tau straight filaments. Williams and colleagues aimed to quantify the pathologic burden and distribution in the various phenotypes of PSP [0] (Williams et al., 2007a). They observed that patients with RS had higher overall mean tau burden than patients with PSP-P or PAFG. The higher the tau burden scores, the more widespread the distribution. In fact, PSP-P patients have been noted to have more restricted, milder tau pathology, usually involving the subthalamic nucleus, substantia nigra, and globus pallidus (Williams et al., 2007a, Jellinger, 2008). Josephs and colleagues examined the relationship of disease duration to lesion burden severity in 97 cases with pure PSP in the Society of PSP Brain Bank (2006). They observed that as duration of illness increases, there is a decrease in density of oligodendroglial tau pathology that is independent of age, gender, APOE ∈4 genotype, Braak stage, or MAPT H1 haplotype.

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Figure 12.13 Gallyas staining of the putamen in a patient with PSP showing a “tufted astrocyte” on microscopy. Courtesy of Dr. Thomas Beach.

Biochemistry Both AD and PSP have accumulation of abnormal tau, though biochemical studies show differences (Dickson, 2008). In AD, the insoluble tau migrates as three major bands (68, 64, and 60 kDa) on Western blots. In contrast, in PSP, the abnormal tau migrates as two bands (68 and 64 kDa), corresponding to the accumulation of 4R tau based on antibodies. Striatal dopamine levels are reduced in PSP, though not in the same degree as in PD.

Mixed pathology We retrospectively reviewed the clinical records of all pathologically confirmed cases of PSP in the Sun Health Research Institute Brain and Body Donation Program from 1996 to 2006 and found 19 PSP cases. Of those, only 11 had pure PSP pathology, while there were 2 cases each of PSP + PD, PSP + AD, and PSP + AD + DLB, and 1 case each of PSP + DLB and PSP + PD + AD (Evidente et al., 2007). Given that PSP primarily involves the elderly, it is not surprising that some patients may have some degree of Alzheimer-type pathology (ATP). In most cases, the AD type of pathology is minor, but in some, it may be sufficient to warrant a diagnosis of concurrent AD. One study found ATP in 69% of 32 PSP cases reviewed over a 17 year period, with only 18.75% fulfilling the CERAD criteria for definite or probable Alzheimer’s disease (Keith-Rokosh and Ang, 2008). The risk factors for AD in the setting of PSP are APOE ∈4 genotype, advanced age, and female sex (Tsuboi et al., 2003). Lewy bodies can be detected in about 10% of PSP cases, though the frequency is similar to normal elderly controls (Tsuboi et al., 2001). Incidental PSP From the Sun Health Research Institute Brain and Body Bank Donation program, we observed 5 cases with histologic findings suggestive of PSP with no parkinsonism, dementia, or movement disorder during life, and who did not fulfill the clinical criteria of possible or probable PSP (Evidente et al., 2011). These cases with “incidental PSP” had a mean age at death of 88.9 years (range 80–94). We compared the mean Gallyas-positive PSP features grading for tau for subjects with incidental PSP to those with clinically manifest PSP. The mean Gallyas-positive PSP features grading was significantly lower in incidental PSP compared to clinical PSP cases. Thus, incidental PSP may represent the early or presymptomatic stage of PSP and presumably has very early disease.

Genetics

Figure 12.14 Gallyas staining of the frontal cortex in a patient with PSP showing “coiled body” on microscopy. Courtesy of Dr. Thomas Beach.

There are rare reports of familial PSP with an autosomal dominant inheritance and reduced penetrance (Uitti et al., 1999; Pastor and Tolosa, 2002). Mutations in the microtubule associated protein tau (MAPT) gene have been identified in patients with a clinical presentation of PSP (Williams et al., 2007c, Morris et al., 2002). A family with autosomal-dominant PSP was described to have linkage to chromosome 1q31.1 (Ros et al., 2005). Only the MAPT locus has been consistently associated with increased risk for sporadic PSP (Baker et al., 1999). The MAPT locus exists as two major haplotypes in European populations: H1 and H2. Inheritance of two copies of the H1 haplotype (H1/H1) is a major risk factor for PSP. A novel H2E’A haplotype in chromosome 17q21 has been observed in

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16% of PSP patients, but not in normal controls (Pastor et al., 2004). Using a pooled genome-wide scan of 500,288 single-nucleotide polymorphisms, a major risk locus was identified in chromosome 11p12-p11 (Melquiest et al., 2007). Although there are some kindreds with LRRK2 mutations that present primarily with tau pathology similar to PSP, mutations in the LRRK2 gene have not been found in a large series of pathologically confirmed PSP (Ross et al., 2006). Progranulin (PRGN) gene mutations, which are associated with FTD linked to chromosome 17 (Baker et al., 2006), have so far not been observed in PSP.

Diagnostic and functional imaging Oba and colleagues compared cranial magnetic resonance imaging (MRI) of 21 patients with PSP, 23 with PD, 25 with MSA, and 31 normal controls, and noted that the average midbrain area in PSP (56 mm2) was significantly smaller than PD (103 mm2) and MSA (97.2 mm2), compared to normal controls (Oba et al., 2005). The authors also proposed the “penguin silhouette” sign, which they observed was present in all PSP patients on the midsagittal MRI (Figure 12.15 a–c). Paviour and colleagues examined the volume of the SCP in 19 patients with clinical PSP, 10 with MSA, 12 with PD, and 12 healthy controls, and observed that SCP atrophy differentiated PSP from other neurodegenerative disorders and controls with a sensitivity of 74% and specificity of 94% (Paviour et al., 2005). (a)

(b)

(c)

Figure 12.15 Cranial magnetic resonance imaging (MRI) showing midbrain atrophy in a patient with PSP. (a) Axial MRI showing atrophy of the midbrain. (b) Sagittal MRI showing atrophy of the midbrain with the penguin silhouette sign. (c) Magnified view of the penguin silhouette sign on sagittal MRI.

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Fluorodeoxyglucose positron emission tomography (PET) scans of the brain have shown glucose hypometabolism in the midline frontal regions, brainstem, and caudate nucleus, and hypermetabolism in the cortical motor areas, parietal cortex, and thalamus (Eckert et al., 2005). Hypometabolism in the midbrain has been proposed to be an early diagnostic sign in PSP (Mishina et al., 2004). Brooks and colleagues examined cranial fluorodopa PET scans in patients with PD, MSA, and PSP (Brooks et al., 1990). Patients with PD showed significant reduced mean uptake of 18F-dopa in the caudate and putamen compared to controls, with the posterior putamen being severely impaired (45% of normal) and the anterior Patients with PSP and MSA had similar depression of mean 18F-dopa uptake in the posterior putamen as in PD, though patients with PSP showed equally severe impairment of mean 18F-dopa uptake in the anterior and posterior putamen. Caudate 18F-dopa uptake was also significantly lower in PSP than in PD patients.

Treatment Symptomatic pharmacotherapy A poor or absent response to levodopa has been published as one of the diagnostic criteria for PSP, with marked or prolonged levodopa benefit being a mandatory exclusion criterion (Litvan et al., 2003). Nevertheless, patients with PSP may have some response to levodopa, though usually not as robust or sustained as PD patients. Lang noted an overall response rate to levodopa of 26% in PSP (Lang 2005). Neiforth and Golbe reported that 38% of 87 PSP patients they retrospectively reviewed benefited from levodopa (mean daily dose of 1015 mg), with the improvement being minimal in 31% and moderate in 6% (Nieforth and Golbe, 1993). Litvan, et al., documented good response (50–70%) in 2 of 15 patients with PSP at the first visit after starting levodopa, though the response was less than 1 year in one patient (Litvan et al., 1996b). Collins, et al. reported a transient response to levodopa in 2 of 10 patients with PSP at an average daily dose of 807 mg (range 500–1500 mg/day) (Collins et al., 1995). Williams, et al. noted that patients with PSP-P had a moderate initial response to levodopa, while those with Richardson syndrome were poorly responsive to levodopa (Williams et al., 2005). Levodopa-induced dyskinesias were noted in 4% of the 103 cases of PSP that they described. Kompoliti, et al., reviewed the clinical profile of 12 autopsy-confirmed PSP patients, 11 of whom received levodopa at a mean dose of 500 mg/day (range 150–1200 mg/day) (Kompoliti et al., 1998). Improvement was marked in one patient (60% improvement) and modest in three others. Duration of effectivity was transient in three and sustained for two years in the patient with an initial marked response. The latter developed some facial

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levodopa-induced dyskinesias toward the end of 2 years of levodopa therapy. Seven patients were treated with dopamine agonists (six with bromocriptine, one with piribedil); only one patient had modest improvement. Five patients received amantadine, with two demonstrating questionable improvement of parkinsonism and neck dystonia. Zolpidem, a GABA agonist of the benzodiazepine subtype receptor BZ1, which is highest in density in the internal pallidum, was found to improve motor function and voluntary saccadic eye movements in ten PSP patients, compared to placebo or levodopa (Daniele, 1999). Zolpidem has also been reported to benefit dystonia in patients suffering from X-linked dystonia-parkinsonism (“lubag”) (Evidente, 2002), although its antidystonia effect in PSP patients has not been studied.

Neuroprotective pharmacotherapy Patients with PSP or MSA were randomized to either riluzole or placebo in a double-blind, randomized trial lasting 36 months, with the primary endpoint of survival and secondary efficacy outcome of rate of disease progression as assessed by functional measures (Bensimon et al., 2009). Riluzole in that study did not have a significant effect on survival or rate of functional deterioration in PSP or MSA. Coenzyme Q10 in combination with vitamin E at 1200 mg/day and 1200 units/day, respectively, has been shown in a small study to possibly slow functional decline in early PD (Shults et al., 2002). Coenzyme Q10 has been observed to increase the ratio of high-energy phosphates to low-energy phosphates on cranial magnetic resonance spectroscopy in 21 PSP patients in a short 6 week trial, with some slight but significant improvement in the PSP rating scale (Stamelou et al., 2008). Its long-term effect, especially as related to disease modification or neuroprotection, remains to be determined. Surgery One patient with possible PSP-P was reported to have had bilateral STN-DBS, though she was initially diagnosed as having advanced PD with dyskinesias and off periods (Bergmann and Salak, 2008). One year after DBS, she developed symptoms often seen in PSP, including emotional lability, marked worsening of balance, dystonic facies, and oculomotor abnormalities (abnormal vergence, pursuits, and saccades, and optokinetic nystagmus in the downward vertical direction). Cranial MRI revealed midbrain atrophy suggestive of PSP. The patient continues to be responsive to DBS 4 years post DBS. Pedunculopontine nucleus (PPN) DBS has been reported to potentially improve freezing of gait and cognition in patients with PD (Stefani et al., 2007). Another case report describes a 70-year-old man with PSP-P who underwent unilateral PPN-DBS, though he did not manifest any improvement of freezing of gait or cognition (Brusa et al., 2009).

Three patients with PSP underwent DBS at Emory University in the 1990s, with no benefit noted (Lubarsky and Juncos, 2008). One patient with PSP misdiagnosed as PD at the time of DBS was reported to be unresponsive to stimulation (Okun et al., 2005).

Prognosis Nath et al. noted that worse survival is associated with older age at disease onset, probable (as against possible) PSP, early falls, speech and swallowing problems, percutaneous gastrostomy tube insertion, and diplopia (Nath et al., 2003). Longer survival is associated with the presence of a tremor and a positive response to levodopa. An initial response to levodopa was reported in 18% of cases. Pathologically confirmed PSP cases without a supranuclear gaze palsy during life have a more prolonged clinical course. O’Sullivan et al., reported that male gender, older age at onset, short interval from disease onset to reaching first clinical milestone, and the Richardson phenotype were associated with shorter disease duration to death (O’Sullivan et al., 2008).

Conclusions Progressive supranuclear palsy is the second most common cause of parkinsonism, next to idiopathic PD, and is the most common cause of atypical parkinsonism. Its clinical hallmarks include parkinsonism, early onset of postural instability and falls, supranuclear vertical gaze palsy and other oculomotor abnormalities, axial rigidity or dystonia, and pseudobulbar palsy (with dysarthria, dysphagia, and emotional lability). Neuroimaging often shows midbrain atrophy, especially in more advanced cases. Microscopic pathology findings include neuronal loss, gliosis, and NFTs affecting predominantly the basal ganglia, diencephalon, and brainstem, with the nuclei most affected being the globus pallidus, subthalamic nucleus, and substantia nigra. Tau-positive astrocytes or processes help confirm the diagnosis on silver staining or immunostaining for tau. Other neuropathologic hallmarks include tufted astrocytes and oligodendroglial coiled bodies. Treatment is largely symptomatic, though often not very helpful. A subset of PSP patients with predominant parkinsonism (PSP-P) may exhibit some levodopa responsiveness, albeit temporary and mild to moderate, at best. Neuroprotective drug trials and DBS for PSP have so far yielded unsuccessful results.

Acknowledgment The author wishes to thank Dr. Thomas Beach of the Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, Sun City, Arizona, for furnishing the neuropathology slides and pictures.

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Chapter 12.4 Corticobasal Degeneration Katrina Gwinn Overview Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disease. It is characterized clinically by dopamine-replacement refractory movement abnormalities and cortical dysfunction. Clinical diagnosis is difficult, as symptoms of CBD are similar to those of other, much more common diseases, particularly Parkinson’s disease (PD) and progressive supranuclear palsy (PSP). Neuropathology is the “gold standard” of diagnosis, and a definitive diagnosis of CBD is possible only after death. The hallmark of CBD pathologically is neuronal loss and atrophy of multiple areas of the brain, including the cerebral cortex and the basal ganglia, and tau pathology in both gray and white matter. CBD was first identified in 1968 by Rebeiz et al., who evaluated three patients and described them as exhibiting a disorder characterized by “severe impairment in control of muscular movements, by abnormalities in posture and by involuntary motor activity [el] [and with] mental faculties [el] relatively spared until the end.” The original paper named the disease corticodentatonigral degeneration with neuronal achromasia; subsequent terms for this disorder have included corticonigral degeneration with nuclear achromasia and cortical basal ganglionic degeneration.

Epidemiology Very little epidemiologic data exists regarding the incidence or prevalence of CBD. Most of the literature is based on case report series. It is estimated that CBD accounts for 4–6% of parkinsonism. A family history of the disorder is rare in CBD, and it is believed sporadic. Age of onset is typically in the seventh decade, with a mean age of onset around age 63 years. Both men and women may present with the disease. Although some believe there may be a slight predominance in women, the data are too sparse to definitively determine this currently. CBD leads to death within approximately 8 years after presentation. Risk factors such as environmental exposures are not known.

Clinical features Because CBD is rare and has many clinical similarities to other neurodegenerative disorders, particularly PD

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and PSP, it is often misdiagnosed, even by neurologists. Cortical features can also cause CBD to be misdiagnosed as Alzheimer’s disease (AD) or frontotemporal dementia (FTD) (Wadia and Lang, 2007). A 1997 study by Litvan et al., showed extremely low sensitivity of the clinical diagnosis of CBD by neurologists (48.3%, at best), with false negatives being primarily diagnoses of PSP (Litvan et al., 1997). False positives were uncommon. In that study, the best clinical predictors of CBD were found to be limb dystonia, ideomotor apraxia, myoclonus, and akinetic-rigid syndrome (parkinsonism), with late onset of gait or balance disturbances. The initial symptoms of CBD are typically asymmetric rigidity, bradykinesis, and dysmetria (Mahapatra et al., 2004). It can present in either the arm or the leg. It is almost invariably asymmetric at onset, though over the course of the disease, CBD typically becomes bilateral and affects both upper and lower extremities. Other initial symptoms may include dysphasia or dysarthria. Some patients may have memory or behavioral problems as the earliest or presenting symptoms, despite the original description of the disorder, which stated that cognitive dysfunction is rare until late in the disease (Belfor et al., 2006). Asymmetrical limb dystonia is seen in almost all patients with CBD at some point in the course of the illness and is often the presenting symptom (FitzGerald et al., 2007). A clenched fist with the thumb adducted to the palm is common. Dystonia in CBD can be painful. Sinusoidal tremor as seen in PD is not common, but tremor due to dystonia or focal myoclonus is seen and mistaken for the tremor of PD in some cases. However, dystonic tremor is not regular and sinusoidal; unlike that of PD, it is jerky and irregular. Myoclonus itself is often elicited with a stimulus. While the name CBD refers to the neuropathologic features of the disease, there may be striking clinical cortical features seen in this disorder that can be useful in distinguishing it from PD and PSP (Scaravilli, Tolosa and Ferrer, 2005). One of the most talked-about features of CBD among phenomenologists, though not necessarily always seen, is alien limb phenomenon (alien hand syndrome). Alien limb phenomenon is believed to be prevalent in roughly 60% of those people diagnosed with CBD. Alien limb phenomenon involves difficulty controlling the movements of a limb, which can seem to undertake movements on its own, or a feeling that the limb is not one’s own or is not obeying the

Corticobasal Degeneration

commands of the patient. The movements of the alien limb are believed to be a reaction to external stimuli and not to occur sporadically or without stimulation (although they may be seen as an avoidance to stimuli). Like most of the movement disorders, alien limb phenomenon presents asymmetrically in those diagnosed with CBD. Mitgehen (continuous tactile pursuit), a sign of frontal dysfunction, can be observed on physical examination (mitgehen means “to go with” in German). Semipurposeful or purposeful activities can occur in the alien limb (such as handling clothing or picking up items). While anecdotally this phenomenon can be quite dramatic (the hand tries to “strangle” the patient, for example), usually this is much less directed and is described as, “The hand won’t do what I want it to do.” The hand may interfere with activities of the normal hand. Additionally, sensory impairment as a result of cortical involvement may also be seen and may have odd characteristics (itching, tingling, formication) characteristic of cortical sensory abnormalities. Ideomotor apraxia is an abnormality seen in CBD, as well as other disorders in which the patient has the motor strength to perform a task but cannot do so; the patient is unable to translate an idea into motion due to fronto-parietal abnormalities. There is no loss of the ability to perform an action automatically, but the action cannot be performed on request. Typically, the patient cannot imitate a meaningless task or symbolic hand gesture. For example, when asked, the patient cannot show the doctor how to comb the hair or brush the teeth. The patient may use the hand as a tool (instead of pretending to use a comb, using the hand across the top of the head) or make other errors in use (pretending to comb the mirror instead of the hair). The patient may have to look at the hand to perform a task and, when not looking at the hand, cannot do so. Ideomotor apraxia can also cause difficulty walking, including trouble initiating walking. This can cause stumbling and difficulties in maintaining balance. Some individuals with CBD exhibit limbkinetic apraxia, which involves dysfunction of more fine motor movements often performed by the hands and fingers. Aphasia in CBD is nonfluent, resulting in disrupted speech patterns and the omission of words. Individuals with this symptom of CBD often lose the ability to speak as the disease progresses (Gorno Tempini et al., 2004). Cortical signs (formerly known as frontal release signs) can be seen, including a grasp, suck, palmomental, and snout reflex. Psychiatric features may include depression, agitation, irritability, or apathy. While the disorder begins asymmetrically, it typically “spreads” to involve both sides and all four extremities. Death is generally caused by pneumonia or other compli-

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cations of a chronic neurodegenerative disorder, such as sepsis or pulmonary embolism.

Diagnostic testing The gold standard of diagnosis is neuropathologic. However, ancillary studies can be helpful in ruling out other disorders in the differential diagnosis and also help enforce a clinical impression or presumptive diagnosis. Electrophysiologic studies, including an EEG (electroencephalogram), may show changes in brain function over time that are consistent with the neurodegeneration. However, EEG is not a common test in the evaluation of CBD. No blood test is available for CBD. Urine, CSF, and other laboratory tests are not diagnostic and typically normal. Magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) in CBD can be normal or nonspecific, particularly early in the disease. Classically, because CBD is associated with cortical atrophy, one may see cortical atrophy on MRI and/or SPECT imaging. In those cases, MRI or SPECT of CBD typically shows asymmetric posterior parietal and frontal cortical atrophy. Corpus callosum atrophy may also be seen (Koyama et al., 2007). Dopamine transporter imaging (DAT, Isoflurane I123) scanning was recently approved by the FDA for the diagnosis of dopamine deficiency disorders; as the use of this imaging technique becomes widespread, it will be interesting to see its utility in evaluation of CBD versus other causes of parkinsonism. Other clinical tests or procedures that monitor the presence of dopamine within the brain (β-CIT SPECT and IBZM SPECT) may also be of future utility (Rizzo et al., 2008; Seritan et al., 2004).

Treatment No treatment is available to slow the course of CBD, and the symptoms of the disease are generally resistant to therapy, including dopamine replacement therapy, as well as other anti-parkinsonian agents. Symptomatic treatment may offer some benefit (Lang, 2005). Tremor and myoclonus may be controlled somewhat with benzodiazepines. Benzodiazepines or baclofen may help reduce rigidity. Botulinum toxin injections may be helpful to the dystonia. Physical therapy exercises may be useful to maintain range of motion of stiff joints. This may prevent pain and contracture and help maintain mobility. Occupational therapy may be used to design adaptive equipment that supports the activities of daily living, thus helping to maintain more functional independence. Speech therapy is used to improve articulation and volume (Hattori et al., 2003).

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Neuropathology Several brain regions are abnormal on postmortem pathologic examination in CBD. The cortex is severely affected, especially frontal and parietal regions. The basal ganglia are also affected, as the name suggests. Histologically, astroglial inclusions are seen, as are astrocytic plaques, especially in the frontal and premotor regions. Like FTD and PSP, CBD has been found to be a tauopathy; that is, CBD, like these other disorders, results from the pathologic aggregation of tau protein (Forman et al., 2002). The pathologic filamentous inclusions in CBD are composed primarily of abnormally phosphorylated tau, similar to many other sporadic and familial neurodegenerative diseases, such as AD, PSP, Pick’s disease, and FTD with parkinsonism linked to chromosome 17 (FTDP-17), collectively referred to as tauopathies (Komori, 1999). In the central nervous system, six tau isoforms are produced by alternative splicing. In AD, the filamentous tau aggregates are composed of all six tau isoforms, but in CBD and PSP, the aggregates are composed predominantly of 4-repeat (4R)-tau. The protein tau is an important microtubule-associated protein (MAP) and is typically found in neuronal axons. However, malfunctioning of the development of the protein can result in unnatural, high-level expression in astrocytes and glial cells. Astrocytic plaques prominently noted in histologic CBD examinations. Neuropathologic diagnostic criteria have been developed by Dickson and colleagues (2002). These include core features of focal cortical neuronal loss, substantia nigra neuronal loss, and cortical and striatal Gallyas/ tau-positive neuronal and glial lesions, especially astrocytic plaques and threads, in both white and gray matter. Supportive features include cortical atrophy, ballooned neurons, and tau-positive oligodendroglial coiled bodies. It is hoped that these criteria will inform the evaluation premortem as well, as they will allow reevaluation of patients who meet these standards postmortem and probably will widen our views regarding what the clinical features of CBD can entail.

Summary CBD is a rare yet underdiagnosed neurodegenerative disease. It manifests with asymmetrical parkinsonism, as well as other movement abnormalities, including myoclonus and dystonia. It also has features of frontoparietal cortical dysfunction. There are no currently meaningful interventions for this disorder, and it is inexorably progressive, with death typically occurring within 8 years of

presentation. It has been found to be a tauopathy, along with PSP and FTD, and it is hoped that research efforts in this area will translate into meaningful therapies for the tauopathies, including CBD.

References Belfor, N., Amici, S., Boxer, A.L., et al. (2006) Clinical and neuropsychological features of corticobasal degeneration. Mech Ageing Dev, 127: 203–207. Dickson, D.W., Bergeron, C., Chin, S.S., et al. (2002) Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol, 61: 935–946. FitzGerald, D.B., Drago, V., Jeong, Y., et al. (2007) Asymmetrical alien hands in corticobasal degeneration. Mov Disord, 22: 581–584. Forman, M.S., Zhukareva, V., Bergaeron, C., et al. (2002) Signature tau neuropathology in gray and white matter of corticobasal degeneration. Am J Pathology, 160 (6): 2045–2053. Gorno-Tempini, M.L., Murray, R.C., Rankin, K.P., et al. (2004) Clinical, cognitive, and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report. Neurocase, 10 (6): 426–436. Hattori, M., Hashizume, Y., Yoshida, M., et al. (2003) Distribution of astrocytic plaques in the corticobasal degeneration brain and comparison with tuft-shaped astrocytes in the progressive supranuclear palsy brain. Acta Neuropathologica, 106: 143–149. Komori, T. (1999) Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration, and Pick’s disease. Brain Pathol, 9: 663–679. Koyama, M., Yagishita, A., Nakata, Y., et al. (2007) Imaging of corticobasal degeneration syndrome. Neuroradiology, 49: 905–912. Lang, A.E. (2005) Treatment of progressive supranuclear palsy and corticobasal degeneration. Movement Disord, 20: S83–S91. Litvan, I., Agid, Y., Goetz, C., et al. (1997) Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study. Neurology, 48 (1): 119–125. Mahapatra, R.K., Edwards, M.J., Schott, J.M., and Bhatia, K.P. (2004) Corticobasal degeneration. Lancet Neurol, 3: 736–743. Rebeiz, J.J., Kolodny, E.H., and Richardson, E.P. (1968) Corticodentatonigral Degeneration with Neuronal Achromasia. Arch Neurol, 18 (1): 20–33. Rizzo, G., Martinelli, P., Manners, D., et al. (2008) Diffusionweighted brain imaging study of patients with clinical diagnosis of corticobasal degeneration, progressive supranuclear palsy, and Parkinson’s disease. Brain, 131 (Pt. 10): 2690–2700. Scaravilli, T., Tolosa, E., and Ferrer, I. (2005) Progressive supranuclear palsy and corticobasal degeneration: lumping versus splitting. Movement Disord, 20: S21–S28. Seritan, A.L., M.F. Mendez, et al. (2004) Functional imaging as a window to dementia: corticobasal degeneration. J Neuropsych and Clin Neurosci, 16: 393–399. Wadia, P.M. and Lang, A.E. (2007) The many faces of corticobasal degeneration. Parkinsonism & Related Disorders, 13: S336–S340.

Chapter 13 Sleep Disorders Sanford Auerbach Departments of Neurology, Psychiatry and Behavioral Neurosciences, Boston University School of Medicine, Boston, MA, USA

Summary • The patterns of sleep in the elderly are determined by the complex effects normal aging has on the physiology of sleep, as well as by their interaction with concurrent medical problems and the drugs used to treat them • Sleep deprivation can cause anxiety, irritability, chronic fatigue, and difficulty performing tasks • Aging is associated with a reduced tolerance of sleep loss but the subjects may either underestimate or overestimate the amount of quality sleep they get

Introduction

Overview of sleep

As in other fields of medicine, the study of sleep in the aging population can be rather complex. First, one must have a background in normal sleep and the disorders of sleep. Then there is the question of understanding the impact of normal aging. An additional challenge is analyzing the impact of the many medical problems that affect the elderly and examining the interaction with sleep. Although an interest in sleep can be traced throughout history, our current knowledge and approach is quite dependent upon the description of the underlying neurophysiology. In 1875, Caton first recorded the brain electrical activity of animals (Caton, 1875), but it was not until 1929 that Berger reported the electroencephalogram (EEG) of man (Berger, 1929). Subsequently, in 1937, Loomis described the EEG features of what is now known as nonrapid eye movement (NREM) sleep (Loomis et al., 1937). He described multiple levels of NREM, with vertex waves, sleep spindles, K complexes, and delta slowing. The next major breakthrough came in 1953 when Kleitman and Aserinsky described rapid eye movement (REM) sleep and the proposed correlation with dreaming (Aserinsky and Kleitman, 1953). Finally, in 1957, Dement and Kleitman provided a description of sleep cycles and a classification system of sleep stages with four stages of NREM and REM (Dement and Kleitman, 1957). This system of description stood the test of time until some recent modifications offered in 2007 by the American Academy of Sleep Medicine (AASM) (Iber et al., 2007a).

Sleep is essential for normal human function. Wakefulness (lack of sleepiness), vigilance, and performance on monotonous tasks deteriorate after a single sleepless night. Further sleep deprivation leads to more inattentiveness and performance failure. Lack of REM sleep is associated with anxiety and excitability, as well as difficulty with concentration and memory. Those deprived of slowwave sleep (SWS) generally report chronic fatigue, aches, stiffness, uneasiness, and withdrawal. “Sleep need” is difficult to define but usually is accepted as the amount of sleep required for optimal function during wakeful periods. Sleep need may vary from one individual to the next ranging from 3 to 10 hours of sleep over a 24-hour period (Williams et al., 1970). These principles apply to sleep that is not interrupted by specific sleep pathology, such as sleep apnea or periodic limb movements. The relationship of subjective to objective measures of sleep deserves further comment. In the general population, self-reports of sleep time often are subject to both overestimates and underestimates. Overestimates can be attributed, in part, to the fact that an arousal must be at least 5–6 minutes in duration if it is to be recalled subsequently as a sustained arousal or period of wakefulness. As a result, sleep punctuated by recurrent yet brief periods of arousal may be described as “sound sleep.” Similarly, overestimates of sleep duration are not uncommon. This overestimation can be further compounded because healthy older adults may simply accept a decrease in sleep efficiency as a part of normal aging. However, aging also is associated with reduced ability to tolerate sleep deprivation. Given these

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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influences, it is clear that objective measures of sleep and sleepiness are critical to the study of sleep and the effects of alcohol on sleep. The nocturnal polysomnogram (PSG) is the standard method of determining the presence and stage of sleep by measuring EEG, electromyographic (EMG), and electrooculographic (EOG) activity (Rechtschaffen and Kales, 1968). Similarly, the Multiple Sleep Latency Test (MSLT) is a standard and accepted measure of daytime sleepiness; it employs polysomnography while a patient is allowed to take naps on five separate occasions throughout a day (American Sleep Disorders Association (ASDA), 1992). Alternative methods may include the mean wakefulness test (MWT) or the subjective Epworth sleepiness scale (ESS). The assessment of average sleep latency with a standardized tool such as the MSLT allows a quantification of “sleepiness.” Sleep need often is translated into the concept of “sleep drive.” Thus, relative sleep deprivation leads to increased sleep drive, whereas napping lends itself to a relative decrease in sleep drive. The change in sleep need with increasing age has been the subject of considerable study, but such studies often are confounded by changes in lifestyle, diet, medication use, napping patterns, and the like.

Sleep architecture Understanding normal sleep is an essential prerequisite to understanding sleep disorders. Sleep is a dynamic process, featuring fluctuations in brainwave activity, muscle tone, eye movement, and autonomic activity. It consists of two discrete states: REM and NREM sleep. Each can be defined in physiologic terms by using the elements of the PSG: EEG, EOG, and ECG. Formal criteria have been elaborated in a manual developed by the AASM (Rechtschaffen and Kales, 1968). Nonrapid eye movement sleep Current nomenclature now considers NREM in three stages (N1–N3). Formerly, NREM was divided into four stages, but N3 now approximates the combined stages 3 and 4. Stage N3 is often referred to as SWS or delta sleep. In brief, each stage is characterized by progressively slower EEG background, lower muscle tone, and decreasing eye movements. Stage N1 marks the transition from wakefulness to drowsiness. Rhythmic activity is replaced by mixed voltage, 3.0–7.0 Hz theta activity, and a decrease in muscle tone. Roving eye movements may be present. Stage N2 features a similar but slower background EEG, with superimposed “spindles” (low-amplitude, highfrequency, centrally predominant bursts) and K-complexes (high amplitude, negative or upgoing potential, immediately followed by lower amplitude, positive or downgoing potential, with some faster, low-amplitude activity). Muscle tone may decrease further, whereas eye movements may disappear entirely. Stages N1 and N2

often are referred to as the “light” stages of NREM sleep because of the relatively low arousal threshold. Stage N3 (SWS) is characterized by high-amplitude (75 μV), slowwave (0.5–2.0 Hz) activity. In N3, K-complexes and spindles are absent and eye movements are not seen. Muscle tone may be further diminished.

Rapid eye movement sleep REM sleep, or stage R, does not fit into the same staging system as NREM sleep and thus sometimes has been referred to as paradoxical sleep. Although EEG activity is relatively active, the muscle tone achieves its lowest state over a 24-hour period (relative muscle atonia). REM sleep is characterized by rapid eye movements scattered through the duration of each REM cycle. REM sleep can be further subdivided into tonic (background EEG, relative muscle atonia, hippocampal theta activity) and phasic (rapid eye movements, brief muscle twitches, “saw tooth” waves on the EEG, and pontogeniculo-occipital spikes, as recorded in animals) components. REM sleep is associated with the well-formed dream. Individuals aroused from REM sleep will recall dreams about 80% of the time. NREM arousals may be associated with recall of isolated images or thought fragments, but not the wellformed images of REM sleep. Nightmares are a reflection of the elements of REM sleep. As the individual initially awakens from a frightening dream and begins to scream, no sound emerges because he or she is still paralyzed with the muscle atonia of REM. It is noteworthy that these components of REM sleep are not rigidly synchronized. Another example of this loose synchronization can be seen in some normal individuals with sleep paralysis as a benign condition, in which the individual is transiently “paralyzed” as he or she awakens from sleep. Sleep rhythms The components of sleep do not occur randomly throughout the course of the night. In fact, a clear pattern emerges from the ultradian or short rhythms of sleep. The “light” stages of NREM are seen first. They are followed by a transition to SWS, followed by lighter stages of NREM again and then REM sleep. Typically, there are three to four NREM–REM cycles, each lasting 90–120 minutes. As the night progresses, the relative amount of time spent in REM increases and the amount of time in SWS decreases. Thus, REM usually is skewed toward the end of the sleep period and SWS toward the beginning. More importantly, sleep–wake rhythms follow a circadian or approximately 24-hour biologic pattern. Sleep–wake is considered a circadian rhythm that is tightly synchronized with circadian variations in the core body temperature. The suprachiasmatic nucleus of the hypothalamus in animals, and an analogous structure in humans, with inputs from the retinohypothalamic pathways, has been identified as the endogenous pacemaker. Although individuals may have

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different periodicities in their clocks (“larks” and “owls”), many factors maintain or influence these rhythms. Although activity levels, social cues, mealtimes, and other external scheduling factors play some role, the most powerful zeitgeber (lightgiver) has proved to be exogenous light. Presumably, light exerts its influence through retinohypothalamic input to the suprachiasmatic nucleus (Czeisler et al., 1991). From a clinical perspective, it is helpful to view the usual pattern of sleep–wake in terms of the shifting pattern of the core body temperature. The usual evening sleep onset occurs as the core body temperature falls during the “primary sleep permissive” zone. Sleep continues as the core body temperature continues to fall and enters the “sleep maintenance zone.” The duration of sleep and REM sleep follows this circadian cycle, with most of REM sleep occurring close to the nadir of the temperature cycle. The temperature then begins to rise, reaching its peak at midday. A secondary dip usually occurs in midafternoon, correlating with a secondary sleep permissive zone, or the so-called “siesta” zone. This nap zone usually is followed by a relative plateau that has been related to the “second wind.” Similarly, a secondary rise occurs in the early morning hours, usually at about 3 am, when a secondary arousal time occurs and the individual is susceptible to wakening from any physical or emotional factor (such as anxiety, pain, or the need to urinate).

Circadian rhythms in normal aging As with normal sleep architecture, changes in normal circadian physiology occur with aging. The two most striking changes are the gradual advancement in circadian phase with aging and the increasing intolerance of rapid phase changes. The advancing rhythm is reflected in a tendency toward an earlier sleep time with an earlier rise time. The increasing intolerance of rapid phase shifts would be reflected in greater difficulties with shift work or a greater sensitivity to the effects of jet lag. Other concerns about changes with aging, such as diminished circadian amplitudes and shortened circadian taus, are equivocal (Monk, 2005).

Sleep changes with normal aging

Disorders of sleep in the elderly

Sleep changes associated with a decrease in sleep efficiency, a decrease in stage N3, and an increase in wake after sleep onset (WASO) with minimal changes on sleeponset latency and REM latency. Elderly also find it hard to adapt to jet lag, shift work, and phase shifts due to changes to circadian rhythm systems.

Sleep disorders are not uncommon, and the prevalence of most sleep disorders increases with advancing age. Among adults over the age of 65, more than 50% complain of difficulty sleeping (Foley et al., 1995). Many factors may contribute to these disturbances, including medical/psychiatric disturbances and medication use. In addition, older adults are susceptible to many of the specific disorders encountered by the general population. We discuss the disorders most commonly encountered in this population.

Sleep architecture in normal aging Normal aging is associated with changes in sleep that progress gradually across the lifespan. Most of these changes can be seen between the ages of 19 and 60, with only minimal changes from age 60 to 102 (Ohayon et al., 2004). Based upon a recent meta-analysis of PSG studies in healthy normal people, the major features appear to be a decrease in total sleep time (TST), a decrease in sleep efficiency, a decrease in SWS, and an increase in WASO. Other features include increases in N1/N2 and a decrease in REM sleep. On the other hand, changes in sleep-onset latency and REM-onset latency are minimal. The observations were comparable for both men and women (Ohayon et al., 2004). Note that these observations are based on an analysis of the “normal” aging. Studies that allow for the co-morbidities that accompany aging show greater changes and a gender difference, with men showing poorquality sleep with aging (Redline et al., 2004).

Napping and excessive daytime sleepiness in normal aging Although regular napping and EDS appear to increase with aging (Metz and Bunnell, 1990; Ohayon, 2002; Young, 2004), these observations are seemingly linked to the presence of comorbidities such as chronic pain and depression (Foley et al., 2007). Healthy older adults are much less likely to report regular napping or EDS. Furthermore, napping appears to have only a modest impact on nighttime sleep and may even contribute to improved daytime performance (Monk et al., 2001; Campbell et al., 2005).

Restless legs syndrome Restless legs syndrome (RLS) was first described by Ekbom in the 1940s. For many years, it was thought to be a rare curiosity, but current epidemiologic studies suggest that it may be one of the most common sleep-related disorders, with a prevalence as high as 10% (Phillips et  al., 2000). Pharmacologic studies have indicated that levodopa and dopamine-receptor agonists are effective therapies for RLS, pointing out that the disorder is associated with a decrease in dopaminergic function in the brain. However, contradictory results have been obtained with 18-fluorodopa positron emission tomography (PET) scans (Trenkwalder et al., 1999). Functional magnetic resonance imaging (MRI) of patients with RLS suggests

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involvement of the cerebellum and the thalamus, with additional activation of the red nucleus, pons, and midbrain when periodic limb movements of sleep (PLMS) are also present (Bucher et al., 1997). Physiologic studies have suggested that a disturbance of inhibitory subcortical pathways, such as the reticulospinal tract, may allow expression of a normally suppressed neural generator at the level of the spinal cord (Bara-Jimenez et al., 2000). About 50% of patients with RLS have a family history of the condition (Winkelmann et al., 2000), and a recent report has described a family with linkage to chromosome 12q (Desautels et al., 2001). Another advancement has been the observation of a relationship with low iron stores in the brain that may be critical in the pathogenesis of RLS (O’Keeffe et al., 1994; Sun et al., 1998; Earley et al., 2000; Allen et al., 2001). The diagnosis of RLS requires the presence of four essential diagnostic criteria (Allen et al., 2003): 1 An urge to move the legs, which may be accompanied by unpleasant sensations. 2 Worsening of symptoms during periods of rest. 3 Partial or total relief of symptoms with movement, such as walking, for at least as long as the activity continues. 4 Worsening of symptoms in the evening or night. RLS is often accompanied by PLMS, which is a polysomnographic finding of recurrent movements of the legs in a triple flexion pattern during sleep. RLS is encountered in both men and women and in all age groups. Parasthesias or a sensation of discomfort is often a part of the urge to move. The severity of the disorder may vary considerably. In some, there may be a significant disruption in sleep onset or the ability to sit still for a long car ride or movie. These paresthesias are usually bilateral, often more prominent in the legs than in the arms. The sensations typically are described as burning, tingling, stabbing, aching, or simple pain. Some patients complain of sensations of ants crawling or worms burrowing. Symptoms usually are subjective and vary over the course of the day. They tend to be worse when the individual is relaxing, especially when preparing for sleep. Patients may have particular difficulties in enclosed areas such as airplanes, cars, or trains. Symptoms are variable and may fluctuate over time, with exacerbations and remissions (Allen et al., 2003). Some patients develop myoclonus or sudden jerking movements. It is not uncommon to find an overlap with PLMS. PLMS, however, occurs during sleep and most commonly in stage N2 sleep. RLS, on the other hand, occurs during wakefulness and interferes with sleep at the transition between wakefulness and sleep. Although PLMS may occur in up to 80% of cases with RLS, PLMS can occur independently. In addition to the impact on sleep, RLS may be associated with reduced health-related quality of life, elevated rates of mood disorders and anxiety disorders, and potentially increased risk of cardiovascular disease (Yang et al., 2005).

The pathophysiology of RLS is unknown. Disorders of iron metabolism within the central nervous system and dopaminergic function have been considered. Many medical problems have been found to aggravate the symptoms. Uremia, anemia, and neuropathies have been implicated in many so-called secondary cases. RLS may be aggravated or triggered by the use of several medications, including antidepressants, lithium carbonate, neuroleptics, and caffeine (Winkelman et al., 2006).

Treatment of restless legs syndrome in the elderly The first step in treatment is identifying the disorder. Older patients, in particular, may not always think to bring these symptoms to the attention of their clinician. Patients who may suffer from a dementing illness or other cognitive impairment may not be capable of describing symptoms, and one needs to suspect the diagnosis based upon careful observation. After the clinical diagnosis is made, careful attention must be directed to treatable causes or other aggravating factors, such as iron deficiency, uremia, or aggravating medications. In some cases, exercise may be helpful. Often it is necessary to consider medications. In a recent evidence-based review, the medications considered to be effective were dopaminergic agents (levodopa, ropinirole, pramipexole) and gabapentin. Ropinirole, pramipexole, and a long-acting formulation of gabapentin are the only agents with formal FDA approval for this indication. Other medications with some potential benefit include opioids, benzodiazepines, and a few other anticonvulsants. Medications considered to be likely effective include carbamazepine, valproate, oxycodone, bromocriptine, and clonidine. Finally, several were considered to be in the “experimental” group, including methadone, tramadol, clonazepam, zolpidem, topiramate, amantadine, magnesium, folate, and dihydroergocriptine (Trenkwalder et al., 2008). Care must be taken in the elderly to consider the potential side effects of these agents. The benzodiazepines, for instance, may pose particular problems.

Periodic limb movements of sleep PLMS is a polysomnographic finding of stereotyped repetitive movements of the legs during sleep. PLMS are characterized by episodes of repetitive, stereotyped limb movements during sleep. Other terms for the condition include periodic leg movement, nocturnal myoclonus, periodic movements of sleep, and leg jerks. The movements usually involve the legs (unilateral, alternating, or bilateral), although the arms also may be involved. Movements consist of extension of the big toe, in combination with partial flexing of the ankle, knee, and (sometimes) hip. The movements often are associated with partial arousal or overturning, usually too briefly for potential awareness. There can be marked night-to-night variability in the number of movements (Billiwise and Clarkson, 1988;

Sleep Disorders

Mosso et al., 1988; Edinger et al., 1992). In some cases, periodic arousals may predominate, with minimal, if any, evidence of limb movements. PLMS have a prevalence of 7.6% in the general population (Scofield et al., 2008) and greater than 40% in community-dwelling individuals aged 65 years or older (Ancoli-Israel et al., 1991). PLMS is present in more than 80% of patients with RLS. However, the clinical relevance of PLMS in the absence of RLS or subjective sleep complaints continues to be debated. PLMS associated with arousal may be of greater importance than the actual number of movements seen during a study. Periodic limb movement disorder (PLMD) is defined as the presence of PLMS in patients with otherwise unexplained hypersomnia or insomnia (Hornyak et al., 2006). Nevertheless, the importance of PLMD remains controversial. As a consequence, few treatment trials are available and most clinicians will use medications otherwise indicated for RLS.

Obstructive sleep apnea Obstructive sleep apnea (OSA) is a common syndrome. It is a treatable disorder that accounts for many of the cases of excessive somnolence and insomnia encountered in most sleep centers. It is one of the few diagnoses that make PSGs reimbursable by third-party payers. OSA is characterized by repetitive episodes of sleeprelated upper airway obstructions, which usually are associated with oxygen desaturation. OSA can be conceptualized as a disorder emerging from an interaction between anatomy and muscle relaxation as it occurs in sleep. As muscles relax, airflow can generate vibrations in the soft tissues of the upper airway, including the soft palate. Such vibration produces the noise or the snoring. The role of upper airway muscle relaxation in the pathophysiology also means that certain medications, such as benzodiazepines or alcohol, may aggravate the severity of the OSA, presumably by the enhanced degree of muscle relaxation. In some patients, the snoring appears in isolation; in such cases, the term primary snoring is applied. Further upper airway restriction can result in difficulties along two other dimensions. Muscle relaxation, especially in the upper airway dilator muscles of the oropharynx (often combined with mild anatomic abnormalities), causes increased airway restriction, which is further enhanced by the negative pressures generated by normal respiration (Guilleminault and Stohs, 1991). The sleep disruption may or may not be apparent to the patient because, as noted earlier, brief physiologic arousals may not be recalled. Daytime somnolence often is the prime complaint, although–-as in other chronic, progressive disorders–-the patient may adapt to and minimize these symptoms. The same patient who denies daytime sleepiness or napping may acknowledge an irresistible urge to doze if allowed to sit in a comfortable chair or when confronted with the monotony of highway driving. Others

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with concurrent anxiety disorders may not experience the ease of falling asleep and will simply not be aware of the sleep deprivation. Similarly, presenting complaints may be related to difficulties in memory or concentration that reflect suppression of REM sleep (REM sleep is especially vulnerable because of the relative muscle atonia). SWS also can be suppressed and may be associated with complaints similar to those associated with fibrositis or fibromyalgia. In addition to sleep disruption, there are several cardiopulmonary consequences. Feedback reflexes may be insufficient to cause arousal (arousal produces return of muscle tone on cessation of the respiratory events). Indeed, one might see significant oxygen desaturation with arrhythmia, systemic and pulmonary arterial hypertension, and polycythemia. These changes can become chronic, and recent epidemiologic studies have suggested that OSA plays a role in the development of often-unrecognized hypertension in the general public (Nieto et al., 2000; Peppard et al., 2000). The severity of OSA thus can be measured in three dimensions: snoring, sleep disruption, and cardiopulmonary consequences. It is not unusual to see some linkage, but the factors may exist independently as well. Manipulation of anatomy or the degree of muscle relaxation can aggravate OSA. Weight gain or supine sleep heightens the anatomic risk factors, whereas use of alcohol, benzodiazepines, and other sedatives enhances muscle relaxation and, thus, the severity of OSA. Determining the severity of OSA is complicated by the arbitrary scoring criteria used in most laboratories, as well as the recent recognition of the upper airway resistance syndrome, where symptoms may be attributed to events that do not meet the formal criteria for the definition of apneas or hypopneas. Fortunately, the establishment of a new scoring system for these events may minimize problems in the future (Iber et al., 2007b). Traditionally, apneas are defined as episodes of 10 seconds in duration during which airflow falls to less than 10% of baseline. Obstructive events imply that there is continued respiratory effort (Gislason et al., 1987), although there is some controversy as to how sensitive the effort markers need to be to determine the absence of effort of the type seen in central apneas. Hypopneas usually are defined as events of 10 seconds during which airflow drops to 50% of baseline or less, with an associated drop in oxygen saturation or a brief arousal. OSA is considered mild if the number of events per hour ≥5, moderate if ≥15, and severe if ≥30. In upper airway resistance syndrome, “unscorable” events may be associated with sleep disruption or frequent EEG alpha arousals. Epidemiologic studies have suggested that snoring occurs in 9–24% of middle-age men and in 4–14% of middle-age women (Koskenvu et al., 1985; Lugaresi and Partinen, 1994), although there is a tendency to

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under-report snoring (Telakivi et al., 1987). The prevalence of OSA in the general male population has been estimated to be 0.4–5.9% (Lavie et al., 1984; Gislason et al., 1987; Gislasen et al., 1988; Cingnotta et al., 1989), with the incidence in men clearly outnumbering that in women. Common risk factors include obesity (Telakivi et al., 1987; Kripke et al., 1997; Phillips and Ancoli-Israel, 2001), smoking (Lavie et al., 1984; Norton and Dunn, 1985; Gislasen et al., 1988), alcohol consumption (Issa and Sullivan, 1982; Kripke et al., 1997), stroke (Shahar et al., 2001), and age (Young et al., 2002).

Treatment of obstructive sleep apnea in the elderly In some respects, the management of OSA in the elderly follows the usual approaches applied to the general population. Interestingly, however, there has never been a demonstration that treatment will have a clear impact on long-term morbidity or mortality in the elderly (Barbe et al., 2001; Marin et al., 2005). Nevertheless, it is clear that patients may benefit from improvements in sleep quality and efficiency. Therefore, an emphasis should be placed upon symptom improvement. Perhaps the first step, after establishing the diagnosis, is to address factors that may be easily addressed. Body position, for instance, may play a role in the severity of the disorder. In some patients, the severity is dependent on the time spent sleeping in the supine position. Often patients spend more time sleeping supine when in the sleep lab because of the imposition of the equipment, thus distorting the final impression of severity. Simply by encouraging nonsupine sleep, the severity may be significantly reduced. Care to reduce nocturnal alcohol consumption or agents that may enhance muscle relaxation may also reduce the severity of the disorder. Weight reduction is another strategy that may be helpful in the obese. The next step is to consider a trial of positive airway pressure (PAP). Care should be taken to monitor for common causes of failure to comply with PAP therapy. Improper education, improper mask fitting, and improper titration are common problems in compliance failure. Untreated anxiety or claustrophobia is yet another cause. Finally, there may also be a failure to recognize the contribution of other factors that may contribute to daytime sleepiness, such as depression or medication effects that may mask the benefit achieved by the PAP therapy. Other options may include dental appliances, usually considered for milder, nonobese cases, or surgical modification. Although tracheostomy is quite effective, it is rarely considered, for obvious reasons. Among the other surgical approaches, the maxillomandibular advancement (MMA) procedure is likely the most promising (Aurora et al., 2010a).

Sleep in degenerative diseases A special situation of abnormal sleep disorders in the elderly is degenerative diseases. Alzheimer’s disease (AD), Parkinson’s disease with dementia (PDD), dementia with Lewy bodies (DLB), multiple systems atrophy (MSA), and prion diseases all pose different challenges and disruptions to sleep.

Sleep and Alzheimer’s disease AD is the most common form of dementia in the United States. Current estimates indicate that 5.1 million Americans are living with AD. The prevalence increases with age, with 60% of those over the age of 85 years affected. By the year 2050, an estimated 11 million to 16 million individuals will have AD (Plassman et al., 2007). Crosssectional studies suggest that approximately 25–35% of individuals with AD have problems sleeping (Dauvilliers, 2007). Sleep disturbances in AD are complex. These patients are susceptible to all of the sleep problems related to aging, as well as to a progressive deterioration and decrease in the number of neurons in the suprachiasmatic nucleus (SCN), which is critical in the homeostatic maintenance of the circadian rhythm (Wu and Swaab, 2007). Common symptoms include nighttime sleep fragmentation, increased sleep latency, decreased SWS, and increased daytime napping.

The interface of Alzheimer’s disease pathology and sleep The relationship between sleep pathology and the pathogenesis of AD may be even more complex. Amyloid-β (Aβ) accumulation in the brain extracellular space is considered to be a hallmark of AD, although the precise role in pathogenesis may be controversial. In a transgenic mouse model, it has been shown that chronic sleep restriction significantly increased and a dual orexin receptor antagonist decreased Aβ plaque formation. Thus, the sleep–wake cycle and orexin may play a role in the pathogenesis of AD (Kang et al., 2009). This relationship between sleep and the pathophysiology of AD may also be reflected in the observation that sleep disturbances should be considered as one of the core noncognitive symptoms of mild cognitive impairment (MCI), a condition often thought to be a precursor to AD (Beaulieu-Bonneau and Hudon, 2009). Certain sleep changes in AD seem to represent an exaggeration of changes that appear with normal aging. AD patients spend an increased amount of time in stage 1 sleep, with increased number and duration of awakenings, compared to age-matched non-AD controls (Prinz et al., 1982b; Reynolds et al., 1985). With disease progression, it is also difficult to separate EEG features of stage 2 sleep from stage N1 sleep. Sleep spindles and K complexes are poorly formed. They are also of lower amplitude and

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shorter duration and are much less numerous (Prinz et al., 1982a; Montplaisir et al., 1995). The proportion of NREM sleep increases with further disappearance of the true delta wave of SWS (Prinz et al., 1982a, 1982b; Reynolds et al., 1984; Reynolds et al., 1985; Montplaisir et al., 1995). The percentage of time spent in REM sleep, which remains stable with normal aging, is reduced in patients with AD. A decrease in the mean REM sleep episode duration and REM sleep percentage can be due to degeneration of the nucleus basalis of Meynert. The nucleus normally exerts an inhibitory influence on the nucleus reticularis of the thalamus, the rhythm generator responsible for NREM sleep (Buzsaki et al., 1988). REM sleep also depends on the abundance and integrity of the cholinergic system. The cholinergic disturbance in AD is accompanied by worsening of REM sleep. In addition, many subcortical structures, such as the basal forebrain, distal and superior raphe nucleus, and reticular formation of the pons and medulla, seem to be involved in the initiation of sleep and oscillation between REM and non-REM states. All these structures may potentially be damaged by the degenerative changes that are part of AD. Their deterioration may explain many of the sleep architecture and rhythm changes in AD (Weldemichael and Grossberg, 2010). The impact of REM may also be reflected in the observation that REM sleep without atonia may be more common in AD, even though the behavioral correlate of REM sleep behavior disorder is relatively uncommon (Gagnon et al., 2006). A progressive deterioration of circadian rhythms also occurs with aging. This includes changes in the sleep– wake cycle manifested by reductions in sleep quality and impairment in cognitive performance (Oosterman et al., 2009; Yu et al., 2009). The main reason for the alteration in sleep–wake cycle is related to alterations in the SCN and melatonin secretion (Swaab et al., 1984; Reynolds et al., 1984). Though not clear, genetic risk factors such as in AD patients who are negative for the APOE-4 allele have also been implicated in the development of sleep problems (Yesavage et al., 2004; Craig et al., 2006). Studies of the circadian core body temperature rhythms in human subjects have shown a reduction in endogenous circadian amplitude and a delay in the endogenous circadian phase of core body temperature in patients with probable AD (Aschoff, 1960; Mills et al., 1978; Satlin et al., 1995; Ancoli-Israel et al., 1997). AD patients, however, have shown only a slight decrease in endogenous circadian amplitude when compared to normal aging, so it is unclear whether this is simply an exaggeration of normal aging (Czeisler et al., 1992).

Impact of commonly used medications in Alzheimer’s disease Acetylcholinesterase inhibitors (ACHEIs) represent a group of agents that have been FDA approved for the

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treatment of AD. The commonly used ACHEIs include donepezil, rivastigmine, and galantamine. These are of particular interest because of the concern that the central cholinergic effect will have an impact on sleep, particularly REM sleep. Donepezil treatment enhanced REM sleep and reduced slow frequencies of REM sleep EEG, suggesting a possible action upon REM-sleep-related cholinergic neurons in patients with AD. Furthermore, REM sleep alpha power may predict the cognitive response to donepezil (Mizun et al., 2004; Moraes et al., 2006). Although some reviews suggest no particular impact of galantamine on REM (Stahl et al., 2004), there are case reports of galantamine causing unusual nightmares (Iraqi and Hughes, 2009) and rivastigmine causing REM sleep behavior disorder (Yeh et al., 2010). The impact of donepezil on REM is not always clear (Cooke et al., 2006), but studies suggest an increase in REM with treatment by donepezil in healthy volunteers after a single dose (Kanbayashi et al., 2002). Donepezil may also reduce decline in recognition performance in individuals vulnerable to the effects of sleep deprivation (Chuah et al., 2009). Of additional note is that cholinergic activity follows a circadian pattern. As a consequence, improved function may be seen during the day, but at night, there is an increased risk of sleep disruption (Davis and Sadik, 2006).

Tauopathies and sleep Tauopathies include the frontotemporal dementias (FTDs) including Pick’s disease, primary progressive aphasia, semantic dementia, FTD with parkinsonism linked to chromosome 17 associated with mutations in the gene encoding tau; corticobasal ganglionic degeneration (CBGD); progressive supranuclear palsy (PSP); and argyrophilic grain disease. Sleep disturbances are prominent in all FTDs, but studies are limited. Nocturnal agitation and wandering may occur in FTDs and should be treated the same as in AD (Anderson et al., 2009). The neuropathology of FTD may explain some of the sleep disturbances. Diffuse severe degeneration of the orbital, frontal, basal forebrain, hippocampus, and temporal areas of the brain may be the direct or indirect cause of sleep–wake disturbances. The frequency of PLMS and associated arousals in patients with FTD is unknown and has not been studied. RLS, on the other hand, has anecdotally been seen with frequency in FTD (Boeve, 2008). Hypersomnia has been anecdotally described in patients with FTD. This was seen as decreased mean sleep latencies and sleep-onset REM periods on multiple sleep latency testing. Medications that are commonly used to treat negative behavior in FTDs may also affect sleep and wakefulness in patients with FTDs. As in AD, they may contribute to daytime somnolence, worsening of cognitive dysfunction, or insomnia.

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Synucleinopathies and sleep Synucleinopathies include PDD, DLB, and MSA. The synucleinopathies have early brainstem dysfunction and cerebral dysfunction, which may account for some of the sleep disturbances seen in this group. PDD and DLB patients have circadian rhythm disorders. Experience has shown more commonly advanced phase disorders, but this has not been systematically studied. Hypersomnia may occur in all the synucleinopathies with more frequency in PDD than in PD without dementia (Boeve, 2008; Compta et al., 2009). Insomnia may also occur in patients with synucleinopathies and is commonly related to medication effect. Medications may contribute to sleep–wake disturbances in PDD and DLB. Dopamine agonists used for treatment of parkinsonism in patients with PDD may cause daytime sleepiness, nighttime stimulation, and hallucinations. Anticholinergics may also have nighttime stimulatory effects and can increase confusion. Acetylcholinesterase inhibitors used for dementia in PDD and DLB may cause insomnia. Antidepressants may contribute to or exacerbate PLMS and REM sleep behavior disorder (RBD). PLMS and RLS occur in this population with unknown frequency, but increased rates have been reported. They are treated with increased doses of dopamine agonist medications during symptomatic times of the day. RBD is a not uncommon feature of the synucleinopathies. It may precede the onset of PDD or DLB by many years. Treatment of RBD is necessary when it leads to selfinjurious behavior or injury to the bed partner, or if it otherwise causes sleep fragmentation. Creating a safe sleep environment is paramount. Melatonin and clonazepam are used for pharmacologic treatment. Melatonin may be more desirable due to fewer effects on gait and cognition than clonazepam (Aurora et al., 2010b). Patients with parkinsonism as seen in PDD, DLB, and MSA also have sleep disturbances related to motor control. Bradykinesia/akinesia, rigidity, tremors, dystonia, and muscle stiffness all contribute to sleep onset and maintenance difficulty. On the other hand, some authors have recognized a sleep benefit on the motor symptoms of PD. Presumably, the gradual increase in dopaminergic stores through the course of the sleep period may contribute to some apparent benefit after a night of sleep. Patients with MSA typically have similar sleep disturbances to patients with PDD and DLB. In addition, however, sleep-disordered breathing may be seen more commonly in patients with MSA. Upper airway obstruction at the glottis level may lead to obstructive sleep apnea, and degeneration of the pontomedullary respiratory centers may lead to central sleep apnea. Vocal cord abductor paralysis may lead to clinical stridor and, more importantly, life-threatening breathing problems.

Prion disorders and sleep Prion disorders such as fatal familial insomnia (FFI), Creutzfeldt–Jakob disease (CJD), and Gerstmann– Straussler–Scheinker disease are rare, and information on sleep disturbances is sparse. Studies of sleep in CJD have shown disturbances ranging from profound hypersomnia to insomnia. Insomnia was more common than hypersomnia. Sleep aids such as benzodiazepines and hypnotic medications were helpful in treating insomnia in these patients (Wall et al., 2005). FFI is a rare prion disease characterized by insomnia, dysautonomia, and motor dysfunction. A case report by Gistau of a patient with FFI showed hormonal dysregulation of the circadian rhythm, and PSG findings were consistent with a global abnormality of the sleep–wake cycle (Gistau et al., 2006). In a study by Krasnianski et al., PSG findings of patients with FFI showed a reduction in rapid eye movements, decreased sleep efficiency, decreased SWS, PLMS, and central apnea (Krasnianski et al., 2008). Clinically, these patients manifested with a wide range of psychiatric symptoms, vegetative symptoms, and autonomic dysfunction. FFI may be confused with CJD because of the rapid cognitive decline and psychiatric symptoms. However, FFI disease progression is usually more prolonged, and signs typical of CJD generally occur late in the disease.

Clinical approaches to sleep disorders The clinical approach to elderly patients with sleep disorders poses certain problems in addition to dealing with specific sleep disorders. Therefore, a systematic approach is critical. 1 The first step is to obtain a careful history of the amount of sleep actually obtained in a 24-hour period. A diary can be used, but a careful history often elicits the necessary information. 2 The next step is to address the issue of timing and to determine the patient’s probable circadian rhythm. This can be complicated by shifting work schedules and other activities. Again, the history is the most powerful tool. A sleep diary may be helpful. 3 Consider the potential for medical or psychiatric issues that can interfere with sleep. These are detected through a careful medical and psychiatric review, including an inventory of medications, exercise, nicotine, alcohol, and other drug use. Give careful attention to symptoms of anxiety, depression, nightmares, and post-traumatic stress. 4 Inquire about possible features of intrinsic sleep disorders. Is there evidence of OSA—snoring, sleep disruption, obesity, hypertension, and morning headache? Is there a reason to suspect PLMS or RLS? Is there a history of sleep-disturbing paresthesias or a history of sleep-related movement disorder?

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5 Inquire about the sleep environment. Is the sleep area conducive to the relaxation required to allow the waketo-sleep transition? This is a relative concept; for example, a television can be hypnotic for some but stimulating for others. Occasionally, additional diagnostic studies are required. Some of these studies are part of the medical evaluation. Expanded use of a diary can be of value. A PSG should be considered if OSA or narcolepsy is suspected. A PSG also is helpful in evaluating parasomnia (abnormal sleeprelated behavior). Finally, an MSLT can be helpful in documenting hypersomnia or the presence of early-onset REM. When the evaluation is complete, the clinician can initiate a strategy to address the sleep problem. This approach needs to consider the addictive disorder because problems underlying the addiction must be addressed and treated. Care must be taken in selecting medications. Whenever possible, associated medical or psychiatric conditions should be treated. Only then can “intrinsic” sleep disorders be treated. For example, RLS and PLMS can be treated with medications that are not subject to abuse. OSA usually is treated with continuous PAP devices. Special attention then can be directed to issues of sleep hygiene, including the following: • The sleep environment should be modified to allow for the relaxation required for the wake-to-sleep transition. It should be separated from work and play areas. Noise and lighting should be modified to allow for optimal relaxation. • The times at which caffeine, nicotine, alcohol, and other medications are used should be assessed and adjusted as necessary. • Regular exercise has been found to improve sleep and should be recommended. • Adoption of a regular sleep–wake schedule should be encouraged. Napping is permissible but will reduce the need to sleep at night. • Finally, the patient needs to be able to separate sleep time from other stressors, allowing for a period of relaxation. The patient should be instructed to leave the bedroom whenever he or she is unable to sleep, to avoid the development of further anxiety. If the patient still has difficulties with sleep, an underlying cause should be sought. Often the cause is some form of anxiety disorder that requires direct attention. Relaxation techniques are helpful to some patients, as are medications. The usual sedating or hypnotic agents can be used for transient problems. However, in working with a patient for whom addiction is an issue, it is wise to consider the sedating antidepressants or the more active agents used to treat other anxietyrelated disorders, such as selective serotonin reuptake inhibitors.

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Chapter 14 Autonomic Dysfunction and Syncope Rohit R. Das Indiana University School of Medicine, Indianapolis, IN, USA

Summary • Three main types of syncope include neurally mediated syncope, cardiac syncope, and situational syncope associated with orthostatic hypotension. • The clinical features of syncopal events are classified as prodromal symptoms, event symptoms, and post-event symptoms. The most prominent early symptoms are dizziness and lightheadedness. Other symptoms include a brief and transient loss of consciousness (TLOC) followed by a short period of confusion, loss of control over volitional movements, and an upward deviation of both eyes at syncopal onset. • ECGs are the first step to assessing syncopes. Tilt table testing is important for assessing neurocardiogenic syncopes. Electroencephalograms (EEGs) help distinguish syncopes from seizures. • Ongoing research is still looking into the best form of treatment.

Definition and classification of syncope Definitions of syncope abound. Syncope is most often defined as a manifestation of transient loss of consciousness (TLOC), the result of decreased cerebral perfusion caused by a sudden decrease in systolic blood pressure with loss of postural tone and recovery without medical intervention–-more specifically, electrical or chemical cardioversion (Kapoor, 2002; Sorajja et al., 2009). Historically, syncope has been both well recognized and well described. Galen believed that syncope represented an abrupt prostration of the vital facilities without respiratory changes; he supposed that this was a sign of a febrile state. He described cardiac syncope as an affliction of the esophagus or mouth of the stomach, acting in sympathy with the heart. Authors ranging from Hippocrates in the fourth century BC to Caelius Aurelianus in the fifth century AD all categorized syncope of cardiac origin as a separate disorder (Papavramidou and Tziakas, 2010). Interestingly, in his Aphorisms, Hippocrates states, “Those who are subject to frequent and severe fainting attacks without obvious cause die suddenly” (Mirchandani and Phoon, 2003). Heaton reviewed Shakespeare’s oeuvre and found at least 18 occasions when a character had a TLOC while in the grip of extremely heightened emotion; in 12 instances, near fainting is described. The Bard uses the term swoon in six instances, fainting in five, and trance in two (Heaton, 2006).

Syncope may be classified into three types based primarily on causative mechanisms: neurally mediated syncope, cardiac syncope, and situational syncope associated with orthostatic hypotension (Kapoor, 2000; Hirsch et al., 2005; Parry and Tan, 2010). Table 14.1 gives a more detailed list of syncopal conditions.

Epidemiology Using the US National Inpatient Sample Database between 2000 and 2005, and adjusting accordingly for the US population as determined by census data, Ashekhlee et al. (2009) determined an incidence of 0.83 to 0.91 per 1000 person-years. The sample included more than 300,000 patients. Syncope has not been well studied in large community-based cohort studies. Data from the Dutch CRANS study, which randomly recruited 35- to 60-year-old subjects in Amsterdam, reported a lifetime incidence of 35%; importantly, the peak age of incidence was 15 years. The most common self-reported syncopal triggers were pain, decreased food intake, a warm external environment, strong emotion, and the sight of blood (Ganzeboom et al., 2006). The Framingham Heart Study examined the incidence and prevalence of syncope in a multigeneration, midlife, community-dwelling cohort. A total of 822 subjects developed at least one syncopal event over an average follow-up period of 17 years. The incidence of a first syncope was

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Table 14.1 Types of syncope Neurally mediated syncope

Cardiac syncope Syncope with orthostatic hypotension

Vasovagal Valsalva syncope Carotid sinus hypersensitivity Situational syncope Needle- or blood-induced syncope Respiratory Micturition Defecation Laughter Postprandial Postexercise Arrhythmias Organic heart disease Primary autonomic failure Secondary autonomic failure Dehydration

Data from Kapoor (2000) and Parry and Tan (2010).

6.2 per 1000 person-years of follow-up and 7.2 per 1000 person-years when adjusted appropriately for age. Syncope was recurrent in 21.6% of those with an initial event (Soteriades et al., 2002). When compared to participants who did not have a syncopal event, those with a history of syncope had a higher prevalence of a history of coronary artery or cerebrovascular disease and were more likely to be taking cardiac and antihypertensive medications. Using the data from Framingham Study participants, Chen et al. (2000) created a nested case-control study to elucidate the risk factors for syncope. Syncope was predicted by a history of cerebrovascular disease, use of cardiac medications, and a history of hypertension. It was unclear whether low body mass index, increased alcohol intake, or diabetes mellitus predicted a syncopal episode. Syncope has also been studied in a variety of circumstances. In a study of medical incidents causing diversions of civilian aircraft, Sand et al. found that syncope was by far the leading in flight medical emergency, accounting for more than half of all aircraft diversion (Sand et al., 2009). Syncope while driving is an important clinical issue. In an analysis of more than 3800 syncopal patients, Moya et al. (2009) found that about 10% had had syncope while driving. Patients who syncopized while driving were more likely to have a history of stroke and/or heart disease and had an average age of 56. In the Framingham Study, syncope was recurrent in 21.6% of those with an initial event; those who had had a cardiac syncope were at the highest risk of recurrence (Soteriades et al., 2002). In the Dutch CRANS study, the median number of syncopal events was 2; the range extended to five lifetime syncopal events (Ganzeboom et al., 2006). Sheldon et al. (2006) found that patients attending a cardiology clinic for vasovagal syncope had

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a median of eight syncopes; the upper limit of the range extended to 20. Only a subset of patients with syncope is actually seen by a physician. A Dutch study estimated that the chief complaint of a fainting spell accounts for between 2 and 9 visits per 1000 made to a primary care physician. To place this figure in perspective, only a tenth as many patient visits were for seizures or epilepsy (Olde Nordkamp et al., 2009). Syncope is a major issue in emergency departments and urgent care settings. Fainting spells account for approximately 1–4% of all emergency room patient encounters and between 4% and 6% of hospital admissions from the ED; this remains consistent in studies conducted in different countries. Nordkamp et al. examined syncope prevalence in an acute care setting in the Netherlands and found that syncope accounted for nearly 1% of all patient visits. In two-thirds of these patients, a definitive etiology was established (Olde Nordkamp et al., 2009). In Ireland, syncope leads to more than 1% of ER visits but nearly 6% of hospital admissions (McCarthy et al., 2010). In Italy, this figure stood at 2.3%, with admissions at 4.2% (Numeroso et al., 2010).

Clinical features The clinical features of syncopal and near-syncopal events may be conveniently classified as prodromal symptoms, event symptoms, and post-event symptoms (Wieling et al., 2009).

Prodromal features These features may be secondary to cerebral hypoperfusion and activation of the autonomic nervous system (ANS). The most prominent early symptom is a nonspecific sensation of dizziness and lightheadedness (Hirsch et al., 2005). Retinal hypoperfusion leads to a darkening of vision with a loss of color vision (van Dijk et al., 2009). The skin may turn pale in color as a result of peripheral vasoconstriction, owing to activation of the ANS. Often there may be a poorly defined sensation of warmth and malaise immediately preceding syncope (Hirsch et al., 2005). Less common features include a fixed stare, mydriasis, drooling, and, rarely, loss of memory for the event (Duvoisin, 1961; Duvoisin, 1962; Wieling et al., 2009). In cases when cerebral hypoperfusion develops less rapidly, patients may recall more features of their fainting spell and, accordingly, preserve memories of the event (van Dijk et al., 2009; Wieling et al., 2009). In a retrospective review, 569 patients with syncope or presyncope were likely to experience symptoms such as diaphoresis, chest pain and palpitations, nausea, vertigo, a feeling of warmth, and dyspnea immediately before syncope (Sheldon et al.,

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2002). The occurrence of prodromal features without progression to loss of consciousness is termed as presyncope (Sheldon et al., 2009).

Symptoms of syncope Syncope is associated with a brief and TLOC followed by a short period of confusion. This phase lasts between 5 and 22 seconds, with a mean of 12 seconds (Wieling et al., 2009). The actual period of unconsciousness exclusive of confusion is probably shorter. Studies have found that during this phase, four-fifth of patients may have involuntary automatisms that include fumbles, lip smacking, and chewing (Wieling et al., 2009). Syncope is associated with a loss of control over volitional movements. Typically brief flaccid paralysis has been noted, though rarely, opisthotonus marked by considerable stiffness has been reported (Cotton and Lewis, 1918; Gastaut and Fischer-Williams, 1957; van Dijk et al., 2009; Wieling et al., 2009). Ninety percent of subjects with syncope studied using video by Lampert et al. developed myoclonic activity, which was characterized by multifocality and the lack of a definite rhythm. Often generalized myoclonus superimposed on this activity (Lempert et al., 1994). The pathophysiology of syncopal myoclonus is unclear; some think that this may be release phenomenon whereby the release of cerebral control over lower (brainstem) centers brings out the myoclonus. (Gastaut, 1974; Wieling et al., 2009). The occurrence of myoclonus may mimic a convulsion, giving rise to the term convulsive syncope. Eye movements during syncope have diagnostic significance and have been well studied. The most important feature is an upward deviation of both eyes at syncopal onset, which may be preceded by downbeating nystagmus (Lempert and von Brevern, 1996). However, this feature appears to be associated with a more rapidly developing syncope; a more gradual cerebral hypoperfusion as demonstrated in ocular globe compression in asymptomatic volunteers led to upward eye deviation in only 20% (Stephenson, 1990). Breathing is typically unaffected, though this may become labored with prolonged syncope. Rarely, deep sighs or snores may be noted (Newman and Graves, 2001). It is important to realize, however, that transient changes in cerebral perfusion do not appear to affect brainstem centers that control respiration (Wieling et al., 2009). Involuntary micturition may occur during syncope. Urinary incontinence can occur in less than a quarter of patients but is typically associated with a rapid onset of syncope (Stephenson, 1990; Hoefnagels et  al., 1991; Newman and Graves, 2001; Wieling et al., 2009). Certain features are clearly not associated with syncope, including tongue biting and fecal incontinence (Wieling et al., 2009).

Postsyncopal symptoms Unlike in a seizure, recovery of consciousness with syncope is rapid. Total duration of syncope from onset to recovery of consciousness ranges from 20 to 30 seconds (Wieling et al., 2009). Although post-event confusion may occur, this more typical of cardiac syncope (Calkins et al., 1995). Less commonly, flushing (more common with Stokes–Adams phenomenon), apnea, retrograde amnesia, and other mental status changes, such as visual and auditory hallucinations, may be noted (Formijne, 1938; Sharpey-Schafer, 1956; Karp et al., 1961; Duvoisin, 1962; Forster and Whinnery, 1988; Stephenson, 1990; Lempert et al., 1994; Wieling et al., 2009).

Differential diagnosis Syncope may be confused with several other related conditions, principally those involving a TLOC. Many, if not all, can be differentiated from fainting by a careful and detailed history.

Epilepsy and/or seizures The most important problem the neurologist faces in this regard is to differentiate a syncopal episode from a seizure. This is important, given that epilepsy carries significant stigma. Additionally, making a diagnosis of epilepsy (two or more unprovoked seizures or one seizure and an underlying condition that may provoke seizures; Berg et al., 2010) leads to the initiation of anti-epileptic medications that may cause significant side effects. A careful and thorough history is without substitute in making the correct diagnosis in cases of TLOC. Partial complex seizures are the most common form of epilepsy in the elderly, and several historical features may facilitate making a diagnosis. Temporal lobe epilepsy often presents with auras of jamais vu or déjà vu and an epigastric sensation that may rise, with the patient losing consciousness before this reaches the throat. Patients with temporal lobe epilepsy may encounter many such auras in the past. Visual hallucinations and illusions may suggest an occipital lobe epilepsy, which is considerably rarer (McKeon et al., 2006; Panayiotopoulos, 2007). Unfortunately, physicians rarely correctly arrive at the appropriate diagnosis of an initial transient event of loss of consciousness. Reviewing written physician notes on 118 subjects with loss of consciousness, physicians came to the appropriate diagnosis in less than a third of all patients. In 16% of patients, the diagnosis was inappropriate (Hoefnagels et al., 1992). Sheldon et al. examined whether a simple rating score could help clinicians differentiate between seizures and syncope

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Table 14.2 A point score to differentiate seizures from syncope Criteria Awakening with a cut tongue after a typical episode History of déjà vu or jamais vu prior to episode Emotional stress associated with episode Head turning during episode Unresponsiveness/unusual posturing/jerking of limbs (all during episode)/no memory post-episode (Any one of these) History of confusion after an episode History of lightheaded spells History of sweating before episodes Association between episodes and prolonged sitting and standing

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Nonepileptic seizures

Point score 2 1 1 1 1

1 −2 −2 −2

An overall score of 1 demarcates seizure from syncope, with scores equal to or >1 suggestive of seizures. Source: Sheldon et al. (2002). Modified with permission of Elsevier.

These events have a variety of appellations and may be referred to as pseudoseizures, psychogenic nonepileptic seizures, psychogenic events, and hysteria. This condition may be associated with up to 30% of referrals to epilepsy clinics and may present as intractable epilepsy (Benbadis, 2006). There is an association with a variety of psychiatric comorbidities. McKeon suggests these events may be differentiated from seizures and from syncope by a careful history; the physician should pay attention to clinical characteristics of the attacks, the patient’s past psychiatric history, and, importantly, a history of prior abuse or trauma (McKeon et al., 2006). Patients with this condition may develop syncope-like symptoms during tilt table testing without any changes in hemodynamic parameters, suggesting a nonphysiologic event (McKeon et al., 2006).

Psychogenic pseudosyncope (Sheldon et al., 2002). The authors studied patients in whom the diagnoses of syncope and seizure had definitely been made and abstracted several historical features from the medical records of these patients. Gold-standard diagnostic studies included confirmatory electroencephalogram (EEG) for seizures, tilt table testing for vasovagal syncope, and appropriate ECG findings for cardiac syncope. Table 14.2 lists the scores used in that study. After tallying the total score, the authors found that a score of 1 sharply discriminated between seizures and syncope, with a number >1 suggesting seizure (Sheldon et al., 2002). The most common and misleading feature that may lead to the diagnosis of epilepsy in a patient with syncope are the myoclonic jerks that may accompany syncope. As discussed earlier in this chapter, these jerks are most likely a brainstem phenomenon, whereas myoclonic jerking in seizures are a cortical phenomenon (Berkovic and Crompton, 2010; Forster and Whinnery, 1988). On a molecular level, genetic syndromes that affect the heart in the familial conditions that predispose to syncope have similar pathogenetic mechanisms to the familial epilepsies, given that both conditions are channelopathies (Berkovic and Crompton, 2010). If seizures are suspected based on history, it is important to obtain neurophysiologic studies, particularly EEG. The EEG has limited sensitivity in detecting epileptiform activity; evidence suggests that an EEG obtained closer temporally to the event may have higher degrees of sensitivity (King et al., 1998; Neufeld et al., 2000). A head MRI is also important in determining whether the patient has a cerebral lesion compatible with seizures, especially mesial temporal lobe sclerosis (McKeon et al., 2006).

Benbedis and Chichkova examined a phenomenon described by the authors as “psychogenic pseudosyncope” (Benbadis and Chichkova, 2006), which likely represents a significant fraction of those patients in whom the cause of syncope is not clearly established. Using a single-center prospective study, the authors identified a total of ten patients over a period of 18 months. Patients had previously undergone an electrocardiogram (ECG), echocardiography, Holter monitoring, and tilt table testing. Typically, the duration of symptoms was about 4 years. Nine of these individuals had a habitual syncope that could be easily triggered by the examining physician. Concomitant electroencephalographic evaluation during the putative syncopal events showed a normal and appropriate alpha background, suggesting the preservation of consciousness during the apparent syncopal event (Benbadis and Chichkova, 2006).

Other conditions Other conditions that rarely may be misdiagnosed as syncope include transient ischemic attacks, migraines, subclavian steal syndrome, and hypoglycemia (Hirsch et al., 2005). The diagnosis of hypoglycemia may be readily made with a blood glucose measurement and a corresponding past medical history, although occasionally this may be a more difficult diagnosis to make. Transient ischemic attacks (with symptoms lasting less than 24 hours but more typically lasting only a few minutes), particularly those of the vertebrobasilar circulation, may present with TLOC but will be accompanied by other neurologic signs that may include nystagmus and/or dysconjugate gaze, cerebellar involvement, and cranial nerve

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involvement (Brust, 2005). Basilar migraine is a migrainous headache with vertigo, dysarthria, and diplopia. In a small fraction of these patients, a confusional state may occur, but unlike with syncope, there is no clear loss of consciousness (Raskin and Green, 2005). Subclavian steal syndrome is characterized by decreased vertebral blood flow, owing to subclavian stenosis and leading to presyncopal symptoms (Hirsch et al., 2005).

Types of syncope Syncope may be classified into three types based primarily on causative mechanisms: neurally mediated syncope, cardiac syncope, and situational syncope associated with orthostatic hypotension.

Neurally mediated syncope Neurally mediated syncope may be best defined as a condition during which the ANS is acutely unable to maintain adequate cerebral perfusion pressures and, occasionally, a heart rate sufficient to maintain cerebral perfusion (Grubb and Karas, 1999; Grubb, 2005). Pathophysiologically, this type of syncope may be defined as arterial vasodilation in the setting of a relative of absolute bradycardia (Mosqueda-Garcia et al., 2000). The chief clinical manifestation of this type of syncope is marked activation of the ANS, characterized by nausea, perspiration, and pallor; these features may be less prominent in older individuals (van Dijk et al., 2009). An important historical feature that differentiates this form of syncope is the presence of a distinct trigger (van Dijk et al., 2009). Several provocative factors are known, including a warm atmosphere, intense exercise, pain, emotional upsets, and long periods of standing (Grubb, 2005). The most common causes are fear and pain, followed by standing (Ganzeboom et al., 2003). Triggered or reflex syncope are episodes of TLOC definitely associated with specific triggers; they are discussed in more detail in this section. The upright human posture provides circulatory challenges to maintaining adequate cerebral perfusion. Therefore, the ANS plays a crucial role. Standing facilitates the trapping of a significant volume of blood in the veins of the lower extremities, which may then lead to a low volume state and hypotension (Kapoor, 2000). Cardiopulmonary baroreceptors and baroreceptors in the arterial system monitor acute changes in blood pressure; this information is transmitted to the central nervous system and is used to regulate ANS responses. Several theories have been developed to explain syncope in the neurally mediated syncopal model. Sharpey-Schafer has theorized that reduced left ventricular volume in the setting of sympathetic activation results in the generation of inhibitory responses that may lead to bradycardia and hypotension (Sharpey-Schafer, 1956; Mosqueda-Garcia et al.,

2000). This is termed the ventricular theory of syncope. Neurohumeral mechanisms that have been considered include the role of increased serum epinephrine and serotonin (Mosqueda-Garcia et al., 2000). Reduced blood volume may have a pathophysiologic role in this condition, given the fact that an increase in salt intake and the use of fludrocortisones both have benefits in treating recurrent syncope. Baroreceptor dysfunction, thereby resulting in “misfiring” of the ANS, has also been implicated (Mosqueda-Garcia et al., 2000). Carotid sinus hypersensitivity is a subtype of neurally mediated syncope. This condition is characterized by brief and transient LOC with drops and falls, most common in elder populations associated with 3 seconds of cardiac asystole, accompanied by a 50 mmHg drop in systolic blood pressure in response to carotid sinus massage. This condition is suspected in up to 50% of patients with falls and syncope (Huang et al., 1988). A clinician diagnoses this condition by performing a carotid sinus massage, which involves 5–10 seconds of sinus palpation, initially on the right and then on the left, first in the supine position and then in the standing position (Tan et al., 2009). The typical indications for performing a carotid sinus massage include fainting after wearing a tight shirt collar, while shaving, or after an abrupt head turn. It should also be considered in elderly adults with repeated falls or syncopal episodes when other investigation are nonrevealing. Contraindications to performing a carotid massage include recent myocardial infarction, stroke, or transient ischemic attack (TIA), as well as a carotid bruit, ventricular fibrillation, and ventricular tachycardia (Miller and Kruse, 2005). The Valsalva maneuver may result in decreased venous return to the heart and may thereby trigger syncope (Hirsch et al., 2005). Carotid sinus massage and Valsalva maneuvers can also be used to evaluate syncope. A variety of situational syncope syndromes have been described and may involve a neurally triggered bradycardia and hypotension leading to syncope (Hirsch et al., 2005). The most common are those associated with micturition, cough, and defecation (Kapoor, 2000). Rarer types of reflex syncope include laughter, post-prandial, and post-exercise syncope (Nishida et al., 2008). Needleand blood-related syncope are fainting spells triggered by the strong emotional stimuli associated with the sight of blood or needles. Twelve percent of British medical students reported at least one syncopal episode while observing surgical procedures (Jamjoom et al., 2009). Overall, 8% of teenaged blood donors developed a syncopal episode (Reiss et al., 2009). Older blood donors have a significantly lower risk of syncope with blood donation (Tondon et al., 2008).

Cardiac syncope Cardiac syncope, more common in geriatric populations, is an important form of syncope with a grave prognosis.

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This form of syncope is characterized by a sudden decrement in cardiac output, resulting in decreased cerebral perfusion. Some evidence implicates the responsiveness of the ANS (van Dijk et al., 2009). In the Framingham Heart Study, cardiac syncope was highly recurrent and doubled the risk of mortality as compared to all participants with syncope (Soteriades et al., 2002). Cardiac syncope can be dichotomized into syncope secondary to cardiac arrhythmias and cardiac syncope secondary to structural heart disease. Cardiac arrhythmias typically cause syncope by abruptly reducing cardiac output, and structural cardiac disease limits the ability of the heart to increase cardiac output in response to increased circulatory need (Brignole, 2007). Clinical features that suggest the involvement of a cardiac arrhythmia include loss of consciousness with no definite prodrome, as well as a history of cardiac problems and a family history of sudden death (Kapoor, 2000). The arrhythmias that lead to syncope may be bradyarrhythmias (sinus node disease, second- or third-degree heart block, malfunctioning cardiac pacemaker, or drug inducement) or tachyarrhythmias (ventricular tachycardia, supraventricular tachycardia, or torsades de pointes). An important historical feature is that arrhythmias typically occur in apparently normal individuals (Kapoor, 2002; van Dijk et al., 2009). Arrhythmias superimpose on structural cardiac disease and contribute to the development of syncope. Syncope may be seen secondary to congestive heart failure (CHF). In a study of 491 patients with CHF (New York Heart Association Grade III and IV), 12% developed at least one syncopal episode (Middlekauff et al., 1993; Gopinathannair et al., 2008). Syncope in CHF is significantly related to ventricular ectopy and ventricular tachycardia (Olshansky et al., 1999). Other etiologies for structural heart disease associated with syncope include valvular heart disease, ischemic cardiac disease, hypertrophic cardiomyopathy, pericardial disease, and pulmonary hypertension (van Dijk et al., 2009).

Syncope secondary to autonomic dysfunction The cardinal features of orthostatic hypotension include dizziness, presyncope, and syncope (Freeman, 2008). Other features of orthostatic hypotension include weakness, fatigue, nausea, and headache. Freeman described an unusual headache phenomenon in these patients that is associated with pain over the back of the neck and shoulders, which bears the appellation of “coat hanger headache” (Freeman, 2008). Although these patients may have hypotension while standing, supine hypertension is a common feature. In this condition, syncope or presyncope typically occurs during a rapid transition from sitting or lying to a standing position, causing acute arterial hypotension. Failure of compensatory mechanisms from a compromised ANS leads to cerebral hypoperfusion

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and subsequent fainting. An additional pathophysiologic mechanism includes a reduced functional circulatory blood volume from peripheral pooling of blood, again due to an impaired ANS (Brignole, 2007). Freeman classifies autonomic hypotension into that caused by central nervous system disorders and that caused by peripheral dysfunction. Central nervous system causes include the synucleinopathies multiple system atrophy (MSA), Parkinson’s disease (PD), and pure autonomic failure. Peripheral nervous system causes are the small fiber neuropathies that are typically caused by diabetes mellitus and amyloidosis, hereditary sensory and autonomic neuropathy type III, and, rarely, B12 deficiency, HIV neuropathy, and porphyria (Freeman, 2008). Mussi et al. examined the frequency of orthostatic hypotension in a review of 259 patients aged 65 or more who were admitted to an emergency department and found a prevalence of 12%, with PD being the dominant etiology (Mussi et al., 2009). Patients with PD develop autonomic dysfunction later in the course of the disease, with motor symptoms beginning first; medications used to treat PD may worsen these symptoms (Freeman, 2008). In a prospective study, nearly a third of subjects with PD had orthostatic hypotension (Lipp et al., 2009). Neihaus et al. found that even PD patients without a history of autonomic dysfunction demonstrated impaired ANS activity in response to tilt testing, as compared to healthy, age-matched controls (Niehaus et al., 2002). In comparison, in Lewy body dementia, where clinically dementia symptoms precede parkinsonism, autonomic dysfunction occurs early in the disease course (Freeman, 2008). Syncope is a core feature of this disease (Geldmacher, 2004). MSA, rarer than either PD or dementia with Lewy bodies, is defined as an adult-onset, progressive, sporadic, neurodegenerative disease characterized by varying severity of Parkinsonian features, cerebellar ataxia, autonomic failure, urogenital dysfunction, and corticospinal disorders (Gilman et al., 2008). Four syndrome complexes are linked to this diagnosis and comprise striatonigral degeneration, Shy–Drager syndrome, olivopontocerebellar atrophy, and amyotrophy-parkinsonism. Shy–Drager syndrome is dominated by autonomic dysfunction and is associated with depletion of sympathetic preganglionic neurons in the spinal cord intermediolateral horns. The post-ganglionic sympathetic neurons are retained; when the patient is in a supine position, plasma norepinephrine levels are normal and do not rise when the patient stands (Louis, 2005). Patients with MSA may have symptomatic or asymptomatic autonomic failure; autonomic dysfunction as a criteria for MSA is defined as a decrease in systolic blood pressure by 30 mmHg or of diastolic blood pressure by 15 mmHg after a three-minute stand, arising from 3 minutes in the recumbent position (Gilman et al., 2008). Lipp and colleagues prospectively examined the

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clinical differences between MSA and PD with autonomic failure. Accuracy of diagnosis is important in this regard, given that MSA has much graver prognosis than PD. The authors found that orthostatic hypotension was almost always present in MSA. The study found that the severity and pattern of autonomic dysfunction, including anhidrosis, in MSA distinguish this condition from PD (Lipp et al., 2009). Patients with Shy–Drager syndrome treated with levodopa often have worsening of orthostatic hypotension (Louis, 2005). Pure autonomic failure is an extremely rare condition that was first described in 1925. It is characterized by severe autonomic hypotension, starting typically after the age of 50 in persons with no other neurologic issues. Lewy bodies are found in autonomic ganglia (Weimer, 2005). Klein et al. studied 18 subjects (average age 63), all with autoimmune antibodies directed against autonomic ganglia. Two different clinical patterns were noted. Patients with high antibody titers had significantly more cholinergic symptoms than those with a low antibody titer. The latter group was identical clinically to pure autonomic failure (Klein et al., 2003). Peripheral nervous system involvement leading to autonomic dysfunction and syncope has been best studied in diabetes mellitus. Overt autonomic neuropathy is delayed for several years after diagnosis of diabetes, although there is evidence that subclinical autonomic dysfunction exists early in the clinical course of type II diabetes mellitus. Factors related to the incidence of diabetic autonomic neuropathy include poor glycemic control, an increased duration of diabetes, higher body mass index, and female sex (Vinik and Erbas, 2001). A large clinical trial, the Diabetes Complications and Control Trial, demonstrated that low long-term blood sugar levels can ameliorate this condition (1995). Other neurologic conditions may be associated with syncope. The population-based CAMERA study demonstrated an increased prevalence of both syncope and orthostatic hypotension in individuals with migraine. The authors were unable to explain the pathophysiologic basis of this finding (Thijs et al., 2006). Case series and case reports have documented syncope and orthostatic hypotension in multiple sclerosis, which, in at least some isolated cases, improved with pulse steroid treatment (Sakakibara et al., 1997; Funakawa and Terao, 1998; Kanjwal et al., 2010).

Investigations Several evidence-based guidelines have addressed the issue of diagnosis and management of syncope. The first step in assessing syncope is to obtain an ECG (Strickberger et al., 2006). The ECG will provide information regarding both cardiac rhythm and junctional abnormalities. In

patients whose history and examination may lead the clinician to suspect a cardiac cause for syncope, the ECG will serve as a confirmatory test. In patients in whom cardiac disease is not suspected, the ECG will provide important information on possible etiology for the fainting spell. The American Heart Association (AHA) consensus statement on syncope notes that the ECG will be able to clearly identify two high-risk groups for which an adverse outcome is likely: hypertrophic cardiomyopathy (a cause of sudden death in young athletes) and pulmonary embolism (Strickberger et al., 2006). A prolonged ECG may be recommended when syncopal events are frequent. The gold standard is the documentation of a cardiac arrhythmia during syncope, thereby establishing causation. The AHA consensus statement suggests placing an ambulatory Holter ECG monitor for 24 to 48 hours. Event-recording devices can be used for up 60 days, and recording is triggered by a patient-initiated button press. However, these devices are complex and are associated with higher rates of patient error. Implantable loop recorders are placed subcutaneously and may record ECG rhythms for approximately 14 months (Strickberger et al., 2006). In patients with syncope and suspected or known ischemic coronary disease, exercise stress testing is recommended. Electrophysiologic cardiac studies involve the placement of cardiac transvenous catheters to assess sinus and AV node function, but they have a low sensitivity in unselected patients (Strickberger et al., 2006). The evidence-based guideline from the European Society of Cardiology also proposed echocardiography to better assess structural cardiac disease, as well as carotid sinus massage when carotid sinus hypersensitivity is suspected. Finally, the European guidelines also suggest a role of psychiatric consultation when functional episodes are suspected (Moya et al., 2009). Tilt table testing is important in the assessment of neurocardiogenic syncope. Specific protocols have evolved with regard to tilt table testing: the Newcastle Protocols (Parry et al., 2009). This procedure should be restricted to cases of syncope in which diagnosis of a neurocardiogenic etiology is unclear from history or examination or when the patient is cognitively impaired, has had syncope while driving, or has had repeated falls with injury. Contraindications to this procedure are few and are limited to critical left ventricular outflow obstruction and mitral stenosis, and severe coronary or cerebrovascular disease (Parry et al., 2009). Patients must be instructed that they are not required to fast or discontinue medications on the day of the procedure. The typical equipment used in this test is a tilt table with foot plate support that can tilt to an upright position from a supine one, through an angle of 70°. ECG and blood pressure monitoring accompany the test (Parry et al., 2009). The patient is typically in the supine position in a resting state for 20 minutes, followed by a

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rapid upright tilt (through 70°) for 40 minutes (Kenny et al., 2000). Pharmacologically enhanced testing using either nitrate or isoproterenol may be used (Bartoletti et al., 2000; Graham et al., 2001; Moya et al., 2009); these drugs enhance resting heart rate. The tilt table provides a confirmatory diagnosis only if the patient’s original syncopal (or presyncopal) symptoms are reproduced along with hypotension and/or bradycardia. A combination of both subjective symptoms and objective signs is required (Kenny et al., 2000). The sensitivity of the tilt table test is not well established, and questions remain about both the validity and reliability of the test (Sagrista-Sauleda et al., 2001). A negative tilt table testing does not exclude a vasovagal etiology to syncope (Moya et al., 2009). EEGs are commonly ordered to differentiate between syncope and seizures. Typically, interictal EEGs are normal in most patients with syncope, as well as a significant number of patients with seizures. European syncope guidelines recommend an EEG when there is considerable suspicion that an episode was a seizure rather than syncope. An EEG is also indicated in psychogenic pseudosyncope when the diagnosis may be made with ease if a typical event is captured during the EEG (Moya et al., 2009). Cranial computed tomograms, head magnetic resonance images, carotid duplex imaging, or transcranial Doppler studies may be ordered only if a clinical indication exists (Moya et al., 2009).

Prognosis and economic impact of syncope Using actuarial analysis techniques and data from the Framingham Study, Soteriaredes et al. found that syncope was associated with increased mortality in a mid- and late-life population. Mortality among all those who had had a syncopal episode was increased by 31%. In participants who had had cardiac syncope, the risk of death was increased twofold. Vasovagal syncope (including orthostatic hypotension) was associated with the least increase in mortality. Participants who had a syncopal episode of unclear etiology had an increased risk of a subsequent myocardial infarction and/or death (Soteriades et al., 2002). Alshekhlee et al. used the US National Inpatient Sample Database to evaluate the prognosis of syncope and found that the overall mortality rate was 0.28%; the odds of mortality from syncope increased sharply after the age of 40 and in those who reported a larger number of comorbidities (Alshekhlee et al., 2009). Hospital admission for syncopal evaluation and management appears to benefit short-term (30-day) outcomes but did not affect outcomes at one year post-event (Costantino et al., 2008). Data from the National Inpatient Sample demonstrates that the median cost of inpatient treatment for syncope in the United States is about $8500. This amount increases

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dramatically, sometimes up to 11-fold, if cardiac pacemakers need to be placed (Alshekhlee et al., 2009). The cost to the Medicare system is approximately $2.4 billion per annum (Sun et al., 2006).

Management The management of syncope is best tailored to the underlying cause of the TLOC. Neurocardiogenic syncope has the best prognosis of all syncopal types. There is very little evidence underlying treatment options for this condition. A beta blocker, atenolol, was effective in a randomized controlled trial at improving syncopal symptoms, as compared to placebo (Mahanonda et al., 1995). In refractory syncope, a trial of paroxetine appeared to improve symptoms (Di Girolamo et al., 1999; Kapoor, 2000). Clinical trials have also been performed on transvenous pacing; the majority of these studies have demonstrated efficacy (Brignole, 2003). The pacemakers were designed to provide cardiac pacing in cases of a concomitant drop in heart rate in patients who had severe syncopal symptoms (Kapoor, 2000). A number of other medications are used in the treatment of syncope without a significant evidence base. These include disopyramide, clonidine, theophylline, ephedrine, dihydroergotamine, and midodrine (Brignole, 2003). An important component of any management strategy of neurocardiogenic syncope is to provide reassurance to the patient that this type of syncope is benign. Patients must be counseled about avoiding triggers of their syncope (Moya et al., 2009). The treatment of orthostatic hypotension can be dichotomized into pharmacologic management and nonpharmacologic mechanisms of treatment. In patients in whom plasma volume expansion cannot be achieved with increased fluid and salt intake, fludrocortisone, a mineralocorticoid, can be used (Freeman, 2008). Because the primary pathophysiologic mechanism in orthostatic hypotension is the lack of norepinephrine release, midodrine, a peripheral and selective alpha adrenergic receptor agonist can be used. This medication, which is the only one approved in the United States by the Food and Drug Administration for orthostatic hypotension, has been noted in clinical trials to improve standing blood pressures (Low et al., 1997; Wright et al., 1998; Freeman, 2008). Pyridostigmine, an acetylcholinesterase inhibitor, has successfully undergone a clinical trial for this condition (Wright et al., 1998; Singer et al., 2006). Other agents that have been used to treat orthostatic hypotension include erythropoietin (Hoeldtke and Streeten, 1993), ephedrine and pseudoephedrine (Jordan et al., 1998), clonidine, and dopamine agonists (Freeman, 2008). Nonpharmacologic interventions must typically be tried first before considering drug therapy. Most important is

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patient education. Patients must be told that they can minimize symptoms from orthostatic hypotension by moving slowly from the supine to the standing position. Through the day, physical maneuvers may be attempted to reduce peripheral pooling of blood: these include tensing the muscles of the lower extremities and crossing and uncrossing legs. Elastic compression stockings for the lower extremities facilitate lower extremity venous return. During rest and sleep, a head raise of 10°–20° reduces supine hypertension that may lead to diuresis and volume depletion. Medications such as diuretics and some antihypertensives must be avoided. Finally, increased salt intake (up to 10 g sodium per day) and increased liquid intake (water) can improve orthostatic hypotension (Freeman, 2008). The treatment of cardiac syncope is complex and is beyond the scope of this chapter. The consensus statement of the European Society of Cardiology provides guidelines on the treatment of cardiac syncope (Moya et al., 2009). Sinus node dysfunction and AV node disease are both treated with cardiac pacemakers. Supraventricular tachycardia and atrial flutter are managed with catheter ablation. A malfunctioning cardiac device causing syncope may need reprogramming or, less commonly, replacement. Where structural heart disease is implicated in the causation of syncope, treatment of the underlying cardiac condition is essential.

Risk prognostication scores in syncope Several prognostication scores can help the clinician make decisions about which patients with syncope need further (often inpatient) workup and which patients can be evaluated as outpatients. This is an important issue because inpatient hospital admission is expensive (Alshekhlee et al., 2009). Three risk prognostication scores have been developed: the San Francisco Syncope Rule (SFSR), Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL), and the European Guidelines in Syncope Score (EGSYS). The SFSR is the simplest (Parry and Tan, 2010). Predictor variables that comprise the SFSR include an abnormal ECG, history of shortness of breath, CHF, hematocrit less than 30%, and a systolic blood pressure less than 90 mmHg on initial examination in the emergency department (Quinn et al., 2004). The authors suggest that considering these variables in clinical decision making allows for the prediction of future adverse events with a sensitivity of 92% and a specificity of 62%, though this data has been challenged (Quinn et al., 2004; Birnbaum et al., 2008). The OESIL score incorporates other predictors, including age greater than 65 years and lack of a prodromal history (Colivicchi et al., 2003). The EGSYS score is the newest prognostication index and incorporates features including a history

of palpitations prior to syncope, syncope during rest or exertion, and the absence of precipitating factors for syncope (Del Rosso et al., 2008).

Syncope in the elderly Syncope accounts for a third of falls in the elderly, a population that is already at high risk of falling from a variety of circumstances (Tinetti et al., 2000). Syncope is incident in about 6% of the elderly; this number rises to 23% of those in assisted living and nursing home facilities (Ungar et al., 2006). Hospitalization for syncope increases with increasing age (Moya et al., 2009). Ungar et al. evaluated syncope in people aged 70 or older. Clinically, syncope more typically occurred from the standing position in older than younger patients. More than 70% of patients had a prodromal symptom immediately prior to the syncopal episode. Neurally mediated (neurocardiogenic and orthostatic) syncope accounted for two-thirds of all cases (Ungar et al., 2006). A precise history regarding syncopal episodes may be difficult to obtain in some older patients, owing to cognitive impairment (Moya et al., 2009). Several factors increase susceptibility to syncope in the elderly, including reduced oral intake and resultant mild dehydration, a predisposition to orthostatic hypotension, and impaired cardiac heart rate variability (Kenny et al., 2002; Strickberger et al., 2006). Many syncopal episodes in the elderly are the result of polypharmacy, most often due to cardiovascular medications (Strickberger et al., 2006). Syncope while driving, an issue with major public safety ramifications, occurs most often in patients in their late 50s or older (Sorajja et al., 2009). In elderly patients, it is important for clinicians to prevent falls and to rapidly identify possible life-threatening conditions. In the elderly, syncope is typically a multifactorial process (Strickberger et al., 2006). Though the assessment of syncope is similar to that with younger patients, special attention should be paid to gait examination, as well as cognitive testing (Moya et al., 2009).

Conclusion Syncope is an important cause of TLOC, with particular importance in older populations. Future directions of research include the development of clinical biomarkers to assist in identifying patients who may be at risk of complications after syncope. Further research is also needed to refine prognostic risk score systems to enable rapid risk stratification of patients with syncope. Finally, there is ongoing research into the best treatment for syncope, especially cardiac syncope (Parry and Tan, 2010). Ultimately, the key to diagnosing and managing syncope is careful history and timely reassurance.

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Autonomic Dysfunction and Syncope

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Chapter 15 Geriatric Epilepsy David V. Lardizabal Epilepsy Program and Intraoperative Monitoring, University of Missouri, Columbia, MO, USA

Summary • Epidemiology: Studies have shown that the incidence of epilepsy increases with age and is much more prevalent in nursing home residents compared to the elderly in the community. • Etiology: Symptomatic causes are often due to cerebrovascular diseases which cause stroke or neurodegenerative diseases such as Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Closed head injuries may also account for epilepsy. • Mechanism: Hypothesized as an imbalance of excitatory and inhibitory neurotransmissions, favoring excitation. Strokerelated seizures are due to biochemical abnormality shortly after the stroke. Chronic processes such as gliosis, removal of inhibitory influences, and synaptic formation, may also induce seizures 2 weeks after stroke. • Clinical Diagnosis: An abnormal and excessive neural discharge that clinically manifests as altered consciousness and motor, sensory, or psychiatric events in a recurrent or stereotyped fashion. • Differential diagnosis: Syncope, migraine, toxic–metabolic derangement, transient ischemic attacks (TIAs), transient global amnesia (TGA), dizziness/vertigo, delirium, and intermittent movement disorders are physiologic nonepileptic events that may be interpreted as epileptic seizures. Additionally, seizures can be caused by psychiatric illness. • Magnetic resonance imaging (MRI) and electroencephalograms (EEGs) are the diagnostic study tools of choice. • Approximately 10% of nursing home residents are treated with antiepileptic drugs (AEDs) or anticonvulsants. Nineteen or more anticonvulsants are available and several more are currently being studied in clinical trials.

Introduction After stroke and dementia, geriatric epilepsy is the third most common neurologic condition (Diamond and Blum, 2008; Hommet et al., 2008; Jetter and Cavazos, 2008; Werhahn, 2009). Epilepsy is a syndromic diagnosis with different clinical seizure features and etiologies. Clinical and epidemiologic studies cite 60 or 65 years of age as the minimum age for geriatric epilepsy. This chapter focuses on the epidemiology, etiology, clinical features or semiology, differential diagnosis, seizure mechanisms, and drug therapy.

Epidemiology of geriatric epilepsy The landmark study by Hauser et al. (1993) provided a good epidemiologic estimate of geriatric epilepsy in North America. The incidence of epilepsy and of all unprovoked seizures was determined among the residents of Rochester, Minnesota, from 1935 to 1984. The ageadjusted incidence of epilepsy was 44 per 100,000 personyears. Incidence in males was significantly higher than in females and was high in the first year of life but highest

in persons aged 75 years and older. It is estimated that half of new-onset epilepsy by 2020 will be from the geriatric population (Pugh et al., 2009). The incidence of any type of first seizure is 50/100,000 for people aged 40–59; this increases to 127,000 in people older than 60 years. The incidence of epilepsy in the elderly seems to rise steadily at the 55- to 64-year age group and increases dramatically after the age of 65. The highest incidence is approximately 160 per 100,000 person-years and occurs among the 75- to 84-year age group (Hauser et al., 1993). Hussain et al. (2006) examined the age-specific incidence and cumulative incidence of epilepsy in a well-defined cohort of elderly people (n = 1919). The rates of epilepsy were also analyzed by sex, race, stroke, dementia, head injury, and depression. Age-specific incidence was 10.6 (per 100,000 person-years) between ages 45 and 59, 25.8 between ages 60 and 74, and 101.1 between ages 75 and 89. Cumulative incidence was 0.15% from age 45 to age 60, 0.38% to age 70, 1.01% to age 80, and 1.47% to age 90. In addition, the difference in cumulative incidence among African-American subjects approached statistical significance (57.6/100,000 person-years vs. 26.1 in Caucasian, p = 0 .10), and the difference in incidence among subjects reporting a history of stroke was significantly elevated

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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(p = 0.029). Incidence of epilepsy was not statistically elevated among males, those with dementia, or individuals reporting a history of head injury or treatment for depression. Among “healthy” subjects without a history of stroke, head injury, or dementia, it was observed that the cumulative risk of epilepsy with onset after age 60 was 1.1%. Little information exists on the incidence of geriatric epilepsy in other ethnic groups. The prevalence in epilepsy increases with age and is estimated to be 5/1000 between 20 and 50 years, 7/1000 between 55 and 64 years, and 12/1000 between 85 and 94 years (Hauser et al., 1996). The prevalence of epilepsy in nursing home residents is much higher than in the community-dwelling elderly (Garrard et al., 2000).

Etiology of geriatric epilepsy Epilepsy in old age is generally an expression of an underlying disease of the brain. The etiology is important because this is usually a determinant of prognosis. Symptomatic causes of epilepsy in the elderly are usually due to a cerebrovascular disease or neurodegenerative disease. Stroke and atherosclerosis account for 34.9% and 14.9% of epilepsy in the elderly, respectively (Ramsay et al., 2004). Hemorrhagic stroke, cardioembolic ischemic strokes, and cortical locations favor the development of epileptic seizures. Population-based studies have shown that stroke multiplies the risk of epileptic seizures by a factor of 23 and multiplies the risk of epilepsy in the first year after the stroke by a factor of 17, compared to the risk in the comparable general population (Werhahn, 2009). Early seizures (less than 2 weeks after a stroke) are due to an acute biochemical abnormality, such as exposure to the excitatory neurotransmitter glutamate. This can occur in 2–8% of patients, usually in the first 24–48 hours after the stroke. About 3–6% may have isolated epileptic seizures. In contrast, late seizures (longer than 2 weeks after a stroke) are due to chronic processes such as the removal of inhibitory influences, gliosis, and formation of new synaptic connections (Werhahn, 2009). Approximately half of these patients develop focal epilepsy in the first 3 years after the stroke. The frequency of epilepsy after stroke is 2–4% and is two to four times higher than the incidence in the same age group without seizures. Neurodegenerative disease accounts for 12% of geriatric epilepsy (Hauser et al., 1993). The prevalence of dementia is estimated to be 6–8% after 65 years of age and may rise to 20–30% in subjects older than 85 years. In patients with dementia, the incidence of seizures is five to ten times greater than expected in a reference population (Hesdorffer et al., 1996). In subjects older than 65 years, dementia and other neurodegenerative diseases account for 9–17% of the epilepsies seen in the elderly (Hommet et al., 2008). An estimated 10–22% of Alzheimer’s patients

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will have at least one unprovoked seizure (Romanelli et al., 1990; Mendez and Lim, 2003). Amatniek et al. (2006) studied the cumulative incidence and predictors of new-onset seizures in mild Alzheimer’s disease (AD), with a cohort followed prospectively. The cumulative incidence of unprovoked seizures at 7 years was nearly 8%. In all age groups, risk was increased compared with a standard population, with an 87-fold increase in the youngest group (age 50–59 years) and more than a threefold increase in the oldest group (age 85+ years). In multivariate modeling, independent predictors of unprovoked seizures were younger age (relative risk (RR) 0.89 per year increase in age; 95% confidence interval (CI), 0.82–0.97), African-American ethnic background (RR 7.35; 95% CI, 1.42–37.98), more severe dementia (RR 4.15; 95% CI, 1.06–16.27), and focal epileptiform findings on electroencephalogram (EEG) (RR 73.36; 95% CI, 1.75–3075.25). It was concluded that seizure incidence was increased in people starting with mild-to-moderate AD. Younger individuals, African-Americans, and those with more severe disease or focal epileptiform findings on EEG were more likely to have unprovoked seizures. In contrast, Scarmeas et al. (2009) showed in a prospective cohort study a low incidence (1.5%) of developing epilepsy among patients with dementia. Closed head injury accounts for about 6.9% of geriatric epilepsy. Head injuries may be secondary to prior falls or car accidents. In a retrospective study by Lees (Lees, 2010) head injuries accounted for 10% of the injuries associated with falls. Even though brain tumors have a minor role (2.7% of cases) as a cause of geriatric epilepsy (Hauser et al., 1993), they have a major impact on the prognosis and quality of life of geriatric patients. Overall, 60% of the primary brain tumors present with epilepsy and another 10–20% develop epilepsy later in the course of the disease (Moots et al., 1995; Hildebrand et al., 2005). The risk for the development of seizures in brain tumor patients is related to the tumor type. Lowgrade gliomas, such as grade II astrocytomas and gangliogliomas, present more frequently with seizures than high-grade tumors. Low-grade tumors present with seizures in 60–85% of patients; seizures are seen in highgrade brain tumors or brain metastases in 15–40% of patients, respectively (Moots et al., 1995). In the middleaged persons and the elderly, malignant gliomas are relatively more common and, if they present with epilepsy other neurologic deficits, are more obvious. Moreover, the location of the tumor is related to seizure development, which is much more common with cortical than white matter lesions. The highest risk of development of epilepsy occurs when the tumor is located in the temporal cortex, the primary sensorimotor cortex, or the supplementary cortex. About one-fourth to one-third of new-onset geriatric epilepsy has no known cause (Scarmeas et al., 2009).

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Among healthy elderly people without a known cause (stroke, trauma, or dementia), the cumulative risk of epilepsy after age 60 is about 1.1% (Hussain et al., 2006).

Postulated mechanisms of geriatric epileptic seizures The exact mechanism of seizure generation in symptomatic epilepsies is not yet fully elucidated. It is believed that the generation of seizures is due to an imbalance of excitatory and inhibitory neurotransmission in which relative excitation is favored over inhibition. The process leading to this imbalance for seizure genesis (or epileptogenesis) is still under intense research. Postulated mechanisms of seizure generation are discussed in this section. In stroke-related seizures, early seizures (less than 2 weeks after a stroke) are due to an acute biochemical abnormality, such as exposure to the excitatory neurotransmitter glutamate. This can occur in 2–8% of patients usually in the first 24–48 hours after the stroke. About 3–6% may have isolated epileptic seizures. In contrast, seizures more than 2 weeks after a stroke (late seizures) are due to chronic processes such as the removal of inhibitory influences, gliosis, and formation of new synaptic connections (Werhahn, 2009). In neurodegenerative diseases, it is postulated that neuronal cell loss in the hippocampus (CA1), presenelin-1 mutations, and amyloid beta and neurofibrillary tangle accumulation may be responsible (Romanelli et al., 1990; Foürstl et al., 1992; Ezquerra et al., 1999; Takao et al., 2001; Mendez and Lim, 2003; Mikolaenko et al., 2006; Shrimpton et al., 2007). Gliosis (astrogliosis) is a common neuropathologic finding among patients with head trauma, neurodegenerative disease, prior stroke, and central nervous system (CNS) infections (Tian et al., 2005; Boison, 2006). Current evidence suggests that astrocyte dysfunction contributes to epileptogenesis and seizure expression in epilepsy. The failure of glia to buffer extracellular glutamate or dysfunctional release of glutamate by glia was shown to contribute to the maintenance of the paroxysmal depolarizing shift that characterizes neuronal dysfunction in epilepsy. Furthermore, it is postulated that gliosis may cause a relative deficiency of adenosine, an endogenous anticonvulsant of the CNS. Experimental evidence also suggests that adenosine receptors and adenosine kinase may be part of the pathologic mechanism in the development of epilepsy and seizure generation (Boison, 2008). Adenosine kinase is responsible for the clearance of adenosine, and overexpression of this enzyme may lower the adenosine levels around gliotic brain tissue. Experiments have shown that decreased adenosine levels by elevated adenosine kinase activity generates seizures (Boison, 2008).

The possible mechanisms for epileptogenicity in primary gliomas include immune-mediated neuronal damage, GABA receptor dysfunction, serotonin transporter gene polymorphism, glutamate excitotoxicity in tumors, brainderived neurotrophic factors in tumor growth, and altered cell cycle and DNA repair. The pathogenesis of seizure development is likely to occur by different mechanisms for high- and low-grade gliomas (Beaumont and Whittle, 2000; Brogna et al., 2008; Berntsson et al., 2009). In fast-growing high-grade gliomas, the focal peritumoral ischemia and deafferentation of cortical areas due to mass effect may be causative factors, where gliosis and chronic inflammatory changes in peritumoral regions of slow-growing gliomas may predispose for epileptic seizures. Increased levels of Fe3+ ions due to small bleedings from blood vessels may contribute to the genesis of seizures and is more likely to occur in high-grade gliomas. Often epileptic seizures from high-grade gliomas are difficult to control.

Clinical diagnosis of geriatric epilepsy Epileptic seizures result from an abnormal and excessive discharge of neurons, and this is clinically manifested by sudden, diverse, transitory symptoms, including altered consciousness and motor, sensory, or psychiatric events (Hommet et al., 2008). Unfortunately, the diagnosis of epilepsy in the elderly is delayed by 1.7 years. Moreover, the clinical features in geriatric epilepsy are not similar in the younger age group and may be the reason for the delay. The seizures are often difficult to diagnose because they present with atypical symptoms, particularly prolonged postictal symptoms (hours to days), memory lapses, confusion, altered mental status, and inattention. Caretakers unfamiliar with seizure symptoms may take “senior moments” for granted. Furthermore, aura and automatisms are not consistent features in geriatric seizures (Pugh et al., 2009). In the diagnosis of epilepsy, the caretaker plays a vital role in the history and description of seizure features. Two important elements about epileptic seizures are relevant in the history. Epileptic seizures are recurrent and stereotyped. Therefore, careful questioning to the caretaker may reveal stereotyped episodes of unexplained confusion or altered awareness. Some elderly patients may not be a reliable source of information. As mentioned earlier, the symptomatic causes of epilepsy are usually stroke and dementia. The diagnosis of seizures and epilepsy may be particularly difficult in elderly patients with dementia. These patients may not remember or complain of seizure symptoms. Some authors have indicated that seizures may occur early (3 months) or, in the later stages, 6 or more years after the onset of dementia (Hommet et al., 2008). Among stroke patients, speech or language impairment may make communication of seizure symptoms difficult.

Geriatric Epilepsy

Conditions confused as epileptic seizures (differential diagnosis) An accurate and detailed history remains a central tenet for the diagnosis and treatment of epilepsy. It is important to remember that not all convulsions are caused by epileptic seizures. Epileptic seizures can be mimicked by nonepileptic events that are common in the elderly age group (Ramsay et al., 2004; Sirven and Ozuna, 2005; Hommet et al., 2007; Marasco and Ramsay, 2009). These nonepileptic events may be physiologic or nonphysiologic. Physiologic nonepileptic events usually signify a systemic single- or multiorgan dysfunction. These physiologic events are syncope, migraine, toxic–metabolic derangement, transient ischemic attacks (TIAs), transient global amnesia (TGA), dizziness/vertigo, delirium, and intermittent movement disorders. Syncope is the most common physiologic event confused with epilepsy (incidence of 3000 per 100,000). It also accounts for approximately 3% of all emergency department visits. Common conditions causing syncope include cardiac arrhythmia, hypovolemia, orthostatic, and sudden drop in blood pressure. Convulsive syncope represents the most confusing feature of this condition. During convulsive syncope, brief abnormal movements, including tonic posturing myoclonus or clonic motor, occur in response to sudden and transient cerebral anoxia and ischemia. However, abnormal movements are also reported to occur in 40– 90% of all syncope cases. The EEG usually shows diffuse theta–delta slowing during the syncopal event. No epileptiform discharges are associated with syncope (Lin et al., 1982; Kapoor et al., 1983a, 1983b; DeMaria et al., 1984; Aminoff et al., 1988; Lempert, 1996). Migraine in the elderly may have focal, generalized, transitory, or stereotyped features. This includes visual hallucinations, marching sensory symptoms, speech disturbance, confusion, and weakness. In contrast to seizures, migraine symptoms develop over minutes. A history of migraine should be sought during interview. The EEG is normal but may sometimes have nonspecific EEG changes during an attack. TIAs can be confused as seizures, but the history can typically differentiate the two. TIAs are associated with a sudden loss of a neurologic function lasting minutes to hours. Seizures are usually shorter, lasting seconds to a few minutes. TIAs are not usually episodic and stereotyped. In rare instances, sudden focal ischemia can cause positive neurologic symptoms, such as focal limb shaking. Strokes involving the nondominant or dominant parietal lobe (transcortical sensory aphasia and Wernicke’s aphasia) can also be confused as seizures. Toxic–metabolic conditions should always be considered in the differential diagnosis of seizures. Occult infections or early systemic infections (sepsis) can present

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with acute or episodic confusion/delirium. Metabolic derangements such as hypoglycemia, hyperglycemia, thyroid storm, and hypercapnia can occur in the elderly. CNS infections should also be investigated in patients with new-onset confusional symptoms (especially with HIV, Creutzfeldt–Jakob disease, syphilis, and encephalitis). Adverse drug reactions can also cause transient neurologic symptoms. The common medications are benzodiazepines, barbiturates, antihistamines, and anticholinergic medications. TGA usually presents with sudden disorientation and confusion. The patient experiences anterograde amnesia and tends to repeat the same questions. This usually lasts 8–24 hours, and patients gradually return to their baseline function. Recent magnetic resonance imaging (MRI) data suggest that a transient perturbation of hippocampal function is the functional correlate of TGA because focal diffusion lesions can be selectively detected in the CA1 field of the hippocampal cornu ammonis. Recent data suggest that the vulnerability of CA1 neurons to metabolic stress plays a pivotal part in the pathophysiologic cascade, leading to an impairment of hippocampal function during TGA (Bartsch and Deuschl, 2010). The incidence is 5–10 per 100,000. About 10–25% have recurrent events. Some movement disorders can be transitory and brief. This can include motor tics, limb or segmental myoclonus, tremor, chorea, and hemifacial spasms. The EEG is typically normal in movement disorders, and some movement specialists employ EEG back-averaging techniques in distinguishing epileptic and nonepileptic movements. The common sleep disorders than can occur in the elderly are confusional arousals, sleepwalking, nocturnal enuresis, and rapid eye movement (REM) behavior disorder. These disorders can be confused for nocturnal seizures. Confusional arousals are characterized by the person awakening from a deep sleep, reacting slowly to commands, and appearing confused. Non-seizure-related enuresis occurs during non-rapid eye movement (NREM) sleep. Sleepwalking involves the patient getting out of bed and wandering about. REM sleep behavior disorder (RBD) typically occurs among men over 50 years of age. RBD has been associated with Lewy body dementia and Parkinson’s disease. Normally during REM sleep, there is body atonia. In RBD, the loss of atonia results in loss of skeletal muscle inhibition, and the patient may act out dreams. The patient may have flailing arm movements and may kick, punch, or yell (Frenette, 2010). Nonphysiologic seizures signify a nonorganic cause of the seizure. This usually indicates a psychiatric illness. These include panic/anxiety attacks, conversion or psychogenic nonepileptic seizures (NES), dissociative states, hyperventilation syndrome, acute psychosis, and malingering. Psychogenic seizures in the elderly can present with simple motor movements, complex motor movements,

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sensory symptoms, loss of responsiveness, or decreased responsiveness (Lancman et al., 1996; Drury et al., 1999; Keraünen et al., 2002; McBride et al., 2002; Kellinghaus et al., 2004a, 2004b; Abubakr and Wambacq, 2005; Kawai et al., 2007; Kipervasser and Neufeld, 2007; ).

Diagnostic studies in geriatric epilepsy After the initial history and physical examination, the physician who suspects epileptic seizures must formulate the etiologic risk factors for the patient’s epileptic seizures. The two most important studies are brain imaging and EEG. The brain imaging of choice is MRI. This usually helps identify the anatomic substrate or symptomatic lesions (stroke, tumors, gliosis, vascular malformations, parasites). High-resolution MRI with and without contrast (if no contraindications) is the modality of choice. The interictal EEG may not always be diagnostic or supportive for epilepsy diagnosis. A study performed by Widdess-Walsh et al. (2005) examined 300 EEG records of elderly patients referred for syncope, encephalopathy, transient unresponsive states, and clinical seizures. Focal and generalized abnormalities were noted in 9% and 30.7% of the EEG records, respectively. Only 13 records demonstrated focal sharp waves, and one record showed generalized epileptiform discharges. Temporal slow of the elderly is a benign variant and should be part of the EEG differentials when temporal slowing is encountered. The EEG should always be correlated with the MRI lesion suspected to generate the seizures. Some MRI lesions may be merely incidental findings. Video EEG studies are an important diagnostic tool in the study of geriatric paroxysmal events or seizures (Lancman et al., 1996; Abubakr and Wambacq, 2005; Kawai et al., 2007; Keraünen et al., 2002; McBride et al., 2002; Kellinghaus et al., 2004a, 2004b; Kipervasser and Neufeld, 2007). Unfortunately, this is an underutilized diagnostic procedure. Video EEG studies have a higher chance of detecting focal or generalized epileptiform discharges. The detection of electrographic seizures confirms the diagnosis of epilepsy. Importantly, the diagnosis of paroxysmal nonepileptic events (physiologic or psychogenic) adds closure to the diagnosis. Epileptic seizures have been diagnosed in about 17–46% of elderly patients admitted for inpatient video EEG monitoring. The diagnosis of nonepileptic events ranged from 25% to 55% (Lancman et al., 1996; Drury et al., 1999; Keraünen et al., 2002; McBride et al., 2002; Kellinghaus et al., 2004a, 2004b; Abubakr and Wambacq, 2005; Kawai et al., 2007; Kipervasser and Neufeld, 2007). NES are a frequent problem in elderly patients. Physiologic and psychogenic NES are equally frequent in the elderly. Loss of responsiveness was seen in only 20% of patients with psychogenic NES.

Although most of the patients did not have any evidence for epilepsy, more than two-thirds of these patients had been placed on anticonvulsive drugs (Kellinghaus et al., 2004a). The ancillary tests are used to identify other causes of paroxysmal nonepileptic events. These include the complete blood counts, complete metabolic panels, toxicologic drug screens, blood gases, X-rays, blood or urine cultures, electrocardiogram, Holter monitors, tilt table testing, and sleep studies. These ancillary tests are tailored to the individual’s differential diagnosis.

Epilepsy syndromes and seizure classification The Commission on Classification and Terminology of the International League against Epilepsy has proposed four categories of epileptic syndromes in elderly patients (Van Cott, 2002): 1 Symptomatic localization-related epilepsy: Signs or symptoms indicate a specific anatomic localization (partial seizures, EEG or brain CT signs of localization). 2 Undetermined epilepsy: The patients are without unequivocal generalized or focal seizures and without any etiologic factors. 3 Isolated, apparently unprovoked epileptic events: Patients have isolated partial or generalized seizures without EEG or CT scan abnormalities. No etiologic factors are identified. 4 Situation-related seizures (acute symptomatic seizures): These can be associated with metabolic disorders or acute injury to the CNS. Complex partial seizures (38.3%) are the most common seizure presentation in geriatric epilepsy (Ramsay et al., 2004). This is followed by generalized tonic– clonic seizures (27.1%), simple partial seizures (14.3%), generalized tonic–clonic seizures and partial seizures (12.8%), and mixed partial seizures (7.5%). In terms of seizure semiology, Kellinghaus et al. (2004b) studied the seizure characteristics of 54 elderly patients 60 years or older at the time of admission. For 21 of them, at least one epileptic seizure was recorded. Nineteen patients had focal epilepsy (nine temporal lobe, two frontal lobe, two parietal lobe, eight nonlocalized), and two patients had generalized epilepsy. Seventy-three seizures of the elderly patients and 85 seizures of the 21 control patients were analyzed. In 9 elderly patients and 14 control patients, at least one of their seizures started with an aura. Eleven elderly patients and 19 control patients lost responsiveness during their seizures. Approximately two-thirds of the patients in both groups had automatisms during the seizures. Both focal and generalized motor seizures (such as clonic or tonic seizures) were seen less frequently in the elderly.

Geriatric Epilepsy

Drug therapy in geriatric epilepsy Numerous review articles focus on the pharmacotherapy of epilepsy in the elderly, but there are few randomized clinical trials in geriatric epilepsy (Brodie et al., 1995; Willmore, 1995, 1998; Brodie et al., 1999; Belmin et al., 2000; Brodie et al., 2002; Lackner, 2002; Alsaadi et al., 2004; Leppik et al., 2004; Leppik, 2005; Rowan et al., 2005; Sendrowski and Sobaniec, 2005; van Breemen and Vecht, 2005; Leppik, 2006; Mayes, 2006; Pugh et al., 2006; Gidal, 2007; Saetre et al., 2007; Sajatovic et al., 2007; Dogan et al., 2008; Ensrud et al., 2008; Pugh et al., 2008; Ramsay et al., 2008; Stefan et al., 2008; Pugh et al., 2010; Saetre et al., 2010). Currently, recommendations are based on expert opinions, and there is a lack of general guidelines/consensus. Recent studies indicate that approximately 10% of nursing home residents are being treated with antiepileptic drugs (AEDs) (Leppik et al., 2004). The choice of AED therapy is complicated by the physiologic changes and comorbid medical conditions. Pharmacokinetics involves the absorption, distribution, biotransformation, and renal excretion of the drug. This includes the genetic background, actual chronologic age, frailty, dietary habits, exposure to voluptuary substances (alcohol, cigarette smoke), serum albumin concentrations, glomerular filtration rate, creatinine clearance, comorbidities, and interaction caused by concomitant medications (Perucca, 2007). The absorption of an AED may be decreased due to the changes in gastrointestinal motility, blood flow, and mucosal absorptive surface. The distribution of the drug may be decreased due to decrease of serum albumin and total body water. Biotransformation is also decreased because of the decrease in liver mass, blood flow, activity of cytochrome P450 enzymes, and phase II conjugation enzymes. Renal elimination is also decreased because of the decrease in renal weight, glomerular filtration rate, renal blood flow, filtration fraction, and tubular function. The clearance of most anticonvulsants is reduced by 20–40% in the elderly, as compared to younger adults. Consequently, this also prolongs the elimination half-life of AEDs (Diamond and Blum, 2008; Hommet et al., 2008; Jetter and Cavazos, 2008; Werhahn, 2009). The pharmacokinetic changes in the elderly indicate that the initial drug dosage should be lower and should be titrated in a slower pace. The target dose may be 50% lower than the recommended dosages for younger patients. It is appropriate to start with one anticonvulsant drug (monotherapy) (St Louis et al., 2009). The therapeutic end point during the titration is no seizures and minimal side effects. AED polytherapy should be avoided as much as possible because of the higher risk of side effects. Age-related pharmacodynamic changes can alter the relationship between serum AED concentration and drug effects. It would not be surprising for the laboratory normal range

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to be “toxic” for the elderly person. When the elderly patient has no seizures with the medication, the serum level taken will be the approximate “therapeutic” level.” This may be lower or within the laboratory normal range. In some instances, it may even be slightly higher than the normal range. It may be tempting to lower the AED dose when the reported serum level is above the normal range. It is important to emphasize that the patient is being treated (not the drug level); .as long as no significant side effects are impairing cognitive or physical abilities, the AED dose should remain the same. Conversely, if the drug dosage is lower than the recommended dose and the patient has no seizures, it is not appropriate to push the medication higher.

Clinical studies of antiepileptic drugs in geriatric epilepsy Nineteen or more anticonvulsants are available in the market. It is beyond the scope of this chapter to discuss each anticonvulsant. About 11 studies address the drug treatment of elderly people with epilepsy (Brodie et al., 1995, 1999, 2002; Alsaadi et al., 2004; Rowan et al., 2005; Mayes, 2006; Saetre et al., 2007; Dogan et al., 2008; Ramsay et al., 2008; Stefan et al., 2008; Saetre et al., 2010). Of these, five were randomized double-blind, controlled trials (Brodie et al., 1995, 1999, 2002; Rowan et al., 2005; Saetre et al., 2007). Brodie et al. (1995) published in 1995 a double-blind study comparing Lamotrigine (LTG) and Carbamazepine (CBZ) in newly diagnosed epilepsy in the elderly. Only 151 of the 260 newly diagnosed geriatric epilepsy patients completed the 48-week study. In terms of efficacy, the proportion of patients who were seizure-free was similar in the LTG group (39%) and the CBZ group (38%). Generalized epilepsies responded more favorably than the focal epilepsies. In terms of tolerability, LTG had fewer drug withdrawals than CBZ (15% vs. 27%), and the most common cause was drug rash (9% vs. 13%). This finding was validated in a multicenter double-blind, controlled study in which LTG (100 mg/day) showed a more favorable efficacy and tolerability profile than CBZ (400 mg/day) (Brodie et al., 1999). In another study published in 2007, Saetre et al. (2007) compared LTG (100 mg/day maintenance dose; 500 mg/day maximum dose) with sustainedrelease CBZ (400 mg/day maintenance dose; 2000 mg/ day maximum dose). The number of subjects who completed the 40-week period and were seizure-free in the last 20 weeks was 48 (52%) in the LTG group and 52 (57%) in the CBZ group. Even though they have no significant difference in effectiveness, the LTG group was better tolerated. Adverse events leading to withdrawal occurred in 13 (14%) subjects in the LTG group and 23 (25%) subjects in the CBZ group.

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Brodie et al. (2002) performed a randomized doubleblind, controlled study comparing Gabapentin (GBP) and LTG in newly diagnosed epilepsy. The dosage range of GBP was 1200 and 3600 mg/day. The LTG dose was 100 and 300 mg/day. A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Eighty (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure-free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drugrelated adverse events. This study showed equal efficacy and adverse events of GBP and LTG. In a similar study, Rowan et al. (2005) studied the relative tolerability and efficacy of LTG and GBP with a traditional AED, CBZ. This involved 593 elderly patients with epilepsy, and they were randomly allocated to different treatment groups: GBP (1500 mg/day), LTG (150 mg/day), and CBZ (600 mg/day). The average age of the patients was 72 years, and the most common cause for the epilepsy was stroke. The seizure remission rate after 12 months of treatment was similar among the three AEDs. Overall, LTG and GBP were better tolerated than CBZ (Rowan et al., 2005). Smaller studies or case series have studied new AEDs among elderly patients with epilepsy. Ramsay et al. (2008) performed a pilot trial among elderly patients with partial seizures treated with Topiramate. Thirty-eight patients were randomized to 50 or 200 mg/day of Topiramate. Seizure control was similar with the two dosages when used as monotherapy. With adjunctive therapy, the 200 mg dosage was more effective. The most common adverse events were similar with the two dosages; the symptoms were somnolence, dizziness, and headache. Cognitive side effects (13%) were noted in both groups, and six of the ten patients who experienced it were in the 50 mg group. A total of 14 patients (18%) discontinued Topiramate due to adverse events. In Germany, Stefan et al. (2008) did an open-label, flexible dosing study of Topiramate among 107 elderly patients with epilepsy. The average dose for monotherapy and adjunctive therapy was 98 mg/day and 153 mg/day, respectively. About 44% of the elderly patients were seizure-free, and 78% had more than 50% reduction of seizures. Quality of life improved and Topiramate was well tolerated. Alsaadi et al. (2004) showed good response in the use of Levetiracetam with 14 elderly patients. Eight of the patients were seizure-free after 6 months of monotherapy. Four out of five patients were seizure-free when it was used as their first-line medication. Four of the nine patients who converted to Levetiracetam monotherapy after failing a previous AED were also seizure-free after 6 months. Four of the 14 patients had more than 50%

seizure reduction, and only one patient had no seizure reduction with Levetiracetam. Dogan et al. (2008) studied 147 elderly patients with newly diagnosed partial epilepsy and were treated with Oxcarbazepine monotherapy. About 62.6% of these patients were in seizure remission for 1 year, with Oxcarbazepine monotherapy at doses of 900 mg per day. About 37.4% of the patients were unresponsive at maximum tolerable doses of Oxcarbazepine. Elderly patients with cryptogenic partial epilepsy had a favorable response (75% remission), while the symptomatic group of elderly patients had a lower remission (51.9% remission). Elderly patients with tumor-related epilepsy had the lowest remission rate in the symptomatic group (36.7% remission). Oxcarbazepine was well tolerated, and one patient had symptomatic hyponatremia.

Summary Geriatric epilepsy is a common neurologic disorder that is usually caused by stroke and neurodegenerative disease (AD). Physiologic and nonphysiologic paroxysmal events may be confused with epileptic seizures. Elderly patients with epilepsy have a favorable response and tolerance to new-generation AEDs. Moreover, the AED dosages are lower due to pharmacokinetic changes that occur in the older age group.

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Chapter 16 Vertigo and Dizziness in the Elderly Terry D. Fife1 and Salih Demirhan2 1 2

Barrow Neurological Institute, and Department of Neurology, University of Arizona College of Medicine, Phoenix, AZ, USA Marmara University School of Medicine, Istanbul, Turkey

Summary • Benign paroxysmal positional vertigo (BPPV) is the most common cause of recurrent vertigo and is characterized by recurrent episodes of vertigo lasting 10–30 seconds. • Other common types of dizziness include vestibular neuritis, an acute peripheral vestibular disorder that usually results in unilateral peripheral vestibular loss but spears hearing, Meniere’s disease, an inner ear disorder that is characterized by recurrent, spontaneous attacks of vertigo and hearing loss, ear fullness, and tinnitus, usually affecting one side, and bilateral vestibular loss (BVL), results from damage of the balance portion of both inner ears. • Lesions in the central nervous system (CNS) vestibular pathways can lead to vertigo and imbalance. • Multiple sclerosis (MS) symptoms include vertigo, dizziness aggravated by head movement, persistent nausea, ataxia, and imbalance, sometimes with nystagmus or diplopia. Sensory ataxia syndromes, cerebellar ataxia syndromes, episodic ataxia syndromes, migraine-associated vertigo (MAV), normal pressure hydrocephalus (NPH), and postural hypertension are further described.

Introduction Disequilibrium and dizziness are common symptoms in older people and account for significant morbidity. In the United States, most individuals over 70 years of age report problems of dizziness and imbalance (National Institute on Deafness and Other Communication Disorders (NIDCD), 1989). Dizziness and imbalance is a leading contributor to reduced mobility and falls. Among Americans 65 years and older, one-third will experience balance-related falls that are the leading cause of deaths related to injury.

The effects of aging on balance Aging leads to functional and morphologic changes in most of the neural structures that mediate balance. With age, the central nervous system (CNS) shows decreases in astrocytes and neurons in the frontal, parietal, and hippocampal cortex, and reduced cerebellar Purkinje cells (Kemper, 1994). Partly as a result, there is loss of CNS plasticity and alterations in neurotransmitter concentrations, with less efficient integration of peripheral signals (visual, somatosensory, and vestibular). In addition, age-dependent declines in judgment, conditioning, muscle strength, joint flexibility, and motor control may

affect balance to varying degrees in many older people (Sudarsky, 1994). The peripheral vestibular end organs also exhibit the effects of age, though to a lesser degree. Loss of mid- and high-frequency hearing and speech discrimination is nevertheless very common. The peripheral vestibular structures show some reduction in hair cells in the cristae and in the maculae, but the loss is usually not pronounced or obvious under observation by light microscopy. The loss of hair cells in these structures, though modest, leads to measurable reductions in vestibular nerve fibers. Overall, however, vestibular end organ decline is less important as a cause of imbalance and falling in older people than is age-related CNS decline and the cumulative effects of combined sensory and CNS disturbances.

Types of dizziness Dizziness is a commonly used term that refers to a disturbance in the perception of spatial orientation. Hence, dizziness is a nonspecific term that can mean vertigo (the illusion of movement, especially rotation), disequilibrium or imbalance, lightheadedness, or near-faintness (Table  16.1). Imbalance and disequilibrium used here indicate reduction in balance when standing or walking, but without vertigo or any feeling of motion.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Table 16.1 Classification of dizziness Type

Symptom description

Example

Vertigo

Spinning, rotation, tilting

Vestibular neuritis, Meniere’s disease, benign paroxysmal positional vertigo (BPPV), brainstem/cerebellar lesions, migrainous vertigo

Presyncope

Lightheadedness, near-faintness, feeling of fading out

Postural hypotension (volume depletion, neurally mediated, other types), cardiogenic

Disequilibrium without vertigo

Imbalance when standing or walking, unsteadiness

Sensory ataxia, cerebellar ataxia, bilateral vestibular loss (BVL), many other causes

Psychiatric dizziness

Chronic floating or rocking, fatigue

Panic disorder, dizziness from anxiety, phobic vertigo

Physiologic dizziness

Motion sickness, visual vertigo, nausea or queasiness, fatigue

Seasickness, carsickness, airsickness, visual vertigoa

a

Visual vertigo is dizziness induced by seeing objects in motion (such as ceiling fans, moving traffic, cinematic scenery motion, grocery store aisles, and movement of crowds of people).

This chapter reviews some of the common causes of vertigo, dizziness, and imbalance that affect older adults. Otologic causes are those related to inner ear balance (vestibular) disorders and are discussed first. Following that, the so-called “central” causes that have some connection to CNS disease are discussed, along with other important causes of dizziness or imbalance.

Otogenic dizziness Benign paroxysmal positional vertigo Benign paroxysmal positional vertigo (BPPV) is the most common cause of recurrent vertigo. The prevalence of BPPV is 11–64 per 100,000. BPPV is also an important health problem in the elderly population because the prevalence of BPPV increases with age (Bloom and Katsarkas, 1989). BPPV is characterized by recurrent episodes of vertigo lasting usually from 10–30 seconds. The spells of vertigo are evoked by moving the head in certain directions, as with looking up or turning over in bed. The Dix–Hallpike maneuver is a simple bedside examination technique that induces the vertigo and nystagmus of the most common form of BPPV (Figure 16.1). Most cases of BPPV relate to

Figure 16.1 Dix–Hallpike test for localization of vertigo detects

most cases of benign paroxysmal positional vertigo related to the posterior semicircular canal.

the posterior semicircular canal, but occasionally, the lateral or anterior semicircular canals can be affected. The directional features of the nystagmus help to identify the side and semicircular canal affected.

Mechanism The semicircular canals located in the membranous labyrinth of the inner ear on each side detect angular or turning movements of the head. Each labyrinth has three semicircular canals: anterior, posterior, and horizontal canals. Each has a different orientation so that together they sense all angular movements. The cupula, located in the ampulla of each canal, is a motion sensor that bends with angular movement and sets off neural activity of the ampullary nerve that is carried via the vestibular nerves to the brain. Each labyrinth also has two otolith structures, the saccule and utricle, that detect linear or translational acceleration. They are referred to as otolith organs because they contain maculae, calcium carbonate crystals (otoliths) embedded in a gelatinous-protein matrix oriented to move in response to horizontal and vertical (gravity) accelerations. The deflection of hair cells in the maculae of these otolith organs causes neural activity that is also carried to the brain by way of the vestibular nerve. BPPV is caused when these calcium carbonate crystals that originate from the macula of utricle become dislodged and inappropriately end up within the lumen of one of the semicircular canals. Because the calcium carbonate crystals are more than twice as dense (specific gravity 2.7 g/cm3) as endolymph (specific gravity 1.0 g/cm3), they move in response to gravity. When calcium carbonate crystals dislodge from the macula of utricle and move within semicircular canals (canalolithiasis), they evoke endolymph flow and activate the cupula in that canal. This results in BPPV. The calcium carbonate crystals may dislodge or fall off the macula of utricle as a result of trauma or viral infections, but most cases are spontaneous. When there is canalolithiasis,

Vertigo and Dizziness in the Elderly

certain head movements that cause the otoliths to move stimulate the ampulla of the affected canal, causing a burst of vertigo. Each canal results in its own pattern of paroxysmal positional nystagmus: the posterior canal type is upbeating and torsional, with the top pole beating toward the downward ear; the anterior canal type is downbeating, sometimes with a minor torsional component; the lateral (horizontal) canal type is horizontal and changes its direction as the head is positioned in the supine right and moved to the supine left positions (direction changing paroxysmal positional nystagmus) (Fife, 2009).

Classification of benign paroxysmal positional vertigo BPPV is classified according to the affected semicircular canal and by whether it is thought to be due to canalolithiasis (otoliths freely moving within the canal in response to gravity) or cupulolithiasis (otoliths adherent to the cupula and hence less responsive to canalolith repositioning procedures). In some instances, more than one canal may be simultaneously affected. Posterior canal type of BPPV is the most common type (85–90%) of BPPV because the opening of the posterior canal is at the bottom of the labyrinth when lying flat (as when sleeping), so the dense otoliths settle preferentially into the posterior canal because of gravity. Diagnosis The history is generally sufficient to make a presumptive diagnosis of BPPV, but observing characteristic nystagmus upon examination is confirmatory. Patients with BPPV describe episodes of spinning triggered by lying back in bed, by turning in bed, by bending and straightening, and with certain tilting movements of the head. Nausea may accompany the spells, but BPPV is not associated with diplopia, slurred speech, sensory changes, or confusion. Occasionally, patients with strong symptoms or who have a propensity for motion sickness report mild nausea and floating dizziness for several hours after the positional vertigo, but most patients feel well between episodes. Spontaneous episodes of vertigo, vertigo lasting more than 1 or 2 minutes, and episodes that never occur in bed or with head position changes should lead one to consider alternative causes. Diagnostic tests The Dix–Hallpike maneuver is used to diagnose the posterior canal type of BPPV (refer to Figure 16.1). The maneuver is performed by rapidly moving the head from an upright position to a head-hanging position, with one ear 45° to the side. Performing the Dix–Hallpike maneuver to the side affected by posterior canal BPPV results in a burst torsional and upbeating nystagmus. Hence, with left BPPV, the nystagmus seen with Dix–Hallpike

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positioning to the left is clockwise torsional admixed with upbeating nystagmus; with right BPPV, the nystagmus is counterclockwise torsional and upbeating. By convention, the direction of the nystagmus is defined by its fast phase. Dix–Hallpike maneuver may sometimes elicit the horizontal (lateral) canal type of BPPV. However, a more reliable technique for evoking horizontal canal BPPV is a supine head turn maneuver, also called the Pagnini– McClure maneuver (Figure 16.2). The nystagmus of horizontal canal type BPPV is horizontal and changes direction depending on the head position. That is, with a quick supine turn of the head to the right, usually the nystagmus is paroxysmal horizontal right beating; when the head is turned to the other side, the nystagmus changes direction (hence the term direction changing), to become left beating. This type of direction-changing horizontal nystagmus is referred to as geotropic, meaning the direction of the fast phase is toward the ground. Geotropictype nystagmus is the most common type of horizontal canal BPPV nystagmus, but there is a less common and more difficult-to-treat form that is apogeotropic, meaning that the nystagmus beats away from the ground in each head position. A variety of specialized maneuvers address this less common type of BPPV, but no maneuver has been established as superior to the others, based on current evidence (Fife, 2009). An even less common anterior canal form of BPPV is characterized by paroxysmal downbeating nystagmus and sometimes torsional component following Dix– Hallpike positioning. Such downbeat positional nystagmus is also seen with CNS lesions of the posterior fossa, so, when it is encountered, appropriate evaluation to exclude structural CNS lesions should be considered.

Differential diagnosis Distinguishing central causes of vertigo from typical BPPV is important because some forms of central

Figure 16.2 Pagnini–McClure maneuver for evoking horizontal canal benign paroxysmal positional vertigo is a supine head-turn maneuver.

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positional vertigo may be life-threatening. Because some brainstem and cerebellar lesions can produce downbeating positional nystagmus, anterior canal BPPV should be diagnosed with caution. The general rule is that if the nystagmus fails to respond readily (same day) to positioning treatments or the direction of nystagmus is atypical, central causes should be considered.

Treatment The main goal of the treatment maneuvers for BPPV is to clear the misplaced calcium crystals (canaloliths) from the posterior canal by moving them back into the vestibule. A number of canalolith-repositioning procedures have been helpful in moving the calcium crystals and treating BPPV. The most commonly used and well-established method of treating posterior canal BPPV is the canalolith repositioning maneuver, which is a modification of the Epley maneuver (Figure 16.3). A second technique, the Semont liberatory maneuver, is equally effective (Figure 16.4) for posterior canal BPPV. If properly done, these treatment methods have nearly the same success rate (85–93%). Generally, antivertiginous medications such as meclizine are unnecessary because the treatment often eliminates all symptoms in a matter of minutes. Rarely, BPPV can be refractory to repositioning maneuvers and requires surgical occlusion of the affected semicircular canal.

Figure 16.4 Semont liberatory maneuver is equally effective as Epley for posterior canal benign paroxysmal positional vertigo.

Prognosis The generally accepted recurrence rate of BPPV after successful treatment is approaching 50% at 5 years of average follow-up. Because the otolithic membrane of the utricle always contains calcium carbonate crystals, recurrences may develop if more calcium breaks loose and becomes lodged within one of the semicircular canals.

Vestibular neuritis (idiopathic vestibulopathy) Vestibular neuritis, also called vestibular neuronitis, labyrinthitis, and neurolabyrinthitis, is an acute peripheral vestibular disorder that usually results in unilateral peripheral vestibular loss. The relatively sudden loss of vestibular function results in acute vertigo that lasts days and slowly recovers over weeks or a few months. The term vestibular neuritis refers to the acute unilateral loss of vestibular function that spares hearing. Labyrinthitis refers to acute unilateral loss of both hearing and vestibular dysfunction due to viral infection. Localization of the effects on the vestibular nerve and labyrinth may vary, leading some to prefer the term neurolabyrinthitis.

Figure 16.3 Canalolith repositioning maneuver; a modification

of the Epley maneuver is used for treatment of posterior canal benign paroxysmal positional vertigo.

Mechanism Although vestibular neuritis is generally attributed to viruses, including herpes simplex virus 1 (HSV-1), compelling confirmatory support for this supposition is lacking in humans. Degeneration of peripheral vestibular nerve fibers and the neuroepithelium of peripheral receptors have been observed on histopathologic examination (Goebel et al., 2001). Many cases of vestibular neuritis selectively involve only the superior division of the vestibular nerve that innervates the horizontal and anterior semicircular canals and the utricle. The inferior vestibular division that innervates the posterior canal and saccule is more often spared (Fetter and Dichgans, 1996). The selective

Vertigo and Dizziness in the Elderly

vulnerability may result from a longer course in a more narrowed pathway in the temporal bone for the superior division, making it susceptible to the effects of swelling and entrapment.

Symptoms The time course of vestibular neuritis and labyrinthitis is similar, usually evolving over a period of 30 minutes to several hours. Vertigo is present in all head positions but is aggravated by head motion; it gradually abates in the days and weeks that follow. Diagnosis Vestibular neuritis should be suspected when there is acute onset of vertigo that persists and is not specifically provoked by position changes (although patients may feel worse with head movement, it is present even at rest initially). A history of recurrent similar episodes should raise suspicion for other causes, such as Meniere’s disease. Examination reveals fast phases of the nystagmus beating away from the affected ear. Importantly, the direction of nystagmus does not alter with changes in head position or gaze. The nystagmus fast phase increases during gaze in the direction of the fast phase and diminishes or abates with gaze away from the fast phase. This is referred to as Alexander’s law and is characteristic of acute peripheral vestibular loss. The nystagmus of acute unilateral vestibular loss decreases within the first 12–36 hours in most cases, so spontaneous nystagmus subsides fairly soon after the onset. A head impulse test remains abnormal indefinitely after significant unilateral vestibular loss (Wuyts, 2008). Differential diagnosis It is important to be certain that there is no central cause of the acute vertigo. Small cerebellar strokes or hemorrhage can also produce acute vertigo that may mimic vestibular neuritis (Lee and Cho, 2004). Cerebellar or brainstem strokes, however, usually exhibit other signs,

383

such as unilateral dysmetria, slurred speech, hemibody numbness, diplopia, or nystagmus that changes direction when changing the direction of gaze (gaze-evoked nystagmus). The head impulse test is typically abnormal in peripheral causes and not in most central causes. Nystagmus of peripheral origin adheres to Alexander’s law, as mentioned, and remains unidirectional. Meanwhile central nystagmus may change direction, depending on the direction of gaze, or may be purely downbeat or torsional. The first attack of Meniere’s might easily be mistaken for vestibular neuritis. Meniere’s attacks, however, usually subside within 8 hours, whereas residual symptoms continue for days to weeks in vestibular neuritis. Recurrences of vertigo in Meniere’s disease are common, whereas a second attack of vestibular neuritis is uncommon (recurrence incidence is 2% over a lifetime).

Diagnostic tests Videonystagmography (VNG) with caloric vestibular testing can help confirm the presence of unilateral peripheral vestibular loss. A greater than 24% asymmetry in caloric vestibular nystagmus suggests a pathologic loss of vestibular function. VNG need not be done in the first days of the vertigo, as unilateral vestibular loss remains detectable for the rest of the patient’s life. Brain MRI or head CT should be obtained in patients with vertigo accompanied by focal neurologic symptoms or severe headache because vestibular neuritis is usually painless. Treatment In the early days following acute unilateral vestibular loss, vestibular suppressants (Table 16.2) may be helpful in ameliorating vertigo and nausea. Within a few days of nausea subsiding, vestibular suppressants should be stopped because these medications may delay or limit CNS adaptation to the acute vestibular loss (Hain and Yacovino, 2005).

Table 16.2 Motion sickness and vestibular suppressant medications Medication

Brand name

Dosage and form

Adverse effects

Dimenhydrinate

Dramanine

50 mg p.o. bid

Urinary retention, dry mouth

Meclizine

Antivert, bonine

12.5–50 mg p.o. tid or qid

Urinary retention, dry mouth

Promethazine

Phenergan

12.5–50 mg p.o. or IM q 4–6 h; 50 mg suppos pr qid

Slightly lowered seizure threshold

Diazepam

Valium

2–7.5 mg p.o. tid or qid

Dose-dependent sedation

Lorazepam

Ativan

0.5–2 mg bid or tid

Dose-dependent sedation

Clonazepam

Klonopin

0.25–1 mg p.o. bid or tid

Dose-dependent sedation

Scopolamine

Transderm scop

Patch 1 q 3 days

Urinary retention, dry mouth

Metoclopramide

Reglan

10–20 mg p.o. q4–6 h; 10–20 mg IV q 6 h

Extrapyramidal effects

Prochlorperazine

Compazine

10–20 mg p.o. q4–6 h; 10 mg IV q 6 h; 25 mg suppos p.r. q 6 h

Extrapyramidal effects

Ondansetron

Zofran

4–8 mg p.o., sl, or IV q 4–6 h

Fatigue, diarrhea

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Table 16.3 Home habituation exercises for recovery from vestibular loss Exercise

Description

1. Fixation during head turning

Turn the head quickly from side to side and then up and down while focusing on your thumb held out directly in front of you. As you move your head, move your thumb so that it is right in front of you and you can keep your focus on it. As you move your head, your focus should be fixed on your thumb. Repeat these exercises for 30–60 s at least five times daily. This exercise helps to improve your ability to focus on things while your head is moving from side to side.

2. Head movement habituation

Practice slowly turning the head from side to side while seated and then later while standing with your feet shoulder width apart. Gradually increase the speed of head movements. The head turning can include side-to-side and up-anddown movements rapidly and repetitively, with eyes open and in good lighting. When you can do this standing still, try to walk (eyes open) forward while turning the head side to side, gradually increasing the speed of head turns. This helps you to become more used to rapid movements of the head, which are often a source of momentary imbalance.

3. Rapid head movement habituation

Practice getting up from the lying-down position to standing as quickly (but carefully) as possible. This may be done on a sofa or bed. Practice getting up toward the left side and toward the right side. Be careful not to fall. Get up quickly five times to each side, gradually trying to increase the quickness but without falling. This helps improve the coordination of quick movements of the head and body. Rapidly bend over and then straighten five consecutive times. Do this exercise twice. Time yourself and try to gradually increase your speed; eventually, try adding an about-face (180° turn) after each bend.

4. Tightrope exercise

Walk heel to toe, as though walking a tightrope. This can be done in a hallway or corridor where there is something to hold on to, if needed. Gradually try to achieve 10 steps (heel touching toe) without holding on or taking a side step. This improves the inner ear balance and cerebellar balance function.

5. Standing balance test

Stand with the feet together (touching) and try to maintain the position for 15 s. After you accomplish that, try closing your eyes, with someone nearby to keep you from falling. Work to eventually be able to stand with feet together and eyes closed for 8 s. This trains you to keep your balance using ankle sensation and inner ear signals. If you are able to do this for 8 s, practice standing on one leg (eyes open) or while standing on a foam pillow. Eventually, try to stand for 10 s on foam with eyes closed and to stand on one leg for 12 s.

6. Walk and quick turns

Walk 10 steps down in a corridor or hallway and then turn right and walk back to the starting point. Do this five times turning to the right, then five times turning toward the left. Time how long it takes you and try to improve your speed, being careful to avoid falling. This helps walking balance and balance with turns.

At that point, the patient should begin moving his head from side to side, extending the activity each day until capable of undergoing more extensive vestibular exercises (Table 16.3). Vestibular exercises accelerate recovery using intrinsic neuroplasticity and cerebellar adaptation (Gittis and du Lac, 2006), allowing the brain to accommodate the unilateral vestibular loss with complete or nearly complete recovery over several months. Studies in primates and humans indicate that vestibular exercises accelerate the recovery from a unilateral vestibular loss and improve the overall balance function (Sadeghi et al., 2007). Acute use of prednisone 60 mg daily for a week, much as one might treat Bell’s palsy, may help reduce the severity of vestibular neuritis if given in the first few days, though more randomized controlled trials are needed to confirm a clinically relevant benefit. One exception is in herpes zoster oticus and Ramsay Hunt syndrome. Both represent a recrudescence of varicella zoster virus that can lead to hearing loss or residual facial paresis. If varicella zoster (shingles) is suspected, the patient should be treated with corticosteroids and either acyclovir, famciclovir, or valacyclovir. Herpes zoster oticus may cause painful vesicles in the sensory distribution of the seventh cranial nerve, usually a small patch

deep in the external ear canal or occasionally behind the ear. When accompanied by ipsilateral Bell’s palsy, the syndrome is referred to as Ramsay Hunt syndrome.

Meniere’s disease Meniere’s disease is an inner ear disorder that is characterized by recurrent, spontaneous attacks of vertigo and hearing loss, ear fullness, and tinnitus, usually affecting one side. The prevalence of Meniere’s disease is about 1:150,000 people, affecting males and females about equally and with a peak incidence between 40 and 60 years of age.

Symptoms Unilateral ear fullness, hearing fluctuation, and change in the pitch of tinnitus may precede typical attacks of Meniere’s disease. Vertigo attacks in Meniere’s disease are random, often severe, and last 1–6 hours. In most cases, patients are unable to walk or move comfortably during attacks, due to prominent nausea and vomiting. In early Meniere’s, fluctuating unilateral low frequencies hearing loss is evident. However, over time (usually years), the hearing loss progresses and becomes permanent.

Vertigo and Dizziness in the Elderly

Occasionally, patients may experience sudden unexpected falls without loss of consciousness. These drop attacks are referred to as “otolithic crises of Tumarkin” and may lead to serious injury. They may occur from abrupt neural surges of the utricle or saccular, which suddenly distort the patient’s sense of vertical, resulting in the fall.

Mechanism Meniere’s disease is idiopathic but seems to result from endolymphatic hydrops. Endolymphatic hydrops refers to the sudden movement of the perilymph into the endolymph compartment, leading to swelling in the labyrinth. The bony labyrinth contains these structures, so actual swelling is limited but stretching of the endolymphatic space causes the acute disturbance of vestibular and hearing function associated with the attacks. The tendency for such endolymph accumulation may be partly mechanical obstruction of endolymph and dysregulation of the electrochemical membrane potential between the endolymph and the perilymph. If the underlying causes of endolymphatic hydrops are known such as syphilis or autoimmune inner ear disease, the terms Meniere’s syndrome and delayed or secondary endolymphatic hydrops may be used to distinguish them from idiopathic Meniere’s disease. Nevertheless, primary (Meniere’s disease) and secondary endolymphatic hydrops often follow a similar clinical course, although bilateral involvement is more common in secondary hydrops. Diagnosis Meniere’s and endolymphatic hydrops are clinical diagnoses based on the history and confirmed by low-frequency hearing loss and vestibular loss on the affected side. Patients with a history of multiple attacks of vertigo but with no hearing loss should receive more careful evaluation for other possible causes, such as migraine-associated vertigo (MAV) or idiopathic recurrent vestibular neuritis. Differential diagnosis Conditions that can produce symptoms that resemble those of Meniere’s disease include perilymph fistula, recurrent labyrinthitis, MAV, luetic otitis, and autoimmune inner ear diseases. Diagnostic testing VNG and audiometry are the most helpful adjunctive tests in those with a suggestive history. The brain MRI is normal in Meniere’s disease. Treatment Acute treatment of Meniere’s disease hinges on mitigation of the vertigo and vomiting using medications

385

(Table  16.2). No treatments are known that effectively restore and arrest hearing loss or tinnitus. However, if attacks of vertigo, ear fullness, fluctuating hearing, and tinnitus all cease, further hearing loss may be prevented. Prevention of further attacks is generally attempted by a sodium-restricted diet of <1500 mg daily often along with a thiazide diuretic such as hydrochlorothiazide 25 mg with triamterene 37.5 mg daily. Betahistine is not approved for interstate transport in the United States but may have a role in some cases of Meniere’s disease and is dosed at 8–16 mg three times daily. Betahistine can be legally compounded in the United States or can be obtained from outside the United States for personal use. If sodium restriction and pharmacologic therapies fail to prevent vertigo attacks, invasive methods include transtympanic gentamicin or corticosteroid injections, endolymphatic mastoid shunting, vestibular neurectomy, or, in those with no serviceable hearing, labyrinthectomy. Bilateral Meniere’s occurs in about 10% of patients. In patients with bilateral Meniere’s, surgical treatment options must be considered carefully because it may not always be possible to determine which labyrinth is the dominant cause of symptoms; treatment of both sides risks creating bilateral vestibular and hearing loss.

Bilateral vestibular loss Bilateral vestibular loss (BVL), referred to as Dandy’s syndrome, results from damage of the balance portion of both inner ears. BVL may have a number of causes, including ototoxic medication exposure, bilateral Meniere’s disease, sarcoidosis, bilateral ear surgery, some congenital disorders, and autoimmune inner ear disease. Among these, the most commonly encountered cause of acquired BLV is vestibulotoxic medication, usually from gentamicin. Nevertheless, in one study, 25% of older patients with an imbalance of unknown origin had previously undetected BVL significantly contributing to their imbalance (Fife and Baloh, 1993).

Mechanism Ototoxins such as aminoglycoside, cisplatin, and some organic solvents may cause BVL. The aminoglycosides selectively damage vestibular or cochlear cells. Streptomycin and gentamicin are the more vestibulotoxic drugs, thus damaging vestibular function more than hearing. On the other hand, neomycin and kanamycin are more cochleotoxic and so can cause hearing loss more than vestibular loss. Tobramycin is intermediary. Aminoglycosides block membrane channels of hair cells and accumulate in hair cells, leading to cellular apoptosis. Cisplatin ototoxicity may be mediated in part by the formation of superoxide anions. A mutation in human

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mitochondrial 12S RNA gene at nucleotide A1555G has been shown to be associated with susceptibility to irreversible hearing loss, but not vestibular loss, caused by aminoglycosides.

Symptoms As vestibular function declines, some vertigo may occur. When BVL is fully present, it causes unsteadiness that is worse when walking, especially in darkness or on uneven ground. However, if the patient makes hand contact with a wall while walking, balance significantly improves. Oscillopsia, the perception of bouncing, jumbled, or blurring vision, is another salient symptom of severe BVL. Oscillopsia, due to vestibular hypofunction, is evident during head motion because the vestibulo-ocular reflex (VOR) is insufficient to stabilize vision during head movements. In a patient reporting new unsteadiness or dizziness who has recently received aminoglycoside antibiotics, BVL should be suspected. The onset of symptoms may begin from 5 to 20 days after exposure. Elevated peak and trough levels of gentamicin, for example, increase the likelihood of toxicity, but some patients develop vestibular loss even when dosage has been properly monitored and administered. Toxicity may occur whether gentamicin is administered intravenously, transtympanically (by injection), or by peritoneal dialysis, but does not occur from gentamicin eye or ear drops. Diagnosis Patients with BLV may exhibit an abnormal Romberg test, bilaterally abnormal head impulse tests, and dynamic visual acuity test. The latter is considered abnormal when visual acuity drops three lines on a Snellen chart or Rosenbaum card during rapid head shaking. There may be some mild nystagmus, but this is generally not prominent if the vestibular loss is symmetric or chronic. Diagnostic testing VNG with caloric testing shows bilaterally reduced nystagmus, and rotational chair testing is confirmatory for BLV when it shows reduced VOR gain responses during chair rotations at all frequencies. Differential diagnosis In addition to ototoxin exposures, other causes of BVL include bilateral sequential vestibular neuritis, idiopathic or heritable BLV, bilateral Meniere’s disease, autoimmune inner ear diseases, meningitis, luetic otitis, trauma, and bilateral acoustic neuromas. Treatment When possible, the underlying cause of BLV should be treated. When the source of the vestibular loss has been

maximally addressed, the next step in treatment is to promote adaptation and substitution, with the goal of improving balance. Vestibular physiotherapy can be helpful in achieving this, in part through exercises such as those outlined in Table 16.3. With severe BLV, the brain must rely on vision and somatosensation to help the patient adjust and improve balance. Studies indicate that vestibular rehabilitation improves dynamic visual acuity, reduces complaints of oscillopsia, and reduces VOR gain asymmetry (Brown et al., 2001).

CNS causes of dizziness and imbalance Lesions in the CNS vestibular pathways can lead to vertigo and imbalance. In general, the brain can adapt and adjust to acute vestibular asymmetry, so acute vertigo usually implies an event leading to sudden vestibular asymmetry. For example, a stroke may lead to sudden onset of vertigo, whereas an acoustic neuroma (vestibular Schwannoma) is very slow growing and does not usually lead to vertigo, even though it causes vestibular loss. Vertigo is not prominent with acoustic neuromas because the loss of vestibular function occurs so slowly that adaptation occurs incrementally. Ascribing a CNS lesion as the explanation of vertigo is a matter of determining whether the lesion is anatomically related to pathways important for vestibular function or balance, as outlined in Table 16.4.

Epileptic vertigo A seizure involving the vestibular cortex is a rare cause of dizziness or vertigo. Rarely, vertigo may occur as an isolated symptom of epilepsy (Bladin, 1998).

Mechanism The cause is a focal seizure in the cerebral cortex near the temporal lobe that processes vestibular signals. Curiously, there is some suggestion that the vestibular cortex is more likely on the right side (Fasold, 2002). Symptoms In most cases, patients are already known to have epilepsy and may have auras or partial seizures manifesting with dizziness. In most cases, other clinical features suggest seizures such as automatisms, loss of awareness, and convulsions that follow the aura of vertigo. Diagnosis MRI imaging should be undertaken when this diagnosis is strongly considered. EEG monitoring may be necessary to confirm a seizure mechanism when there is no structural lesion in brain imaging.

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Table 16.4 CNS regions that may be associated with vertigo, nystagmus, or ataxia Anatomic location

Structures affected

Signs or symptoms

Lesion example

Dorsolateral medulla

Vestibular nuclei, root entry zone CN 8

Nausea, nystagmus, vertigo, ataxia

Medulloblastoma, metastasis, MS

Floor fourth ventricle

Vestibular nuclei, especially superior vestibular nucleus

Nausea, nystagmus, vertigo, ataxia

Medulloblastoma, cysts

Anterior cerebellar vermis

Cerebellar connections

Ataxia

Alcohol-related cerebellar ataxia

Dorsal cerebellar vermis

Flocculus, nodulus, uvula connections; dorsal vermis; fastigial nucleus

Nystagmus, ataxia, possibly vertigo, saccadic dysmetria

Cerebellar degeneration

Superior cerebellar peduncle

Cerebellar efferents

Positional vertigo

MS

Middle cerebellar peduncle

Pontocerebellar fibers

Ataxia, dysarthria, ipsilateral limb clumsiness

Pontine infarct, cavernous malformation

Inferior cerebellar peduncle

Vestibulocerebellar afferents

Anterior cerebellum

Flocculus, nodulus, uvula

Vertigo, ataxia, gaze-evoked nystagmus

Basilar meningitis

Vestibular cortex

Superior temporal gyrus

Vertigo

Partial epilepsy

Dorsal midbrain

riMLF, iCajal

Dysconjugate vertical/torsional nystagmus, vertical gaze disorders

Cavernous malformation, pinealoma, AVM

Cavernous malformation, AVM

MS, multiple sclerosis; AVM, arteriovenous malformation; riMLF, rostral interstitial nucleus of the medial longitudinal fasciculus; iCajal, interstitial nucleus of Cajal.

Differential diagnosis Depending on the duration of spells, transient ischemic attacks, migrainous vertigo, and episodic ataxia may cause similar episodes. Treatment Antiepileptic treatments aimed at managing partial epilepsy are advised when the underlying cause cannot be readily eliminated.

Craniocervical junction syndromes The vestibulocerebellum and posterior medulla are key vestibular structures located at the craniocervical junction, and lesions in this area may lead to vertigo. Conditions that occur at this location include Chiari malformation, atlantoaxial subluxation, and, more rarely, basilar impression. A Chiari malformation is a congenital condition in which the cerebellar tonsils did not fully migrate rostrally during development, leaving the caudal-most cerebellum (the cerebellar tonsils) wedged in the foramen magnum. In severe cases, this may lead to vertigo, occipital headaches, nystagmus, and ataxia in early childhood. In other cases, these features develop much more insidiously and may not present until adulthood. Midsagittal MR brain imaging reveals inferiorly located cerebellar tonsils (>5 mm below the foramen magnum), and treatment in appropriately selected cases entails suboccipital decompression surgery.

Atlantoaxial subluxation is a serious medical condition that is usually due to erosion or malformation of the ligaments holding C1 and C2 together. It may occur from trauma but occurs more commonly in patients with Down’s syndrome and patients with rheumatoid arthritis. Patients with rheumatoid arthritis and Down’s syndrome reporting severe headaches, neck pain, and vertigo should be evaluated with flexion and extension cervical spine radiographs. Cervical spine and brain MRI studies may fail to show the laxity of the ligaments, so they are not sufficient to exclude this condition. A final anatomic condition that may lead to central vertigo related to the cervicomedullary junction is basilar impression or basilar invagination. In this condition, the floor of the skull becomes distorted or the tip of the dens (odontoid process of C2) is pushed up rostrally, narrowing the foramen magnum and compressing the medulla or vascular structures of the lower brainstem. In older adults, the conditions most likely to cause this include Paget’s disease of the bone and osteogenesis imperfecta.

Vascular causes, brainstem and cerebellar strokes, and hemorrhage Vascular causes such as strokes, or TIA involving the vestibular cortex, are rare causes of dizziness or vertigo.

Mechanism Vertebrobasilar insufficiency refers to transient episodes of inadequate blood flow through the vertebral and

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basilar arteries that supply the brainstem and cerebellum. Focal vascular narrowing by atherosclerosis is the most common cause. Rarely, occlusion or stenosis of the subclavian artery just proximal to the origin of the vertebral artery causes reversal of blood flow in the ipsilateral vertebral artery. Hence, it is called subclavian steal syndrome because the subclavian “steals” flow from the vertebrobasilar syndrome to supply the upper limb. Vertigo and other symptoms of vertebrobasilar insufficiency are precipitated by exercise of the upper extremities. Angiography can localize the site of the narrowing and the reversal of blood flow.

Symptoms Transient ischemic attacks (TIA) in the vertebrobasilar vascular system may cause vertigo, imbalance and ataxia, slurred speech, nystagmus, diplopia and drop attacks, headaches, and visual hallucinations or visual field defects. Vertigo may be an isolated initial symptom of vertebrobasilar insufficiency (Fife et al., 1994) or may go along with other brainstem symptoms, as mentioned earlier (Grad and Baloh, 1989). In most cases, treatment of vertebrobasilar insufficiency consists of controlling vascular risk factors and using antiplatelet drugs. Table 16.5 details clinical features of several brainstem vascular syndromes that may be associated with vertigo. Cerebellar strokes due to occlusion of the vertebral artery, posterior inferior cerebellar artery (PICA), anterior inferior cerebellar artery (AICA), or superior cerebellar artery (SCA) can lead to isolated cerebellar infarction (Amarenco, 1991). If the infarct affects portions of the cerebellum that carry vestibular inputs, vertigo and ataxia will likely follow. Small cerebellar infarctions in the cerebellar hemispheres are less apt to cause vertigo or substantial ataxia than are midline or parasagittal lesions or those affecting the flocculus or nodulus. Spontaneous intraparenchymal cerebellar may occur as a late effect of hypertensive vasculopathy. The initial symptoms may include vertigo, nausea, vomiting,

headache, and inability to stand or walk. Involvement of the cerebellum can usually be distinguished from peripheral vestibular vertigo because the former results in dysmetria and limb clumsiness, neither of which occurs with peripheral vestibular lesions.

Diagnosis The diagnosis is suspected when a patient has vascular risk factors with symptoms and signs localizing to the brainstem or cerebellum. Diagnostic tests A CT of the head readily and rapidly detects intracranial hemorrhage. A brain MRI with diffusion weighted imaging can confirm acute or recent stroke. MR angiography and CT angiography are the most commonly employed imaging studies to flow in the cerebral arteries. Differential diagnosis Conditions that can produce focal neurologic findings that are fleeting and in whom no vascular occlusive disease is seen include disorders leading to cardiogenic thromboemboli (including paradoxical emboli), hyperviscosity syndromes, Bickerstaff’s basilar migraine, and mitochondrial cytopathies. Treatment Treatment should focus on ameliorating the underlying cause by addressing vascular risk factors, as well as the use of cholesterol-lowering and antiplatelet aggregation medications. A variety of endovascular approaches are finding a role in acute stroke management, including administration of intra-arterial tPA, angioplasty, stenting, and mechanical thrombolysis (Nogueira et al., 2009). For patients with completed infarction, the same issues apply, but with the addition of physical therapy to accelerate and improve overall recovery and return of function.

Table 16.5 Selected vascular syndromes associated with vertigo and ataxia Vascular syndrome

Blood supply

Common cause

Features

Vertebrobasilar TIA

Vertebral arteries, basilar artery, Atherosclerosis PICA or AICA, rarely SCA

Vertigo, clumsiness, dysarthria, diplopia, drop attacks, ataxia

Lateral medullary stroke (Wallenberg’s syndrome)

PICA

Atherosclerosis or vertebral artery dissection

Vertigo, ipsilateral facial numbness, limb dysmetria, Horner’s syndrome, diplopia, lateral pulsion of saccades, asymmetric gaze nystagmus, slurred speech, falling to one side, contralateral loss of pain and temperature sensations

Lateral pontine stroke

AICA

Atherosclerosis

Vertigo, ipsilateral facial numbness, facial weakness, hearing loss, limb dysmetria, Horner’s syndrome, diplopia, lateral pulsion of saccades, asymmetric gaze nystagmus, slurred speech, falling to one side, contralateral loss of pain and temperature sensations

AICA, Anterior inferior cerebellar artery; PICA, Posterior inferior cerebellar artery; SCA, Superior cerebellar artery.

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Large cerebellar infarcts that produce edema can have life-threatening consequences if the edema compresses the fourth ventricle or dorsal brainstem. Hence, large cerebellar infarcts and cerebellar hemorrhages are potential neurosurgical emergencies.

Multiple sclerosis Multiple sclerosis (MS) is usually considered a disease of younger people between ages 20 and 40 years, but about 10% of patients have onset after the age of 50. Equilibrium disorders caused by involvement of spinal cord, brainstem, and cerebellar structures are common in patients with MS. However, peripheral vestibular disorders such as BPPV are also quite common among patients with a history of MS (Frohman et al., 2000), so a CNS should not necessarily be assumed to be the cause of patients with MS. Mechanism MS is an inflammatory, demyelinating disease of the CNS. Pathologically, it is characterized by inflammatory monocytes and lymphocytes around blood vessels and regions of loss of oligodendrocyte-derived myelin, referred to as plaques, that localize predominantly in the CNS white matter. Demyelinating lesions in parts of the brain that are interrelated with the vestibular system can result in vertigo and nystagmus (Table 16.4). Among the more notorious locations for a plaque to lead to vertigo or ataxia is the nodulus, midline or parasagittal cerebellum, middle cerebellar peduncle, and dorsolateral medulla at the root entry zone of the vestibulocochlear nerve. Symptoms Possible symptoms include vertigo, dizziness aggravated by head movement, persistent nausea, ataxia, and imbalance, sometimes with nystagmus or diplopia. Diagnosis The presence of persisting nystagmus, particularly gazeevoked nystagmus or spontaneous vertical nystagmus or other central types of nystagmus (such as periodic alternating nystagmus or seesaw nystagmus) indicate CNS localization and MS as the cause. A new plaque may not always be visible by MR imaging, so further workup may be needed in some cases to exclude peripheral vestibular causes. Diagnostic tests Brain MRI with contrast is one of the most sensitive studies for detecting new plaques in a relevant part of the CNS. Quantitative vestibular testing may reveal localizing ocular motor findings and examines the functional integrity of the peripheral vestibular system.

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Differential diagnosis The main differential diagnostic considerations are peripheral vestibular disorders and migrainous vertigo. Treatment Treatment should be directed at the underlying mechanism. If due to MS, clinical judgment should dictate whether the symptom justifies using intravenous corticosteroids or changing immunomodulating medications. If it is peripheral vestibular in origin, vestibular physical therapy or temporary use of some of the medications described in Table 16.2 may be helpful.

Sensory ataxia syndromes Many patients use the term dizziness to describe poor equilibrium. A category of disorders that result in poor balance on the basis of somatosensory dysfunction or spinal cord ataxia may produce this kind of unsteadiness.

Mechanism This group of disorders is varied, but the cause of imbalance results from disruption of spinal cord or peripheral nerve afferent sensory inputs to the brain. Hence, joint position sensation and loss of vibratory sensation in the lower limbs become impaired. These disorders thus are sometimes referred to as sensory ataxia syndromes. These disorders may include dorsal root ganglionopathies, large fiber demyelinative peripheral neuropathies (ataxic neuropathy), severe polyneuropathies, and lesions affecting white matter tracts (dorsal columns) of the spinal cord, as may occur in tabes dorsalis from syphilis or subacute combined degeneration from vitamin B12 deficiency. The list of such conditions is long and beyond the scope of this chapter, but clinicians should be aware of this type of disorder when patients complain of dizziness but actually mean unsteadiness and imbalance. Symptoms With sensory ataxias, there is impairment of distal joint position and vibration sensation that may be described as feeling numb in the feet or feeling like walking in thick socks. Patients note balance difficulty, particularly in darkness. Diagnosis With some spinal cord disorders affecting pyramidal (corticospinal) tracts, deep tendon reflexes in the lower limbs may be brisk, possibly with extensor plantar responses. With diseases of the dorsal root ganglia, dorsal roots or peripheral nerve reflexes may be absent. Sensory loss may include joint position sense and vibratory sense, sometimes also with loss of pain and temperature sensations, depending on the type of sensory fibers affected. The Romberg test is typically positive.

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Diagnostic tests Motor and sensory nerve conduction velocity measurements, and sometimes somatosensory-evoked potentials (SSEPs), may help to localize whether large fiber, small fiber, sensory or motor, or mixed nerves are affected; gauge conduction block; and assess whether the process is likely related to abnormal spinal cord dysfunction. Cerebrospinal fluid (CSF) studies may show elevated CSF protein in certain demyelinating neuropathies, and nerve biopsy may also be indicated to assess for demyelinating neuropathy or vasculitic neuropathy. MR imaging of the spinal axis excludes structural lesions within the spinal cord and extramedullary lesions compressing the cord. When there is no sensory level or other more localizing clues, MR imaging of the cervical, thoracic, and lumbosacral regions is sometimes necessary. Treatment Treatment varies widely, depending on the cause. Demyelinating neuropathies may be responsive to plasma exchange or intravenous immunoglobulin. Vasculitis neuropathies may respond to corticosteroids, cyclophosphamide, or a variety of other immunomodulating medications. Subacute combined degeneration may improve with vitamin B12 supplementation. Tabes dorsalis due to syphilis may be treated with intravenous aqueous penicillin G. HIV-1 associated vacuolar myelopathy may improve with highly active antiretroviral therapy.

Cerebellar ataxia syndromes Various late-life cerebellar syndromes may cause imbalance and dizziness.

Mechanism The underlying cause of most ataxias is cerebellar degeneration with loss of cerebellar Purkinje and granule cells. The cause for this in some of the dominantly inherited ataxias relates to CAG trinucleotide repeats. CAG is the codon for the amino acid glutamate. Hence, excessively long polyglutamine strands form in certain proteins. The mechanism by which the glutamine repeats lead to cell death is the focus of ongoing research. Other ataxias may be due to recessively inherited causes, or at least appear sporadic, as there is no family history. Some of these represent more purely cerebellar degenerative disorders, and some exhibit prominent cerebellar features but are part of a wider multiple system atrophy and are termed MSA-C. Their precise mechanism is unknown. Friedreich’s ataxia is a recessively inherited disorder caused by expanded GAA repeats that lead to transcription of deficient amounts of frataxin, a protein important

in mitochondrial regulation desulfurase functions. This condition usually has onset in childhood or young adulthood but may continue on to later adulthood. Subacute cerebellar degeneration is a paraneoplastic disorder associated with anti-Purkinje cell (anti-Yo) antibodies associated usually with ovarian carcinoma. Gluten ataxia is a controversial entity due to gluten sensitivity and is associated with anti-gliadin antibodies that presumably improves with avoidance of dietary gluten (Hadjivassiliou et al., 2002; Lock et al., 2005). Fragile X ataxia tremor syndrome (FXTAS) is a genetic neurodegenerative disorder affecting mostly men that is due to an increased number of cytosine-guanine-guanine (CGG) repeats in the fragile X (FMR1) mental retardation gene on the X chromosome. If the number of CGG repeats is extensive (>200 repeats), the patient develops fragile X syndrome. Carriers are those with a permutation that may be passed along to their daughters, who, in turn, have a 50% chance of passing it along to their children; in some cases, this leads to an expansion to the full fragile X syndrome. Finally, a variety of neurodegenerative disorders may initially present with dizziness and a feeling of poor equilibrium before telltale signs become apparent. Nascent progressive supranuclear palsy, corticobasilar degeneration, various extrapyramidal disorders, and multiple system degenerations can be perplexing in an older person when the only initial symptom is mild imbalance. The development of tone changes, ocular motor abnormalities, or cognitive findings eventually clarifies the diagnosis.

Symptoms Most ataxias are characterized by slowly progressive limb and gait ataxia, dizziness, dysarthria, and abnormal eye movements. Patients report imbalance and poor limb coordination, declining handwriting, and worse balance when fatigued. Dysarthric speech is also commonly aggravated by fatigue. These ataxias may present with dizziness or simply poor balance and may have onset late in life. FXTAS usually has onset at about age 60 years and affects men and only rarely women. Symptoms of FXTAS include new-onset anxiety; reclusive behavior; cognitive decline, including impairment of memory and executive functions, but less commonly overt dementia; ataxia; and intention tremor (Jacquemont et al., 2003). Diagnosis Horizontal gaze-evoked nystagmus and impaired smooth pursuit are probably the most commonly encountered clinical signs, along with truncal ataxia and limb clumsiness. Spontaneous downbeat nystagmus may be seen with any cerebellar ataxia but is particularly common in SCA6. Central positional downbeating nystagmus may also be observed, along with limb dysmetria and impaired diadochokinesis. The gait base widens in time, and steppage becomes visibly clumsy.

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Diagnostic test Patients with cerebellar ataxia should have a brain MRI to exclude structural lesions. Genetic testing is available for Friedreich’s ataxia, many of the autosomal dominant spinocerebellar ataxias, and FXTAS (DNA test for the FMR1 gene). In addition, a characteristic region of increased signal on a T2-weighted brain MRI can be seen in the middle cerebellar peduncles, and cerebellar white matter is present in FXTAS (Brunberg et al., 2002). Treatment Few treatments exist for the ataxias in general. Vitamin E deficiency ataxia can be treated with vitamin E. Gluten ataxia may improve with avoidance of dietary gluten. Physical therapy may result in some functional improvements in some ataxia patients (Ilg et al., 2009).

Episodic ataxia syndromes The episodic ataxias (types 1–6) represent a relatively rare group of sporadic and heritable ataxia disorders characterized by recurrent episodes of vertigo and ataxia. While onset may begin in childhood or early adulthood, symptoms may continue undiagnosed well into late adulthood.

Mechanism These syndromes are due to abnormal ion channels due to various mutations in the P/Q-type voltage-sensitive calcium channel (CACNA1A), in the case of episodic ataxia type 2 (EA2). Episodic ataxia type 1 (EA1) is due to mutations in the voltage-gated potassium channel (KCNA1). Symptoms Episodic ataxia type II manifests with recurrent vertigo and ataxia often associated with other signs and symptoms, such as diplopia, vertical nystagmus, and dysarthria. The episodes may begin in childhood and continue into adulthood. Spells often last minutes to several days and are often periodic. They represent an important treatable cause of vertigo because ataxia and vertigo attacks may subside with the use of acetazolamide (Diamox). EA1 differs from EA2 because the attacks of vertigo and ataxia are shorter in duration, myokymia is present even between attacks, and attacks do not respond as well to acetazolamide. Diagnosis The diagnosis should be suspected in a patient with a long history of recurrent bouts of unexplained vertigo associated with slurred speech and ataxic gait. Downbeat spontaneous or positional nystagmus even between spells lends further support for the diagnosis but is not present in all cases. Responsiveness to acetazolamide is further confirmation of the diagnosis of EA2.

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Diagnostic tests No specific diagnostic tests for this diagnosis exist. Brain MRI may show midline cerebellar vermis atrophy, but this is not always present. There are no commercially available genetic studies for the episodic ataxias at present, so diagnosis is made by history and response to acetazolamide. Differential diagnosis Considerations include transient ischemic attacks from vertebrobasilar insufficiency, MAV, and, in some cases, incipient Meniere’s disease without hearing loss. The presence of dysarthric speech during spells or interictal myokymia in the case of EA1 should help exclude Meniere’s and other otogenic causes of vertigo. SCA6 may be characterized by episodic vertigo and ataxia in some cases. Treatment Treatment with acetazolamide is often effective for EA2, but treatment for the other episodic ataxia subtypes is not well established.

Migraine-associated vertigo Migraine is a common syndrome characterized by severe headaches, nausea, and altered bodily perceptions. Though migraine is more common among younger people, it is also fairly common in older people (Wijman et al., 1998; Haan et al., 2007). Migraine may also be associated with vestibular symptoms such as episodic vertigo and chronic motion sensitivity. Vertigo and motion sickness unaccompanied by headache may also occur with migraine and together are referred to as migrainous vertigo, MAV, or vestibular migraine.

Mechanism The cause of MAV is not completely understood. However, evidence suggests a likely CNS origin, possibly leading to hypersensitization of brainstem nuclei to sensory information, including nociception (headache, allodynia), auditory stimuli (phonophobia), vestibular stimuli (vertigo, motion sickness, visual vertigo), vision (photophobia), and olfaction (osmogenic headaches and nausea) (Cuomo-Granston and Drummond, 2010). Both environmental and genetic factors participate in MAV mechanisms. Symptoms The vertigo comprises recurrent vertigo episodes, general motion sensitivity and motion sickness, and visual vertigo. Visual vertigo, also called optokinetic motion sickness, is a syndrome in which observing objects in motion causes dizziness, nausea, and many of the symptoms of

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motion sickness, even though the individual is not in motion (Guerraz et al., 2001). Migraine headaches are also fairly common in MAV, even if they are not temporally associated with the vertigo attacks.

Diagnosis Patients’ descriptions of vertigo in MAV are often different from those of other diseases that lead to vertigo attacks. In MAV, the duration of vertigo varies widely (Neuhauser et al., 2001), whereas most otogenic vestibular disorders have stereotypic duration: Meniere’s attacks last hours, benign positional vertigo lasts 10–30 seconds, and vestibular neuritis goes on for days to weeks. Vertigo and headache do not always occur at the same time as vertigo in MAV; in fact, vertigo is often present in the absence of migraine headache (Cutrer and Baloh, 1992; Neuhauser et al., 2001). Hence, the diagnosis is clinical and partly based on exclusion of other causes, along with a family or personal history of migraine. Diagnostic tests Vestibular studies may show minor degrees of positional nystagmus, but often these studies are normal. Hearing is unaffected in MAV. Brain MRI is also normal. Differential diagnosis Fluctuating unilateral hearing loss should point to Meniere’s. In patients with vascular risk factors, transient ischemic attacks should be considered. If the vertigo is evoked by turning in bed or changing head position, benign positional vertigo should be considered. Treatment MAV is not life-threatening, so mild cases require no specific treatment and can be managed with antivertiginous medications (Table 16.2). Avoiding triggers such as stress, certain foods, irregular sleep, and skipped meals may be helpful. When the symptoms are frequent or severe and interfere with the quality of life, migraine prophylactic medication may be necessary. These may include the daily use of verapamil, propranolol or similar beta-adrenergic blockers, tricyclic amines, topiramate, or sodium divalproex. MAV has been found to have an association with Meniere’s disease. In such patients, Meniere’s should be concurrently managed with sodium restriction and diuretics.

Normal pressure hydrocephalus Normal pressure hydrocephalus (NPH) is characterized by a triad of progressive gait disturbance, cognitive deficits, and urinary incontinence. It is most commonly seen in older adults.

Mechanism NPH develops gradually when the rate of CSF absorption slows and is gradually outpaced by its production. Prior subarachnoid hemorrhage, meningitis, and trauma may predispose to this process. Most commonly, the hydrocephalus is communicating, though mild cases of aqueductal stenosis and slowly decompensating longstanding overt ventriculomegaly of adulthood (LOVA) can present similarly later in life. In NPH, the ventricles gradually enlarge until the point that the elastic capacity of the brain tissue is exceeded and CNS function becomes impaired. Symptoms The most common and first symptom of NPH is gait disturbance. Gait disturbance in patients with NPH ranges in severity from mild imbalance to inability to walk. Patients may have difficulty turning and can therefore be mistakenly diagnosed with Parkinson’s disease. Patients typically report poor balance, unsteadiness, and difficulty walking but do not report spinning vertigo. Cognitive deficit is presented as mild dementia with a loss of interest in daily activities, forgetfulness, difficulty dealing with routine tasks, and slowed mental processing. Impairment in bladder control ranges from urinary frequency to complete loss of bladder control. All three symptoms of the triad (gait disturbance, cognitive deficits, and urinary incontinence) are common in older people, which can create a challenge to clinicians. It is nevertheless important to try to exclude NPH because patients may respond remarkably well to CSF shunting when the diagnosis is correct. Diagnosis Making a diagnosis of NPH depends on history, examination, response to CSF removal, and brain imaging. The presence of the entire triad (gait imbalance, urinary incontinence, and dementia) is not necessary to make a diagnosis. As mentioned, the earliest feature is a decline in gait, with short, slow steps; apraxia of gait; and general slowing. Because distinguishing clinically among early extrapyramidal syndromes may be difficult, a trial of carbidopa/levodopa is sometimes advisable. Diagnostic testing Brain MRI or CT shows enlarged cerebral ventricle that is disproportionate to any cortical atrophy. Thus, ventriculomegaly, along with a history of slowly progressive gait disturbance, should raise suspicion for NPH. Common steps for clarifying the diagnosis include CSF studies, measurement of opening pressure, and removal of 30–40 mL CSF on a trial basis to see if the patient improves. A 3-day lumbar CSF drain is also helpful but controversial, due to the expense and invasive nature of this assessment.

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Differential diagnosis Other causes of gait impairment should be excluded before making a diagnosis of NPH. Patients with dementia but a fairly normal gait are unlikely to have NPH. Patients with gaze-evoked nystagmus are more likely to have a late cerebellar degeneration and will not benefit from shunting. The condition most commonly confused with NPH is probably striatonigral degeneration (MSA-P) or dopa nonresponsive parkinsonism. Treatment The most common treatment for NPH and the only widely accepted treatment is CSF shunting. Shunting is surgically implanting a CSF catheter, usually in the right lateral ventricle, that is attached to a valve regulator, sometimes with an anti-siphon valve apparatus, which is then attached to another longer catheter placed under the skin that drains into the peritoneum. The shunt channels CSF away from the brain to the peritoneum, where it can be absorbed. Improvement can be dramatic in some patients immediately following shunt placement.

Psychological causes of dizziness Psychological factors contribute to symptoms in many patients with dizziness (Furman et al., 2001; Savastino et al., 2007). Dizziness and vertigo often lead to a sense of loss of control, which seems to foster anxiety more than do other recurrent or chronic medical symptoms. Vertigo from a vestibular disorder may evoke anxiety or may exacerbate previously well-controlled psychiatric conditions (Staab and Ruckenstein, 2003). Psychiatric disorders therefore both cause and result from dizziness. In addition, fear of falling is a common problem among the elderly, and dizziness reinforces this fear (Arfken et al., 1994). Patients with chronic dizziness have a variety of common symptoms that, in some cases, may be part of the underlying cause of vertigo and dizziness or may be a secondary consequence of anxiety due to their symptoms. The so-called “brain fog” and difficulty concentrating is common. Depression, frustration, irritability, and loss of confidence in doing previously easy tasks (such as driving, speaking in public, and traveling) are all reasonably common but must be viewed not only as the possible result of the dizziness symptoms, but also as a response to the process of seeking and obtaining medical care in the health-care system and functioning with their symptoms in society. In many cases, establishing rapport with the patient, explaining the interplay between anxiety and dizziness, and treating any remediable otogenic vestibular disorders goes a long way to unwinding the patient’s anxiety. In some cases, working with a vestibular physical therapist

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can help restore confidence and improve patients’ anxiety and function (Meli et al., 2007). A number of psychiatric disorders appear to predispose to dizziness as well. These may include panic disorder, generalized anxiety, and some of the phobias. In these disorders, the dizziness is more commonly described as floating, rocking, or simply impending loss of control; when severe, agoraphobia may develop. Any underlying otogenic or other cause of dizziness should be treated first, or the ongoing symptoms will confound treatment of the secondary anxiety issues. When medication becomes necessary to manage the anxiety symptoms, intermittent use of a benzodiazepine such as diazepam, lorazepam, alprazolam, or clonazepam can be helpful. When symptoms occur daily, serotonin reuptake inhibitors (Staab and Ruckenstein, 2005) or serotonin norepinephrine reuptake inhibitors may be helpful and allow benzodiazepines to be used more sparingly.

Postural hypotension Postural or orthostatic hypotension is common in older people (Hiitola et al., 2009). What constitutes a clinically significant decline in blood pressure varies, but in general, a drop in systolic blood pressure of 20 mm Hg or more upon assumption of the upright position compared to lying or sitting is considered abnormal. How low the blood pressure drops and patients’ reported symptoms are also relevant to determining whether orthostatic intolerance should be treated. Syncope will occur if blood pressure declines enough, but some patients have enough forewarning and instinctively avoid syncope by sitting as soon as they feel the onset of the dizziness. Consequently, not all patients with problematic orthostatic hypotension report syncope.

Mechanism Any condition that transiently reduces global cerebral blood flow can cause postural hypotension. Cardiac causes include heart failure, valvular heart disease, bradycardia, and other dysrhythmias. Neurally mediated hypotension, also known by other names such as vasovagal near-syncope and neurocardiogenic near-syncope, are due not to cardiac dysfunction, but to transient and inappropriate autonomic function. This may occur at random times or be delayed (Gibbons and Freeman, 2006) so that initial orthostatic vital signs are normal, but as the patient remains standing, the blood pressure later drops.

Symptoms Low blood pressure causes symptoms such as dizziness, faintness, or lightheadedness, often described as on

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the verge of passing out; only infrequently is spinning reported. Patients may report feeling warm, sweaty, or cold and clammy and feeling nauseated when the blood pressure declines. In older patients, these autonomic responses to hypotension may be muted, and patients simply feel weak or feel like they may fall.

Diagnosis The diagnosis of orthostatic hypotension should be suspected when lightheadedness occurs initially upon standing or there is a history of syncope or near-syncope. Measurement of orthostatic vital signs can be confirmatory but may miss some causes, such as delayed orthostatic hypotension (Gibbons and Freeman, 2006) and many cases of vasovagal hypotension (Ward and Kenny, 1996).

Diagnostic tests Tilt table testing is currently the test of choice for patients with unexplained syncope or those in whom hypotension is suspected but not easily documented (Tan et al., 2009).

Treatment Correcting the underlying cause is the most direct treatment, when that is possible. Reducing the dosage or altering antihypertensive medications may help in some cases. Fludrocortisone or midodrine may help increase blood pressure, but one must be careful to avoid supine hypertension. Pyridostigmine, indomethacin, and, in some instances, pindolol may be indicated for some forms of postural hypotension. Lifestyle activities to avoid prolonged standing or to pause upon initially getting up may be enough for some patients to avert serious symptoms.

References Amarenco, P. (1991) The spectrum of cerebellar infarctions. Neurology, 41: 973–979. Arfken, C.L., Lach, H.W., Birge, S.J., and Miller, J.P. (1994) The prevalence and correlates of fear of falling in elderly persons living in the community. Am J Public Health, 84: 565–570. Bladin, P.F. (1998) History of ‘epileptic vertigo’: its medical, social, and forensic problems. Epilepsia, 39: 442–447. Bloom, J. and Katsarkas, A. (1989) Paroxysmal positional vertigo in the elderly. J Otolaryngol, 18: 96–98. Brown, K.E., Whitney, S.L., Wrisley, D.M., and Furman, J.M. (2001) Physical therapy outcomes for persons with bilateral vestibular loss. Laryngoscope, 111: 1812–1817.

Brunberg, J., Jacquemont, S., Hagerman, R.J., et al. (2002) Fragile X premutation carriers: characteristic MR imaging findings in adult male patients with progressive cerebellar and cognitive dysfunction. Am J Neurol Radiol, 23: 1757–1766. Cuomo-Granston, A. and Drummond, P.D. (2010) Migraine and motion sickness: what is the link? Prog Neurobiol. 91: 300–312. Cutrer, F.M. and Baloh, R.W. (1992) Migraine-associated dizziness. Headache, 32: 300–304. Fasold, O., von Brevern, M., Kuhberg, M., et al. (2002) Human vestibular cortex as identified with caloric stimulation in functional magnetic resonance imaging. Neuroimage, 17: 1384–1393. Fetter, M. and Dichgans, J. (1996) Vestibular neuritis spares the inferior division of the vestibular nerve. Brain, 119: 755–763. Fife, T.D. (2009) Benign paroxysmal positional vertigo. Semin Neurol, 29: 500–508. Fife, T.D. and Baloh, R.W. (1993) Disequilibrium of unknown cause in older people. Ann Neurol, 34: 694–702. Fife, T.D., Baloh, R.W., and Duckwiler, G.R. (1994) Isolated dizziness in vertebrobasilar insufficiency: clinical features, angiography, and follow-up. J Stroke Cerebrovasc Dis, 4: 4–12. Frohman, E.M., Zhang, H., Dewey, R.B., et al. (2000) Vertigo in MS: utility of positional and particle repositioning maneuvers. Neurology, 55: 1566–1568. Furman, J.M., Balaban, C.D., and Jacob, R.G. (2001) Interface between vestibular dysfunction and anxiety: more than just psychogenicity. Otol Neurotol, 22: 426–427. Gibbons, C.H. and Freeman, R. (2006) Delayed orthostatic hypotension. a frequent cause of orthostatic intolerance. Neurology, 67: 28–32. Gittis, A.H. and du Lac, S. (2006) Intrinsic and synaptic plasticity in the vestibular system. Curr Opin Neurobiol, 16: 385–390. Goebel, J.A., O’Mara, W., and Gianoli, G. (2001) Anatomic considerations in vestibular neuritis. Otol Neurotol, 22: 512–518. Grad, A. and Baloh, R.W. (1989) Vertigo of vascular origin: clinical and electronystagmographic features in 84 cases. Arch Neurol, 46: 281–284. Guerraz, M., Yardley, L., Bertholon, P., et al. (2001) Visual vertigo: symptom assessment, spatial orientation, and postural control. Brain, 124: 1646–1656. Haan, J., Hollander, J., and Ferrari, M.D. (2007) Migraine in the elderly: a review. Cephalalgia, 27: 97–106. Hadjivassiliou, M., Grünewald, R., Sharrack, B., et al. (2002) Gluten ataxia in perspective: epidemiology, genetic susceptibility, and clinical characteristics. Brain, 126: 685–691. Hain, T.C. and Yacovino, D. (2005) Pharmacologic treatment of persons with dizziness. Neurol Clin, 23: 831–853. Hiitola, P., Enlund, H., Kettunen, R., et al. (2009) Postural changes in blood pressure and the prevalence of orthostatic hypotension among home-dwelling elderly aged 75 years or older. J Hum Hypertens, 23: 33–39. Ilg, W., Synofzik, M., Britz, D., et al. (2009) Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology, 73: 1823–1830. Jacquemont, S., Hagerman, R.J., Leehey, M., et al. (2003) Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet, 72: 869–878. Kemper, T.L. (1994) Neuroanatomical and neuropathological changes during aging and dementia. In: M.L. Albert and J.E. Knoefel (eds), Clinical Neurology of Aging, 2nd edn. New York: Oxford University Press.

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Lee, H. and Cho, Y.W. (2004) A case of isolated nodulus infarction presenting as a vestibular neuritis. J Neurol Sci, 221: 117–119. Lock, R.J., Pengiran Tengah, D.S., Unsworth, D.J., et al. (2005) Ataxia, peripheral neuropathy, and anti-gliadin antibody. guilt by association? J Neurol Neurosurg Psychiatry, 76: 1601–1603. Meli, A., Zimatore, G., Badaracco, C., et al. (2007) Effects of vestibular rehabilitation therapy on emotional aspects in chronic vestibular patients. J Psychosom Res, 63: 85–90. Neuhauser, H., Leopold, M., von Brevern, M., et al. (2001) The interactions of migraine, vertigo, and migrainous vertigo. Neurology, 56: 436–441. National Institute on Deafness and Other Communication Disorders (NIDCD). (1989) Prevalence and cost of vestibular disorders. In: A Report of the Task Force on the National Strategic Research Plan. Bethesda, MD: National Institute on Deafness and Other Communication Disorders and National Institutes of Health. Nogueira, R.G., Schwamm, L.H., and Hirsch, J.A. (2009) Endovascular approaches to acute stroke, part 1: drugs, devices, and data. Am J Neuroradiol, 30: 649–661. Sadeghi, S.G., Minor, L.B., and Cullen, K.E. (2007) Response of vestibular-nerve afferents to active and passive rotations under normal conditions and after unilateral labyrinthectomy. J Neurophysiology, 97: 1503–1514.

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Savastino, M., Marioni, G., and Aita, M. (2007) Psychological characteristics of patients with meniere’s disease compared with patients with vertigo, tinnitus, or hearing loss. ENT Journal, 86: 148–156. Staab, J.P. and Ruckenstein, M.J. (2003) Which comes first? psychogenic dizziness versus otogenic anxiety. Laryngoscope, 113: 1714–1718. Staab, J.P. and Ruckenstein, M.J. (2005) Chronic dizziness and anxiety: effect of course of illness on treatment outcome. Arch Otolaryngol Head Neck Surg, 131: 675–679. Sudarsky, L. (1994) Gait Disturbances in the Elderly. In: M.L. Albert and J.E. Knoefel (eds), Clinical Neurology of Aging, 2nd edn, pp. 483–492. New York: Oxford University Press. Tan, M.P., Duncan, G.W., and Parry, S.W. (2009) Head-up tilt table testing: a state-of-the-art review. Minerva Med, 100: 329–338. Ward, C. and Kenny, R.A. (1996) Reproducibility of orthostatic hypotension in symptomatic elderly. Am J Med, 100: 418–422. Wijman, C.A., Wolf, P.A., Kase, C.S., et al. (1998) Migrainous visual accompaniments are not rare in late life: the framingham study. Stroke, 291: 1539–1543. Wuyts, F. (2008) Principle of the head impulse (thrust) test or Halmagyi head thrust test (HHTT). B-ENT, 4 (Suppl. 8): 23–25.

Chapter 17 Disorders of the Special Senses in the Elderly Douglas J. Lanska Neurology Service, Veterans Affairs Medical Center, Great Lakes Health Care System, Tomah, WI, USA

Summary • Age-related changes in the visual, auditory, olfactory, and gustatory systems are often believed to represent “normal” aging, but they generally represent a combination of normal aging changes in the sensory systems, combined with cumulative toxic insults, medication effects, and the effects of comorbid disease. • The risks of drug toxicity are increased by age-related changes in drug metabolism or drug clearance from the body, by frequent polypharmacy in this patient population, by a greater likelihood of comorbid disease often involving multiple organ systems, and by a lower general capacity to maintain homeostasis in the setting of any toxic or metabolic disruption. • Modality-specific perceptions can be impaired in several different ways: decreased sensitivity to sensory stimuli (decreased acuity), abnormal or distorted quality of sensory stimuli (illusions), and perceptions without stimulation (hallucinations). • Regardless of sensory modality, disorders of the special senses in the elderly can be conveniently divided into conductive, sensorineural, and central disorders, where (1) conductive disorders involve transmission of the sensory stimuli to the sensory receptors (usually but not always by impeding transmission), (2) sensorineural disorders involve dysfunction of the sensory receptors or conduction of signals from the sensory receptors to the brain, and (3) central disorders involve dysfunction of processing of sensory information within the central nervous system, particularly within the brainstem and cerebrum. In general, treatment of conditions causing a conductive loss of one of the special senses is more likely to result in significantly improved function than is treatment of a condition causing a sensorineural loss. • Illusory misperceptions are particularly common with impairments in function of the corresponding sensory modality. Clinically disabling presentations of illusions and hallucinations in the elderly most commonly involve the special sense of vision, less so that of hearing, and least so the chemosensory domains of smell and taste. • Release hallucinations are spontaneous sensory phenomena that occur in the setting of sensory loss, and when possible should be distinguished from hallucinations with an “irritative” mechanism. • Many of the common disabling visual disorders of the elderly are primarily ocular and, therefore, fall within the primary domain of the ophthalmologist or optometrist. These include presbyopia, cataracts, vitreal separations, macular degeneration, and glaucoma. • Functionally significant hearing loss is common in the elderly (affecting about a third of those age 70 or older). Hearing loss in the elderly can adversely affect quality of life and compromise an older individual’s ability to carry out routine activities and interact socially, thereby contributing to isolation, frustration, disappointment, and depression. • Disorders of the chemosensory senses, smell and taste, are usually less disabling than disorders of the other special senses (vision and hearing). Nevertheless, olfactory impairment is a significant contributor to perceived disability and lower quality of life among elderly patients and is a significant predictor of subsequent cognitive decline. Gustatory disorders in the elderly that are not secondary to olfactory disorders should prompt consideration of systemic factors, including medication use, toxin exposures, autoimmune disorders, nutritional disorders, depression, psychosis, cancer, and endocrine and metabolic disorders.

Elderly individuals have a different profile of dysfunction of the special senses than younger individuals, due in part to a constellation of physiologic aging-related changes in the individual sensory systems, the frequent occurrence

of multiple comorbid disease states, and a greater likelihood of toxic effects of medications. Certainly, age-related changes in the visual, auditory, olfactory, and gustatory systems (such as presbyopia, presbycusis, presbyosmia,

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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and presbygeusia) often are believed to represent “normal” aging. However, they generally represent a combination of normal aging changes in the sensory systems, combined with cumulative toxic insults, medication effects, and the effects of comorbid disease. In addition, many clearly pathologic conditions are strongly agerelated and are much more common among the elderly than among younger individuals. For example, among the most common conditions causing a marked loss of visual acuity are cataracts, open-angle glaucoma, and macular degeneration. All these conditions are strongly age-associated and are much more common in the elderly. The elderly are also more likely to be receiving medications to treat diseases and are generally much more susceptible to the toxic side effects of such medications. The risks of drug toxicity are increased by age-related changes in drug metabolism or drug clearance from the body (for example, resulting from changes in liver and kidney function), by frequent polypharmacy in this patient population (with associated, often pronounced increases in adverse effects from drug interactions), by a greater likelihood of comorbid disease (often involving multiple organ systems), and by a lower general capacity to maintain homeostasis in the setting of any toxic or metabolic disruption. Furthermore, any new symptoms, impairments, or disabilities resulting from a new insult to homeostasis in the elderly are likely to act synergistically with existing impairments and disabilities to produce disproportionate declines in functional performance. Unfortunately, although many (but not all) toxic effects of medications are potentially reversible if caught early, side effects of medications in the elderly are often overlooked, being erroneously attributed to aging itself or to comorbid disease states, and cause unnecessary disability and even mortality.

General considerations Clinically, modality-specific perceptions can be impaired in several different ways: decreased sensitivity to sensory stimuli (decreased acuity), abnormal or distorted quality of sensory stimuli (illusions), and perceptions without stimulation (hallucinations). Not generally considered among misperceptions in clinical contexts are ambiguous stimuli that can be variously interpreted or misinterpreted by normal individuals (optical illusions).

Sensory deficits Decreased (or absent) vision, hearing, smell, and taste are referred to, respectively, as visual loss or impairment (blindness), hearing loss or impairment (deafness or anacusis), hyposmia, microsmia, or olfactory hypesthesia (anosmia), and hypogeusia or gustatory hypoesthesia (ageusia). Each of these sensory deficits may have a “conductive” or sensorineural basis (depending on the author or

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circumstance, conductive is sometimes stated conversely as obstructive). Thus, for example, decreases in visual acuity may be conductive (obstructive) if impediments are preventing the conveyance of light to the photoreceptors of the retina (as with corneal opacities, cataracts, or intraocular hemorrhage). Similarly, conductive hearing loss occurs if there are impediments to the conveyance of sound through the external and middle ears to the cochlea (for example, impacted cerumen or middle ear effusion), conductive hyposmia occurs if there are impediments to the conveyance of odorants to the olfactory neuroepithelium (as with chronic rhinosinusitis or nasal polyps), and conductive hypogeusia occurs if there are impediments to the conveyance of gustatory (sapid) stimuli to the taste buds (as with thrush, glossitis, radiation-induced xerostomia, Sjögren’s syndrome, or anticholinergic medications). Because saliva plays such an important role as a transport medium for tastants, conductive hypogeusia often results from conditions that interfere with saliva production. Sensorineural disorders involve the receptors themselves (“sensory”) or the afferent neural pathways involving the respective cranial nerves, tracts, or central processing centers of the brain (collectively, “neural”). Sensorineural disorders can be further subdivided by types of receptors involved, extent and location of receptor involvement within the sensory organ, and location and extent of involvement within the neural pathways. Sensorineural visual impairment, hearing impairment, and hyposmia are all fairly common as isolated entities in the elderly, whereas sensorineural hypogeusia or ageusia as an isolated problem is extremely rare, even in highly selected referral populations (Pribitkin et al., 2003). In general, treatment of conditions causing a conductive loss of one of the special senses is more likely to result in significantly improved function than is treatment of a condition causing a sensorineural loss (Seiden et al., 1992). For example, cataract surgery, removal of impacted cerumen, drug treatment of chronic sinusitis, and discontinuation of anticholinergic drugs may all significantly benefit conductive losses of different special senses. Still, in many examples, sensorineural loss may be treated and functional performance may be improved with appropriate interventions, including optical magnification and adjustment of contrast for macular degeneration, and utilization of hearing aids for sensorineural hearing loss.

Distortions and other misperceptions If an abnormal sensory percept has no evident corollary in the external milieu, the percept is considered to be internally derived (a hallucination); if there is an external correlate that has been distorted or misinterpreted, the percept is considered to be externally derived but aberrantly processed (an illusion). However, in elderly patients with multifactorial sensory impairments and cognitive dysfunction, clearly distinguishing between illusions and

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hallucinations may be difficult. In any case, in many situations, both categories of misperceptions occur as part of the same disease process or as a result of concomitant disease. Illusory misperceptions are particularly common with impairments in function of the corresponding sensory modality. These can include distortions of form (as with dysmorphopsia), size (as with macropsia or micropsia), distance (as with pelopsia or teleopsia), character (as with achromatopsia, aliosmia, or dysgeusia), or location (as with allesthesia) of a stimulus, as well as multiplicity illusions (such as monocular diplopia, polyopia, or diplacusis) and perseverations (such as palinopsia) (Ffytche and Howard, 1999). Hallucinations can occur with or without impairments in function of the corresponding sensory modality and can be simple (as with phosphenes, photopsias, or subjective tinnitus) or complex (as with formed complex visual hallucinations [VHs], or voices, or musical hallucinations). Clinically disabling presentations of illusions and hallucinations in the elderly most commonly involve the special sense of vision, less so that of hearing, and least so the chemosensory domains of smell and taste. Visual misperceptions generally indicate either dysfunction in the eye and/or neural visual pathways, comorbid medical or neurologic conditions, alcohol or sedative/hypnotic withdrawal, and drug toxicity (as with anticholinergic or dopaminergic medications). The frequency of both categories of visual misperceptions is markedly increased in the presence of confusional states, delirium, and various neurodegenerative diseases (such as Parkinson’s disease [PD], dementia with Lewy bodies [DLB], Alzheimer’s disease [AD], and various other dementing disorders). Patients with delirium have specific visual perceptual deficits that cannot be accounted for by the degree of general cognitive impairment (Brown et al., 2009). Whether misperceptions affect a sensory modality globally or are in some sense restricted may give valuable localizing information. For example, visual misperceptions that are monocular (such as metamorphopsias and photopsias) indicate prechiasmal pathology, whereas binocular misperceptions generally indicate retrochiasmal pathology. Homonymous misperceptions indicate unilateral retrochiasmal pathology that may be further localized, depending on both the extent to which the misperceptions are restricted within the visual fields and the presence of any associated symptoms and signs. In trying to characterize the VHs observed among nonpsychotic patients with visual impairments, Cogan usefully distinguished what he called “release” hallucinations from other types of hallucinations, particularly those associated with “irritative” processes (Cogan, 1973). Release hallucinations are spontaneous sensory phenomena that occur in the setting of sensory loss. Sufficient impairment or removal of normal afferent inputs to the primary visual cortex apparently allows, disinhibits, or “releases” spontaneous activity

within the corresponding visual association cortex that is interpreted as a perception, even though there is no corresponding sensory stimulus (a hallucination). A release mechanism for hallucinations is supported by (1) a sensory deficit in the same modality as unimodal hallucinations, with onset of hallucinations in conjunction with or following the sensory deficit; (2) variable content; (3) awareness of the hallucinatory nature of the perception; and (4) no evidence of seizures or other irritative phenomena (including no other positive motor or sensory phenomena, not paroxysmal in character, no epileptiform discharges on electroencephalography, and unresponsive to administration of anticonvulsant medications) (Cogan, 1973; Lanska et al., 1987a; Lanska and Lanska 1993; Braun et al., 2003; Lanska, 2005). Release hallucinations can occur in normal individuals with pansensory deprivation (Heron et al., 1956; Heron, 1957). Similarly, modality-specific release hallucinations can occur experimentally (Heron, 1957) or pathologically (Lanska et al., 1987a; Lanska and Lanska, 1993) with unimodal sensory deprivation. In contrast, an “irritative” mechanism for hallucinations is supported by any of the following: (1) stereotyped content; (2) lack of awareness of the hallucinatory nature of the perception (termed hallucinosis); and (3) evidence of a potentially irritative process (such as migraine, tumor, or seizure) (Cogan, 1973; Braun et al., 2003). However, the clinical distinction between epileptic and release hallucinations is not always clear, and both types can occur in the same patient (Table 17.1). Spontaneous neuronal discharges, which can occur with both seizures and deafferentation, may be involved with both mechanisms (Levison et al., 1951; Echlin and Battista, 1963; Chattha and Lombroso, 1972; ). Table 17.1 Comparison of ictal hallucinations and release hallucinations Characteristic

Ictal hallucinations

Release hallucinations

Duration

Brief (s to min)

Variability

Often stereotyped

Content Sensory deficit in modality of hallucination Environmental triggers

Simple or complex No (except possibly incidental)

Often persistent (min to h) Usually variable and change over time; rarely stereotyped Simple or complex Yes

No

Often Associated ictal behavior, including alterations of consciousness Epileptiform Often discharges or seizures demonstrated on EEG

Common (low light, closing or opening eyes, saccadic eye movements) No

No

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The VHs that occur in patients with Lewy body alphasynucleinopathies (such as PD and DLB), other dementias, and delirium are dealt with separately in the section on vision. Such VHs are not adequately accounted for within Cogan’s simple dichotomy of nonpsychotic hallucinations into release and irritative types.

Examination Clinical examination of the special senses in an elderly patient by a geriatrician or neurologist requires careful general physical and neurologic examinations augmented by several office examination techniques. In many cases, further assessment by an ophthalmologist (for ocular disturbances), audiologist and otolaryngologist (for auditory disorders), or otolaryngologist (for auditory, olfactory, or gustatory disorders) is appropriate. Office testing of vision as part of a neurologic examination in elderly patients should include visual acuity testing of each eye with and without pinhole (to check for uncorrected refractive errors), Amsler grid testing of each eye to check for disorders of the central visual fields (such as scotomata and metamorphopsia), monocular and binocular confrontational assessments of the peripheral visual fields, pupillary reflex testing, and ophthalmoscopy. The penlight shadow test is a helpful screening test for a narrow anterior chamber depth—tangential illumination of the eye from the lateral side normally illuminates the entire iris, but with an abnormally narrow anterior chamber, the iris is bowed forward and the nasal iris is at least partly in shadow (not illuminated) (Lanska, 2006). Generally when 50% or less of the nasal iris is illuminated with the penlight shadow test, there is a moderate or high risk of angle closure with pharmacologic pupillary dilation (Townsend, 1991). If there is no history of glaucoma and if screening with a penlight is performed accurately and the results are negative, the risk of dilating a potentially occludable angle is less than 0.3% (Patel et al., 1995). Gonioscopy by an ophthalmologist or optometrist is the definitive test for determining anterior chamber depth. Elderly individuals who have obvious hearing difficulty or recognize that they have hearing impairment should have otoscopy and audiometry (Nondahl et al., 1998; Bagai et al., 2006). Elderly individuals who are asymptomatic from a hearing perspective should be screened for hearing loss, preferably with the whispered voice test (Uhlmann et al., 1980; Pirozzo et al., 2003; Bagai et al., 2006), the calibrated finger rub auditory screening test (CALFRAST; Torres-Russotto et al., 2009), or a handheld audiometer. Application of the whispered voice test produces the greatest gain in diagnostic certainty of any of the available bedside screening tests among both demented and nondemented elderly patients. Asymptomatic elderly individuals who perceive a whispered voice generally require no further testing, while those unable to perceive a whispered voice require audiometry (Bagai et al., 2006).

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Tuning fork tests (the Rinne, Weber, and Bing tests) are not useful for general bedside hearing screening and can be abandoned for this purpose (Bagai et al., 2006); even in diagnostic situations, the results of these tests can be misleading (Stankiewicz and Mowry, 1979; Miltenburg, 1994; Pirozzo et al., 2003; Vikram and Naseeruddin, 2004; Bagai et al., 2006; Boatman et al., 2007). Hearing loss as measured with audiometry is categorized commonly according to American National Standards Institute references for signal intensity: normal, 10–26 dB; mild loss, 27–40 dB; moderate loss, 41–55 dB; moderately severe loss, 56–70 dB; severe loss, 71–90 dB; and profound loss, 91+ dB (Campbell, 1998). Categorization of the degree of hearing loss is generally based on the pure tone average of three standard frequencies in the speech range (the average of air-conduction thresholds at 500, 1000, and 2000 Hz) but may be specified for each frequency region (low, mid, or high frequencies on the audiogram) (Campbell, 1998). Office testing of smell can include well-standardized, commercially available tests (such as the University of Pennsylvania Smell Identification Test, or UPSIT) or crude approaches utilizing identification of a few readily available odorants (such as oil of wintergreen or oil of cloves) (Doty et al., 1984a, 1984b; Doty, 2007a); more complicated odor identification and detection tests are also available but are rarely practical outside specialized diagnostic laboratories (Doty, 2007a). The UPSIT is a forced-choice olfactory discrimination test that uses microencapsulated odorants in standardized “scratch ‘n’ sniff” booklets. UPSIT scores are standardized by gender and age, and can be used to identify degrees of hyposmia and some malingerers. Irritant substances, such as ammonia, are sometimes employed when psychogenic or malingered anosmia is a consideration, because such substances are perceived via trigeminal afferent pathways instead of through the olfactory system. Office testing of gustatory function remains somewhat crude (Schuster et al., 2009). Testing of taste thresholds is problematic because salivary function and size of the tongue area stimulated influence threshold assessment, taste intensity may be depressed even with normal recognition thresholds, and changes in threshold detection do not necessarily correlate with suprathreshold taste intensity. Nevertheless, complicated and time-consuming procedures are available for whole-mouth assessment of thresholds for each of the four primary tastes (sweet, sour, salty, and bitter) (Yamauchi et al., 2002a, 2002b). Newer technologies, such as using flavor-impregnated taste strips (similar to currently available commercial breath-freshening strips) or tasting tablets are in development and can potentially include assessment at multiple thresholds for all of the primary tastes, including umami (savory) gustatory sensation (Ahne et al., 2000; Smutzer et al., 2008; Landis et al., 2009).

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Categorization of sensory disorders by modality and level of dysfunction Regardless of sensory modality, disorders of the special senses in the elderly can be conveniently divided into conductive, sensorineural, and central disorders, where (1) conductive disorders involve transmission of the sensory stimuli to the sensory receptors (usually but not always by impeding transmission); (2) sensorineural disorders involve dysfunction of the sensory receptors or conduction of signals from the sensory receptors to the brain; and

(3) central disorders involve dysfunction of processing sensory information within the central nervous system, particularly within the brainstem and cerebrum. This is essentially the classical categorization for auditory disorders, but it can also be applied to visual and chemosensory disorders (Table 17.2). Especially for the visual system, central disorders can be further divided by the involvement of precortical afferent pathways, primary sensory cortex, and association cortex), but such considerations are beyond the scope of this chapter.

Table 17.2 Selected disorders of the special senses in the elderly Modality

Category Conductive

Sensorineural

Central

Vision

Presbyopia Dermatochalasis Astigmatism Myopia Hyperopia Cataracts Monocular diplopia Vitreal detachment Vitreal hemorrhage

Age-related macular degeneration Diabetic retinopathy Retinal detachment Glaucoma Amaurosis fugax Retinal artery occlusion Retinal vein occlusion AION (nonarteritic and arteritic) Progressive painless optic neuropathy (paraneoplastic, neoplastic) Bonnet syndrome

Late-life migraine accompaniments Retrochiasmal visual field defects (MCA- or PCA-territory stroke) Poststroke unilateral inattention or neglect Visual agnosia Anton’s syndrome Heidenhain variant of CJD Epileptic visual hallucinations Visual hallucinations with retrochiasmal visual field defects Visual hallucinations in neurodegenerative diseases and delirium

Hearing

Cerumen impaction Serous otitis media Objective tinnitus

Pure word deafness Auditory agnosia Auditory hallucinations Brainstem auditory hallucinosis

Olfaction

Upper-respiratory infection Chronic rhinosinusitis Nasal polyposis Dentures

Presbycusis Noise-induced hearing loss Ototoxic drugs Sudden SNHL Herpes zoster oticus Superficial siderosis Meningitis Carcinomatous meningitis Subjective tinnitus Presbyosmia Drug toxicity Tobacco smoking Head injury Hypothyroidism Influenza-like infection Subfrontal meningioma

Gustation

Poor oral hygiene Lingual plaque Dental caries or periodontal disease GERD Upper-respiratory illness Thrush Oral cancer Xerostomia

Presbygeusia Drug toxicity Nutritional deficiencies (such as niacin, cobalamin, or zinc) Hypothyroidism Diabetes Bell’s palsy Influenza-like infection Burning mouth syndrome

Depression Stroke Hypogeusia in PD and DLB

Epileptic olfactory auras Hyposmia in PD and DLB Hyposmia in other neurodegenerative diseases

AION, anterior ischemic optic neuropathy; CJD, Creutzfeldt–Jakob disease; DLB, dementia with Lewy bodies; GERD, gastroesophageal reflux; MCA, middle cerebral artery; PCA, posterior cerebral artery; PD, Parkinson’s disease; SNHL, sensorineural hearing loss. Note: Disorders in bold font are discussed in greater detail later. These disorders were selected because of their general importance in a geriatric population (based on frequency, impact on quality of life and disability, and so on), the strength of association of disease prevalence or incidence with aging, diagnostic concerns (such as frequency with which the diagnosis is missed), conceptual factors (for example, to contrast different etiologies), treatment implications, and the need for the special expertise of a geriatrician or geriatric neurologist. Other topics are not further discussed or are mentioned briefly.

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Vision Many of the common disabling visual disorders of the elderly are primarily ocular and, therefore, fall within the primary domain of the ophthalmologist or optometrist. These age-related conditions include presbyopia, cataracts, vitreal separations, macular degeneration, and glaucoma. Nevertheless, it is essential for geriatric neurologists and geriatricians to recognize these disorders, to appropriately direct referrals and minimize unnecessary or inappropriate evaluations. Furthermore, the geriatrician and geriatric neurologist should ensure that risk factors for the development of disabling visual impairment are appropriately addressed, that primary and secondary prevention is undertaken when appropriate (including use of antioxidants and mineral supplements for secondary prevention of severe macular degeneration), and that rehabilitation approaches are utilized that maximize residual visual function (including use of accessible publishing and adaptive low-vision aids). Maximizing vision can help patients achieve their functional potential, improve overall quality of life, and minimize problems with multisensory disequilibrium, falls, falls with injury, depression, and cognitive impairment. The most important disorders contributing to vision impairment in the elderly include senile cataracts, agerelated macular degeneration, primary open angle glaucoma, and diabetic retinopathy. In the Framingham Eye Study, at age 75–85 years, approximately half had cataracts, more than a quarter had age-related macular degeneration, and about 7% (about 1 in 14) had primary open angle glaucoma and a similar proportion had diabetic retinopathy (Kini et al., 1978). About 20% of individuals age 70 years and older have functionally significant vision impairment, and about 2% report blindness in both eyes (Campbell et al., 1999). Severe visual impairment is particularly disabling for elderly patients and is a risk factor for various complications, including falls and hip fractures (Lamoreux et al., 2008; Kulmala et al., 2009). Even normal elderly have lost the ability to accommodate and generally have difficulty in conditions of low contrast and low luminance.

Conductive visual disturbances Visual disturbances can be categorized as conductive if they interfere with light transmission to the photoreceptive retina. Such disturbances can be unilateral or bilateral. Examples commonly seen among geriatric patients include dermatochalasis (when redundant or dehiscent skin from the eyelid droops across the path of light to obscure at least a portion of the cornea); corneal abnormalities (a pterygium extending to cornea); abnormalities of ocular shape that interfere with proper focusing of an image on the retina (astigmatism, myopia, or hyperopia); or age-related changes in the crystalline lens that preclude

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focusing at near (presbyopia), interfere with light transmission (cataracts), or disrupt light transmission between the lens and the retina (posterior vitreal detachment). Dermatochalasis and pterygia are obvious by visual inspection; dermatochalasis characteristically produces superior temporal visual field defects in affected eyes, and pterygia can produce astigmatism or visual field defects. Cataracts are readily recognized by loss of a red reflex with pupillary reflex testing using a penlight and, if dense, can interfere with ophthalmoscopy. A useful clinical test for many conductive visual disturbances is the pinhole test. By looking through a “pinhole” (a small-diameter hole measuring 1–2 mm in an otherwise opaque card or occluder), the patient views through a narrow visual angle. This minimizes existing focusing problems, such as problems from inadequately corrected astigmatism, myopia, hyperopia, or presbyopia, or from corneal or lenticular irregularities. Demonstrating an improvement in measured visual acuity using a pinhole (a “positive” pinhole test) establishes a conductive (ocular) basis contributing to the impairment in visual acuity. For similar reasons, a pinhole can also be used to assess patients with complaints of monocular diplopia. Monocular diplopia typically occurs when light is multiply directed along different trajectories because of aberrations in the light-transmitting portions of the eye (typically the cornea or lens). Ocular causes of monocular diplopia include refractive problems (such as astigmatism), poorly fitting contact lenses, corneal abnormalities (such as resulting from dry eye or prior ocular surgery), iris abnormalities (such as iridotomy or iridectomy), lenticular abnormalities (such as cataracts or positioning problems with intraocular lens implants), or retinal abnormalities (such as epiretinal membrane). Usually with monocular diplopia, the second image is a less distinct and partially superimposed “ghost” or “halo” of the first image. Eliminating this second image when viewing through a pinhole confirms a conductive (ocular) basis for the complaint, which may (depending on the cause) respond to refraction, a trial of artificial tears, or a contact lens trial. Several conductive visual disorders that are common in geriatric patients—including presbyopia, senile cataracts, and posterior vitreal detachment—are discussed in further detail.

Presbyopia Presbyopia is a normal age-related condition (literally “elderly vision” or “old age vision”) in which the lens of the eye gradually loses its ability to accommodate, making it difficult to see objects up close and often leading to squinting, eyestrain, and headaches. Accommodation is the process by which the eye changes optical power to maintain a clear image (focus) on an object as the distance to the object changes. The focusing power of the eye

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depends on the elasticity of the crystalline lens, which gradually declines as people age, partly as a result of continued growth of the lens throughout life. People usually notice symptoms of the condition in their late 40s, as they need to hold reading materials farther away to focus on them; by this time, accommodation amplitude has decreased sevenfold, from 7 diopters at age 15 to about 1 diopter at age 40. By age 60, the eyes have usually lost most of the elasticity needed to focus up close. Symptoms can include difficulty reading fine print, particularly in low-light conditions; eyestrain when reading for long periods; blur at near distances; and transient blur when transitioning between viewing distances. Some patients report that their arms have become “too short” to hold reading material at a comfortable distance. Presbyopia, like other focusing defects, is much less noticeable in bright sunlight because then the iris closes to a smaller diameter (in effect, accomplishing the same thing as a clinical “pin hole” acuity test). Presbyopia can be corrected with reading glasses or half-glasses for those who do not need glasses for distance vision or with bifocals or contact lenses for those who do. Inexpensive over-the-counter reading glasses are readily available with corrective lenses that cover a wide range of magnification levels. Some people choose to correct one eye for near vision and one eye for distance vision using different contact lenses; this approach, called “monovision,” eliminates the need for bifocals or reading glasses, although it can affect depth perception and some elderly patients may not tolerate it. Newer bifocal or multifocal contact lenses also can correct for both near and far vision with the same lens. In addition, surgical procedures can provide solutions for those who do not want to wear glasses or contacts. In some patients, presbyopia can be corrected by intraocular lens implants at the time of cataract surgery. Although eye exercises and various devices (such as glasses with an array of pinholes) have been marketed to delay or improve presbyopia, their effectiveness has not been demonstrated.

Senile cataracts Senile cataracts are due to age-related opacification of the crystalline lens of the eye, a result of progressive denaturation and aggregation of lens proteins. The condition usually affects both eyes, but typically with asymmetric onset. Cataracts produce slowly progressive visual loss and are potentially blinding if untreated. Cataracts also cause loss of contrast sensitivity so that contours, shadows, and colors are less vivid. Early in cataract development, the power of the lens may be increased (as a result of lenticular swelling), causing or exacerbating myopia. The gradual yellowing and opacification of the lens may reduce perception of blue colors. Glare, and occasionally monocular diplopia or polyopia, can also occur as light is scattered by the cataract into the eye. An affected eye has

an absent red reflex, and the opacified lens may compromise adequate ophthalmoscopy. Over time, the lens cortex liquifies to form a milky white fluid (Morgagnian cataract), which can cause severe inflammation if the lens capsule ruptures. Untreated cataracts can also cause secondary angle-closure glaucoma (phacomorphic glaucoma) due to lens swelling (intumescence). In the final stage, lens shrinkage is associated with complete loss of transparency. According to estimates by the World Health Organization, age-related cataracts are responsible for blindness in 18 million people, or approximately half of the cases of blindness around the world. In addition to advanced age, cataracts may be caused or accelerated by long-term ultraviolet light exposure, cigarette smoking, radiation, diseases (such as diabetes, hypertension, and glaucoma), drugs (such as corticosteroids and quetiapine), and ocular trauma. Risk factors for moderate nuclear opacities include female gender, nonwhite race, and smoking (AgeRelated Eye Disease Study Research Group, 2001a). When a cataract is sufficiently developed to require surgery, the most common approach is capsulotomy with extracapsular cataract extraction (ECCE), in which only the front of the lens is removed, while the back of the lens capsule remains intact and provides support for the lens implant. Ultrasound is sometimes used to break up the cataractous lens, in conjunction with simultaneous irrigation and aspiration (phacoemulsification). The cataractous lens is replaced with a permanent plastic intraocular lens implant. Although traditional intraocular lenses are monofocal, newer multifocal lenses can minimize subsequent dependence on glasses. Cataract operations are usually performed as day surgeries under local anesthesia. Potential complications of cataract surgery include endophthalmitis, posterior capsular opacification, and retinal detachment.

Posterior vitreous detachment Posterior vitreous detachment (PVD) is a common agerelated condition in which the vitreous humor separates from the retina. As a person ages, the delicate collagen framework of the vitreous gel deteriorates, causing the vitreous to shrink and develop pockets of liquefaction, and potentially to suddenly separate from the retina. When this happens, symptoms can include monocular flashes of light (photopsias), a sudden marked increase in the number of floaters, or a ring of floaters located to the temporal side of the central vision. PVD by itself does not normally threaten sight, but it may lead to traction and distortion of the retina, as well as retinal tears or detachment. Acute symptoms generally subside over a period of several days to several months. Approximately two-thirds of individuals over age 70 have evidence of PVD. Risk factors for PVD include age and myopia (Akiba, 1993; Morita et al., 1995;

Disorders of the Special Senses in the Elderly

Yonemoto et al., 1996; Hayreh and Jonas, 2004). PVD is rare in emmetropic people under age 40 years, but it increases progressively with age to a prevalence of greater than 80% among those in their 90s (Akiba, 1993). People with myopia greater than 6 diopters are at higher risk of PVD at all ages. Because the underlying changes develop symmetrically in both eyes with age, PVD may develop in the second eye within a few years of developing in the first eye (Hikichi, 2007). As a PVD proceeds, areas of adherent vitreous may pull on the retina. Vitreous traction may stimulate the retina, with resultant flashes that can look like a circle. If enough traction occurs, the retina may tear at these points. If there are only small point tears, these can allow glial cells to enter the vitreous and proliferate to create a thin epiretinal membrane that distorts vision. In more severe cases, vitreous fluid may seep under the tear, separating the retina from the back of the eye and creating a retinal detachment. Retinal vessels may tear in association with a retinal tear, or occasionally without the retina being torn. If a retinal vessel is torn, leakage of blood into the vitreous cavity is often perceived as a “shower” of floaters. The risk of retinal tears and detachment associated with vitreous detachment is higher in elderly individuals, patients with severe myopia and myopic retinal degeneration, and those with a familial or personal history of previous retinal tears or detachment. Retinal detachment is the separation of the neurosensory layer of the retina from the underlying choroid and retinal pigment epithelium, a situation that rapidly produces ischemic degeneration of photoreceptors. Presenting symptoms in the affected eye include the sudden onset of photopsias (flashing lights), new and more prominent floaters (often with PVD), decreased visual acuity, and metamorphopsia (wavy distortion of viewed objects). Vision loss may be curtain-like, filmy, or cloudy. Permanent vision loss can be minimized or prevented by rapid diagnosis and prompt treatment. Prompt examination of patients experiencing vitreous floaters combined with expeditious treatment of any retinal tears is the most effective means of preventing associated retinal detachments (Byer, 1994). The risk of retinal detachment is greatest in the first 6 weeks following a vitreous detachment, but it can occur more than 3 months after the event. Patients initially diagnosed as having uncomplicated PVD have a greater than 3% chance of developing a retinal tear within 6 weeks, but the risk is greater if at least 10 new floaters develop or if vision is subjectively reduced during this period (Hollands et al., 2009). Patients with the acute onset of monocular floaters or flashes, and patients with known PVD and a change in symptoms, should be urgently evaluated by an ophthalmologist for high-risk features of retinal tear and detachment. The prevalence of a retinal tear under these circumstances is approximately one in seven (Hollands

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et al., 2009). Subjective visual reduction is the most important symptom associated with retinal tear, so visual acuity should always be assessed in this situation (Hollands et al., 2009). The success of retinal reattachment surgery is now greater than 90%. The major cause of failure is development of proliferative vitreoretinopathy (PVR), a complex inflammatory reaction involving development of epiretinal membranes, which are essentially scars formed chiefly by cells of pigment epithelial and glial origin. Epiretinal membranes can exert traction and reopen previously closed retinal tears, create new tears, bulge and distort the macula (macular pucker), obscure the macula, or cause macular edema (Machemer, 1988; Asaria and Gregor, 2002). Often, this results in visual distortions that are visible as bowing, blurring, or segmental size alterations when looking at lines on an Amsler grid or on chart paper. Surgeons can remove or peel the epiretinal membrane through the sclera in conjunction with vitrectomy and improve vision by two or more lines on the Snellen chart. The chance of visual improvement is reported to be approximately 80–90%. Surgery is not usually recommended unless the distortions are functionally disabling, because of potential but rare surgical complications, including endophthlamitis, retinal detachment, glaucoma, retinal bleeding, cataract progression, and recurrence of the membrane.

Sensorineural visual disturbances Sensorineural visual disturbances involve the retinal elements and the transmitting neural pathways to the lateral geniculate nucleus (optic nerves, optic chiasm, and optic tracts). Examples of sensorineural visual disturbances seen among geriatric patients include age-related macular degeneration, glaucoma, amaurosis fugax, embolic branch retinal artery occlusions, arteritic anterior ischemic optic neuropathy (from giant cell arteritis), and progressive painless optic neuropathy. VHs associated with sensorineural vision loss (such as Bonnet hallucinations) also are considered here—the primary pathology is typically at a sensorineural level, although the hallucinations themselves are generated centrally. Among the sensorineural disorders, those that affect the sensory elements in the retina are initially identified and assessed with tonometry (to measure intraocular pressure [IOP] and assess for glaucoma), visual acuity measurement, visual field testing (including central visual field testing with the use of an Amsler grid), ophthalmoscopy, and collateral cerebrovascular studies and cranial imaging if there is evidence by history or examination of ocular vascular compromise or embolic phenomena (for example, a history of amaurosis fugax or ophthalmoscopic evidence of branch retinal emboli, including Hollenhorst plaques, which are cholesterol emboli seen at bifurcations of retinal arterioles). Sensorineural visual disorders that

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affect the retro-retinal neural (anterior visual) pathways are typically identified and assessed in clinical office practice by visual field testing, visual acuity testing, pupillary light reflex testing, and the swinging flashlight test for an afferent pupillary defect. Sudden onset of a unilateral optic neuropathy in the elderly often indicates a vascular problem (such as embolic, atherosclerotic vaso-occlusive, or arteritic), whereas a unilateral painless progressive optic neuropathy may indicate a malignancy (such as paraneoplastic process, metastasis, or carcinomatous or lymphomatous meningitis) (Lanska et al., 1987b). Several sensorineural visual disorders that are commonly encountered in geriatric patients and that preferentially affect the elderly are discussed in further detail. These include age-related macular degeneration, glaucoma, the arteritic anterior ischemic optic neuropathy seen with giant cell arteritis, and nonarteritic anterior ischemic optic neuropathy (NAION).

Age-related macular degeneration Age-related macular degeneration (abbreviated variously as AMD or ARMD) affects older adults (typically >60 years) and results in a progressive loss of central vision because of damage to the retinal macula. Visual loss from AMD is often disabling and greatly impacts quality of life, to a degree with moderate disease similar to that of severe cardiac angina or a fractured hip; severe disease adversely affects quality of life more than that of dialysis, and very severe disease adversely affects quality of life to a degree comparable to end-stage prostate cancer or a catastrophic stroke (Brown et al., 2005). In particular, the loss of central vision and loss of visual acuity can irreversibly result in loss of reading, facial recognition, and driving (Ehrlich et al., 2008). AMD is the leading cause of irreversible severe vision loss and of legal blindness in patients over age 60 years (Klein et al., 1997b). In the “dry” (nonexudative) form, yellow deposits of cellular debris called drusen accumulate between the retinal pigment epithelium and the underlying choroid, whereas in the later and more severe “wet” (exudative) form, neovascularization develops from the choroid behind the retina. Vision loss generally progresses relatively slowly in dry AMD (over years), whereas wet AMD may progress rapidly (over weeks). Although only about 10–15% of people with AMD have the wet form, it causes most of the vision loss associated with the condition; 85% of those with wet AMD lose all central vision and have acuity measured in the 20/200–20/400 range (that is, can read the big E or the second line of the eye chart). Most people with early pathologic changes of dry AMD have preserved vision. As drusen increase in size and number, the retinal pigment epithelium under the macula is increasingly disturbed and becomes atrophic, causing secondary degeneration of the overlying macular retinal photoreceptors and the development of a blurred

and dim spot in central vision (a central scotoma). Drusen can also cause pigment epithelial detachment (patients are often told that they have a “blister” or “bump” on the retina). As the entire macula becomes affected in the late stages of dry AMD, so-called geographic atrophy of the macula develops. In wet AMD, brittle blood vessels break down and fragile new blood vessels grow under the macula (choroidal neovascularization from the choriocapillaris through Bruch’s membrane into the subretinal space). These blood vessels are prone to leak blood and fluid, often causing extensive macular damage and, ultimately, development of a discaform (disc-shaped) gray scar. “Advanced” AMD is considered to include the late stage of dry AMD along with wet AMD. AMD affects approximately 10% of patients 66–74 years of age, and 30% of patients 75–85 years of age. Risk factors for AMD or progression to advanced AMD include age, female gender, family history, race (higher in Caucasians than people of African descent), hypertension, hypercholesterolemia, high fat intake, obesity, cigarette smoking, and lower dietary intake of long-chain polyunsaturated fatty acids and fish (Age-Related Eye Disease Study Research Group, 2000, 2001a; Clemons et al., 2005; Age-Related Eye Disease Study Research Group et al., 2007; SanGiovanni et al., 2007, 2008, 2009). The strongest and most consistent risk factors are smoking and age (Hyman and Neborsky, 2002). Several genes have also been associated with the development of AMD, including a major risk variant within the complement factor H gene (CFH). Evidence regarding the role of sunlight is conflicting. The most common symptom of dry AMD is blurred vision, which is limited to the center of the visual field. Objects of regard (in the center of vision) often look distorted and dim, and colors look faded due to a loss of contrast sensitivity. Reading print and seeing other fine details becomes increasingly impaired, but affected patients can generally see well enough to walk and perform most routine activities. As the disease progresses, patients may need more light to read or perform everyday tasks. The central scotomas gradually get larger and darker, and in the later stages, recognition of faces becomes increasingly difficult unless the faces are very close to the affected individual. In wet AMD, straight lines may appear distorted and wavy (metamorphopsia) when fluid from the leaking blood vessels gathers and lifts the macula. Although loss of central vision in AMD profoundly affects visual function, markedly impairs performance in certain activities (such as reading and driving), and can lead to legal blindness, it never causes complete blindness. The macular area affected by AMD is approximately only half of a centimeter in diameter and comprises about 2% of the retinal surface, while the remaining 98% of the retinal surface (which is responsible for peripheral vision) remains unaffected by AMD. Although the

Disorders of the Special Senses in the Elderly

macula corresponds to such a small fraction of the total visual field, at least half of the visual cortex is devoted to processing macular information (Horton and Hoyt, 1991; McFadzean et al., 1994). Persons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Outside of an ophthalmologic practice, central vision should be assessed by measuring visual acuity and by using an Amsler grid. An Amsler grid is a simple office tool for assessing macular health that is essentially a pattern of regularly spaced, intersecting, horizontal and vertical lines resembling graph paper with a fixation spot marked in the middle as a black dot. With normal vision, all lines surrounding the black dot look straight and evenly spaced, with no missing or distorted areas; with AMD or other macular diseases, the lines can look bent or otherwise distorted, and sections may be missing. Further ophthalmologic diagnostic procedures may include fluorescein angiography and optical coherence tomography (OCT). Although there is no known way to prevent macular degeneration, lifestyle modification has been advocated based on identified risk factors, including the following: abstinence from tobacco; a healthy diet that is high in fruits, green leafy vegetables, nuts, and fish, and low in red meat and animal fat; regular exercise; a normal blood pressure; and a healthy weight. Currently, there is insufficient evidence to support the role of dietary antioxidants, including the use of dietary antioxidant supplements, for primary prevention of early AMD (Chong et al., 2007). People with established AMD may benefit from secondary prevention with dietary supplements, as used in the Age-Related Eye Disease Study (AREDS; Age-Related Eye Disease Study Research Group, 2001b). The AREDS formula consisted of antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta-carotene, 15 mg) plus zinc (80 mg, as zinc oxide) and copper (2 mg, as cupric oxide). However, beta-carotene has been found to increase the risk of lung cancer in smokers, vitamin E has been associated with an increased risk of heart failure in people with vascular disease or diabetes, and zinc has been associated with an increase in hospitalization for genitourinary conditions (Lonn et al., 2005; Johnson et al., 2007; Evans, 2008; Gallicchio et al., 2008; Tanvetyanon and Bepler, 2008). Because peripheral vision is not affected in AMD, affected individuals can learn to use their remaining vision to continue most activities, although they may need extra ambient light or magnification to perform optimally. Accessible Publishing provides a variety of fonts and formats for published books to make reading easier, including much larger fonts for printed books, audiobooks, and books with both text and audio. Adaptive low-vision aids can also help patients with AMD use remaining vision more effectively and can improve the quality of life. Adap-

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tive devices include inexpensive handheld magnifying glasses, magnifiers mounted on height-adjustable stands, special eyeglass lenses, and reading telescopes (mounted on eyeglasses or handheld). More expensive video magnifiers project printed material on a closed-circuit television (CCTV) monitor, television, or computer screen and allow adjustments of magnification, brightness, and contrast. A more portable device is also available that rests on reading material and projects a magnified image onto a pair of eyeglasses. In 2010, the Food and Drug Administration (FDA) approved an implantable (intraocular) telescope for treatment of AMD. Although no established medical or surgical treatment is available for dry AMD, treatments for wet AMD may include anti-angiogenics (anti-Vascular Endothelial Growth Factor, or anti-VEGF agents), laser photocoagulation, and photodynamic therapy. Anti-VEGF agents, including ranibizumab and pegaptanib, can cause regression of the abnormal blood vessels and improvement of vision when injected every 4–6 weeks directly into the vitreous humor of the eye; complications can include endophthalmitis, increased IOP, traumatic cataract, and retinal detachment. Laser photocoagulation seals newly developed choroidal blood vessels to lessen the chance that the vessels will damage the macula, but in the process, it produces small retinal scars and associated scotomas; because of this, laser photocoagulation has increasingly been replaced by newer treatments, including use of anti-VEGF agents and photodynamic therapy. Photodynamic therapy uses a low-energy laser to activate a prodrug (verteporfin) as it passes through the retinal blood vessels; the light-activated drug stops and sometimes reverses neovascularization.

Glaucoma Glaucoma is a group of eye diseases with progressive optic neuropathy associated with loss of retinal neurons and the nerve fiber layer, due to impaired drainage of aqueous humor, typically with abnormally elevated IOP (above 21 mm Hg or 2.8 kPa, with normal values of 16 ± 5 mm Hg), “cupping” of the optic nerve head (with enlargement of the optic cup so that the cup-to-disc, or C/D, ratio is >0.5), and visual field defects related to the optic nerve damage. Glaucoma is more prevalent in the elderly, even compensating for the fact that mean IOP slowly rises with increasing age (Patel et al., 1995). Aqueous humor is produced by the ciliary bodies, enters the posterior chamber (bounded posteriorly by the lens and the zonules of Zinn and anteriorly by the iris), and flows through the pupil of the iris into the anterior chamber (bounded posteriorly by the iris and anteriorly by the cornea). Aqueous humor is drained from the anterior chamber of the eye through a trabecular meshwork via Schlemm’s canal into scleral vascular plexuses. IOP is a function of the production of liquid aqueous humor by

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the ciliary bodies of the eye and its drainage through the trabecular meshwork. Two main categories of glaucoma exist: closed angle and open angle. Both forms typically present after age 50 (Patel et al., 1995). Closed-angle glaucoma (also known as “narrow-angle” or “angle-closure” glaucoma) is the less common category, representing approximately 10% of the cases in the United States but up to half of the cases in Asian countries. Closed-angle glaucoma can present as a medical emergency, with the sudden onset of severe eye pain and redness, often with associated symptoms and signs: headache; malaise; nausea and vomiting; halos seen around bright lights; blurred vision and reduced visual acuity; a fixed, mid-dilated pupil; corneal clouding (due to edema); and severely elevated IOP (>30 mm Hg) (Lanska, 2006). Closed-angle glaucoma can produce irreversible vision loss in a matter of hours (Lanska, 2006). This type is so named because the iridocorneal angle of the anterior chamber of the eye (the junction of the cornea and sclera externally with the iris internally) is narrow or occluded, which blocks sufficient absorption of aqueous humor through the canal of Schlemm. In individuals with primary closed-angle glaucoma, the angle is congenitally narrow. This may be exacerbated with age and the development of synechiae (effectively “scars” due to prolonged contact between the iris and the trabecular meshwork seen on slit-lamp examination), ultimately resulting in symptomatic disease; other individuals with some forms of secondary glaucoma may acquire a similar defect (for example, as a result of a mature cataract or diabetic neovascularization). Closed-angle glaucoma should be considered in the differential diagnosis of any patient with new-onset headache developing after age 50, especially with an acute red eye and reduced vision, but also with short-duration headaches (4 hours or less) that do not meet criteria for a defined headache syndrome (Shindler et al., 2005; Lanska, 2006). The more common major category of glaucoma—primary open-angle glaucoma (POAG), in which there is reduced flow through the trabecular meshwork—presents more insidiously with progressive, painless visual loss without acute attacks. Unfortunately, in many patients, this is not recognized until significant visual loss has occurred. Most affected patients are, in fact, asymptomatic, even at the point at which significant vision loss has already occurred. Signs of open-angle glaucoma include elevated IOP, visual field loss, and glaucomatous disc changes. Both categories of glaucoma can ultimately result in complete blindness if untreated. Physical findings that suggest glaucoma include elevated IOP, large C/D ratios, and asymmetric cupping between the two eyes. Although elevated IOP may result in a hard globe clinically, tonometry is required to properly assess this. Signs of glaucoma progression include increasing C/D ratio, development of disc pallor, disc

hemorrhage, nasal displacement of disc vessels, and progression of visual field damage. Although elevated IOP is the strongest-known risk factor for glaucoma, it is neither necessary nor sufficient to induce vision loss. Nevertheless, there is a exposure–response relationship between IOP and the risk of damage to the visual field. Because IOP varies during the day, with the highest readings in the early morning, a single normal tonometry reading does not rule out glaucoma. The term ocular hypertension is used for cases having constantly elevated IOP without evident associated optic nerve damage; the term normaltension (or low-tension) glaucoma is used when typical glaucomatous visual field defects are associated with a normal or low IOP. The C/D ratio attempts to quantify the extent of axonal (nerve fiber) loss by comparing the diameter of the cup to the diameter of the optic nerve head (disc). Increases in cupping or nerve fiber loss indicate poorly controlled glaucoma. In end-stage glaucoma, the nerve may be “completely cupped”—pale and atrophic. Visual fields, even using careful perimetric techniques, are often not helpful for diagnosis in the early stages because a considerable number of neurons must be lost before visual field changes can be detected. Glaucomatous field loss mainly involves the central 30° of vision. The earliest changes are enlargement of the blind spot, nasal scotomas (nasal step) followed by peripheral arcuate (Bjerrum) defects extending from the blind spot to the horizontal raphe. With further progression, further constriction of the visual field may progress to “tunnel vision” and total blindness. Risk factors for developing glaucoma include elevated IOP, older age (older than 50 years), family history of glaucoma in a first-degree relative (especially in a sibling), myopia, diabetes, cardiovascular diseases, black race, Hispanic ethnicity, and the presence of disc hemorrhages. Glaucoma is a leading cause of blindness among African Americans and Hispanics. Regardless of race or ethnic group, individuals older than age 60 are “at risk” for developing glaucoma and should get eye examinations at least every 2 years. Although there is no “cure” for glaucoma, early diagnosis and treatment can control glaucoma before vision loss or blindness occurs or prevent further progression if damage has already occurred. Treatment of glaucoma usually includes prescription eye drops and/or surgery to lower IOP. Several different classes of medications are used to treat glaucoma, each of which may have local and systemic side effects. Prostaglandin analogs (such as latanoprost, bimatoprost, and travoprost) increase uveoscleral or trabecular outflow of aqueous humor. Parasympathomimetic agents (such as pilocarpine) cause contraction of the ciliary muscle, which opens the intertrabecular spaces and thereby allows increased outflow of aqueous humor. Beta-adrenergic receptor antagonists (such as timolol, levobunolol, and

Disorders of the Special Senses in the Elderly

betaxolol) and carbonic anhydrase inhibitors (such as dorzolamide, brinzolamide, and acetazolamide) decrease aqueous humor production by the ciliary body. Alpha2-adrenergic agonists (such as brimonidine and apraclonidine) work in a dual fashion by both decreasing aqueous humor production and increasing outflow. Unfortunately, poor compliance with medications and follow-up visits is a major reason for vision loss in glaucoma patients. Acute angle-closure glaucoma is a medical emergency and is initially treated with topical miotics (for example, pilocarpine 2%, one drop every 15–60 minutes, up to 2–4 doses total), beta blockers (for example, timolol 0.5%, one drop), and alpha-adrenergic agonists (for example, apraclonidine 1%, one drop), in conjunction with oral or intravenous carbonic anhydrase inhibitors (for example, acetazolamide 500 mg by mouth or IV) (American Optometric Association, 2001; Lanska, 2006). Surgery is indicated when glaucomatous optic neuropathy worsens (or is expected to worsen) and the patient is on maximum tolerated medical therapy. Surgical treatments for closed-angle glaucoma include Nd-YAG laser peripheral iridotomy or surgical iridectomy. Laser iridotomy creates an opening in the iris to allow the aqueous humor to move more easily to the drainage site; because the risk of binocular closed-angle glaucoma is high, the procedure is usually done on both eyes even if only one eye is initially symptomatic. Laser iridotomy prevents further attacks of acute glaucoma, but some individuals with chronic angle closure still have elevated IOPs and require eye drops indefinitely. Some patients require peripheral iridectomy (surgical removal of a section of the peripheral iris); this creates an opening between the anterior and posterior chambers to relieve the pressure difference between the two compartments, which helps to open the angle. Cataract surgery can also prevent attacks of acute narrow-angle glaucoma because removal of the swollen cataractous lens allows the iris to move posteriorly, opening the angle. Argon laser trabeculoplasty (ALT), which applies the argon laser to the trabecular meshwork to facilitate outflow of aqueous, can be used as an adjunct to medical therapy for open-angle glaucoma. Filtering procedures bypass the normal drainage mechanisms of the eye by allowing direct access of aqueous from the anterior chamber to the subconjunctival tissue, either by trabeculectomy or by insertion of a silicone drainage tube.

Amaurosis fugax Amaurosis fugax (literally “fleeting blindness”) is as transient monocular visual loss that is attributed to ischemia or vascular insufficiency (Amaurosis Fugax Study Group, 1990). Patients usually report diminished or absent vision in one eye that progresses over a few seconds and lasts for seconds to minutes, followed by complete recovery (Amaurosis Fugax Study Group, 1990). Amaurosis fugax episodes last 5 minutes or less in about

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two-thirds of patients, 15 minutes or less in about fourfifths of patients, and only occasionally for an hour or more (Goodwin et al., 1987). Although amaurosis fugax episodes are usually short-duration “negative” visual phenomena (scotomas), a significant minority of patients have long attacks or positive visual phenomena such as scintillations, flashing lights, and shimmering. Therefore, among patients with transient monocular visual loss, clinical symptoms alone do not adequately discriminate episodes due to carotid atherosclerosis from those due to so-called “retinal migraine” (which is more properly labeled as presumed retinal vasospasm) (Goodwin et al., 1987; Hill et al., 2007). Patients with altitudinal (usually with the “shade coming down” rather than “up” to the horizontal raphe) or lateralized transient monocular visual loss are more likely to have carotid artery stenosis, ulcerated carotid artery plaques, cardiac sources of emboli, or visible retinal emboli than patients with other visual loss patterns, such as diffuse, constricting, patchy, or sectorial visual loss (Bruno et al., 1990). Apparently, the altitudinal and lateralized transient monocular visual loss patterns are typically caused by embolism to retinal branch vessels, whereas the other visual loss patterns are typically caused by nonembolic mechanisms. Recurrent events tend to follow the same pattern. Transient central scotomas are not part of the clinical spectrum of amaurosis fugax (Goodwin et al., 1987; Bruno et al., 1990). Episodes most commonly result from embolism into the ophthalmic circulation from the ipsilateral common carotid artery and its branches. Examination may demonstrate an ipsilateral anterior cervical bruit and possibly ophthalmoscopic evidence of retinal emboli, such as one or more Hollenhorst plaques (bright copper or yellowish glinting of reflective cholesterol emboli, often lodged at bifurcations of retinal arterioles), or migrating white plaques or fixed white plugs associated with platelet-fibrin and calcific emboli (Fisher, 1959; Hollenhorst, 1961; David et al., 1963; Marshall and Meadows, 1968; Hooshmand et al., 1974; Ellenberger and Epstein, 1986). Such microemboli are most commonly associated with atheromatous lesions of the ipsilateral carotid artery, but they can originate from the aortic arch or carotid siphon or, less commonly, from calcific cardiac valvular disease. However, atheromatous microemboli responsible for amaurosis fugax can also elude ophthalmoscopic confirmation because such emboli usually fragment quickly and disappear from view (even if evidence of their presence can be shown with fluorescein angiography) (Muci-Mendoza et al., 1980). Hollenhorst plaques do not occlude the arterioles and are themselves uncommonly associated with visual symptoms (and hence are usually noticed in asymptomatic people), in contrast to the white plugs associated with platelet-fibrin and calcific emboli, which are usually noticed when examining

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symptomatic patients (David et al., 1963; Ellenberger and Epstein, 1986). Particularly in the elderly, amaurosis fugax is an important marker of generalized atherosclerotic disease. Men overwhelmingly predominate among cases of amaurosis fugax in older people, approaching 90% among individuals older than 50 years (Parkin et al., 1982). In the elderly, about two-thirds of the cases are attributable to significant stenosis, ulceration, or occlusion of the ipsilateral carotid artery or occlusion of the ipsilateral common carotid artery (Parkin et al., 1982; Adams et al., 1983). Most of the remainder have no significant ipsilateral internal or common carotid artery pathology, but a minority have other identifiable pathology (such as ophthalmic artery stenosis, migraine accompaniments or equivalents, giant cell arteritis, NAION, cardiac emboli, polycythemia, thrombocytosis, other hyperviscosity syndromes, congestive heart failure, or papilledema) (Marshall and Meadows, 1968; Adams et al., 1983). In Caucasian populations, carotid artery pathology responsible for amaurosis fugax is predominantly extracranial, whereas in Asian populations, amaurosis fugax is typically due to thromboembolism from intracranial carotid artery atheromatous lesions (most commonly with internal carotid artery stenosis at the siphon) (Terao et al., 2000). Other possible etiologies include micro-thromboemboli from the heart or aorta, and hemodynamic retinal vascular insufficiency (Terao et al., 2000). Antiplatelet therapy is least likely to be effective when amaurosis fugax is due to hemodynamic mechanisms (Terao et al., 2000). Although amaurosis is a significant risk factor for ipsilateral cerebral infarction (especially when it occurs in association with an occluded or severely stenosed ipsilateral internal carotid artery), patients with isolated amaurosis fugax are at less risk for completed strokes than are otherwise similar patients with cerebral hemispheric transient ischemic attacks (TIAs) (Marshall and Meadows, 1968; Hurwitz et al., 1985; Poole and Ross Russell, 1985). Amaurosis fugax is associated with significantly increased risks of myocardial infarction, death from myocardial infarction, and sudden death, compared with the general population adjusted for age (Pfaffenbach and Hollenhorst, 1973; Hurwitz et al., 1985; Poole and Ross Russell, 1985), and overall life expectancy is significantly reduced (Poole and Ross Russell, 1985). The most frequent cause of death is myocardial infarction (Pfaffenbach and Hollenhorst, 1973; Poole and Ross Russell, 1985). Although amaurosis fugax associated with atherosclerotic occlusive disease may precede central retinal artery occlusion, branch retinal artery occlusion, or NAION, visual sequelae from retinal infarction are uncommon, affecting 6% of cases in one series (Parkin et al., 1982), and are largely unpredictable (Marshall and Meadows, 1968).

Retinal artery occlusion The central retinal artery, the first branch of the ophthalmic artery, supplies blood to the inner retina. The central retinal artery enters the eye at the optic disc, where it bifurcates into superior and inferior branches, each of which then bifurcates into nasal and temporal branches. Retinal artery occlusion most commonly involves the central retinal artery, less commonly a branch retinal artery, and rarely a cilioretinal artery. Central retinal artery occlusion (CRAO) deprives the entire inner retina of its blood supply unless a cilioretinal artery is present (an anatomic variant present in about 15–30% of eyes in which a branch of a short posterior ciliary artery exits the optic disc separately from the central retinal artery and typically supplies a portion of the macula). Branch retinal artery occlusion (BRAO) affects specific retinal artery branches, most commonly the temporal vessels. CRAO rapidly causes retinal infarction (ocular stroke) and is typically associated with sudden, painless, monocular blindness that is often permanent. Partial loss of the visual field may occur with BRAO. There may be a history of antecedant amaurosis fugax. On examination, visual acuity with CRAO is typically finger counting or worse, unless a cilioretinal artery is present, in which case central vision may be preserved. With CRAO, the pupil may be dilated with a minimal, sluggish reaction to light. Funduscopic examination in CRAO shows retinal pallor and edema, a “cherry-red spot” at the fovea (due to visualization at the fovea of the preserved underlying choroidal vascular bed, which is supplied by the posterior ciliary arteries), and attenuation of retinal arterioles with interrupted columns of blood within the retinal vessels (so-called “boxcarring,” for its resemblence to train boxcars). In contrast, with BRAO, fundoscopic examination shows retinal pallor and edema in the distribution of the affected vessel only. Occlusion of a cilioretinal artery produces macular edema and typically affects central vision. Risk factors for retinal artery occlusion include age older than 70 years, atherosclerosis, diabetes, hypertension, giant cell arteritis, hypercoagulable states, migraine, glaucoma, and optic nerve head drusen. CRAO and BRAO are most often associated with atheromatous disease but can be associated with giant cell arteritis in 5–10% of the cases. Occlusion of a cilioretinal artery in an elderly patient is considered prima facie evidence of giant cell arteritis, although it can also be seen with retinal vein occlusion or in isolation due to nonarteritic conditions (Hayreh et al., 2009). Animal studies have demonstrated that irreversible ischemic damage can occur after approximately 100 minutes following complete CRAO, whereas recovery is possible for shorter periods of complete CRAO (Hayreh and Weingeist, 1980; Hayreh et al., 1980). However, complete occlusion of the central retinal artery is rare in humans,

Disorders of the Special Senses in the Elderly

so some degree of recovery is occasionally possible even after 2–3 days of ischemia. In any case, because irreversible damage may occur within hours of occlusion, patients should be referred immediately to an ophthalmologist for emergent management. Immediate actions that may be beneficial prior to ophthalmologic consultation include digital massage of the eyeball and various techniques to increase retinal perfusion pressure. Ocular massage is performed by the patient, who is instructed to digitally massage the affected eyeball through closed eyelids for 15–30 minutes. Ocular massage produces a fluctuating IOP, which may facilitate disintegration of the embolus and movement of embolus fragments into distal branches of retinal vessels, thereby minimizing the area of retinal infarction and helping to preserve vision. Techniques intended to improve retinal perfusion pressure that nonophthalmologists can administer in the emergency room include supine positioning of the patient and intravenous administration of acetazolamide (500 mg), although the relative utility and marginal benefit of these approaches is unclear (Beatty and Au Eong, 2000). Although aggressive stepwise regimens have been promoted based on small case series, the role of these approaches is unclear, as is the role of individual components of these regimens, including administration of systemic osmotic agents (such as intravenous mannitol or oral glycerol) and anterior chamber paracentesis (Rumelt et al., 1999). Techniques that are no longer in favor because of doubtful clinical benefit or recognized complications include inhalation of carbogen (95% oxygen and 5% carbon dioxide), retrobulbar injection of vasodilator drugs, and systemic administration or thrombolytic agents (Beatty and Au Eong, 2000). Marginally higher rates of good visual outcomes (visual acuity of 20/40 or better) have been reported with selective intraarterial injection of fibrinolytic therapy with urokinase or tissue plasminogen activator (TPA) into the ophthalmic artery, but the technique is not universally available and may be associated with serious complications (Beatty and Au Eong, 2000). Long-term management includes dietary counseling, promotion of smoking cessation, risk factor modification (including hypertension, diabetes, and hyperlipidemia), administration of antiplatelet therapy (generally aspirin), and appropriate management of comorbid, contributing, or causal factors (such as coronary artery disease, carotid stenosis, giant cell arteritis, hypercoagulable states, cardiac valvular disorders, and complex arrhythmias). As with amaurosis fugax, the most common cause of death in patients with retinal artery occlusions is cardiovascular disease. Visual prognosis varies depending on the level of occlusion, the presenting visual acuity, and the duration of visual impairment (Beatty and Au Eong, 2000; Mason

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et al., 2008; Hayreh et al., 2009). The visual outcome after CRAO is typically poor (when the macula is not supplied by a cilioretinal artery), with final visual acuity of finger counting or worse in the affected eye in about two-thirds of the patients, and final visual acuity of 20/40 or better in only about one-fifth of the patients (Beatty and Au Eong, 2000). In contrast, the visual outcome with BRAO is relatively good, with 60–90% of patients with permanent BRAO having visual acuity of 20/40 or better at followup (Mason et al., 2008; Hayreh et al., 2009).

Anterior ischemic optic neuropathy Anterior ischemic optic neuropathy (AION) is a stroke syndrome of the optic nerve head and anterior optic nerve, characterized by acute, painless, (generally) unilateral visual loss associated with optic disc edema and other manifestations of optic nerve dysfunction. Findings include loss of central vision, achromatopsia (generally in proportion to the loss of visual acuity), nerve fiber layer visual field abnormalities (with altitudinal defects most commonly, but also possibly central or cecocentral scotomas, or arcuate patterns), a relative afferent pupillary defect, and commonly associated disc and peripapillary nerve fiber layer hemorrhages (Hayreh, 1974a). Optic disc edema starts to resolve in 7–10 days and is followed by optic atrophy after approximately 1–3 months (Hayreh, 1974b; Hayreh and Zimmerman, 2008b). The edema and atrophy may involve the entire disc or may be restricted to a sector (Hayreh, 1974b). AION may be either arteritic (as with AAION, due to giant cell arteritis) or nonarteritic (as with NAION, due to causes other than giant cell arteritis). NAION is the most common type and one of the most prevalent visually crippling diseases in the elderly (Hayreh, 2009). Although less common, arteritic AION is an ocular emergency that requires early diagnosis and immediate treatment with systemic highdose corticosteroids to reduce the amount of residual vision loss in the affected eye and to prevent irreversible vision loss in the contralateral eye (Lueck, 2010).

Nonarteritic anterior ischemic optic neuropathy Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy and one of the most common causes of sudden vision loss in the elderly (Hattenhauer et al., 1997). NAION typically presents with sudden monocular visual loss, often noted upon awakening. Vision in that eye is described as being obscured by a dark shadow, often involving just the upper or lower half of vision. Most cases of NAION involve the loss of either the upper or the lower half of the visual field (a hemifield), although a small proportion present with almost total loss of vision or a scotoma. Normal visual acuity does not rule out NAION—indeed, about half the eyes with NAION present with almost normal visual acuity (20/30 or better)

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at the initial visit (Hayreh and Zimmerman, 2008b). There is generally no pain, although a dull orbital ache may be noted in up to 10% of the cases. Unlike CRAO or arteritic AION, premonitory symptoms, such as amaurosis fugax, are absent in NAION. Acutely with NAION, the optic disc edema is pale pink or even hyperemic with frequent associated flame-shaped hemorrhages; in arteritic AION, half show chalky-white edema of the optic disc with rare hemorrhages (Hayreh, 1974b). Segmental or diffuse pallor without cupping is the typical end-stage disc appearance after NAION (Danesh-Meyer et al., 2001). In contrast with classical NAION, incipient NAION is characterized by asymptomatic optic disc edema with no visual loss attributable to NAION. A diagnosis of incipient NAION should be considered when a patient presents with unilateral asymptomatic optic disc edema, particularly in those who have had classic NAION in the fellow eye and in those with other identified risk factors for NAION, particularly diabetes (Hayreh and Zimmerman, 2007a). Visual impairment with NAION may progress over several days but is then generally stable thereafter. About 40% of NAION eyes with moderate or severe impairment at presentation experience spontaneous improvement in visual acuity within the first 3–6 months (Hayreh and Zimmerman, 2008b; Hayreh, 2009). After 3–6 months, visual acuity and visual fields generally do not change significantly (Hayreh and Zimmerman, 2008b). Final visual acuity is 20/40 or worse in about half of the affected eyes, 20/70 or worse in about a quarter, and finger counting or worse in about an eighth (Hayreh and Zimmerman, 2008b). Blood flow velocities of the nasal short posterior ciliary arteries and the central retinal artery are considerably reduced in patients with acute NAION, compared with controls (Kaup et al., 2006). The posterior ciliary arteries are the predominant blood supply to the prelaminar and laminar portions of the optic nerve, as the pial plexus is the predominant blood supply (with contributions from the posterior ciliary arteries, extraneural branches of the central retinal artery, and small penetrating orbital arteries) for the immediate retrolaminar optic nerve. Predisposing factors for NAION include a congenitally “crowded” small optic disc with a small C/D ratio (<0.2) and raised IOP (Katz et al., 1990). A “crowded” disc can be noted on ophthalmoscopy and is referred to as a “disc at risk.” The laminar and prelaminar vessels have high extramural pressures because of IOP; any sudden decrease in blood pressure or increase in IOP can decrease perfusion pressure to the optic nerve head and compromise blood flow to this area, causing infarction, with resulting edema, compression, and further ischemia (Eagling et al., 1974). The determining factor for development of AION is the perfusion pressure in the anterior portion of the optic

nerve (the difference between blood pressure in the posterior ciliary arteries and IOP). The posterior ciliary arteries do not need to be occluded to produce AION (Hayreh, 1974a). As would be expected of a stroke syndrome, the nonarteritic form of AION is often associated with vasculopathic risk factors, including hypertension, diabetes, smoking, hypercholesterolemia, ischemic heart disease, and hyperhomocysteinemia, as well as low vitamin B6 (pyridoxine) levels (presumably through the effect of pyridoxine on homocysteine metabolism) (Salomon et al., 1999a; Pianka et al., 2000; Weger et al., 2001; Giambene et al., 2009). In addition, a high proportion (>2/3) of patients with NAION have sleep apnea, which may partly explain why approximately three-fourths of patients with NAION discover visual loss on first awakening or when they first use vision critically after sleeping (Mojon et al., 2002). Indeed, obstructive sleep apnea is the most frequent disorder associated with NAION, and affected patients should undergo overnight pulse oximetry or preferably polysomnography (Palombi et al., 2006; Li et al., 2007). Finally, although the risk of NAION after cataract extraction is low, with approximately 1 occurrence in every 2000 cases (McCulley et al., 2001), patients with unilateral NAION are at a significantly higher risk of developing NAION in the fellow eye after cataract extraction (McCulley et al., 2001, 2003; Lam et al., 2007). Although NAION has been anecdotally reported with the use of phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction (ED) (Pomeranz et al., 2002; Pomeranz and Bhavsar, 2005; Danesh-Meyer and Levin, 2007), particularly in those with a small C/D ratio (Pomeranz et al., 2002), a causal relationship has not been established. Because ED and NAION share common risk factors, some men with ED are expected to develop NAION. Although the World Health Organization and the FDA have labeled the association between use of PDE5i and risk of NAION as “possibly” causal (DaneshMeyer and Levin, 2007), available data do not suggest an increased incidence of NAION in men who took sildenafil for ED (Gorkin et al., 2006). Sildenafil is generally well tolerated at a dose of 50 or 100 mg in elderly men with ED (Giuliano et al., 2010). The incidence of NAION in men receiving sildenafil treatment for ED was estimated using pooled safety data from global clinical trials and European observational studies (Gorkin et al., 2006). Based on clinical trial data in more than 13,000 men and on more than 35,000 patient-years of observation in epidemiologic studies, the estimated incidence of NAION is 2.8 cases per 100,000 patient-years of sildenafil exposure, which is similar to estimates reported in general US population samples (2.52 and 11.8 cases per 100,000 men aged ≥50 years). Similarly, a meta-analysis of 67 double-blind, placebocontrolled trials and a postmarketing safety database did not reveal any new safety risks relating to NAION

Disorders of the Special Senses in the Elderly

(Giuliano et al., 2010). Nevertheless, sudden vision loss in one or both eyes warrants immediate cessation of PDE5i use and urgent assessment (Hatzimouratidis, 2007). NAION rarely affects the same eye more than once, presumably because infarcted axons in a tight scleral canal relieve the crowding and reduce the chances of a subsequent attack (Quigley et al., 1985). However, in a person with a history of NAION, the unaffected eye has a 15% risk of developing NAION within 5 years; increased incidence of NAION in the fellow eye is associated with poor baseline visual acuity in the incident eye and with diabetes (Newman et al., 2002). Aspirin (325 mg per day) may be effective in reducing the frequency of second eye involvement with NAION (Salomon et al., 1999b), although available evidence for this is conflicting (Newman et al., 2002). To minimize the risk of further visual loss in the fellow eye or the same eye, risk factor modification is essential. Because arteritic AION is similar in presentation to NAION, elderly patients with suspected NAION must be evaluated to exclude arteritic AION. An erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level should be obtained emergently, and if any clinical feature suggests giant cell arteritis, a temporal artery biopsy should be performed (regardless of the ESR) (Lueck, 1996). In the absence of clinical features of giant cell arteritis, an elevated ESR, or bilateral simultaneous AION, temporal artery biopsy is unlikely to be positive and is considered unnecessarily invasive (Lueck, 1996). In any case, it is generally prudent to obtain ophthalmology consultation in such cases. Additional diagnostic studies recommended in the evaluation of NAION include a complete blood count, fasting blood glucose, hemoglobin A1c, fibrinogen, serum protein electrophoresis, fasting lipid profile, and fluorescein angiography (Lueck, 1996, 2010). Although high-dose oral corticosteroids have long been advocated (Hayreh, 1974c), high-quality evidence has not supported this recommendation. Recent trials have provided more convincing support for the contention that systemic steroid therapy during early stages in NAION (and nonarteritic posterior ischemic optic neuropathy [PION]) has a significant beneficial effect for visual outcome (Hayreh, 2009). NAION eyes treated during the acute phase with systemic corticosteroids resulted in a significantly higher probability of improvement in visual acuity and visual fields than in the untreated group (Hayreh and Zimmerman, 2008a). Both visual acuity and visual fields improved for up to 6 months after onset of NAION but were static thereafter (Hayreh and Zimmerman, 2008a). It appears that rapid initiation of steroid therapy is essential to achieve maximal improvement and to minimize axonal injury and permanent damage (Hayreh and Zimmerman, 2008a). Presumably, the faster resolution of optic disc edema with corticosteroids (Hayreh and Zimmerman, 2007b) decreases compression

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and thereby improves blood flow in the capillaries at the optic nerve head. This improves function and helps preserve surviving axons (Hayreh and Zimmerman, 2008a). Several other treatments have been proposed for NAION, but available evidence is inadequate to support their use. For example, results of treatment with intravitreal injection of high-dose triamcinolone acetonide are limited and conflicting. Although this treatment has been anecdotally reported to improve recovery of visual acuity and optic disc edema (but not visual fields) in patients with NAION (Kaderli et al., 2007), particularly in patients with a relatively short history of visual loss due to NAION (Yaman et al., 2008), other case series suggest it is not markedly effective in increasing visual acuity after acute NAION (Jonas et al., 2007). Furthermore, at least theoretically, intravitreal injection in NAION eyes could be harmful because this increases the volume in the eyeball, with a resultant rise in IOP, and could potentially further compromise the perfusion pressure of the ischemic optic nerve head (Hayreh and Zimmerman, 2008a). The use of levodopa has also been proposed for the treatment of recent-onset NAION (Johnson et al., 1996, 2000) but is unproven (Simsek et al., 2005), based on the conflicting results of several small trials. Side effects of levodopa (such as dizziness, orthostatic hypotension, vomiting, and cardiac arrhythmia) were noted during the most recent trial (Simsek et al., 2005).

Visual loss with giant cell arteritis (arteritic AION or AAION) Giant cell arteritis (GCA) (also known as temporal arteritis, cranial arteritis, or granulomatous arteritis) is a systemic, necrotizing, large-vessel vasculitis seen in patients typically over age 50, with incidence increasing progressively with age; it is most common in Causasians over age 70 years (González-Gay and García-Porrúa, 2001; González-Gay, 2005; Watts et al., 2005). GCA is a medical emergency because there is a high risk of developing permanent blindness in one or both eyes if diagnosis is delayed or if the disease is improperly managed; fortunately, blindness is almost entirely preventable if GCA is identified quickly and treated urgently and aggressively with systemic corticosteroids. Therefore, it is essential to maintain a high degree of clinical suspicion for GCA, especially in Caucasians over age 60 years (González-Gay, 2005). Polymyalgia rheumatica (PMR) is a much more common but closely related inflammatory disorder of elderly patients. It consists of pain and stiffness in the shoulder and pelvic girdles, often with associated fever, weight loss, nonspecific somatic complaints (such as malaise), and an elevated ESR; it typically responds rapidly and completely to small doses of prednisone (typically much smaller than required for GCA). GCA and PMR may be manifestations of the same underlying disease and often coexist—GCA occurs in about 20% of patients with PMR.

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GCA should be suspected when an elderly patient complains of sudden visual loss, new-onset headache, jaw claudication, or the musculoskeletal manifestations of PMR. Clinical manifestations of GCA can include acute visual loss, headache, tenderness and sensitivity on the scalp, fever, jaw claudication, tongue claudication and necrosis, diplopia, and tinnitus. Clinical criteria most strongly suggestive of GCA include jaw claudication, CRP above 2.45 mg/dl, neck pain, an ESR of 47 mm/h or more, and age greater than 75 years, in approximately that order (Hayreh et al., 1997). CRP is more sensitive (98–100%) than ESR (76–92%) for detection of GCA, but ESR combined with CRP provides the best sensitivity and specificity (close to 100% for both test indices) (Hayreh et al., 1997; Parikh et al., 2006). Physical examination may demonstrate abnormalities in the temporal arteries (such as tenderness, induration, or lack of pulsatility) or other cranial arteries (for example, in the facial artery as it crosses the mandible). Patients with GCA also frequently have hematologic abnormalities, including thrombocytosis (an acute phase reactant), leukocytosis, and anemia, but the platelet count, white cell count, hemoglobin, and hematocrit do not alone or collectively significantly improve diagnosis of GCA compared with the combination of CRP and ESR (Costello et al., 2004). About half of the patients with biopsy-confirmed GCA present with ocular involvement due to ischemia (Hayreh et al., 1998b). Ocular symptoms almost always include visual loss of varying severity but may also include a history of amaurosis fugax (in about a third of cases) and, uncommonly, transient diplopia or eye pain (Hayreh, 1991; Hayreh et al., 1998b). Both eyes are involved in about half of the patients with ocular symptoms (a rare situation with NAION). Blindness with GCA is usually due to AION (∼80%), but occasionally, patients demonstrate cilioretinal artery occlusion, posterior ischemic optic neuropathy, and, rarely, ocular ischemia (Hayreh, 1991; Hayreh et al., 1998b). In almost all patients with GCA, fluorescein fundus angiography demonstrates occlusive disease of one or more of the posterior ciliary arteries, in occasional patients combined with CRAO (the central retinal and posterior ciliary arteries often arise by a common trunk from the ophthalmic artery, and arteritic involvement of this trunk results in both distal vessels becoming occluded) (Hayreh et al., 1998b). Arteritic AION (AAION) in GCA is distinguished from NAION by early massive visual loss, chalky-white optic disc swelling acutely (if present, in about half of cases), frequently associated cilioretinal artery occlusion, high ESR and CRP levels, nonfilling of the choroid on fluorescein fundus angiography, and characteristic pathologic changes on temporal artery biopsy (Hayreh, 1974b; Hayreh, 1990). Patients with AAION generally have more severe visual loss than do patients with NAION—

although only a few cases of NAION result in near total loss of vision, most cases of AAION involve nearly complete vision loss. Also, eyes affected with AAION show significant excavation and enlargement of the optic cup when compared with contralateral uninvolved eyes (Danesh-Meyer et al., 2005b). In contrast to the global or sectorial optic disc atrophy without cupping seen as a late ophthalmoscopic finding with NAION, the end-stage optic disc appearance in AAION is cupping (DaneshMeyer et al., 2001; Hayreh and Jonas, 2001). About 20% of patients with GCA and visual loss do not have any systemic symptoms suggestive of GCA (Hayreh et al., 1998a). Therefore, in the elderly, amaurosis fugax or acute visual loss with an acute ocular ischemic lesion (particularly AION), in combination with an elevated CRP level, should raise a high index of suspicion for GCA, regardless of the ESR or the presence of systemic symptoms. A markedly elevated CRP level or ESR in association with other clinical features of the disease strongly suggests GCA, whereas a normal ESR makes GCA unlikely (Smetana and Shmerling, 2002). ESR is low (less than 50 mm/h) in only a small percentage of patients with GCA (≤5%) (Wise et al., 1991; Salvarani and Hunder, 2001), and most such patients have a history of PMR or corticosteroid therapy (Wise et al., 1991). GCA patients with a low ESR are less likely to present with visual symptoms or to develop blindness (Salvarani and Hunder, 2001). A biopsy should be performed to confirm a suspected diagnosis of GCA, especially because long-term management with corticosteroids may be required, often with associated toxicity and significant secondary morbidity (Elliot et al., 1983; Hall et al., 1983; González-Gay et al., 2001a; González-Gay, 2005). Because of the high cost of blindness, decision analyses suggest that suspicion of disease must be very low (less than 1.4%) not to biopsy (Elliot et al., 1983). Bilateral biopsy is the cheapest initial diagnostic procedure (although, in practice, this is rarely done), and if a unilateral biopsy is negative, a second biopsy is always cost effective (Elliot et al., 1983). Temporal artery biopsy is performed under local anesthesia and should be done at the most symptomatic site. There is no consensus on the optimal specimen length for a temporal artery biopsy—although temporal artery biopsy specimens of from 2 to 5 cm in length have been advocated to confirm a suspected diagnosis of GCA (partly because of purported spotty inflammatory involvement of vessels in GCA, so-called “skip lesions”) (Klein et al., 1976; Kent and Thomas, 1990), a temporal artery biopsy length of at least 0.5 cm may be sufficient to make a diagnosis of GCA (Mahr et al., 2006); others have found a minimum length of 1.5 cm necessary to optimize diagnostic sensitivity allowing for tissue shrinkage (González-Gay, 2005; Taylor-Gjevre et al., 2005), and still others have reported that segments of at least 2.5 cm are needed

Disorders of the Special Senses in the Elderly

(González-Gay et al., 2001a, 2001b; González-Gay, 2005). In general, about 40–65% of patients referred for temporal artery biopsy have positive results (Allison and Gallagher, 1984; Smetana and Shmerling, 2002). Temporal artery biopsies in GCA classically show marked intimal thickening, a mononuclear cell infiltrate predominating at the media-intima junction, or, in the media, giant cells and histiocytic inflammation related to disrupted elastic tissue (Allison and Gallagher, 1984; Mahr et al., 2006). Giant cells and granulomatous inflammatory changes are not essential for diagnosis, but their absence is considered atypical (Allison and Gallagher, 1984; Mahr et al., 2006). The frequency of a positive temporal artery biopsy varies as a function of the timing of the biopsy relative to initiation of corticosteroid therapy—in one study of cases diagnosed on the basis of clinical findings, ESR, and plasma viscosity, temporal artery biopsy was positive in 82% of those biopsied prior to corticosteroid therapy, in 60% of those biopsied within 1 week after starting corticosteroid therapy, and in only 10% of those biopsied more than 1 week after starting corticosteroid therapy (Allison and Gallagher, 1984). Other authors have found higher rates of positive biopsy results after starting steroids and have found that temporal artery biopsy may be diagnostically useful even several weeks after institution of corticosteroids (Achkar et al., 1994; Ray-Chaudhuri et al., 2002). In any case, temporal artery biopsy should generally be done before patients are committed to long-term corticosteroid therapy (Hall et al., 1983; González-Gay, 2005). Patients with biopsy-proven GCA have more severe disease with a higher risk of severe ischemic complications and permanent visual loss compared with biopsynegative patients (González-Gay et al., 2001a). A small number of clinical features are helpful in predicting the likelihood of a positive temporal artery biopsy among patients with a clinical suspicion of disease. In a systematic review, the only historical features that substantially increased the likelihood of GCA among patients referred for biopsy were jaw claudication and diplopia (Smetana and Shmerling, 2002). The absence of any temporal artery abnormality (such as beading, prominence, and tenderness) was the only clinical factor that modestly reduced the likelihood of disease (Smetana and Shmerling, 2002). In patients with visual symptoms, chances of clinical improvement are better with early diagnosis and immediate institution of corticosteroid therapy. All affected patients must be treated on a long-term basis with adequate amounts of systemic corticosteroids to prevent further visual loss in either eye and to manage the systemic manifestations of GCA. Unfortunately, visual loss due to GCA is often profound (mean visual acuity of 20/400) and subsequent visual recovery is uncommon—only about 4–5% of GCA patients with visual loss show any visual improvement with high-dose steroid therapy, as

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judged by improvement in both visual acuity and central visual fields, and 4–27% develop further visual loss despite high-dose steroid therapy (Hayreh et al., 2002; Hayreh and Zimmerman, 2003a, 2003b; Danesh-Meyer et al., 2005a; Loddenkemper et al., 2007). If visual deterioration occurs after starting appropriate corticosteroid therapy, it is usually within the first 5 or 6 days of treatment (Hayreh and Zimmerman, 2003a, 2003b; DaneshMeyer et al., 2005a). Risk factors for early visual deterioration include older age, elevated CRP, and disc swelling (Loddenkemper et al., 2007). Risk factors for an increased risk of permanent visual loss include a history of transient visual ischemic symptoms, jaw claudication, and an elevated platelet count (González-Gay et al., 1998; Liozon et al., 2001). Although a number of authorities have advocated intravenous megadose steroid therapy (1 g of IV methylprednisolone daily for 3 days) for patients with GCA who have experienced vision loss (González-Gay, 2005), no convincing evidence shows that this approach is more effective than high-dose oral prednisone therapy (60–80 mg per day) in improving vision or preventing visual deterioration due to GCA (Hayreh and Zimmerman, 2003a, 2003b). Other immunosuppressant medications, such as methotrexate, have been used with mixed results in GCA, usually for potential steroid-sparing in patients with unacceptable side effects from corticosteroid therapy (Pipitone et al., 2005). Evidence from observational studies suggests that adding low-dose aspirin to traditional corticosteroid therapy may decrease the risk of visual loss and strokes in patients with GCA (Nesher et al., 2004a, 2004b); until randomized, controlled trial data are available, the expected risks and potential benefits the implementation of this approach (Hellmann, 2004). The most reliable and sensitive parameters to regulate and taper steroid therapy are the ESR and CRP levels, not the presence or absence of systemic symptoms (Hayreh and Zimmerman, 2003a). Patients should be maintained on high-dose prednisone until both the ESR and CRP stabilize at low levels (usually after several weeks), after which prednisone can be very slowly tapered, using ESR and CRP levels as guides. Although somewhat controversial, in general it takes at least 2–3 years (and, not uncommonly, 5–7 or more years) to reach the lowest maintenance dose of prednisone (the dose at which the ESR and CRP remain low and stable) (Kyle and Hazelman, 1990; Hayreh and Zimmerman, 2003a). Most patients need to be maintained indefinitely on modest doses of prednisone (16 mg per day or less) (Hayreh and Zimmerman, 2003a). Less than 10% of the patients are ultimately able to stop prednisone entirely and maintain stable ESR and CRP levels (Hayreh and Zimmerman, 2003a). Monitoring for corticosteroid-associated side effects (such as osteoporosis and diabetes) and for relapses and flare-ups is essential for chronic management of GCA.

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Positive spontaneous visual phenomena with blindness (Bonnet syndrome) In the late eighteenth century, Charles Bonnet reported VHs in elderly persons who were cognitively normal (including Bonnet’s 89-year-old grandfather, Charles Lullin, and, later, Bonnet himself) (Berrios and Brook, 1982; Eperjesi and Akbarali, 2004; Jacob et al., 2004; Lanska, 2005). In 1936, de Morsier eponymously recognized Bonnet’s report and designated Bonnet syndrome as a syndrome of VHs in elderly persons with ocular lesions and intact cognition (de Morsier, 1936; Ffytche and Howard, 1999). Three decades later, though, de Morsier tried to remove ocular disease from the syndromic definition and, by that time, considered Bonnet hallucinations as VHs occurring among the elderly with intact cognition, regardless of etiology (de Morsier, 1967). The eponym of Bonnet syndrome (sometimes referred to as Charles Bonnet syndrome) is now most commonly used to refer to VHs in visually impaired individuals with full alertness and unimpaired cognition (this is the operational definition used for this chapter) (Lanska, 2005). Other definitions are also employed, however, which leads to confusion—indeed, because of the varying definitions, a number of authors have argued that the eponym is no longer useful (Cole, 2001; Burke, 2002; Lanska, 2005). Some authors accept as Bonnet hallucinations cases with unformed VHs (photopsias), cases without visual impairment, or cases with dementia or other cognitive impairment, while others restrict cases to elderly patients, to patients with complex formed VHs, or to cases with prechiasmal visual impairment. However, limiting the definition of Bonnet hallucinations to complex VHs may have no localizing value or etiologic specificity (Lepore, 1990; Santhouse et al., 2000; Burke, 2002; Wilkinson, 2004). Therefore, most now accept that these hallucinations can include both simple and complex VHs, including geometric shapes, animals (zoopsias), human figures, buildings, or landscape scenes. Bonnet hallucinations are usually well defined and clear, often elaborate, VHs without associated olfactory, gustatory, auditory, or tactile hallucinations. They may appear suddenly, are not under voluntary control, and are persistent though usually intermittent. The hallucinations may be stationary or in motion, altered in size (small or “Lilliputian” figures), sometimes grotesque or distorted, and frequently chromatic (colored). Patients generally have full or partial retention of insight, without delusions or psychosis, and without associated intoxication or withdrawal. The hallucinations are generally neutral or pleasant and nonthreatening, but they may cause distress, especially because patients are aware that the visual images are not “real.” The frequency of Bonnet hallucinations may range from daily to weekly, and the duration of individual VHs is usually a few minutes but may be shorter or longer, from

seconds up to a full day. Triggers for Bonnet hallucinations can include low light levels, fatigue, and emotional stress. Bonnet hallucinations often occur with eyes open and disappear with eyes closed. Some patients can terminate their hallucinations with closing or opening their eyes, attempting to fixate vision on or away from the hallucination, or making saccades to one side. Although it has been suggested that Bonnet syndrome may be an early marker for dementia, most studies do not indicate any cognitive impairment in most patients with Bonnet syndrome. Nevertheless, some patients are afraid to report such hallucinations to their physicians because they are concerned that these indicate mental illness or the incipient development of dementia and therefore fear that reporting such experiences will compromise their autonomy. Many affected patients express relief when they are informed that such hallucinations are relatively benign and are not related to insanity or dementia. Many authors have suggested a “release” mechanism associated with modality-specific sensory deprivation as the basis of Bonnet hallucinations, and some have referred to this phenomenon as “phantom vision” akin to phantom limbs in patients with loss of somatosensory input after an amputation. In support of a release mechanism for Bonnet hallucinations, sensory deprivation and a low level of arousal favor development of the hallucinations but are not required for their development (Teunisse et al., 1996). Deafferentation produces an increase in excitability of the deafferentated neurons and an increase in spontaneous activity (Levison et al., 1951; Echlin et al., 1952; Lance, 1976; Eysel et al., 1999; Burke, 2002). High-frequency bursts of synchronized, though nonepileptic, neural activity in areas of deafferentated cortex may be necessary for these hallucinations (Burke, 2002). Single-photon emission computed tomography (SPECT) studies of patients with Bonnet syndrome have shown hyperperfusion in the lateral temporal cortex, striatum, and thalamus, presumably representing the results of central nervous system plasticity and compensation (Adachi et al., 2000). Functional magnetic resonance imaging (MRI) studies indicate that Bonnet hallucinations are associated with increased ventral extrastriate activity, which persists even between hallucinations (Ffytche et al., 1998). The location of increased activity correlates with the type of hallucination, with colored VHs associated with activity in the posterior fusiform area, faces associated with activity in the left middle fusiform area, objects associated with activity in the right middle fusiform area, and textures associated with the collateral sulcus (Ffytche et al., 1998). The relative frequency of certain complex forms (such as faces) may reflect the amount of association cortex devoted to representing these forms or the magnitude of the distributed network processing such forms (Lance, 1976; Wilkinson, 2004).

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Bonnet hallucinations may terminate spontaneously, upon improving or stabilizing of visual loss; with improved lighting; or on improving grief, loneliness, or social isolation (Sonnenblick et al., 1995; Razavi et al., 2004). Diverse treatments have also been reported to alleviate Bonnet hallucinations, but almost all of these are anecdotal reports, being based on small samples (often single cases) in uncontrolled trials. Bonnet hallucinations are generally not resolved or improved with anticonvulsants, atypical antipsychotic medications, antidepressants, or benzodiazepines, although there are anecdotal reports of occasional patients who seem to respond to such medications. In rare cases of Bonnet syndrome associated with visual impairments from temporal arteritis, steroid treatment can result in prompt resolution of VHs, even with persistent visual loss (Sonnenblick et al., 1995; Razavi et al., 2004); the implications of this are not fully clear but may suggest that other mechanisms may be involved in continuing such hallucinations beyond simple “release” mechanisms.

Central visual disturbances

Late-life migrainous accompaniments and equivalents In the 1980s, Fisher distinguished so-called “late-life migrainous accompaniments” from TIAs, both of which can be accompanied by headache (Fisher, 1980, 1986). As with other migrainous auras, late-life migrainous accompaniments (or sans headache, preferably termed “late-life migrainous equivalents”), by definition, occur in individuals older than 40 years of age, particularly in the elderly. Painful cephalic vasodilation (perceived as headache) may not occur in older patients with transient migraine accompaniments because of vascular rigidity and atherosclerosis (Aring, 1972; Meyer et al., 1998). Late-life migrainous accompaniments and equivalents occur more frequently in men than women (Fisher, 1986). Patients with late-life migraine accompaniments experience a “build-up” and “progression” of symptoms, often with a characteristic “march” of symptoms from one area of the body to another, with symptoms that are not typical of acute strokes or TIAs (Fisher, 1986): TIAs and sensory stroke are sudden in onset and usually not reversible (Fisher, 1982; Dennis and Warlow, 1992). The typical duration of the march of a late-life migraine accompaniment or equivalent (15–60 minutes and generally 15–25 minutes) is longer than a seizure march (usually 1–2 minutes) and most TIAs, although migraine equivalents and accompaniments may have a shorter duration (4–15 minutes in about a third of cases), and the duration of migraine accompaniments/equivalents overlaps the usual range of duration for TIAs (Martí-Vilalta et al., 1979; Levy, 1988; Bots et al., 1997; Wijman et al., 1998; Kidwell et al., 1999; Weimar et al., 2002). Migrainous accompaniments and equivalents are occasionally prolonged (over 1 hour), in

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which case they are classified as prolonged migraine aura. Visual symptoms are the most common symptom category for late-life migraine accompaniments and include scintillating scotomata, transient blindness, homonymous hemianopsia, blurring of vision, and difficulties with visual focusing (Fisher, 1980, 1986). Typical visual aura consisting of scintillating scotomas are highly characteristic of migraine, especially when they are gradual in onset and progressive (Aring, 1972). Less common symptoms include aphasia, tinnitus, deafness, dysarthria, paresthesias, ataxia/incoordination, and syncope. Clinical features supporting a diagnosis of late-life migrainous accompaniments or equivalents include the following: • Scintillating scotomata that gradually expand and migrate. • A “march” of paresthesias, scotoma, or other symptoms. • Serial progression of migrainous accompaniments in a course atypical for or inconsistent with cerebrovascular disease (such as from visual symptoms to paresthesias to aphasia). • Occurrence of at least two identical attacks (because stereotyped episodes are common with migraine accompaniments/equivalents and are unlikely with cerebral emboli), especially if attacks occur over a prolonged period of several years (because persistence of stereotyped spells over a prolonged course is unlikely with cerebrovascular disease of any type). • Associated headache (in ∼50% of cases). • Duration of 15–60 minutes, and usually 15–25 minutes (much longer than a typical seizure and shorter than most TIAs). • A benign course without permanent sequelae. • Normal vascular imaging (if performed). Although older theories of migraine attributed migraine auras solely to cerebral vasoconstriction and the subsequent headache to cerebral vasodilation, such archaic theories are now recognized as inadequate to explain fundamental features of migraine. Although cerebral blood flow does change during the course of classic migraine headaches with relative hypoperfusion during the aura, headache actually begins during the period of hypoperfusion (Olesen et al., 1990). Newer theories recognize neurogenic and electrochemical processes as critical for triggering and propagating migraine auras and for producing the associated headache, perhaps by stimulating local vascular nociceptors (Olesen et al., 1990). Migrainous auras are now thought to represent the clinical manifestations of the so-called “spreading depression of Leão,” a wave of electrocortical hyperactivity followed by a wave of inhibition, usually beginning in the visual cortex, progressing across the cortex at approximately 2–5 mm/min, and potentially involving sequentially sensory cortex, motor cortex, and language areas (Leao, 1944; Lauritzen,

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1994; Porooshani et al., 2004; Tfelt-Hansen, 2010). Initiation and propagation of cortical spreading depression depend partly on increased extracellular potassium ion concentration and excitatory glutamate. Late-life migraine accompaniments and equivalents are typically benign events that generally do not require an elaborate diagnostic evaluation. Persistent neurologic deficits are rare, even when attacks continue for years. Standard migraine therapy may be helpful to treat accompanying headaches, although vasoconstricting agents (such as ergotamines and triptans) are best avoided in the elderly, especially if there are significant cardiovascular or cerebrovascular comorbidities or vascular risk factors. Medications for aborting migraine headaches are usually not necessary to treat late-life migraine equivalents (sans headache) because the phenomena are transient and unaccompanied by headache.

Heidenhain variant of Creutzfeldt–Jakob disease A form of Creutzfeldt–Jakob disease (CJD) with predominant visual symptoms in the early stages and rapid progression was described by Heidenhain in 1929 and is now known as the Heidenhain variant (Heidenhain, 1929; Meyer et al., 1954; Foundas et al., 2008). The Heidenhain variant occurs in some 10–20% of cases of CJD (Kropp et al., 1999; Lueck et al., 2000). Visual manifestations can include blurred vision, visual field restriction, dyschromatopsia, metamorphopsia, VHs, visual agnosias, cortical blindness, and anosognosia for blindness (Anton’s syndrome) (Kropp et al., 1999). Because of visual difficulties, patients typically stop reading and watching television even before marked dementia has developed (Kropp et al., 1999). Ophthalmologic examination does not reveal marked abnormalities, and new glasses do not significantly improve function in such patients. The vast majority of Heidenhain cases are homozygous for methionine at codon 129 of the prion protein gene (PRNP) (Kropp et al., 1999). This is the same PRNP genotype as the myoclonic variant, PcPCJD type 1 or CJDM/M1 (Parchi et al., 1996). EEG findings are more prominent over the occipital lobes; periodic sharp-wave complexes are evident on EEG in most cases (Kropp et al., 1999; Foundas et al., 2008). Cerebrospinal fluid (CSF) studies typically show 14-3-3 protein and may show elevated levels of neuron-specific enolase (Kropp et al., 1999). When the Heidenhain variant is suspected, MRI with proton-weighted imaging, fluidattenuated inversion recovery (FLAIR), and diffusionweighted imaging (DWI) should be obtained to confirm the diagnosis (Kropp et al., 1999; Shiga et al., 2004). MRI T2- and proton-weighted sequences frequently show symmetric hyperintensities in the basal ganglia and may show a pronounced increase in signal intensity in the calcarine and extra-calcarine occipital cortex, as well as focal atrophy of the visual cortex (Kropp et al., 1999). Pathologically, Heidenhain variant cases demonstrate degeneration

throughout the visual pathways, with loss of ganglion cells and bipolar cells in the retina, demyelination in the optic nerve, neuronal loss in the lateral geniculate ganglion, and severe degeneration in the occipital cortex, particularly the calcarine cortex (Foundas et al., 2008). Pathologic changes in the occipital lobe of Heidenhain variant cases are more prominent than in non-Heidenhain cases of CJD, whereas damage is less severe in the cingulated gyrus and basal ganglia in the Heidenhain cases than in the others (Kropp et al., 1999).

Visual hallucinations due to central pathology Medication-induced visual hallucinations Drugs associated with VHs in the elderly include drugs with anticholinergic properties (atropine, diphenhydramine, and amitriptyline), dopaminergic properties (L-dopa and dopamine agonists), and various psychotropic agents (bupropion, doxepine, and lithium). In most cases, these appear to affect central nervous system neurotransmission, involving particularly cholinergic, dopaminergic, or serotonergic pathways. As such, they can affect brainstem centers involved with both arousal and sleep and, in particular, can affect brainstem reticular centers involved in generating rapid eye movement (REM) sleep. Epileptic visual hallucinations Epileptic VHs are typically brief, stereotyped, and fragmentary simple VHs that may be associated with other manifestations of seizures; epileptic complex VHs can occur but are rare (Manford and Andermann, 1998). As demonstrated by intracranial EEG recordings and direct cortical stimulation studies, epileptic VHs are due to pathologic excitation of visual cortical areas. Electrical stimulation of the occipital cortex produces simple VHs in the contralateral visual hemifield, while electrical stimulation of the temporo-occipital or parieto-occipital cortex produces complex VHs (for example, involving people, animals, or scenes) in both visual hemifields (Penfield and Perot, 1963). Focal cortical resections can produce complete remission of epileptic complex VHs, demonstrating that visual association cortex is both necessary and sufficient for their generation (Manford and Andermann, 1998). Visual hallucinations (Bonnet syndrome) with retrochiasmal visual field defects Bonnet hallucinations are most commonly identified in elderly patients with bilaterally decreased visual acuity, but similar VHs also occur in patients with visual field defects, and even occasionally in patients with visual field defects and normal central visual acuity (Lance, 1976; Kolmel, 1985; Wender, 1987; Cole, 1999, 2001). From a definitional perspective, patients with unstructured lights (such as flashes, sparkles, and zig-zag lines—referred to

Disorders of the Special Senses in the Elderly

by some as phosphenes), simple structured images (such as geometric figures occurring in a repetitive pattern— referred to by some as photopsias), and complex VHs (such as people, animals, and landscapes) had similar lesions on brain imaging (Vaphiades et al., 1996), suggesting no unique anatomic area for each type of positive spontaneous visual phenomena. Although some have referred to these as Bonnet hallucinations, the appropriateness of that eponym in this circumstance has been reasonably questioned (Cole, 2001). In patients with VHs related to visual field defects, the VHs are typically restricted to the abnormal visual field. Retrochiasmal lesions associated with hallucinations are typically smaller than those causing a hemianopsia without associated Bonnet hallucinations and frequently spare the visual association cortex. Large lesions destroying the anterior visual association cortex appear to preclude development of such hallucinations, suggesting that some intact visual association cortex is necessary to experience these complex hallucinations (Vaphiades et al., 1996). The complex nature of the VHs also presumably indicates that they are generated in the visual association cortex. In some cases of complete cortical blindness (as in Anton’s syndrome), patients may be unaware of their deficit.

Central visual disorders in parkinsonism Visual symptoms are common in PD and include complaints of dry eyes, reading difficulties, difficulty estimating spatial relations, and complex VHs (Biousse et al., 2004; Archibald et al., 2009). Nevertheless, visual abnormalities in PD are usually clinically occult and unlikely to be uncovered during routine neurologic examination or by ordinary high-contrast visual acuity testing (Rodnitzky, 1998). With the use of special examination techniques, though, defects have been identified in visuospatial orientation, visual object and facial recognition, visual acuity, color vision, contrast sensitivity and discrimination, the blink reflex, pupil reactivity, ocular convergence, saccadic and smooth pursuit movements, and visual evoked potentials (Rodnitzky, 1998; Biousse et al., 2004; Armstrong, 2008). The decreased blink rate and use of anticholinergic medications may contribute to ocular surface irritation, altered tear film generation or persistence, and xerosis (Biousse et al., 2004). In neurodegenerative disorders with parkinsonism as a prominent feature, VHs occur predominantly in disorders with Lewy body pathology, such as PD and DLB). In contrast, VHs occur rarely in progressive supranuclear palsy (PSP, a tauopathy) and multiple system atrophy (MSA, an alpha-synucelinopathy, but without Lewy bodies) (Williams and Lees, 2005; Williams et al., 2008). In one study, VHs occurred in 50% of the patients with PD, 73% of the patients with DLB, and only 7% of the patients with non-Lewy body parkinsonism (Williams

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and Lees, 2005). Therefore, among patients with unclassifiable or undetermined forms of parkinsonism, VHs are a strong indicator of underlying Lewy body pathology (PD or DLB) (Williams and Lees, 2005; Williams et al., 2008). The distribution of Lewy bodies in the temporal lobe among patients with PD or DLB is more strongly related to the presence and duration of VHs than to the presence, severity, or duration of dementia. Cases with well-formed VHs have high densities of Lewy bodies in the amygdala and parahippocampus, and cases with early VHs have higher densities of Lewy bodies in parahippocampal and inferior temporal cortices (Harding et al., 2002). Visual hallucinations in Parkinson’s disease VHs have been reported in a large percentage of patients with PD, from 8% to 60%, with most estimates approximating 40% at some point in the illness (Fénelon et al., 2000; Barnes et al., 2003; de Maindreville et al., 2005; Diederich et al., 2005; Meral et al., 2007; Papapetropoulos et al., 2008). VHs in patients with PD can be associated with behavioral problems and are a risk factor both for nursing home placement and for mortality (Goetz and Stebbins, 1993, 1995). In patients with PD, illusory visual misperceptions often precede VHs (Diederich et al., 2005). Hallucinations in patients with PD are typically complex visual images, occurring during wakefulness with eyes open and without clear precipitants, but less frequently, they can involve other sensory modalities (occasionally auditory or, rarely, olfactory or tactile) (Goetz et al., 1998; Inzelberg et al., 1998; Fénelon et al., 2000; Barnes and David, 2001; Fénelon et al., 2002; de Maindreville et al., 2005; Papapetropoulos et al., 2008). They are commonly mobile and last for periods of seconds to minutes. The content is variable within and between affected individuals and can include people, animals, buildings, or scenery. Since the availability of levodopa in the late 1960s and 1970s, it has become clear that dopaminergic medications (and also anticholinergic medications) can trigger the onset of hallucinations. This has led to discussion and even controversy over the relative contribution of medications, the underlying disease process, and various comorbidities to the development of hallucinations in patients with PD. VHs occur even in the absence of delirium, dementia, or major depression, suggesting that hallucinations can be part of the disease process itself (Biousse et al., 2004). Nevertheless, VHs are significantly more frequent in patients with PD and concomitant delirium, dementia, or depression, and also significantly more frequent in PD patients treated with dopaminergic or anticholinergic drugs. Risk factors for VHs in PD include older age, longer duration of illness, more severe motor impairment, axial rigidity, olfactory impairment early in the disease course,

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ocular disorders (including worse visual acuity), cognitive decline or dementia, depression, sleep disturbances, autonomic dysfunction, and various medications (SanchezRamos et al., 1996; Klein et al., 1997a; Kraft et al., 1999; Fénelon et al., 2000; Barnes and David, 2001; Holroyd et al., 2001; Onofrj et al., 2002; Barnes et al., 2003; Kulisevsky and Roldan, 2004; de Maindreville et al., 2005; Pacchetti et al., 2005; Papapetropoulos et al., 2005; Williams and Lees, 2005; Matsui et al., 2006b; Onofrj et al., 2006; Oka et al., 2007; Barnes et al., 2010; Stephenson et al., 2010). Patients with a diagnosis of PD who developed early dopaminergic drug-induced VHs (within 3 months of starting dopaminergic therapy) often had hallucinations during daytime and nighttime, frightening hallucinatory content with paranoia, and accompanying nonvisual hallucinations; within 5 years, such patients are typically found to have an underlying psychiatric illness or another neurodegenerative disorder (Goetz et al., 1998). Therefore, the early onset of dopaminergic drug–related VHs should prompt consideration of alternative diagnoses, either a comorbid psychotic illness or an evolving parkinsonism-plus syndrome, DLB, or AD with extrapyramidal signs (Goetz et al., 1998). VHs in PD are not adequately accounted for within Cogan’s simple dichotomy of nonpsychotic hallucinations into release and irritative types; they depend on attentional and visual perceptual impairments, as well as the interactions of multiple processes within scene perception, rather than simply the activation or release of specific visual areas (Collerton et al., 2005). Indeed, various authors have suggested that VHs in PD may result from a combination of faulty perceptual processing of environmental stimuli, less detailed recollection of experience, frontal executive dysfunction, involvement of brainstem sleep centers, impaired attention, and altered levels of arousal, combined with intact image generation (Manford and Andermann, 1998; Barnes et al., 2003; Barnes and David, 2001; Stebbins et al., 2004; Collerton et al., 2005; Diederich et al., 2005; Ozer et al., 2007; Barnes and Boubert, 2008; Barnes et al., 2010; Goetz et al., 2010; Koerts et al., 2010; Bronnick et al., 2011). PD with VHs is associated with increased activation in the visual association cortex and deficits in the primary visual cortex (Holroyd and Wooten, 2006). Association of impaired vision, or impaired visual object processing in occipital and temporal extrastriate visual cortices, supports a contribution from impaired “bottom-up” visual processing in the development of VHs in patients with PD (Meppelink et al., 2009). A wide range of neuropsychological deficits can contribute to the emergence of VHs in PD, including poorer performance in language, verbal learning, semantic fluency, and visuoperceptive functions (RamírezRuiz et al., 2006). Patients with PD and VHs sleep less than nonhallucinating patients and also have increased awakenings, reduced sleep efficiency, and increased

daytime sleepiness, suggesting that VHs in some PD patients may be a symptom of inadequate sleep and prolonged daytime sleepiness (Barnes et al., 2010), or that pathways involved in the generation of VHs are related directly or indirectly to pathways involved with sleep. However, although PD patients with VHs often have concurrent sleep disorders, sleep disorders in the absence of VHs do not seem to be predictive of the subsequent development of VHs (Goetz et al., 2010). Cholinergic and serotonergic pathways are associated with both sleep disturbances and VHs in PD (Manford and Andermann, 1998; Manganelli et al., 2009). Involvement of cholinergic and serotonergic brainstem centers (such as cholinergic pedunculopontine nuclei and serotonergic raphe nuclei) may account for overlaps between PD and REM behavior disorder, and between VHs seen with PD and those seen with LSD, peduncular hallucinosis, and narcolepsy. REM sleep-related dream imagery intruding into wakefulness may account for VHs in some PD patients, as part of a REM sleep disorder that may include sleep-onset REM periods in the daytime, Stage 1 REM during the night, and post-REM delusions at night (Arnulf et al., 2000; Nomura et al., 2003; Kulisevsky and Roldan, 2004). Dysfunction of frontal areas associated with attention could precipitate VHs through abnormal processing of relevant and irrelevant visual stimuli (Ramírez-Ruiz et al., 2008). Preliminary attempts have been made to model the development of VHs in PD (Collerton et al., 2005; Diederich et al., 2005; Papapetropoulos, 2006). According to one such multicomponent model, VHs in patients with PD may represent a dysregulation of the gating and filtering of external perception and internal image production (Diederich et al., 2005). Contributing factors to the development of VHs in such patients can include impaired primary vision, aberrant activation of visual association and frontal cortices, lack of suppression or spontaneous emergence of internally generated imagery (pontogeniculo-occipital system), intrusion of REM dreaming imagery into wakefulness, changes of perceptual filtering capacities through fluctuating vigilance, and medicationrelated overactivation of mesolimbic systems (Diederich et al., 2005). PD patients with VHs had gray matter volume reductions in the lingual gyrus and superior parietal lobe (Ramírez-Ruiz et al., 2006). Hypoperfusion of the visual pathway was closely related to VHs in Parkinson’s disease—patients with PD and VHs had significant perfusion reductions in the bilateral inferior parietal lobule, inferior temporal gyrus, precuneus gyrus, and occipital cortex, compared with nonhallucinatory patients (Matsui et al., 2006a). The relative regional cerebral glucose metabolic rate was greater in the frontal areas in PD patients with VHs, particularly in the left superior frontal gyrus (Nagano-Saito et al., 2004). Cases with well-formed VHs have high densities of Lewy bodies

Disorders of the Special Senses in the Elderly

in the amygdala and in frontal, temporal, and parietal cortical areas, with early VHs relating to higher densities in parahippocampal and inferior temporal cortices (Harding et al., 2002; Papapetropoulos et al., 2006, 2008). The alpha-synuclein burden (presumably as an indicator of Lewy body pathology) in limbic regions, particularly the amygdala and anterior cingulate gyrus, is strongly related to dementia in PD, as well as to VHs when there is an underlying dementia (Papapetropoulos et al., 2006; Kalaitzakis et al., 2009). VHs in PD are a considerable cause of morbidity and are an important predictor of cognitive decline, placement in institutional care, and mortality (Goetz and Stebbins, 1993; Klein et al., 1997a; Goetz et al., 1998; Aarsland et al., 2000; Archibald et al., 2009). In patients with PD and so-called “benign hallucinations” (with retained insight), hallucinations seldom stay benign (Goetz et al., 2006). Most progress to loss of insight or develop delusions within 2 years, and most require either a reduction in Parkinson’s disease medications to treat hallucinations or, less commonly, treatment with neuroleptic medications. Thus, the concept of benign hallucinations is prognostically misleading, as these hallucinations herald serious consequences in a relatively short time frame of several years. VHs in patients with PD and dementia may resolve with acetylcholinesterase inhibitors (donepezil), dual inhibitors of acetylcholinesterase and butylcholinesterase (such as rivastigmine), and atypical antipsychotic medications (such as clozapine or quetiapine) (Diederich et al., 2000; Bullock and Cameron, 2002; Fernandez et al., 2009). These do not appear to act by normalization of sleep architecture (Kurita et al., 2003; Sobow, 2007; Fernandez et al., 2009). Visual hallucinations in dementia with Lewy bodies Parkinsonism and VHs are critical elements in the clinical diagnosis of DLB in conjunction with dementia and fluctuating levels of cognition. Recurrent complex VHs are, in fact, a core clinical feature of DLB, occurring in about twothirds to three-quarters of the affected patients (McKeith et al., 1996; Del Ser et al., 2000; Olichney et al., 2005; Williams and Lees, 2005). For diagnosis of probable DLB, the consensus criteria require progressive cognitive decline of sufficient severity to significantly interfere with social or occupational functioning, with at least two of the following: recurrent VHs; fluctuating cognition with pronounced variations in alertness and attention; and spontaneous motor manifestations of parkinsonism (McKeith et al., 1996). Other supportive features may include repeated falls, syncope, neuroleptic sensitivity, systematized delusions, hallucinations in other sensory modalities, urinary incontinence preceding severe cognitive dysfunction, and a rapidly progressive course (Hansen et al., 1990;

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Perry et al., 1990; Del-Ser et al., 1996; McKeith et al., 1996, 2000). Some cases diagnosed as PD in earlier reports would probably now be diagnosed as having DLB. VHs typically occur early in the course of DLB, whereas, in contrast, they generally occur only in the second half of the disease course in PD (Williams and Lees, 2005). Because VHs are commonly present in both PD and DLB, VHs by themselves are not good predictors of DLB pathology; the absence of VHs early in the disease course, though, suggests that the patient does not have DLB, but is instead highly predictive of PD with dementia (Harding et al., 2002). VHs in DLB are most common during periods of diminished consciousness but are nevertheless much more persistent than the transient perceptual disturbances that occur in other dementias or delirium (McKeith et al., 1996). VHs in DLB are also exacerbated by visual impairment or low-light environments and may be temporarily relieved by increased environmental stimulation, including increased social interaction (McKeith et al., 1996). They are usually detailed and may be of normal size or Lilliputian. Typically, they consist of faces, people, or animals, but they can be of three-dimensional inanimate objects (such as buildings, trees, or flowers). VHs of people are usually of strangers, although it is not uncommon for affected patients to see images of living or deceased friends or relatives. Hallucinations in other sensory modalities may also occur in patients with DLB, but nonvisual hallucinations are much less common than VHs. Emotional responses to these hallucinations are variable (typically ranging from indifference to amusement or, less often, fear), but some degree of insight into their unreality is often maintained (McKeith et al., 1996). In addition to VHs, patients with DLB frequently have visuospatial and visuoconstructive disabilities, visual agnosias, and delusional misidentification syndromes (Mori et al., 2000). Visuospatial and visuoconstructive abilities are more severely affected in DLB than in AD, with corresponding relative decreases in occipital blood flow and glucose metabolism in the primary visual cortex and in the visual association cortex (Mori et al., 2000). Structural and functional central nervous system changes have been linked to VHs in DLB. DLB and PD patients with VHs had more frontal gray matter atrophy than nonhallucinators, with the impairment being greater in the DLB group (Sanchez-Castaneda et al., 2010). VHs in DLB are related to dysfunction of the parietal and occipital association cortices, whereas misidentifications are related to dysfunction of the limbic–paralimbic structures (Nagahama et al., 2010). Deficits in the cholinergic system are pronounced in DLB and are more severe in patients with VHs (Satoh et al., 2010). VHs in DLB are associated with impaired glucose metabolism in the medial occipital cortex (Satoh et al., 2010). Donepezil treatment can be

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effective in treating VHs in DLB, with concomitant reduction in glucose metabolism in the medial occipital cortex (Satoh et al., 2010).

Visual hallucinations in Alzheimer’s disease VHs are also common in various non-Lewy body neurodegenerative diseases, including AD. Cognitive impairment alone (from whatever cause) can be associated with VHs, even in the absence of visual impairment. VHs and other neuropsychiatric symptoms (such as agitation, aggression, delusions, and perseverative verbal or motor behavior) are very common in patients with dementia, often refractory to available treatments, and associated with increased caregiver burden and poor outcomes for patients, including precipitation of institutionalization (Sink et al., 2005). When environmental modification is not effective, various medications can be considered to treat hallucinations, delusions, paranoia, and aggression that are causing distress. However, the efficacy of available medications— including typical and atypical antipsychotics, antidepressants, various “mood stabilizers,” cholinesterase inhibitors, and memantine—is, at best, marginal for treating VHs and other problematic neuropsychiatric manifestations in patients with dementia (Sink et al., 2005). These agents can be associated with many side effects, some of which are severe. Pharmacologic treatments of dementiarelated behavioral symptoms should therefore be used cautiously at minimum dosages, monitored closely for side effects and efficacy, and evaluated for tapering or discontinuation within 6 months of stabilization of symptoms and every 6 months thereafter. Visual hallucinations in delirium Abnormal perceptions are common in acutely confused patients and may include illusions and hallucinations. Whereas illusions are the distortion or misinterpretation of an actual physical stimulus, hallucinations are unprovoked perceptual experiences that occur in the mind in the absence of an external physical stimulus. Hallucinations in acute confusional states are typically visual or a combination of visual and auditory, but polymodal hallucinations can occur with delirium (unlike release hallucinations or irritative hallucinations, which are unimodal). Particularly with delirious states, hallucinations of any type may be terrifying and associated with paranoid delusions. Psychotic hallucinatory–delusional behavior may at times obscure the deficit in attention that is the fundamental clinical feature of acute confusional states. Indeed, the prominence of secondary psychotic behavior in a confused patient may result in the incorrect diagnosis of a functional psychosis. Although confused patients present acutely with impaired attention and often with an altered level of arousal, memory impairment, and disorientation, patients with functional psychoses, such

as schizophrenia and manic-depressive psychosis, have a history of preexisting abnormal behavior and are alert and generally attentive (unless attention is disrupted by active hallucinations), with preserved memory and orientation. In general, psychiatric illness does not cause severe confusion, disorientation, or an altered level of consciousness. In addition, the hallucinations in confusional states are generally visual or mixed and vary throughout the day, generally being worse at night. The hallucinations of functional psychoses, on the other hand, are generally auditory and less susceptible to diurnal variation. Furthermore, the delusions of confused patients are commonly paranoid but generally relate to the immediate situation and change rapidly in content; the delusions of paranoid schizophrenics are stable and systematized, typically concerning expansive, global ideas such as worldwide plots or the FBI. The causes of VHs in delirium are likely varied, depending on the type (agitated, apathetic) of delirium and the underlying causes.

Hearing Functionally significant hearing loss is common in the elderly, affecting about a third of those age 70 or older (Campbell et al., 1999). This can adversely affect quality of life and compromise an older individual’s ability to carry out routine activities and interact socially, thereby contributing to isolation, frustration, disappointment, and depression (Mulrow et al., 1990). Ability to understand spoken speech is often interpreted as an indicator of cognitive abilities, especially in the elderly, so impaired hearing often negatively influences how other people perceive and interact with an elderly person; it also contributes not infrequently to inappropriate diagnoses of dementia by clinicians. In addition, hearing impairment is a significant predictor of postural imbalance and falls in older individuals (Viljanen et al., 2009).

Conductive hearing disturbances The most common causes of conductive hearing loss in the elderly is impacted cerumen. Objective tinnitus can also be considered a “conductive” hearing problem—in this case, not a “negative” symptom (due to impairment or impedance of conduction), but rather a “positive” symptom produced by conduction of vascular and other persistent or rhythmic cranial noises to the cochlea.

Cerumen impaction Cerumen is a yellowish, waxy substance secreted in the outer cartilaginous portion of the external auditory canal. Cerumen consists of shed layers of skin and a combination of viscous secretions from sebaceous glands and modified apocrine sweat glands. Cerumen protects the skin of the canal, assists in cleaning and lubrication, and

Disorders of the Special Senses in the Elderly

may provide some protection from water and infectious agents. Excess or impacted cerumen can impair hearing by blocking sound transmission through the canal or by interfering with movement of the eardrum, both of which produce conductive hearing loss. Physiologic cleaning of the ear canal occurs as a result of a “conveyor belt” process of epithelial migration, aided by jaw movement. The cerumen in the canal is also carried outward, taking with it any dirt, dust, and particulate matter that may have gathered in the canal. Jaw movements assist this process by dislodging debris attached to the walls of the ear canal. Several techniques can effectively remove problematic cerumen from the external auditory canal, including cerumenolysis (using softeners, or cerumenolytics), syringing with warm water (sometimes with so-called “ear wash” devices), and manual removal with a curette. Although softeners are more effective than no treatment, it is unclear which specific softeners are most effective (Burton and Doree, 2009; Clegg et al., 2010). Commercially or commonly available cerumenolytics include various oils (such as olive oil and baby oil); glycerol; carbamide peroxide (6.5%) with glycerine; urea, hydrogen peroxide, and glycerine; sodium bicarbonate in water; and sodium bicarbonate with glycerine. Generally, a cerumenolytic should be used 2–3 times daily for 3–5 days prior to cerumen extraction. Even if impacted cerumen is not resolved by using a softener, such agents generally facilitate removal by subsequent syringing or curettage. The effectiveness of irrigation methods or mechanical removal is equivocal based on available data (Clegg et al., 2010). Proper technique is essential—potential complications of syringing include perforation of the drum (the most common injury resulting in significant disability), iatrogenic otitis externa, and iatrogenic physiologic vertigo (from using an irrigating solution at a temperature other than body temperature) (Wilson and Roeser, 1997; Ernst et al., 1999). The liquid used to irrigate the ear canal is usually water, normal saline, a solution of sodium bicarbonate, or a solution of water and vinegar. To avoid injuring the canal and the tympanic membrane, the water stream should not be instilled at an uncomfortable rate or force—it is much better to irrigate slowly for a long period than to irrigate too forcefully and risk a significant injury. Curettage is most appropriate when the ear canal is only partially occluded and the material is not adhering to the skin of the ear canal. Otoscopy should be performed after removal of cerumen, to ensure that the canal is clear and that no irritation of the canal or other injury has occurred. Use of cotton swabs should be discouraged because they tend to push most of the earwax farther into the canal. If not used carefully, they can also irritate or abrade the canal, result in external otitis media, or produce a tympanic membrane perforation.

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Objective tinnitus Objective tinnitus is a perceived sensation of sound that occurs in the absence of external acoustic stimulation but that the examiner can also hear (for example, by placing a stethoscope over the patient’s external auditory canal, orbit, cranium, and neck). Objective tinnitus results from transmission of sounds generated near the ear from respiration, vascular noises, or muscular contractions. Objective tinnitus is much less common than subjective tinnitus, but it often has an identifiable cause and may be curable, whereas subjective tinnitus is often idiopathic and is seldom curable (Lanska, 2013a). Objective tinnitus may be associated with a variety of vascular noises arising from vascular stenoses (particularly of the carotid arteries), the internal jugular vein or jugular bulb, arteriovenous malformations or fistulas, cavernous hemangiomas, aneurysms, and vascular tumors (Lanska, 2013a). Audiometry is generally normal with pulsatile tinnitus, but occasional cases may have associated conductive or sensorineural hearing loss. Unilateral pulsatile tinnitus is by far the most common type of objective tinnitus, but it may also be subjective (Lanska, 2013a). Usually, it is a benign symptom resulting from normal vascular sounds, possibly exacerbated by anxiety, insomnia, caffeine, or exercise. Pulsatile tinnitus, however, can be a symptom of a more serious problem. Pulsatile tinnitus is generated from cardiac or arterial noises and is usually harsh and synchronous with the pulse. It may occur because of blood turbulence near areas of arterial narrowing (such as carotid bruits), near areas of abnormal blood flow (such as arteriovenous malformations, carotid-cavernous fistulas, or vascular tumors), by increased blood flow (such as anemia, thyrotoxicosis, or hypertension treated with agents that lower peripheral vascular resistance), by transmission of heart sounds (such as aortic stenosis or mechanical heart valves), or as a result of intracranial hypertension (Sismanis, 1998, Jun et al., 2003; Sismanis, 2003). Pulsatile tinnitus may occur with Paget’s disease, apparently because of neovascularization and the formation of arteriovenous fistulae within the temporal bone (Sismanis, 1998). Pulsatile tinnitus following head trauma may indicate a traumatic arteriovenous malformation, carotid-cavernous fistula, or carotid dissection. Although vascular loops in contact with the eighth cranial nerve are generally considered a normal variant, individuals with unilateral hearing loss are twice as likely to have such loops in the symptomatic ear than in the asymptomatic ear, and individuals with pulsatile tinnitus are reportedly 80 times more likely to have a contacting vascular loop on the symptomatic side than individuals with nonpulsatile tinnitus (Chadha and Weiner, 2008). Patients with hydrocephalus commonly develop pulsatile tinnitus. Pulsatile tinnitus with increased intracranial pressure may result from several (not mutually exclusive) mechanisms: (1) turbulence as blood flows from the

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hypertensive intracranial vessels to the lower-pressure jugular bulb; (2) augmentation of venous and cerebrospinal fluid pulsations because the accompanying arteriolar dilation allows a greater transmission of the arterial pulse; and (3) transmission of systolic CSF pulsations to the walls of the venous sinuses, which, in turn, produces turbulent flow in the sinuses. The noise may be unilateral because of asymmetries of jugular vein flow, with the bruit occurring on the side of greatest jugular vein flow. It is attenuated by maneuvers that decrease jugular vein flow (such as jugular vein compression ipsilateral to the tinnitus, a Valsalva maneuver, or turning the head). It also remits transiently with lumbar puncture or permanently with definitive treatment of intracranial hypertension (such as with shunting). In patients with pulsatile tinnitus, clinical evaluation should include assessment of vascular risk factors, funduscopy to exclude papilledema, otoscopy to exclude a retrotympanic mass, assessment of the effect of jugular bulb pressure on the tinnitus, auscultation for cranial and carotid bruits, and examination for evidence of occlusive vascular disease elsewhere in the body. Head MRI with gadolinium enhancement should be obtained in patients with unexplained unilateral tinnitus (with or without hearing loss) and in patients with hearing loss suspicious for retrocochlear pathology. Suspected carotid stenosis can be evaluated with duplex ultrasonography, magnetic resonance angiography, computed tomography (CT) angiography, or, less commonly now, with conventional angiography. In patients with evidence of increased intracranial pressure (such as headache and papilledema), CT or MRI should be performed to exclude a mass lesion; in addition, lumbar puncture should be performed if there is communicating hydrocephalus and no mass lesion on brain imaging. Angiography or magnetic resonance venography may be helpful if dural sinus thrombosis is suspected. In patients with a retrotympanic lesion on otoscopy, it is important to distinguish an aberrant carotid artery, abnormal jugular bulb, and glomus jugulare tumor; CT of the temporal bones is recommended (Sismanis, 1998), but other structural and vascular imaging studies may also be helpful. Forms of pulsatile tinnitus related to vascular pathology may be curable with surgery or endovascular procedures (Shah et al., 1999; Zenteno et al., 2004). For example, pulsatile tinnitus resulting from carotid stenosis may be cured with carotid endarterectomy (Louwrens et al., 1989; Carlin et al., 1997; Norman et al., 1999; Kirkby-Bott and Gibbs, 2004), carotid ligation (Carlin et al., 1997), or angioplasty and stenting (Emery et al., 1998). Pulsatile tinnitus caused by hydrocephalus remits transiently with lumbar puncture or permanently with definitive surgical treatment of intracranial hypertension. The cervical venous hum, another common cause of objective tinnitus, is caused by turbulence in the internal

jugular vein, which causes the vessel walls to vibrate. It is an innocuous murmur but is often mistaken for more sinister sounds. Most patients with venous hums are asymptomatic, but occasionally venous hums are the source of disturbing objective tinnitus. Objective tinnitus associated with a venous hum is a continuous murmur with pulse-synchronous (diastolic) accentuation of variable character (from a hum, to a musical whistle, to a roar) that can be heard in the anterior neck and sometimes the upper chest. Clinically, it is best detected with the bell of a stethoscope, and it is typically loudest beneath the lower lateral border of the sternal attachment of the sternocleidomastoid muscle and just superior to the medial end of the clavicle. It can be unilateral or bilateral, but when unilateral, it is typically present on the right side. It can be precipitated or accentuated with turning the head away from the auscultated side as the internal jugular vein is stretched and pulled against the transverse process of the atlas and as the contraction of the ipsilateral sternocleidomastoid muscle removes pressure on the vein and, thus, increases flow on that side. Clinically, it can be confirmed by eliminating the sound with moderate pressure over the internal jugular vein a few inches above the clavicle with a finger pressed lateral to the thyroid cartilage (which is insufficient to interfere with the carotid artery pulse), and often accentuated with release of this pressure or by pressure on the contralateral internal jugular vein. A venous hum is a normal finding in the vast majority of cases and can be detected by appropriate examination in 25–50% of the older adults (Jones, 1962; Fowler and Gause, 1964; Lanska, 2008, 2011a). Less commonly, it may occur or be accentuated (to the point that it is symptomatic) in various disease states (as with anemia; aortic insufficiency; thyrotoxicosis; intracranial arteriovenous malformations that produce increased cerebral blood flow; high cardiac output states, such as with fever; in dialysis patients with anemia and arteriovenous fistulas; or with pulmonary or other arteriovenous fistulas). Venous hums may be bilateral with hyperdynamic cardiac states and may be associated with cranial or orbital bruits if the underlying cause of a secondary venous hum is an intracranial arteriovenous malformation. Symptomatic secondary venous hums may resolve with treatment of the underlying condition or, in selected cases, by an external device to compress the internal jugular vein, by mastoidectomy, or by internal jugular vein ligation. Internal jugular vein ligation typically results in immediate and permanent relief of the pulsatile tinnitus associated with venous hums, although there is a theoretical risk of precipitating a venous hum on the opposite side because of the increased contralateral flow postsurgically. Angiography is recommended prior to internal jugular vein ligation, to exclude other vascular pathology and to ensure normal venous drainage on the opposite side.

Disorders of the Special Senses in the Elderly

Objective tinnitus associated with abnormal clonic muscular contractions of palatal or middle ear muscles may occur as an intermittent series of sharp, regular clicks, or with palatal myoclonus as a fairly regular, continuous clicking sound. Clicks occur over a wide frequency range (from 10 to 300 Hz). Several distinct entities can produce this type of objective tinnitus: (1) symptomatic palatal myoclonus (associated with brainstem and cerebellar dysfunction); (2) essential palatal myoclonus (without associated neurologic dysfunction or neuropathology); and (3) stapedial myoclonus (restricted to the stapedius muscle) (Deuschl et al., 1990). In patients with rhythmic tinnitus from palatal myoclonus, the key to diagnosis is to recognize the palatal contractions. Pressing a gloved finger on the affected side of the palate in the direction of the Eustachian tube opening can result in temporary cessation of tinnitus, even while the muscular contractions continue. Stapedius myoclonus may be precipitated by loud sounds and is often associated with facial nerve pathology (such as hemifacial spasm and sometimes Bell’s palsy). The clicking sounds associated with palatal myoclonus have been localized to the opening of the Eustachian tube, presumably with release of sound energy as the surface tension holding the tube closed is suddenly broken. As a result, tympanometry may demonstrate rhythmic changes in middle-ear compliance (Slack et al., 1986). Symptomatic palatal myoclonus is usually caused by a lesion in the Guillain–Mollaret triangle (between the dentate nucleus, the inferior olive, and the red nucleus); typically, the cause is vascular, especially in the elderly but, less commonly, demyelination, head trauma, syphilis, electric shock, and other causes may be responsible. These lesions produce hypertrophic degeneration of the inferior olive, as well as secondary rhythmic, synchronized discharges that act on a variety of brainstem motor nuclei, causing nystagmus, palatal contractions, extrapalatal tremors (of the chin and platysma), and sometimes ear clicks. Essential palatal myoclonus is less well understood but is thought to result from a distinct brainstem oscillator that stimulates the trigeminal motor nucleus, causing rhythmic contraction of the tensor veli palatini muscle, Eustachian tube opening, and ear clicks (Deuschl et al., 1990). Injections of Clostridium botulinum toxin into the levator veli palatini and tensor veli palatini muscles may be the most useful approach to suppressing the tinnitus associated with palatal myoclonus (Saeed and Brookes, 1993, 1996; Bryce and Morrison, 1998). The most common side effects of Clostridium botulinum treatment are paresisinduced Eustachian tube obstruction and velopharyngeal weakness, with nasal regurgitation and dysphagia (Saeed and Brookes, 1993; Bryce and Morrison, 1998); tympanostomy tube placement can relieve discomfort associated with Eustachian tube dysfunction, and careful titration can minimize side effects (Bryce and Morrison, 1998). Patients may also receive some benefit from tinnitus

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masking (Saeed and Brookes, 1993). Palatal myoclonus has anecdotally been reported to respond to various oral medications, but results with oral medications are inconsistent, at best (Deuschl et al., 1990). Several surgical procedures to treat the associated tinnitus have also been reported with variable results; in some cases, the surgical procedures have made the patients worse. Psychotherapy, application of cocaine to the nasopharynx, otic ganglion blockade with anesthetic agents, stimulation of the corneal reflex, acupuncture, hypnosis, relaxation exercises, and other approaches have also been tried without much success. Objective tinnitus associated with a patulous Eustachian tube may be described variously as a blowing sound, an ocean roar, a low-pitched sound, a flapping sound, or a click. It is synchronous with respiration and usually more marked in the upright position. It is more common in women and has been associated with weight loss and mucosal atrophy (due to atrophic rhinitis or radiotherapy) (Peifer et al., 1999; Ng and van Hasselt, 2005). Physical examination and audiometry are usually normal, although occasionally, the tympanic membrane may be observed to move synchronously with respiration, or tympanometry can demonstrate oscillations synchronous with respiration (Ng and van Hasselt, 2005; Takasaki et al., 2008). A suspected patulous Eustachian tube can be confirmed by temporary resolution of tinnitus with the head recumbent, or with sniffing, snorting, or a Valsalva maneuver (McCurdy, 1985; Ciocon et al., 1995).

Sensorineural hearing disturbances Healthcare professionals and family members can improve communication with hearing-impaired patients by facing the person (so that the impaired person can easily see face and lip movements); speaking in a lower register with short, simple sentences; and eliminating extraneous background sounds when possible. Hearing aids are the principal form of rehabilitation for sensorineural hearing loss (SNHL) and can specifically improve communication and reduce hearing handicap (Working Group on Communication Aids, 1991; Gates and Rees, 1997). Hearing aids are effective for treating mild to moderate hearing loss when the device is appropriately selected and fit for the patient, and when the patient is motivated and able to use the device. Even in demented patients, hearing aids are generally well tolerated and reduce disability caused by hearing impairment, so dementia is not a reason to preclude evaluation for a hearing aid; however, hearing aids do not reduce cognitive dysfunction, behavioral problems, or psychiatric manifestations in such patients (Allen et al., 2003). In addition, assistive devices (such as a built-in telephone amplifier, low-frequency doorbells, amplified ringers, close-captioned television decoders, flashing alarm clocks, flashing smoke detectors, and alarm bed

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vibrators) and training in “speech reading” (using visual cues to help determine what is being spoken) are helpful for many elderly patients with presbycusis and other forms of SNHL (Gates and Rees, 1997; Working Group on Communication Aids for the Hearing-Impaired, 1991). Instruction in sign language should be considered for those with severe hearing loss not corrected by a hearing aid. For selected patients with profound hearing loss that is not improved by a simple hearing aid, a cochlear implant device may provide functional hearing; there is no absolute age threshold for this procedure for appropriate patients. Cochlear implantation may improve audiologic performance and quality of life in elderly patients, even into their 80s (Kunimoto et al., 1999; Eshraghi et al., 2009; Sprinzl and Riechelmann, 2010). Pain and transient vertigo are the most common complications reported in elderly patients following cochlear implantation (Eshraghi et al., 2009). Common causes of SNHL in the elderly include aging (presbycusis), noise exposure, and vascular occlusive disease (Gates et al., 1993). Distinguishing among these various causes is facilitated by attention to history (noise or toxin exposure, trauma, and so on), onset and course of hearing loss, whether the hearing loss is unilateral or bilateral, the distribution of hearing loss as a function of sound frequency, associated manifestations (such as vertigo), and family history. Subjective tinnitus is often associated with SNHL and therefore is considered in this section, although the perceived abnormal sounds are generated centrally, probably by a “release” mechanism akin to that proposed for Bonnet VHs.

Presbycusis Presbycusis (literally “elderly hearing” or “old age hearing”) is the gradual loss of hearing that occurs in most people as they grow older. The term presbycusis is generally used to incorporate all processes that contribute to hearing loss over time, including both extrinsic insults (noise, ototoxic agents, and disease) and age-associated physiologic degeneration. Presbycusis affects about onethird of the people aged 65 and older, and up to half of the people aged 75 and older, although some estimates place the proportion of elderly patients affected much higher (Sprinzl and Riechelmann, 2010). Hearing loss associated with presbycusis is usually a fairly symmetric sloping high-frequency SNHL that results primarily from accumulated damage to the inner ear, particularly a loss of sensory hair cells in the cochlea (sensory presbycusis). Some individuals may have contributions from other sources, including central (brainstem), neural (ganglion cell loss), strial or “metabolic” (strial atrophy), and possibly cochlear conductive or mechanical (stiffness of the basilar membrane) sources (Working Group on Speech Understanding and Aging, 1988; Gates and Rees, 1997; Bao and Ohlemiller, 2010).

Environmental noise exposure is a major contributor to sensory presbycusis, the most common type of presbycusis. Neural and central types of presbycusis are rare but are significant because amplification typically does not benefit patients with purely neural or central lesions (in contrast with the significant benefit often afforded to those with sensory presbycusis). Low-frequency hearing loss is considered typical of strial or “metabolic” presbycusis, and this type of presbycusis is associated with comorbid cardiovascular disease, especially in women (Gates et al., 1993). The term metabolic presbycusis for presbycusis associated with strial atrophy is so named because the stria vascularis is the metabolic pump that generates the endocochlear potential (Gates and Rees, 1997). Patients affected by presbycusis find that the speech of others sounds mumbled or muffled, and they have particular difficulty perceiving or discriminating highpitched consonants (ch, f, k, s, t, or th), compared with lower-pitched vowel sounds. They have more difficulty hearing the higher-pitched voices of women and children than they have hearing men’s voices, and they typically have difficulty understanding conversations when there is background noise. Some sounds may be distorted or perceived as overly loud—when talking at a regular pitch and volume, the patient may have difficulty discriminating speech sounds, whereas compensatory efforts by the speaker to talk in a lower register and more loudly can produce an irritated response from the patient (“You don’t have to yell!”). Presbycusis is often associated with subjective tinnitus. In addition, it contributes significantly to isolation and depression in the elderly. Risk factors for presbycusis include repeated exposure to loud noises, smoking, certain medications (such as cancer chemotherapy, particularly with cisplatin; some antibiotics, particularly aminoglycosides; loop diuretics; and aspirin and other anti-inflammatory agents), several comorbid conditions (such as cardiovascular disease, hypertension, diabetes, and renal failure), and a family history of presbycusis. Folic acid may be helpful in slowing the decline of hearing in the speech frequencies (0.5–2.0 kHz) due to presbycusis in populations without folic acid food fortification programs (Durga et al., 2007). The effect of folic acid supplementation in countries that have folic acid food fortification programs (such as the United States, Great Britain, and Hungary) is not clear.

Noise-induced hearing loss Worldwide, approximately one-sixth (16%) of disabling hearing loss in adults is attributable to occupational noise exposure, with significant variation in different subregions (Nelson et al., 2005). The effects of exposure to occupational noise are higher in males than in females because of differences in both workforce participation and the type of occupations. With aging, prior noise-induced cochlear

Disorders of the Special Senses in the Elderly

damage and resulting SNHL are compounded by other factors that compromise hearing (such as ototoxins and age-related organ damage) (Lanska, 2013b). Most of this disability is preventable with appropriate engineering controls to reduce noise generation or propagation and with appropriate use of hearing protectors (Lanska, 2013b). Occupational noise exposure is the most important preventable cause of hearing loss in the United States, but it accounts for less than 10% of the burden of hearing loss (most of the rest is age-related) (Dobie, 2008). Noiseinduced hearing loss (NIHL) is generally attributable to unprotected exposures above 95 dBA. It often becomes clinically apparent in middle-aged or elderly individuals when age-related threshold shifts are added to prior noise-induced shifts. Other factors that can synergistically augment the effect of noise in damaging cochlear hair cells include hereditary predisposition and certain environmental exposures, such as smoking and exposure to toxic solvents in car paints. Patients with NIHL typically present with the gradual onset of bilateral, high-frequency SNHL (Fransen et al., 2008). They usually have a history of recreational or occupational noise exposure, usually without hearing protection, occurring over many years. With continued noise exposure, hearing loss is progressive. Although NIHL is typically bilateral, it may be worse in one ear. In shotgun or rifle users, NIHL is typically worse on the side opposite the patient’s dominant hand, whereas handgun users may have worse hearing loss on the same side as the dominant hand. NIHL adversely affects quality of life (Muluk and Oguztürk, 2008). Patients may hear vowels better than consonants because vowels have predominantly low-frequency content, whereas consonants have predominantly high-frequency content. High-frequency voices (such as children’s voices) may be difficult for these patients to understand, especially with background noise. Shouting does not help understanding because it primarily increases the intensity level of vowels rather than consonants; in addition, loud sounds are often uncomfortable for such patients because of recruitment. Sounds are also frequently distorted, so that a pure tone may be heard as a buzz, broad-band noise, or a complex mixture of tones. Some patients experience diplacusis (the perception of a single auditory stimulus as two separate sounds, which may differ in pitch or in time). Subjective tinnitus is a common associated feature of NIHL and, for some patients, may be the most troubling symptom. Tinnitus intensity levels established with loudness matching techniques correlate with hearing levels at the frequency of most severe hearing loss (Man and Naggan, 1981). In the presence of normal hearing, however, tinnitus should not necessarily be ascribed to noise exposure, as the presence of tinnitus in those with normal

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hearing is not associated with present noise level, duration of noise exposure, or cumulative noise exposure (Rubak et al., 2008). NIHL results from cochlear damage, particularly near the base of the cochlea. Brief exposure to loud noise (hours to days) may produce only a temporary threshold shift (Osguthorpe and Klein, 1991). More prolonged exposure to loud sounds, even at levels that are not uncomfortable or painful, results in permanent injury and loss of cochlear hair cells (Osguthorpe and Klein, 1991). Damage to cochlear hair cells is often initially confined to a small area 5–10 mm from the base of the cochlea, the area involved in sensing frequencies around 4000 Hz. Hearing at 4000 Hz is important for speech discrimination in noisy environments (Osguthorpe and Klein, 1991). Hair cells undergo apoptosis in response to noise damage, but the supporting cells are not able to regenerate (Cotanche, 2008). Considerable cochlear hair cell damage can occur before hearing thresholds are affected. The basis for the relatively selective damage to the basal cochlea is not clear, but mechanical, vascular, and toxic-metabolic theories have been proposed—the mechanical theory postulates shear forces from a “jet effect” at this location, whereas the vascular theory maintains that this region is susceptible to ischemia because it is at the juncture of the main cochlear and cochlear ramus arteries, and the toxic-metabolic theory implicates late development of free radicals in mitochondria followed by excitotoxic neural swelling and induction of apoptotic cell death in the organ of Corti (Lim and Melnick, 1971; Yamane et al., 1995; Henderson et al., 2006; Le Prell et al., 2007). Noise sensitivity tends to aggregate in families, and twin studies have implicated a genetic component to NIHL (Heinonen-Guzejev et al., 2005). Nonmodifiable risk factors associated with NIHL include increasing age, male gender, and genetic predisposition; modifiable risk factors include voluntary exposure to loud noise, lack of hearing protection, smoking, lack of regular exercise, poor diet, poor dentition, diabetes, and cardiovascular disease (Wild et al., 2005; Daniel, 2007; Lanska, 2013b). Some of these risk factors may simply be noncausal associations (such as lack of regular exercise, poor diet, and poor dentition). With acute noise exposure, the threshold shift may be temporary, with hearing gradually returning to baseline levels over the period of approximately a day (Osguthorpe and Klein, 1991). With repeated noise exposure, hearing only partially returns to baseline levels, and the threshold shift becomes permanent and progressive. Independent risk factors for NIHL include older age, male sex, and greater noise exposure (Bauer et al., 1991; Neuberger et al., 1992). Common associated symptoms include tinnitus, sound distortion, and diplacusis. Audiograms show bilateral SNHL, often with a characteristic notch at 4000 Hz (Bauer et al., 1991; Osguthorpe

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and Klein, 1991; Neuberger et al., 1992; Griest and Bishop, 1998; McBride and Williams, 2001). A 6000 Hz notch is variable and of limited importance (McBride and Williams, 2001). With progression of SNHL, this “noise notch” at 4000 Hz deepens and hearing loss extends into lower frequencies. Speech discrimination is not affected until late in the disease process. Otoacoustic emissions may provide earlier identification of noise-induced damage than pure tone thresholds alone and may identify cochlear dysfunction extending beyond the frequency range suggested by the audiogram (Balatsouras, 2004). Although a variety of definitions have been proposed in the literature, SNHL can be considered asymmetric if the interaural difference in pure tone thresholds is at least 10 dB at two frequencies or at least 15 dB at one frequency (Urben et al., 1999). Asymmetric SNHL is fairly common as a result of noise exposure or on an idiopathic basis (Chung et al., 1983; Pirila, 1991; Pirila et al., 1992; Urben et al., 1999). However, asymmetric SNHL can rarely be an indication of retrocochlear pathology (Urben et al., 1999; Baker et al., 2003) or of tertiary syphilis. Patients with asymmetric SNHL may be followed with serial audiograms (every 6 months) if they have known significant asymmetric noise exposure or have no recent changes in hearing or word recognition, no risk factors for syphilis (or a negative fluorescent treponemal antibody test), and no associated symptoms (such as vertigo) (Urben et al., 1999). Patients without a history of significant asymmetric noise exposure or other known cause of asymmetric SNHL, as well as those with progression of asymmetric SNHL, should undergo brainstem auditory-evoked response (BAER) testing (Urben et al., 1999). MRI is not a cost-effective screening technique for retrocochlear lesions among all patients with asymmetric SNHL; it should be reserved for cases with a high clinical suspicion or cases with abnormal or inconclusive results from BAER testing (Urben et al., 1999). The “rule 3000” is a clinical decision rule that can help guide a more cost-effective approach to utilization of MRI in patients with asymmetric SNHL—if asymmetric SNHL of at least 15 dB is present at 3000 Hz, MRI should be performed; if there is less than 15 dB of asymmetry at this frequency, patients can be followed biannually with audiometry (Saliba et al., 2009). Although affected patients may be fitted with hearing aids, this does not generally restore hearing to normal, and sounds are often distorted. Therefore, prevention is essential. At-risk subjects should routinely use hearing protection when in loud environments. Education is critical because many affected individuals are reluctant to wear hearing protection, and many who wear it do not wear it consistently or, in some cases, do not use it correctly. If feasible, environmental controls should be placed to control noise exposure.

In an occupational setting in the United States, the Occupational Safety and Health Administration (OSHA) requires baseline and annual audiometric pure-tone airconduction threshold testing of both ears for employees exposed to at least 50% of the permissible noise exposure level. Hearing protection is recommended for timeweighted average sound exposure levels of 85 dBA or more; it is required for levels of 90 dBA or more. Hearing protection is also required if a worker has experienced a significant threshold shift, even if occupational exposure is less than 90 dBA time-weighted average. Hearing protection must decrease the employee’s noise exposure to less than 85 dBA time-weighted average. However, even at somewhat lower noise levels, some employees may develop permanent NIHL (Osguthorpe and Klein, 1991). Furthermore, OSHA regulations do not cover many workers exposed to excessive noise, including farmers, construction workers, and employees of small businesses. Recreational noise exposure is usually less frequent and of shorter duration than occupational noise exposure, but it may readily compound occupational noise damage. Many power tools, lawnmowers, firearms, and sound speakers exceed safe sound exposure levels. For example, approximate dBA sound levels are 90 for a lawnmower, 100 for a chain saw, and 140 for a shotgun blast. Hearing protection should be worn if individuals have to raise their voice to carry on a conversation easily. Hearing aids (most of which are vented) are inadequate for hearing protection. Hearing protection devices commonly available include earmuffs or earplugs. Earmuffs usually have higher noise-reduction ratings than earplugs, but some individuals find earmuffs to be hot, cumbersome, or cosmetically unappealing, any of which can adversely affect usage (Arezes and Miguel, 2002). For difficult-to-fit external auditory canals, custom earplugs can be made from an earmold impression. Special ear plugs are also available for special needs (for cosmetic considerations, hunting, singing, or specific work environments). Poorly fit earplugs or ear muffs are much less effective and may not adequately protect hearing. Earplugs can be worn in combination with earmuffs in extremely high-noise environments, but combination use disrupts sound localization (Simpson et al., 2005) and the maximum noise reduction is approximately 50 dB because of bone conduction through the skull (Osguthorpe and Klein, 1991).

Sudden deafness “Sudden” deafness is defined as SNHL of 30 dB or more in at least three contiguous frequencies (on a standard audiogram), occurring over less than 3 days (Lanska, 2013c). Although generally a monophasic illness, recurrences can occur with some etiologies. Depending on the etiology and on damage to associated structures, associated manifestations may include aural fullness or pressure, tinnitus, vertigo, nausea and vomiting, and various

Disorders of the Special Senses in the Elderly

brainstem and cerebellar signs. In patients with sudden SNHL, tinnitus is associated with worse high-frequency hearing loss, whereas aural fullness and pressure sensations are typically associated with low-frequency hearing loss (Sakata et al., 2008). Tinnitus and sensations of aural fullness improve with improvements in hearing (Ishida et al., 2008). The condition occurs most commonly in the fifth and sixth decades, but cases among the elderly are not unusual, particularly for bilateral involvement and/ or cases of vascular etiology (Oh et al., 2007). Sudden deafness typically occurs with the interruption of sensorineural structures involved with hearing, but it can rarely occur with brainstem or cerebral damage. Cochlear or eighth nerve infarction may occur in isolation or with concomitant infarction of the labyrinth, brainstem, and cerebellum. Acute bilateral hearing impairment suggests vertebrobasilar occlusive disease, but hearing loss associated with vertebrobasilar insufficiency is most frequently unilateral. Viral infections, inflammatory conditions, or autoimmune disorders that produce sudden hearing loss generally involve the labyrinth or eighth nerve. Ménière syndrome involves the labyrinth. Tumors and meningitis that produce sudden hearing loss generally involve the eighth nerve. The frequent spontaneous recovery of hearing loss and improvement with steroid therapy suggest that, in many cases, there is a potentially reversible metabolic inner-ear process disrupting the endocochlear potential rather than immediate hair-cell degeneration (Sismanis, 2005). Sudden hearing loss can be caused by a variety of disorders, including inner ear or eighth-nerve ischemia, viral infection of the labyrinth or cochlear nerve, Ménière disease, intralabyrinthine membrane rupture, and autoimmune or inflammatory causes (Lanska, 2013c). Uncommon causes include retrocochlear masses, demyelinating disease, syphilis, Lyme disease, meningitis, carcinomatous meningitis, arteritis, perilymph fistula, toxins, barotrauma, head injury (especially with temporal bone fracture, but also with inner ear concussion), and otologic surgery (Lanska, 2013c). The putative cause is identified in about 15% of the cases, and the remainder is almost always unilateral and considered idiopathic after evaluation (Rauch, 2008). Only a small minority (∼1%) has an identified retrocochlear cause (such as a mass, demyelinating disease, or stroke) (Rauch, 2008). Rare bilateral cases may be due to malingering, conversion disorders, and neurologic causes (such as vertebrobasilar occlusive disease, carcinomatous meningitis, paraneoplastic syndromes, encephalitis, or meningitis) (Koda et al., 2008; Rauch, 2008). Mitral valve prolapse, mitral leaflet thickening, mitral regurgitation, and left atrial enlargement are risk factors for “idiopathic” sudden SNHL, and presumably, these associations reflect an increased risk of cochlear or eighth-nerve ischemia (Vazquez et al., 2008).

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Various mechanisms have been proposed, including those attributing sudden deafness to vascular insults, infectious (especially viral) agents, autoimmune or inflammatory mechanisms, or disruption of labyrinthine membranes. Of the nonidiopathic cases, vascular and infectious etiologies are the most common, and the pathophysiology of these is best understood. The blood supply to the inner ear is via the internal auditory artery (also called the labyrinthine artery), which typically originates from the anterior inferior cerebellar artery (AICA). The internal auditory artery and its branches are end arteries, so even transient ischemia can cause permanent inner-ear damage (Lanska, 2013c, 2013d). The organ of Corti within the cochlea is particularly sensitive to ischemia. Obstruction of either the internal auditory artery or inferior cochlear vein produces rapid loss of function; electrical activity deteriorates within 60 seconds of interruption of blood flow. Cochlear function may return to normal if blood flow is restored within 8 minutes of complete obstruction, but not if blood flow is interrupted for more than 30 minutes. External hair cells and the ganglion cells of the cochlea are particularly vulnerable to arterial obstruction, whereas the vestibular end organs are relatively resistant. Arterial obstruction produces histologically evident changes in cochlear hair cells within 30 minutes, followed in a few hours by extensive necrosis and, ultimately, severe fibrosis and ossification by 6 months. Inner ear ischemia occurs most commonly in the setting of thromboembolic disease of AICA or the basilar artery, or uncommonly with migraine, fat emboli, thromboangiitis obliterans, severe hyperlipidemia, macroglobulinemia, leukemia, and other causes of hypercoagulation or hyperviscosity. Sudden deafness in AICA infarction is often due to cochlea dysfunction from ischemia, but mixed central and peripheral dysfunction also occurs, making recognition of the components difficult. AICA supplies the inner ear as well as the lateral pons, middle cerebellar peduncle, flocculus, and anterior part of the cerebellar lobules. As a result, AICA-territory infarction can cause ipsilateral hearing loss with or without tinnitus, as well as a range of labyrinthine, brainstem, and cerebellar symptoms and signs. Other manifestations include nystagmus, ipsilateral facial numbness, ipsilateral facial paresis, vertigo, dysarthria, vomiting, unsteadiness, ipsilateral hemiataxia, and contralateral loss of pain and temperature sensation on the limbs and body. Occasionally, isolated vertigo or isolated auditory disturbance may occur as TIAs preceding AICA-territory infarction (Amarenco et al., 1993; Lee and Cho, 2004). Bilateral sudden deafness may occur as a prodrome of AICA-territory infarction in the presence of severe vertebrobasilar occlusive disease. Although AICA-territory infarction can be confused with posterior inferior cerebellar artery (PICA) territory infarction (Wallenberg syndrome), because of shared signs

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(such as Horner syndrome, facial sensory impairment, vestibular signs, dysmetria, and contralateral impairment of pain and temperature sensation), severe facial paresis, hearing loss, and tinnitus are atypical for PICA-territory infarctions, and their presence should alert the clinician to AICA-territory infarction. The clinical manifestations of superior cerebellar artery syndrome include ipsilateral Horner syndrome, ipsilateral limb ataxia, contralateral SNHL (due to involvement of the lateral lemniscus carrying decussated ascending auditory information), contralateral superficial sensory loss, vertigo, nystagmus, nausea, and vomiting (Murakami et al., 2005). Hearing loss occurs in about one-fifth of patients with vertebrobasilar insufficiency and vertigo (Yamasoba et al., 2001). Deafness associated with vertebrobasilar insufficiency mainly involves the cochlea rather than central auditory pathways (Yamasoba et al., 2001; Lee and Baloh, 2005). Tinnitus and vertigo are frequent accompaniments, as are a wide range of brainstem and cerebellar symptoms and signs (Lee et al., 2003; Sauvaget et al., 2004). Ischemia may also occur with vascular obstruction in the venules and capillaries draining the inner ear. Venous obstruction produces early epithelial edema, followed by hemorrhage into the epithelium and perilymphatic and endolymphatic spaces, hair cell damage with secondary ganglion cell degeneration, and later fibrosis and ossification. The most common cause of venous obstruction causing sudden deafness is increased blood viscosity. The “hyperviscosity syndrome” includes a number of diverse clinical manifestations, including sudden or progressive hearing loss, headache, fatigue, vertigo, nystagmus, visual disturbances, and mucosal hemorrhages (Nomura et al., 1982; Andrews et al., 1988). Ophthalmoscopic findings include markedly distended and tortuous (“sausageshaped”) retinal veins and retinal hemorrhages, similar to the pattern seen in retinal vein occlusion. Viral neurolabyrinthitis may be part of a systemic viral illness or may be an isolated viral infection of the labyrinth and eighth nerve. Many patients report an upper respiratory illness within 1–2 weeks prior to the onset of symptoms. The manifestations are unilateral and may include clinically evident aural or vestibular symptoms, or both. When hearing loss is incomplete, it is usually most severe at high frequencies. Some cases may develop posterior semicircular canal benign paroxysmal positional vertigo with preservation of lateral semicircular canal function (Karlberg et al., 2000). Herpes zoster oticus may be associated with vesicles in the external auditory canal, burning pain in the ear, unilateral Bell’s palsy, unilateral hearing loss, tinnitus, vertigo, and transient spontaneous nystagmus. Pathologic studies in patients with viral neurolabyrinthitis and sudden deafness have shown evidence of viral damage to the cochlea and auditory nerve, similar to that seen in patients with well-documented viral

disorders (such as mumps). A large number of viruses have been associated with viral neurolabyrinthitis, but Herpes simplex virus type 1 and herpes zoster oticus have been particularly associated with sudden SNHL (Wilson, 1986; Rabinstein et al., 2001). Proof of viral etiology in individual cases is difficult to establish, with the exception of herpes zoster oticus, where the clinical features are often fairly obvious and characteristic. Sudden SNHL in the elderly may also occur from medications, including nonsteroidal anti-inflammatory drugs (McKinnon and Lassen, 1998) or aminoglycosides. Rapid ototoxic hearing loss is much more common in patients with poor renal function. Initial evaluation should include careful history and examination to identify likely toxic, otologic, or systemic causes, including evaluation of Lyme titers and syphilis serologies. Audiograms should also be obtained to demonstrate the pattern and severity of hearing loss, which are helpful prognostically. Audiograms should be obtained before and within 24–48 hours after initiation of treatment and then serially over the course of a year (for example, at 2, 6, and 12 months after onset) (Rauch, 2008). MRI and possibly BAER testing should be considered to exclude a retrocochlear lesion in unilateral cases, whether or not apparent improvement or recovery with steroid therapy is taking place. Cranial imaging is also important to exclude brainstem or cerebellar lesions, and MRI may identify a number of other pathologies (such as vascular abnormalities and demyelination), but MRI does not visualize the inner ear well enough to reliably identify infarction and is insensitive to abnormalities (such as enhancement) associated with cochleitis or labyrinthitis. In patients who cannot have an MRI, CT and BAER studies should be considered, although these are less sensitive than MRI for detection of retrocochlear pathology. As a result of a high rate of spontaneous recovery, and because a large proportion of cases are ultimately considered to be idiopathic even after extensive evaluation, some authorities have advocated a staged approach to diagnostic testing. Patients with likely systemic causes or clinically evident neurologic abnormalities should have diagnostic testing without delay. In patients without other clinical findings, further diagnostic evaluation can possibly be delayed for a month to see if spontaneous improvement occurs. Note, though, that improvement with steroids (in the absence of MRI or BAER) can result in failure to identify important clinical conditions, including retrocochlear masses. If improvement does not occur or if other symptoms or signs develop, more extensive diagnostic testing is indicated and should include cranial imaging. Additional diagnostic studies can include imaging of cerebral vessels, BAER, electronystagmography with bithermal caloric irrigation, vestibular-evoked myogenic potentials, lumbar puncture, and various blood studies.

Disorders of the Special Senses in the Elderly

BAER studies may show absence of wave I or all waveforms, but may also show absence of wave I with delay of wave III and wave V if dysfunction is also occurring in the retrocochlear eighth nerve and brainstem auditory nuclei and pathways (Verghese and Morocz, 1999). Electronystagmography with bithermal caloric testing may demonstrate ipsilateral horizontal canal paresis. In cases of clinically suspected sudden hearing loss resulting from hyperviscosity, the following blood studies can be considered: serum viscosity determination, complete blood count, syphilis serologies, ESR, serum protein, serum protein electrophoresis, and lipid studies. The overall prognosis depends on the underlying etiology, but a high rate of spontaneous resolution occurs overall (in about two-thirds of cases) (Eisenman and Arts, 2000; Yimtae et al., 2001; Penido Nde et al., 2005; Stahl and Cohen, 2006). Most patients show either initial rapid recovery or a gradual and slow recovery (Harada, 1996), but the spontaneous recovery that occurs typically is within the first 2 weeks after onset (Mattox and Simmons, 1977). Improvement in hearing levels tends to occur mostly in the low to mid frequencies and is better in those with preserved otoacoustic emissions (Ishida et al., 2008). Those with initial rapid recovery have the best prognosis, with a smaller degree of hearing loss at the first examination, greater degree of hearing improvement, and smaller degree of residual hearing loss once stable (Harada, 1996). Patients with upsloping or with loweror middle-frequency hearing loss generally have a better prognosis (Eisenman and Arts, 2000; Zadeh et al., 2003). Putative negative prognostic factors include old age, longer time since onset of symptoms before treatment, more severe hearing loss, flat or downsloping audiograms, tinnitus, vertigo, elevated ESR, and associated diabetes. Audiovestibular residua or late effects can also include tinnitus, benign paroxysmal positioning vertigo, and Ménière syndrome. In isolated inner ear infarction, the vertigo, nystagmus, and autonomic manifestations resolve over days to weeks, but deafness and canal paresis typically remain (Millikan and Futrell, 1990; Watanabe et al., 1994; Kim et al., 1999; Lanska, 2013d). If no brainstem symptoms develop and brain imaging is normal, the risk of recurrence or subsequent stroke is rare (Millikan and Futrell, 1990; Kim et al., 1999). Patients with labyrinthine ischemia due to vertebrobasilar insufficiency can have an overall good prognosis with anticoagulation or antiplatelet therapy (Fife et al., 1994) or, rarely, with surgical or endovascular correction (Strupp et al., 2000). However, patients with inner ear infarction combined with brainstem or cerebellar infarcts have a worse prognosis (Gomez et al., 1996), particularly if associated with occlusive disease of the basilar artery (Ferbert et al., 1990; Huang et al., 1993). Sudden SNHL is associated with an increased risk of stroke within 5 years of onset; in one cohort study, 13%

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of the patients with SNHL had a stroke within 5 years, compared with 8% in the controls. After adjusting for other risk factors, those with SNHL had a risk of stroke 1.6 times greater than controls (Lin et al., 2008). Management is complicated in part because the underlying etiology is not known in most patients. Oral corticosteroids (prednisone or methylprednisolone) are considered the “current standard treatment” of idiopathic sudden deafness (Rauch, 2008) and may be modestly effective according to several observational studies and small randomized, controlled trials, although systematic reviews and meta-analyses indicate that the value of steroids remains unclear because of conflicting evidence from available trials and because of technical limitations of available studies. Most of the reported benefit of steroids is within the first 1–2 weeks after onset (although this is also the typical timeframe for spontaneous recovery), and little, if any, benefit can be expected if initiated 4 weeks or longer after onset (Rauch, 2008). Steroids can also be considered in patients with sudden hearing loss and known recent viral infections, autoimmune disease, or meningitis. Intratympanic steroids are not inferior to oral steroids and can provide a therapeutic option if steroids are contraindicated, although administration of intratympanic steroids is moderately uncomfortable, inconvenient, and more costly (Rauch et al., 2011). Associated vertigo and the concomitant nausea and vomiting should be treated symptomatically with medications. Vestibular rehabilitation should be begun early (Lanska, 2009). The efficacy of antiviral agents, anticoagulants, vasodilators, rheologic agents, free radical scavengers, hyperbaric oxygen, ginkgo products, and other drugs is unproven in patients with idiopathic sudden hearing loss (Kanzaki et al., 2003; Conlin and Parnes, 2007a, 2007b; Rauch, 2008). Most studies have been uncontrolled trials, and results are not clearly different than the natural history of this condition. Except for cases of herpes zoster oticus—which should be treated with acyclovir— available data also do not suggest a benefit of antiviral agents in clinically diagnosed viral neurolabyrinthitis (Stokroos et al., 1998).

Superficial siderosis Superficial siderosis is an uncommon (though increasingly recognized) potentially devastating syndrome caused by recurrent subarachnoid hemorrhage with accumulation of hemosiderin and other iron-containing pigments in the leptomeninges, superficial cerebral cortex, brainstem, cerebellum, cranial nerves, and spinal cord (Lanska, 2013e). Common features include progressive SNHL, cerebellar ataxia, pyramidal signs (such as spastic paraparesis and quadriparesis), ataxia, and headache (Lanska, 2013e). The progressive SNHL may be the presenting or predominant symptom, may be slowly progressive over many years, and may be caused by a combination of retrocochlear

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and cochlear damage (Lanska, 2013e). Superficial siderosis should be considered in all patients presenting with progressive SNHL and ataxia. In conjunction with hearing loss, some patients develop peripheral vestibular disorders with associated caloric weakness, disequilibrium, dizziness, and vertigo (Lanska, 2013e). Associated cranial nerve abnormalities can include anosmia or hyposmia, anisocoria, optic neuropathy, visual field deficits, fourth nerve palsy, diplopia, nystagmus, trigeminal neuropathy, hemifacial spasm, SNHL, intermittent vertigo, and dysarthria (Lanska, 2013e). Other clinical features seen in a minority of patients include seizures, cranial nerve abnormalities, spinal myoclonus, polyradiculopathy and sciatica, neck- or backache, urinary incontinence, somatosensory deficits, and acute intracranial pressure crises superimposed on chronic intracranial hypertension. Neuropsychological testing has demonstrated impairments in speech production, visual recall memory, and executive functions (van Harskamp et al., 2005). A significant number of cases may be asymptomatic, possibly reflecting a milder form of disease or a presymptomatic state. A wide variety of conditions may cause superficial siderosis, including cerebral amyloid angiopathy (Alafuzoff, 2008; Feldman et al., 2008), cerebral or spinal arteriovenous malformations, cavernous malformations, intracranial aneurysms, cerebellar tumors, pontine hematoma, and spinal surgery complicated by a dural tear and pseudomeningocele formation (Cohen-Gadol et al., 2005). Superficial siderosis is caused by recurrent subarachnoid hemorrhage with dissemination of heme by circulating cerebrospinal fluid, with subsequent accumulation of intracellular and extracellular hemosiderin and other iron-containing pigments in the leptomeninges, brain surface, brainstem, cerebellum, cranial nerves, and spinal cord (Koeppen and Dentinger, 1988; Koeppen et al., 2008; Lanska, 2013e). Large mononuclear phagocytes containing granules of hemosiderin (siderophages) can be demonstrated pathologically. Histology demonstrates severe damage to the eighth cranial nerve and cerebellum, presumably because glial catabolism of ferritin within these structures preferentially facilitates deposition of heme in these locations. When superficial siderosis is suspected, a thorough evaluation is needed to localize the source of bleeding. MRI is the most important diagnostic study, in conjunction with lumbar puncture and selective use of angiography (Lanska, 2013e). MRI studies demonstrate hemosiderin deposition along the superficial surfaces of the brain, brainstem, cerebellum, and spinal cord (Pelak et al., 1999; Kumar, 2007). Hypointense rims around involved central nervous system structures are commonly seen on T2-weighted images, and hyperintense rims may be demonstrated on T1-weighted images. CT may show widespread meningeal enhancement or cerebellar atrophy. Although CT may suggest the

diagnosis of superficial siderosis, MRI is more sensitive and specific. When superficial siderosis is diagnosed on brain imaging and no source is identified, spinal imaging is essential. Dural diverticula, pseudomeningoceles, and other dural defects (including transdural leaks) are usually best shown on myelography or CT myelography. Angiography may reveal various vascular malformations. In some cases, vascular malformations identified on angiography were not identified with MRI or myelography. In many cases, angiography also does not identify the source of bleeding, probably because of the small volume of ongoing, intermittent blood leakage. Lumbar puncture may demonstrate recurrent or persistent xanthochromia, red cells, a slightly elevated white cell count, increased protein, increased iron and ferritin levels in the cerebrospinal fluid, and siderophages. CSF may be normal because bleeding is typically intermittent and of small volume (Kumar, 2007). Although used in the past (Willeit et al., 1992), there is little current role for diagnostic brain biopsy. Nevertheless, even with thorough diagnostic evaluation, the source of bleeding remains unidentified in many cases (Miliaras et al., 2006; Kumar, 2006, 2007). The prognosis is often poor—the condition may be progressively disabling or fatal (Lanska, 2013e). Management is directed primarily at resection of the source of bleeding. Symptomatic treatment can be helpful in treating secondary manifestations, including headaches and seizures. Even with successful surgical resection of the causative lesion (when that is identified), significant functional recovery cannot be anticipated (Lanska, 2013e). However, generally progression is lessened or averted, at least in the short periods of follow-up reported (Schievink et al., 1998). Bilateral profound hearing loss from superficial siderosis is not an absolute contraindication for cochlear implants, although results are inconsistent and often disappointing (Lanska, 2013e).

Herpes zoster oticus Herpes zoster oticus (sometimes referred to as Ramsay Hunt syndrome when associated with facial paresis) is caused by reactivation of varicella-zoster virus (VZV) that had been dormant in the seventh and eighth nerves following previous infection with chicken pox (Lanska, 2013f). VZV, a member of the alpha-subfamily of Herpesviridae, is an enveloped DNA virus, whose genome consists of a linear double-stranded molecule of DNA. Primary infection with VZV causes chickenpox, an acute, generally mild infection of children. Following chickenpox, VZV remains latent in sensory ganglia and reactivates in about 15% of infected people over their lifetimes, resulting in herpes zoster, or “shingles” (Wigdahl et al., 1986). Approximately two-thirds of patients with herpes zoster are 65 years of age or older (Lin and Hadler, 2000). Both the incidence and severity of herpes zoster increase

Disorders of the Special Senses in the Elderly

sharply with age (Hope-Simpson, 1965; Edmunds et al., 2001). An initial episode of herpes zoster does not apparently protect against or significantly increase the risk of a subsequent episode (Hope-Simpson, 1965). Risk factors for herpes zoster in adults include increasing age, bone marrow and organ transplants, lymphoma, HIV infection, treatment of AIDS with protease inhibitors, and systemic lupus erythematous (Lanska, 2013f). There is no significantly increased risk of a subsequent diagnosis of malignancy following the onset of herpes zoster; therefore, there is little evidence to support an aggressive search for malignancy in patients diagnosed with herpes zoster, although some data suggest that the sites of primary tumor or local radiotherapy may predispose to development of herpes zoster in that specific location (Lanska, 2013f). Herpes zoster oticus often presents with preeruptive (pre-herpetic) pain, allodynia, burning, or itching, generally localized to the ear and mastoid region. An erythematous maculopapular rash progresses to clusters of clear vesicles on an inflamed base; such skin lesions may variably affect the tympanic membrane, the external auditory canal, the auditory meatus, and, less commonly, the external ear, adjacent skin of the mastoid process, the mucous membranes of the soft palate (presumably via the greater superficial petrosal nerve), and the anterior two-thirds of the tongue (presumably via the chorda tympani nerve) (Shapiro et al., 1994). Vesicle fluid quickly changes from clear to purulent. The vesicles crust over after 3–5 days. Associated constitutional symptoms can include lymphadenopathy, headache, malaise, and fever. Ultimately, the skin lesions heal over 2–4 weeks, often leaving residual scarring and pigmentary changes. Otologic complications include tinnitus, SNHL, hyperacusis, vertigo, nystagmus, and skew deviation. Abnormal hearing is associated with otalgia and herpetic rash, but not with severity of facial paresis (Wayman et al., 1990). Audiologic findings demonstrate both sensory (cochlear) and neural (retrocochlear) hearing impairment (Abramovich and Prasher, 1986; Wayman et al., 1990). Hyperacusis is not simply attributable to seventh nerve dysfunction as a result of loss of the stapedial reflex (McCandless and Schumacher, 1979) because hyperacusis is also described with an intact stapedial reflex (Citron and Adour, 1978; Wayman et al., 1990); in some cases, hyperacusis may result from damage to inhibitory efferent fibers in the seventh nerve (Citron and Adour, 1978). Facial palsy may precede, occur simultaneously with, or follow the rash in Ramsay Hunt syndrome (Aizawa et al., 2004; Kim and Bhimani, 2008). In most cases, in adults, the rash occurs slightly before or around the same time as the facial paresis (DeVriese and Moesker, 1988; Kim and Bhimani, 2008). Facial palsy can be associated with decreased lacrimation and hypogeusia or dysgeusia on the anterior two-thirds of the tongue. Facial paresis is

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usually maximal within 1 week of onset, and increasing severity of paresis is associated with increasing age. Ramsay Hunt syndrome is more likely than Bell’s palsy to be associated with a complete clinical facial paralysis (Robillard et al., 1986; Adour, 1994). Herpes zoster may also occur as a cranial polyneuropathy. In unusual cases, other central nervous system structures may be involved, with manifestations including cerebellar abnormalities, multifocal vasculopathy and posterior circulation strokes, hemiparesis, encephalitis, and aseptic meningitis. Causes of these symptoms may include meningeal involvement, demyelinating events, and vasculitic involvement (Ortiz et al., 2008). Impaired cell-mediated immunity is an important factor in the reactivation of VZV and development of clinical herpes zoster, whereas humoral immunity has little or no role in preventing virus reactivation and development of clinical herpes zoster (Ikeda et al., 1996; Arvin, 2005). VZV-specific T cells are thought to be critical for maintaining the virus-host equilibrium and preventing herpes zoster. This is consistent with known risk factors for herpes zoster, including leukemia and lymphoma, bone marrow transplant, and HIV infection. Waning of the cellmediated immune response to VZV with age may help explain the marked increase in herpes zoster with age. Pathologic findings include perivascular, perineural, and intraneural round-cell infiltration of the seventh and eighth nerves and, in some cases, the modiolus and organ of Corti in the cochlea, and the skin of the external auditory meatus (Guldberg-Moller et al., 1959; Blackley et al., 1967; Zajtchuk et al., 1972). Although the geniculate ganglion may show scattered lymphocytic infiltration, most of the neurons in the ganglion are well preserved (Guldberg-Moller et al., 1959; Blackley et al., 1967; Zajtchuk et al., 1972). VZV DNA is present in the geniculate ganglia of affected patients (Furuta et al., 1992; Wackym et al., 1993; Furuta et al., 1997; Wackym, 1997; Thiel et al., 2002) in neurons and in perineuronal satellite cells (Gilden et al., 2000). VZV DNA may also be present in the auditory and vestibular primary afferent ganglia, and in the facial nerve sheath, CSF, middle ear mucosa, and vesicles on the auricles or oral cavity (Wackym et al., 1993; Wackym, 1997; Murakami et al., 1998; Ohtani et al., 2006). Latent VZV is not integrated into the human chromosome, but instead may exist in a circular or end-to-end arrangement (Clarke et al., 1995). The live-attenuated varicella vaccine (Varivax) was licensed by the FDA in 1995. VZV vaccination can prevent or reduce the occurrence of chickenpox, herpes zoster, and associated complications among those immunized (Oxman, 1995; Anonymous, 1996; Seward et al., 2002; Goldman, 2005; Vázquez and Shapiro, 2005; Yih et al., 2005). As a result of introducing this vaccine, there has been a dramatic decline in the incidence of varicella

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in surveillance areas with moderate vaccine coverage (Seward et al., 2002; Goldman, 2005; Yih et al., 2005). However, while the incidence of varicella decreased dramatically as varicella vaccine coverage in children increased, the incidence of herpes zoster increased (Yih et al., 2005). Although several potential explanations are possible, it seems likely that the observed increase in herpes zoster is because of a loss of “immunologic boosting” (including loss of exposure to wild-type VZV) for those previously infected with varicella-zoster (Goldman, 2005). This loss of immunologic boosting would allow a waning of cellmediated immunity and would lead to a relative increase in herpes zoster incidence in the population. Secondary prevention of herpes zoster is now possible for older adults previously infected with chickenpox. In 2005, Oxman et al. reported a large randomized, double-blind, placebo-controlled trial of a high-potency, live-attenuated VZV vaccine (Arvin, 2005; Gilden, 2005; Oxman et al., 2005). More than 38,000 adults over age 60 were enrolled. The VZV vaccine markedly reduced the morbidity from both herpes zoster and postherpetic neuralgia among older adults. After a median of more than 3 years of surveillance, VZV vaccine reduced the incidence of herpes zoster by 51%, the burden of illness due to herpes zoster by 61%, and the incidence of postherpetic neuralgia by 67%. Local reactions at the vaccination site were generally mild, and the vaccine had low rates of serious adverse events, hospitalization, and death. The FDA licensed this vaccine (Zostavax) in 2006 for use in people age 60 years and older. The live VZV vaccine has a minimum potency at least 14 times greater than the minimum potency of the vaccine licensed to prevent varicella because a much higher potency is needed to produce a significant increase in cell-mediated immunity to VZV in older adults (Oxman et al., 2005). The vaccine is administered as a single subcutaneous injection, preferably in the upper arm. Herpes zoster oticus can usually be diagnosed clinically, although the difficulty is increased in the absence of a rash or in the presence of other neurologic manifestations (such as hemiparesis or cranial polyneuropathy). In high-risk settings (such as hospitals and nursing homes), rapid case identification is important to prevent susceptible people at high risk (such as immunocompromised or pregnant individuals) from developing serious complications of VZV infection. Laboratory testing for VZV is not routinely required, but it can be helpful in selected cases to confirm the diagnosis (Gilden et al., 1998; Gilden et al., 2000; Sweeney and Gilden, 2001). Laboratory diagnosis or VZV infection can include (1) varicella-zoster IgM antibody in blood or CSF, or a significant rise in serum IgG antibody level; (2) isolation of VZV from vesicles, blood, or CSF in immunocompromised patients, although VZV is labile and difficult to recover from swabs of cutaneous lesions;

(3) demonstration of VZV antigen by direct fluorescent antibody testing in material swabbed from the base of a freshly unroofed fluid-filled vesicle or in lesion crusts; or (4) detection of VZV DNA by polymerase chain reaction (PCR) tests performed on clinical specimens from cutaneous lesions, tears, saliva, or blood monocytes. Because viral proteins persist after the virus is no longer replicating, direct fluorescent antibody tests may be positive when viral cultures are negative. Virus isolation should be attempted in cases with severe disease, especially in immunocompromised cases. Virus can usually be cultured from zoster lesions for 7 days or longer, and results may be available within 2–3 days. CSF may be normal or may show lymphocytosis and occasionally a modest elevation of protein concentration. Almost two-thirds of patients have a modest CSF pleocytosis (<250 cells/mm3). VZV IgM antibody and VZV DNA (by PCR techniques) can be demonstrated in CSF (Gilden et al., 1998; Gilden et al., 2000), which can be diagnostically helpful in some cases of zoster sine herpete. Variations in commercial, real-time PCR tests can impact the sensitivity of diagnostic testing. The membranous labyrinth normally appears on T1-weighted MRI images as a nonenhancing intermediate-signal-intensity structure surrounded by the lowsignal intensity of the petrous temporal bone (Downie et al., 1994). In approximately 50–70% of cases with facial nerve palsy due to the VZV, variable degrees of gadolinium enhancement occur in the seventh and eighth cranial nerves, the labyrinth, the geniculate ganglion, and the internal and external auditory canals. In rare cases, there may also be enhancement of the pontine facial nerve nucleus. Gadollinium enhancement of inner ear structures and cranial nerves following VZV infection typically lasts less than 6 weeks but may persist for at least 6 years in rare patients (Zammit-Maempel and Campbell, 1995). However, such protracted resolution of gadollinium enhancement warrants consideration of other causes of labyrinthitis or intracanalicular mass lesions. Some studies have found no clear prognostic indicators based on MRI images. Others, however, have suggested that enhancement limited to the geniculate ganglion and to the labyrinthine segment of the facial nerve indicates a good prognosis for facial nerve recovery, whereas widespread enhancement of the facial nerve is often associated with a poor prognosis (Berrettini et al., 1998). Recovery of hearing loss following herpes zoster oticus is generally excellent, although incomplete in some patients (Wayman et al., 1990; Adour, 1994). Prognostic indicators of poor hearing recovery include advanced age, retrocochlear hearing loss, hearing loss affecting the speech frequencies (∼250–8000 Hz), vertigo, and male gender (Wayman et al., 1990). Elderly patients, in particular, can be disabled by severe and persistent imbalance (Adour, 1994). Herpes zoster oticus is more likely than

Disorders of the Special Senses in the Elderly

Bell’s palsy to be associated with a complete clinical facial paralysis and a less complete clinical recovery. Facial paresis in herpes zoster oticus completely resolves in about one-half to two-thirds of patients after incomplete loss of function, usually within about 2 months; complete recovery is achieved in only about 10% of the patients after complete loss of facial nerve function. The majority of the remaining cases are left with mild residual signs, but about 10% are left with an “unsatisfactory” outcome (Heathfield and Mee, 1978). Factors associated with less complete recovery are older age, vertigo, diabetes mellitus, and hypertension (Yeo et al., 2007). Acyclovir facilitates healing of VZV infections, has a low rate of toxicity, and may help prevent postherpetic neuralgia. In particular, immunocompromised patients with VZV infection should be promptly treated with high-dose acyclovir (800 mg 5 times per day orally, or 10 mg/kg 3 times per day intravenously). Treatment is typically given for 7–10 days. Longer treatment or the addition of steroids does not apparently improve the outcome (Wood et al., 1994), and no randomized, controlled trials have assessed the utility of corticosteroids as an adjuvant to antiviral therapy in herpes zoster oticus (Uscategui et al., 2008). An alternative to acyclovir is famciclovir (500 mg 3 times daily in adults), although the latter is more toxic. Especially during the first few days, vestibular sedatives may help alleviate acute vertigo when the eighth nerve is involved. With severe peripheral facial paresis, a major consideration is ensuring protection of the ipsilateral eye, especially when the eyelid does not close fully, either volitionally or during sleep. Such patients have poor reflex eye closure and may have inadequate lacrimation; therefore, they are susceptible to corneal abrasions and infections. An ophthalmic lubricant should be placed in the affected eye (a viscous product is preferred especially at night). The eyelid can be held closed with tape, or an inflexible convex eye shield can be placed over the eye for protection. A hydrophilic soft contact lens has also been used to bandage the cornea in such cases to prevent injury (Yamane, 1980). It is potentially dangerous to use flexible eye patches or to attempt to keep the lid closed by applying a dressing held with pressure and tape over the eye; in such cases, the eye often opens under cover and is abraded by the patch or dressing.

Ototoxicity A number of drugs are ototoxic, including aminoglycosides, aspirin, furosemide, and alkylating agents used in cancer chemotherapy. Aminoglycoside antibiotics can cause both auditory and vestibular toxicity (Keene et al., 1982; Bath et al., 1999; Lanska, 2013g)—gentamicin, streptomycin, and tobramycin are relatively specific toxins for the vestibular system, whereas kanamycin, neomycin, netilmicin, and amikacin are more cochleotoxic (Bath et al., 1999). Aspirin and loop diuretics typically cause

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reversible cochleotoxicity, and alkylating agents uncommonly cause a mixed ototoxicity (Keene and Hawke, 1981). Unlike other common antibiotics, aminoglycosides are concentrated in endolymph and perilymph, which partially accounts for their predilection for ototoxicity. Aminoglycoside toxicity has been thought to result from an inhibition of mitochondrial protein synthesis because of a similarity between mitochondrial ribosomes and bacterial ribosomes (where aminoglycosides allow misreading of mRNA during translation). A highly conserved region of ribosomal RNA binds aminoglycosides, and mutations in this region may result in increased susceptibility to aminoglycoside-induced ototoxicity in humans (Prezant et al., 1993; Hutchin and Cortopassi, 1994; Smith, 2000). Other potential contributing factors include free radical formation via binding of iron and subsequent formation of oxidative compounds, reversible impairment of sensory transduction by blocking calcium-sensitive potassium channels, and excessive N-methyl-D-aspartate (NMDA) receptor activation and excitotoxicity due to aminoglycoside agonist activity at the NMDA subtype of glutamate receptors (Basile et al., 1996; Ernfors et al., 1996; Schacht, 1998; Smith, 2000). Risk factors for aminoglycoside-induced ototoxicity include older age, family history of ototoxicity, high serum levels, higher total dose, longer duration of therapy (beyond 7–10 days), intrathecal administration, previous exposure to ototoxins, concomitant use of other nephrotoxic or ototoxic drugs (such as vancomycin, loop diuretics, cis-platinum, or metronidazole), renal impairment, and fever (Fee, 1980; Keene and Hawke, 1981; Prezant et al., 1993; Fischel-Ghodsian et al., 1997; Triggs and Charles, 1999; Peloquin et al., 2004; Lanska, 2013f). Whenever possible, the following precautions should be followed to minimize ototoxicity (Campbell and Durrant, 1993; Matz, 1993; Triggs and Charles, 1999; Lanska, 2013g): document preexisting hearing loss or vestibular dysfunction before prescribing vestibulotoxic or ototoxic medications; administer aminoglycosides for no longer than 1 week; avoid aminoglycosides in patients whose calculated creatinine clearance is less than 1.2 L/h; monitor peak and trough aminoglycoside levels, and adjust dosing accordingly; use extended dosing intervals (such as once daily instead of multiple daily administration); avoid combinations of aminoglycosides with other nephrotoxic or ototoxic drugs; and discontinue ototoxic agents when clinical vestibulotoxicity or ototoxicity is detected. Aminoglycoside therapy should cease as soon as symptoms of either auditory or vestibular ototoxicity appear, to avoid permanent impairment (Halmagyi et al., 1994). If identified early, much of the symptomatic toxicity is reversible (Wallner, 1949; Fee, 1980; Black et al., 1987). Mutations in a highly conserved region of the mitochondrial 12S rRNA gene have been identified in a

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significant proportion (17%) of patients with aminoglycoside-induced ototoxicity, particularly in families with aminoglycoside-induced deafness. Many of these cases have a family history of aminoglycoside-induced ototoxicity, suggesting that ototoxicity could have been prevented with an adequate clinical interview (FischelGhodsian et al., 1997). Therefore, it is essential to obtain a family history of drug-induced ototoxicity in all patients before administering aminoglycosides. To prevent further cases within the family, sporadic cases of aminoglycosideinduced ototoxicity should be screened, with molecular tests for the presence of known mutations (Casano et al., 1999). In identified families, the inheritance pattern of susceptibility to ototoxicity has matched that of a mitochondrially inherited trait (with maternal transmission) (Prezant et al., 1993). Therefore, maternal relatives in families with known familial aminoglycoside-induced deafness or vestibular dysfunction should avoid aminoglycosides (Prezant et al., 1993). Most familial cases received aminoglycoside antibiotics for a much shorter period and at a lower total dose than sporadic cases. Hair cells do not regrow following ototoxic insults from aminoglycosides. In addition, damage may progress for months after the responsible drug is discontinued because the drugs are bound to inner ear membranes. Damage is usually complete by 6 months after aminoglycoside discontinuation.

Subjective tinnitus Subjective tinnitus is a perceived sensation of sound that occurs in the absence of external acoustic stimulation and cannot be heard by the examiner (Lanska, 2013h). Subjective tinnitus is usually described as ringing, buzzing, roaring, or clicking. Subjective tinnitus is the most common form of spontaneous auditory phenomena, and it is distinct from objective tinnitus (tinnitus heard by the examiner) and more complex sounds characteristic of auditory hallucinations (voices and music). The incidence of subjective tinnitus increases with age. By age 70, at least 25% of patients experience constant tinnitus (Schwaber, 2003). Men are more often affected than women, perhaps partly because of greater occupational and recreational noise exposure. Key clinical features of subjective tinnitus from the history include onset (insidious or sudden), duration, temporal pattern (episodic or continuous, progression over time), location (unilateral, bilateral, or nonlocalizable), pitch (high or low), amplitude (loud or soft), rhythm (steady, gradually fluctuating, or rhythmic), associated symptoms (hearing loss, aural fullness, otalgia, vertigo, insomnia, anxiety, depression, headache, and neurologic dysfunction), as well as family history, previous head injury, noise exposure, medication use, previous ear infections, and previous ear surgery (Ciocon et al., 1995; Peifer et al., 1999; Rubak et al., 2008; Lanska, 2013h). Subjective

tinnitus is generally most apparent and most bothersome at night, when the masking ambient noise is less. Severe tinnitus is almost always associated with hearing loss; tinnitus intensity levels established with loudness-matching techniques correlate with hearing levels at the frequency of the most severe hearing loss (Man and Naggan, 1981; Ochi et al., 2003). It is helpful if the patient can compare the sound of the tinnitus to an identifiable sound in the environment. High-pitched tinnitus may be described as ringing, steam- or windlike, or clicking, whereas low-pitched tinnitus is often roaring, grinding, or like the sound of a seashell held to the ear. The tinnitus associated with Ménière syndrome is typically low pitched (below 1000 Hz, and usually 125–500 Hz). When associated with middle-ear disease, it is typically low- or midrange in frequency (250–2000 Hz). When associated with acoustic trauma or noise exposure, it is typically around 4,000 Hz. When associated with presbycusis, ototoxicity, and other sensorineural causes, it is typically high pitched (2000 Hz and greater). When associated with normal hearing, subjective tinnitus of any frequency can occur (Man and Naggan, 1981; Chung et al., 1984; Campbell, 1998). Subjective tinnitus is frequently associated with depression (in up to half of the patients), anxiety, annoyance, anger, frustration, and insomnia (Nondahl et al., 2002; Dobie, 2003; Zoger et al., 2006; Belli et al., 2008; Heinecke et al., 2008). Although the causal direction is not always clear, tinnitus may produce significant psychological stress, anxiety, and depression. Patients may excessively focus on their tinnitus, with detrimental effects on occupational and social functioning; these patients often rate their tinnitus as louder than nondistressed patients, even though such reports are inconsistent with objective measures of tinnitus loudness using masking (Schleuning et al., 1980). Perceived tinnitus severity correlates much more strongly with sleep disturbance than with the loudness of tinnitus as measured with a balance procedure using external sounds that match the tinnitus pitch. Clinical examination of patients with any form of tinnitus should include funduscopy, otoscopy, tests of hearing, neurologic examination, auscultation for objective tinnitus (such as from arterial bruits or venous hums), observation for palatal myoclonus, palpation of the neck or oral cavity for masses, examination of the temporomandibular joint, and audiometry. Otoscopy can identify impacted cerumen, a perforated eardrum, middle ear fluid, and various mass lesions. Blood studies should include a complete blood count, serum lipids, blood sugar, thyroid stimulating hormone, ESR, Lyme titers, and syphilis serologies (Ciocon et al., 1995; Peifer et al., 1999; Hannan et al., 2005). Audiometry is essential in the evaluation of subjective tinnitus. In particular, at a minimum, a pure-tone audiogram should be performed along with an assessment of

Disorders of the Special Senses in the Elderly

speech reception thresholds and word recognition. The pattern of hearing loss, when present, is helpful in identifying possible causes. Several common configurations or patterns of SNHL exist: a notched pattern (as with NIHL); a symmetric bilateral downward sloping pattern (as with presbycusis); and a low-frequency trough pattern (as with Ménière syndrome). In elderly patients with bilateral subjective tinnitus, NIHL and presbycusis are among the most commonly identified causes. Retrocochlear lesions in patients with subjective tinnitus should be suspected when SNHL is asymmetric or when word recognition is asymmetric or decreased out of proportion to threshold hearing level. Tympanometry and acoustic reflexes are sometimes recommended (Ciocon et al., 1995) but often add relatively little to the evaluation of subjective tinnitus or retrocochlear hearing loss; they are less sensitive and specific than BAER studies or MRI in the detection of retrocochlear masses (Campbell, 1998). Otoacoustic emissions can be helpful in differentiating between cochlear and retrocochlear SNHL (Campbell, 1998). They generally reflect cochlear pathology (assuming no significant conduction abnormality) and are relatively insensitive to neurologic abnormalities. In particular, otoacoustic emissions can be helpful in interpreting absent responses on BAER testing (Campbell, 1998). If evoked responses are absent and otoacoustic emissions are normal, the problem is neurologic and cannot be attributed to peripheral hearing loss; if both are absent, hearing loss is probably peripheral. It is helpful to determine whether subjective tinnitus is either unilateral or bilateral, to determine whether focal neurologic findings exist, and to perform an audiogram to distinguish cases with conductive hearing loss or SNHL. Subjective tinnitus may result from a wide variety of lesions of the external or middle ear, the cochlea or auditory nerve, or the central nervous system, but a large proportion are ultimately designated as “idiopathic” (Lechtenberg and Shulman, 1984). The most commonly identified causal factor is NIHL. Subjective tinnitus may be bilateral or unilateral, regardless of whether it is associated with conductive hearing loss or SNHL. Subjective tinnitus associated with conductive hearing loss may be caused by impacted cerumen, osteomas, or serous otitis media. Bilateral subjective tinnitus associated with SNHL may be caused by ototoxic drugs, noise exposure, or presbycusis (Miller and Jakimetz, 1984; Campbell, 1998; Rubak et al., 2008). Subjective tinnitus is common with NIHL and may be the most troubling symptom for some patients. Unilateral subjective tinnitus associated with progressive SNHL should suggest the possibility of an acoustic neuroma or other eighth nerve lesion. Other causes of subjective unilateral tinnitus associated with SNHL include Ménière syndrome, labyrinthine concussion, neurolabyrinthitis, autoimmune hearing loss, and perilymphatic fistula.

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Microvascular compression of the cochlear and vestibular nerves in the cerebellopontine angle or the internal auditory canal has also been considered a potential cause of various audiovestibular symptoms, including fluctuating, pulsatile, or continuous tinnitus (usually unilateral), as well as hearing loss, hyperacusis, diplacusis, vertigo, and imbalance. However, the existence of this disorder remains controversial. A specific clinical presentation for microvascular compression, if any, has not been clearly defined, although proponents have considered associated brief vertiginous spells and hemifacial spasm as suggestive features. Acute-onset subjective tinnitus with sudden deafness is often due to viral neurolabyrinthitis, labyrinthine ischemia, or labyrinthine concussion. Episodic subjective tinnitus may occur with Ménière syndrome, perilymphatic fistula, or lesions of the cerebellopontine angle (Espir et al., 1997). Central nervous system causes of subjective tinnitus in the elderly are often associated with central neurologic findings: head trauma, brainstem stroke, vascular abnormalities (such as arteriovenous malformations), palatal myoclonus, demyelination, mass lesions in the posterior fossa, meningeal carcinomatosis, and meningitis (Lechtenberg and Shulman, 1984; Espir et al., 1997). Patients with subjective tinnitus and either focal neurologic findings or progressive SNHL should have an MRI with and without gadolinium contrast to exclude mass lesions and brainstem stroke. BAER studies can be helpful in those with subjective unilateral tinnitus and either normal hearing or unilateral SNHL of unclear duration and course; an increased wave I to wave V interval should prompt MRI scanning to exclude a mass lesion involving the internal auditory canal or the cerebellopontine angle. Despite thorough evaluation, the cause of tinnitus is not identified in many patients, particularly in those with nonlocalized and continuous tinnitus or those with normal hearing without neurologic findings. Referral to an otolaryngologist should be considered for patients with subjective tinnitus and either (1) conductive hearing loss (not attributable to impacted cerumen or otitis media), (2) mixed hearing loss, or (3) a retrotympanic mass. The pathophysiology of subjective tinnitus is poorly understood, but a number of different mechanisms may be responsible (Lanska, 2013h). With conductive hearing loss, internal auditory signals (vascular noises and otoacoustic emissions) may be more apparent because of the reduction of ambient sound. Cochlear damage (from noise or ototoxins) or eighth-nerve damage may result in abnormal afferent signals (altered rate or rhythm), which the brain interprets as tinnitus. Pressure on the eighth nerve may damage the myelin sheath, allowing ephaptic transmission, or “crosstalk,” between axons (Espir et al., 1997); this mechanism usually is considered with posterior fossa

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tumors, but it has been argued that vascular anomalies (such as a tortuous AICA or PICA) may also compress the eighth nerve and cause tinnitus. Either absence or significant decrement in afferent auditory nerve impulses may also “release” central auditory pathways akin to VHs with blindness, as well as “phantom limb” tactile and kinesthetic hallucinations following amputations (Cogan, 1973; Ross et al., 1975; McNamara et al., 1982; Hammeke et al., 1983; Lanska et al., 1987a; Arnold et al., 1996; Giraud et al., 1999; Cacace et al., 2003; Moller, 2003; Weiss et al., 2004, 2005; Saunders, 2007). In addition, most adults experience tinnitus in anechoic environments, perhaps because of such release mechanisms or because of perception of otoacoustic emissions from the cochlea that are normally masked by ambient noise (Pulec et al., 1978; Del Bo et al., 2008). A variety of evidence supports the concept that central auditory pathways participate maladaptively in the pathophysiology of tinnitus: (1) tinnitus or peripheral origin can persist after recovery of cochlear function, labyrinthectomy, or eighth-nerve neurectomy; (2) unilateral tinnitus can be suppressed by either homo- or contralateral noise; (3) damage to the inner ear produces substantial structural, neurochemical, and physiologic neural changes in the auditory pathways of the brainstem and cerebrum, including enhanced sound-driven activity, increased spontaneous neural activity, altered neural firing (such as bursting discharges and neural synchrony), reorganization of the tonotopic representation of frequency in the brainstem and cerebral cortex, and extension of spontaneous cortical activity associated with tinnitus into nonsensory areas (Saunders, 2007). Studies using positron emission tomography and magnetoencephalography have suggested that tinnitus is related in part to plastic changes in the auditory association cortex (Arnold et al., 1996; Lockwood et al., 1998; Muhlnickel et al., 1998; Giraud et al., 1999; Mirz et al., 1999; Cacace et al., 2003; Moller, 2003). Two-thirds of patients report tinnitus as annoying, yet only about one-third seek professional help—and less than 10% receive treatment (Sindhusake et al., 2003). The prognosis depends heavily on the etiology. Most cases of subjective tinnitus cannot be cured, and many are refractory to treatment, particularly those that are bilateral or nonlocalizable. Symptomatic treatment of tinnitus, as well as treatment of any associated depression, anxiety, and insomnia, can be helpful, even if the associated tinnitus cannot be eliminated (Dobie, 2003). Symptomatic treatment of tinnitus can include reassurance, various psychological treatments (such as supportive psychotherapy, biofeedback, hypnosis, or habituation therapy), masking techniques, drugs, electrical stimulation, and, rarely, surgery (Andersson and Lyttkens, 1999; Berry et al., 2002). The most widely employed treatments include reassurance, masking techniques, and various drugs, but many patients receive little apparent benefit from these.

Biofeedback does not reduce tinnitus loudness, but it may reduce muscular tension and anxiety, may facilitate coping with the tinnitus, and may be better accepted by patients than psychological counseling. Removal of cerumen may help some patients with subjective tinnitus, partly because it increases ambient sound and assists with masking, and partly because cerumen on the tympanic membrane can produce tinnitus through local effects on the conduction pathway. For patients who are particularly bothered by tinnitus at night, a bedside radio (possibly with a pillow speaker) tuned between stations can often provide effective masking and allow them to get to sleep. White noise generators, white noise tapes, and tapes of “ocean surf” produce similar results. Similarly, a hearing aid may result in improved hearing and communication and may decrease the tinnitus by amplifying ambient sound and providing some masking. Tinnitus-masking devices can be worn like a hearing aid, and “tinnitus instruments” combine a masking device with a hearing aid. Unfortunately, longterm efficacy of tinnitus-masking units is, at best, variable and, in some studies, poor; results in one small randomized trial were no better than placebo (Erlandsson et al., 1987). In some patients, a high level of masking is required (above 10 dB), and often the patient finds the masking signal to be too distracting (Campbell, 1998). In others, either bilateral tinnitus is not relieved with masking devices or the application of bilateral masking devices makes it difficult for patients to hear environmental sounds (Campbell, 1998). Multiple drugs have been investigated in the hope that a long-acting oral medication could be found to effectively treat subjective tinnitus (Murai et al., 1992). Unfortunately, in general, drug therapies have not been successful, to date, for long-term tinnitus reduction (Murai et al., 1992; Campbell, 1998; Hannan et al., 2005), and available clinical trials of pharmacologic agents have had significant deficiencies (Murai et al., 1992). Surgical treatment of subjective tinnitus has also generally been disappointing. Nevertheless, a variety of surgical procedures have been advocated, including cochlear implantation, cochlear nerve section, and surgical microvascular decompression. Surgical case series have reported variable results, but many cases with subjective tinnitus do not benefit from surgery with a reduction in tinnitus, even if the surgery was necessary and helpful in other ways; some actually worsen. Even ablation of the cochlea or the eighth nerve may not substantially alter the tinnitus in some patients with dysfunction of these structures, suggesting that tinnitus may be maintained in central auditory pathways, even if it had its genesis in the dysfunction of peripheral auditory structures. Patients most likely to develop postoperative tinnitus are those with poorer hearing preoperatively or surgically induced hearing loss.

Disorders of the Special Senses in the Elderly

Because no highly effective medical or surgical therapy is available for subjective tinnitus associated with ototoxicity or NIHL, prevention is essential. The patient’s prescribed and over-the-counter medications, substance use, and toxin exposures should be reviewed to identify possible sources of ototoxicity (such as salicylates, nonsteroidal anti-inflammatory agents, aminoglycosides, furosemide and other loop diuretics, anticancer drugs, and quinine) and substances that may exacerbate tinnitus (such as aminophylline, nicotine, caffeine, alcohol, and marijuana) (Campbell, 1998). Hearing protection and environmental controls should be utilized to control noise exposure.

Central hearing disorders

Cortical deafness, pure word deafness, and auditory agnosia The auditory cortex is located in the posterior superior aspect of both temporal lobes, with the primary auditory cortex located in the transverse temporal gyri of Heschl. Rarely, cases of sudden deafness can be due to cortical deafness from bilateral temporal lobe infarcts (Kneebone and Burns, 1981; Buchman et al., 1986; Bahls et al., 1988; Murray and Fields, 2001; Leussink et al., 2005). Cases reported as cortical deafness (due to a primary sensory audiologic deficit) overlap clinically both with cases of “pure word deafness” (or auditory verbal agnosia, impaired ability to understand speech sounds, even though the patient can hear them) and with cases of generalized auditory agnosia (impaired ability to interpret both verbal and nonverbal sounds, even though the patient can hear them) (Buchman et al., 1986; Kaga et al., 2004). Moreover, patients with diagnoses of word deafness who had formal testing of linguistic and nonlinguistic sound comprehension and musical abilities showed evidence of a more pervasive auditory agnosia (Buchman et al., 1986). Some reported cases show evolution of clinical features from one category to another (Bahls et al., 1988; Murray and Fields, 2001). Because common features can be delineated in reported cases of pure word deafness, auditory agnosia, and cortical deafness, Buchman and colleagues suggested that these disorders form a continuum rather than being three distinct syndromes (Buchman et al., 1986). Although all reported cases of word deafness have exhibited additional auditory deficits, word deafness is the most distinctive deficit on clinical examination; for this reason, patients with disorders on this spectrum are categorized under the rubric of “word deafness” (Buchman et al., 1986). Word deafness most frequently stems from strokes causing bitemporal cortico-subcortical lesions, presumably on a cardioembolic basis (Buchman et al., 1986). Neurodegenerative disorders (such as frontotemporal dementias and CJD) can also produce cortical deafness and related syndromes (Tobias et al., 1994; Otsuki et al., 1998; Kaga et al., 2004; Jörgens et al., 2008).

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Auditory hallucinations due to central nervous system lesions In humans, the primary auditory cortex is located deep within the lateral fissure on a small patch of the transverse gyrus of Heschl, on the upper surface of the temporal operculum of the insula of the cortex, whereas the lateral superior temporal gyrus is involved in processing complex acoustic signals, including speech. Post-lesional auditory (“release”) hallucinations can result from lesions anywhere along the auditory pathway from the cochlea to the auditory cortex, including the brainstem, akin to Bonnet hallucinations with visual loss (Ross et al., 1975; Hammeke et al., 1983; Cascino and Adams, 1986; Lanska et al., 1987a; Lanska and Lanska, 1993; Griffiths, 2000). Musical hallucinosis in deafness may also involve widely distributed networks, distinct from primary auditory cortex, that are responsible for perception and imagery of pattern in segmented sound (Griffiths, 2000). Post-lesional auditory hallucinations may be simple (as with subjective tinnitus) or complex (voices or music). Such patients are likely to be elderly and typically have hearing impairments such as distortion, poor localization, hypoacusis, or deafness. As with VHs, auditory hallucinations may have an irritative basis. Electrical stimulation of the temporal cortex (in either hemisphere) may produce reports of auditory hallucinations (Penfield and Perot, 1963). Ictal auditory hallucinations are most common in patients with temporal lobe epilepsy (but can occur less commonly with foci in other lobes). Complex auditory hallucinations (voices or music) are typically associated with temporal cortex stimulation or irritation, while simple auditory hallucinations (such as tinnitus with hissing, buzzing, or ringing) can occur with cortical, subcortical, or insular stimulation or irritation. Auditory hallucinations are less common than VHs in patients with PD (Inzelberg et al., 1998; Fénelon et al., 2000; de Maindreville et al., 2005). Auditory hallucinations in PD occur particularly in patients who have VHs and are cognitively impaired or depressed (Inzelberg et al., 1998). Auditory hallucinations occur repeatedly, and the content is typically of human voices, which are nonimperative, nonparanoid, and often incomprehensible (Inzelberg et al., 1998).

The chemosenses: smell and taste Disorders of the chemosensory senses, smell and taste, are usually less disabling than disorders of the other special senses (vision and hearing).

Smell Olfactory impairment is a significant contributor to perceived disability and lower quality of life among elderly patients, and is a significant predictor of subsequent

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cognitive decline (Miwa et al., 2001; Murphy et al., 2002; Wilson et al., 2007b; Schubert et al., 2008). Patients with olfactory symptoms generally report loss of olfactory sensation (hyposmia or anosmia) and only rarely report forms of distorted olfaction (dysosmia or parosmia). When dysosmia is reported, the perception is almost universally unpleasant, a condition referred to as aliosmia (the perception of unpleasant odors from nominally pleasant odorants); it may involve a sensation either of fecal or rotten smells (cacosmia) or of chemical or burned smells (torquosmia). In addition, complaints of impaired “taste” are often symptoms of olfactory dysfunction because much of the flavor of a meal derives from olfactory stimulation. Indeed, the complex sensory experience of “flavor” during consumption of foods and drinks cannot be constructed simply from combinations of the basic taste qualities (sweet, salty, sour, bitter, and umami/savory). Medications that can alter olfactory function in elderly patients are numerous and varied, and include levodopa, bromocriptine, lithium, opiates, various lipid-lowering drugs, calcium-channel blockers, beta blockers, antimicrobials, and antineoplastics (Rollin, 1978; Schiffman, 1997; Spielman, 1998). Some medications interfere with the process of sensory transduction (for example, by interfering directly with the receptor or its components, such as G-proteins, adenylate cyclase, or receptor kinase); others interfere with neurotransmitters involved in olfactory processing; and still others are directly toxic to olfactory neuroepithelium or the nerves themselves. For example, chemotherapy agents cause hyposmia by direct toxicity to mucosa and nerves and by inhibition of mucosal cell growth and replacement. In addition, zinc-induced anosmia as a result of necrosis of nasal neuroepithelium occurred with intranasal application of zinc gluconate gel in commercial cold preparations, but this formulation has been withdrawn (Alexander and Davidson, 2006; Smith et al., 2009).

Conductive olfactory disturbances Odorants reach the sensory receptors in the olfactory neuroepithelium by two pathways: orthonasally through the nostrils or retronasally through the nasopharynx (Duffy et al., 1999). With retronasal olfaction, odorants are delivered in a liquid or semiliquid phase during eating or drinking, are volitalized, and are then combined with gustatory and somatosensory sensations to form a composite sensation of flavor. This process requires adequate mastication to release volatile odorants, and sufficient mouth and swallowing movements to effectively pump the odorants retronasally. Conductive (or “transport”) olfactory problems impede the passage of odorants either orthonasally or retronasally, and generally cause hyposmia (rather than anosmia) because the obstruction is usually incomplete. Some common problems that produce conductive olfactory

disturbances include upper respiratory infections, chronic rhinosinusitis, and nasal polyposis. In addition, elderly patients with complete or palate-covering dentures have lower olfactory sensitivity than those who are dentate or who wear dentures that do not cover the palate, apparently in part, because of impairment with chewing and mouth movements, and interference with movement of odorants retronasally (a conductive defect) (Duffy et al., 1999).

Sensorineural olfactory disturbances The olfactory receptors are located in the olfactory neuroepithelium on the superior-nasal septum and lateral wall of the nasal cavity. The dendritic end of these bipolar sensory cells projects into the overlying nasal mucous, while the unmyelinated axons project through the cribriform plate of the ethmoid bone via small bundles that comprise the filaments of the short olfactory nerve to ultimately synapse in the olfactory bulb. With sensorineural olfactory problems, the odorants contact the olfactory receptors of the bipolar neurons in the olfactory neuroepithelium, but dysfunction of these components prevents the information from being processed. Sensorineural olfactory problems can be caused by head trauma, tobacco smoking, other toxins, drugs, nutritional disorders (including zinc deficiency, vitamin A deficiency, cobalamin deficiency), influenza-like viral infections, various comorbid medical conditions (hypothyroidism, diabetes, Sjögren’s syndrome, renal failure, and liver disease including cirrhosis), and structural lesions involving the area of the cribriform plate (such as subfrontal meningioma). Mechanisms of posttraumatic olfactory dysfunction include direct injury to the olfactory epithelium (causing a sensory olfactory deficit), shearing effect on the fragile olfactory fibers at the cribriform plate (causing a neural deficit), or potential brain contusion or intraparenchymal hemorrhage (causing a central olfactory deficit). Hyposmia in smokers is common, occurs in a dose-dependent fashion, and apparently results from increased death of olfactory sensory neurons, which eventually overwhelms the regenerative capacity of the olfactory neuroepithelium (Collins et al., 1999; Vent et al., 2004; Hummel and Lötsch, 2010). Hyposmia is common in hypothyroidism, occurring in about 20% of cases, and contributes to anorexia and lack of interest in eating, but it largely reverses with replacement hormone therapy (McConnell et al., 1975). In the absence of local nasal disease, unilateral anosmia suggests a structural lesion of the olfactory nerve filaments, bulb, tract, or stria. An olfactory groove meningioma, for example, may cause ipsilateral sensorineural anosmia, in conjunction with optic atrophy in the ipsilateral eye (due to optic nerve compression) and papilledema in the contralateral eye (due to increased intracranial pressure), a constellation of manifestations designated eponymically as Foster Kennedy syndrome.

Disorders of the Special Senses in the Elderly

Presbyosmia Presbyomsia (literally “elderly olfaction” or “old age olfaction”) is the gradual loss of olfactory abilities that occurs in most people as they grow older. Age-related losses of smell (presbyosmia) and taste (presbygeusia) are common in the elderly and result from normal aging, certain diseases (especially PD, DLB), medications, surgical interventions, and prior environmental exposures (Doty et al., 1984c; Doty, 1989; Schiffman, 1997; Elsner, 2001a, 2001b; Murphy et al., 2002; Mackay-Sim et al., 2006; Rawson, 2006). Because chemosensory impairment is so prevalent among the elderly, many elderly people complain that food lacks flavor and the elderly account for a disproportionate number of accidental gas poisoning cases (Doty et al., 1984c). The components related to aging, per se, are relatively small (but significant), while the majority of the age-related functional declines of the chemosenses are attributable to accumulated insults to the sensory system, smoking, medications, and comorbid disease (Murphy et al., 2002; Mackay-Sim et al., 2006). Olfactory senescence starts by the fifth decade and accelerates with advancing years, preferentially involving pleasant odors (Doty et al., 1984c; Hawkes, 2006; Doty, 2008). Almost two-thirds of the patients aged 80 and older have olfactory impairment (Murphy et al., 2002). Clinically significant olfactory loss is common in the elderly but frequently unrecognized, in part, because deficits typically accumulate gradually over decades—indeed, self-reported olfactory impairment significantly underestimates prevalence rates obtained by olfactory testing (Murphy et al., 2002). The elderly have higher olfactory thresholds, perceive suprathreshold odors less intensely, and are less able to discriminate odors or to recognize and identify common odors (Cain and Stevens, 1989; Schiffman, 1997; Doty, 2008). Smell identification ability declines markedly after the seventh decade—major olfactory impairment is present in about one-third to one-half of those aged 65–80, and in some two-thirds to four-fifths of those over age 80 (Doty et al., 1984c; Murphy et al., 2002; Doty, 2008; Lafreniere and Mann, 2009). Part of the decline in olfactory abilities with age results from degeneration of the olfactory bulb—the number of mitral cells and glomeruli in the olfactory bulb declines markedly with age, at an approximate rate of 10% per decade, so that less than 30% of these elements remain by the ninth and tenth decades (Meisami et al., 1998). Functional imaging shows significantly lower activation among the elderly in brain regions receiving primary olfactory projections (piriform cortex, entorhinal cortex, and amygdala) (Cerf-Ducastel and Murphy, 2003). Male gender, current smoking, medications, cumulative exposure to toxic fumes, prior head trauma, and comorbid conditions (such as nasal congestion, upper respiratory tract infection, sinusitis, systemic viral illness, epilepsy, cerebrovascular disease, and neurodegenerative

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diseases) are associated with an increased prevalence of olfactory impairment in the elderly (Schiffman, 1997; Elsner, 2001b; Murphy et al., 2002; Nguyen-Khoa et al., 2007). Anosmia associated with chronic allergic rhinitis, nasal polyposis, and chronic sinusitis may respond to glucocorticoids, especially if administered systemically. Results with zinc sulfate therapy, even in patients with documented deficiency, have been mixed. For patients with olfactory dysfunction, the prognosis depends primarily on etiology and the degree of residual function, but also secondarily on gender, parosmia, smoking habits, and age (Hummel and Lötsch, 2010). Male gender, initial presence of parosmia, smoking, and older age are negative prognostic factors (Hummel and Lötsch, 2010).

Central olfactory disturbances The olfactory bulb may constitute the “olfactory thalamus” (although it has also been suggested more provocatively that the olfactory bulb may instead serve as the primary olfactory cortex) (Haberly, 2001; Kay and Sherman, 2007; Benarroch, 2010). Second-order neurons from the olfactory bulb travel posteriorly as the optic tract in the olfactory sulcus on the orbital surface of the frontal lobes. The optic tracts divide into medial and lateral striae, with fibers from the medial striae decussating in the anterior commissure to terminate in the contralateral cerebral hemisphere, while fibers from the lateral striae project to the ipsilateral primary olfactory cortex, amygdala, septal nuclei, and hypothalamus. Because of the bilateral cortical representation for smell in the piriform cortex, unilateral lesions distal to the decussation of the olfactory fibers generally do not cause clinically important olfactory dysfunction, although deficits in olfactory discrimination and detection may be detected with major unilateral damage to the frontal or temporal lobes. Disorders that can interfere with central olfaction include epilepsy, head injury (particularly with contusion of the temporal tips against the anterior portion of the middle fossa), and various neurodegenerative conditions (such as PD, DLB, and AD).

Lewy body alpha-synucleinopathies PD is a multisystem alpha-synucleinopathy, in which Lewy bodies are the histologic hallmark. Lewy bodies are composed of intraneuronal cytoplasmic aggregations of alpha-synuclein and ubiquitin, and are present in pigmented neurons within the substantia nigra, the locus ceruleus, the dorsal motor nucleus of the vagus, and the substantia innominata. Olfactory deficits— involving odor detection, identification, and discrimination—are common early in the course of PD and are present in more than 90% of patients with early-stage PD (Hudry et al., 2003; Doty, 2007b; Boesveldt et al., 2008; Duda, 2010). Occasionally, patients with PD may

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develop pleasant olfactory hallucinations (phantosmias) (Landis and Burkhard, 2008). Impaired olfaction can predate the motor symptoms of PD by at least 4 years (Ross et al., 2008). Idiopathic olfactory dysfunction in first-degree relatives of PD patients is also associated with an increased risk of developing PD within 2–5 years (Ponsen et al., 2010). Olfactory defects in PD do not progress markedly with development of motor manifestations (Doty, 2007b) and do not correlate well with most other manifestations of the disease (Verbaan et al., 2008), except with autonomic defects (Goldstein et al., 2010) and cognitive dysfunction, including memory impairment (Baba et al., 2011). Anosmia in PD is associated with autonomic failure, including baroreflex failure and noradrenergic denervation of the heart and other organs, independently of parkinsonism or striatal dopaminergic denervation (Goldstein et al., 2010). Olfaction in patients with PD does not improve with levodopa therapy (Huisman et al., 2004; Rösser et al., 2008), apparently at least in part, because dopamine inhibits olfactory transmission in the olfactory glomeruli, and there is a paradoxical increase in the number of periglomerular dopaminergic neurons in the olfactory bulb in PD (Huisman et al., 2004). DLB is closely allied with both PD and AD, and is characterized anatomically by the presence of Lewy bodies in both the neocortex and subcortical structures. There is a loss of dopamine-producing neurons in the substantia nigra similar to that seen in PD, and a loss of acetylcholine-producing neurons in the basal nucleus of Meynert similar to that seen in AD. In DLB, as in PD, olfactory dysfunction is nearly universal, develops early (before any movement or cognitive disorder), and is often severe (Hawkes, 2006). Nevertheless, addition of anosmia to the consensus criteria for DLB did not significantly improve overall diagnostic performance (McShane et al., 2001; Olichney et al., 2005; Williams et al., 2009). Odor identification is also impaired in patients with REM sleep behavior disorder (RBD), a common and very early feature of Lewy body alpha-synucleinopathies (Stiasny-Kolster et al., 2005; Fantini et al., 2006; Miyamoto et al., 2009; Postuma et al., 2009; Miyamoto et al., 2010). Markedly reduced olfaction in a parkinsonian patient is supportive of PD or DLB (Wenning et al., 1995), while normal smell identification is rare with these conditions and should prompt review of the diagnosis (unless possibly if the patient is female with tremor-dominant disease) (Hawkes, 2006). Preserved or mildly impaired olfactory function in a parkinsonian patient is more likely to be related to atypical parkinsonism such as vascular parkinsonism, MSA, PSP, or corticobasal degeneration (CBD) (Katzenschlager et al., 2004; Hawkes, 2006). However, these heuristic clinical rules are not absolute—some patients with CBD, for example, have moderate or severe impairment (Pardini et al., 2009).

Olfactory loss in PD and DLB is not due to damage to the olfactory epithelium, but instead results from central nervous system abnormalities (Hubbard et al., 2007; Witt et al., 2009; Baba et al., 2011). Pathology of the olfactory bulb and tract occurs prior to motor signs of PD (Hubbard et al., 2007). In synucleinopathies, olfactory dysfunction relates specifically to Lewy body pathology and correlates with cardiac sympathetic denervation, independently of striatal dopamine deficiency or parkinsonism (Goldstein and Sewell, 2009). Impaired olfaction in PD is associated with the presence of Lewy bodies and neuronal loss in the olfactory bulb and tract, with a strong correlation between neuronal loss and disease duration (Pearce et al., 1995). In PD, the olfactory bulb contains numerous Lewy bodies, and severe neuronal loss is present in the anterior olfactory nucleus (Kovács et al., 2003). Immunolabeling for alpha-synuclein in the olfactory bulb and tract occurs prior to clinical signs of parkinsonism in DLB (Hubbard et al., 2007). The presence of Lewy body alpha-synucleinopathy in the olfactory bulb accurately predicts the presence of Lewy body pathology in other brain regions (Beach et al., 2009). The pathophysiology of hyposmia in Lewy-body alpha-synucleinopathies is not well understood and may have multiple components, including those resulting from degenerative changes in the olfactory bulb and primary olfactory cortex, as well as limbic dysfunction and possibly prefrontal dysfunction (Hudry et al., 2003; Bohnen et al., 2008; Westermann et al., 2008; Bohnen et al., 2010; Baba et al., 2011). Functional imaging indicates that reduced neuronal activity in the amygdala, hippocampus, and piriform cortex (uncus) contributes to olfactory dysfunction in PD (Westermann et al., 2008; Baba et al., 2011). Hyposmia in PD is more closely associated with cholinergic denervation of limbic archicortex (hippocampus and amygdala) than with nigrostriatal dopaminergic denervation (Bohnen et al., 2010). However, because olfactory threshold and odor identification in PD are not related to duration of disease, to current therapy with levodopa or anticholinergic drugs, or to “on” and “off” states, olfactory impairment in PD likely involves mechanisms that are not due to dopaminergic or cholinergic denervation and that are not influenced by pharmacologic manipulation of dopaminergic or cholinergic status (Quinn et al., 1987).

Other age-associated neurodegenerative conditions Although hyposmia is a frequent and early abnormality in PD and DLB, this is not so in other forms of parkinsonism, including MSA, vascular parkinsonism, PSP, or CBD, nor is hyposmia a feature of essential tremor (Wenning et al., 1995; Katzenschlager and Lees, 2004; Shah et al., 2008; Pardini et al., 2009). Most studies of olfaction in CBD have reported relatively mild deficits, but olfactory dysfunction can be moderate or severe in this disorder

Disorders of the Special Senses in the Elderly

(Pardini et al., 2009). A mild olfactory loss develops later in the course of MSA (Katzenschlager and Lees, 2004), associated with characteristic glial cytoplasmic inclusions in the olfactory bulb and some degree of neuronal loss in the anterior olfactory nucleus, but it is not clear that this is of clinical significance (Kovács et al., 2003). Olfactory deficits may also occur with motor neuron disease (MND), but smell testing is not likely to be of clinical value in this condition (Elian, 1991; Hawkes, 2006). Some degree of olfactory loss has also been reported in various other dementing disorders, including AD and frontotemporal dementia (Doty et al., 1987; Westervelt et al., 2007; Wilson et al., 2007a; Williams et al., 2009). Olfactory impairment is more marked early in the course of the disease in patients with DLB than in those with either AD or frontotemporal dementia (Williams et al., 2009). Nevertheless, olfactory deficits have been reported in AD (Doty et al., 1987; Solomon et al., 1998; McCaffrey et al., 2000; Li et al., 2010), and these deficits may be detectable before the appearance of overt memory loss (Li et al., 2010), increase with severity of dementia (Murphy et al., 1990; Serby et al., 1991; Wilson et al., 2009), and correlate with density of neurofibrillary tangles in the entorrhinal cortex and hippocampus (Wilson et al., 2007a) and with cortical Lewy body pathology (McShane et al., 2001). It remains unclear, though, whether AD is associated with clinically meaningful hyposmia in the absence of Lewy body pathology (McShane et al., 2001). Olfactory dysfunction, if apparent in AD, can sometimes help in the differential diagnosis with depression (Solomon et al., 1998; McCaffrey et al., 2000). Frontotemporal dementia is also associated with relatively mild olfactory deficits, which are comparable to those seen in AD (McLaughlin and Westervelt, 2008).

Taste In patients with hypogeusia or dysgeusia, the medical history should address medication use, toxin exposures, autoimmune disorders (particularly Sjögren’s syndrome), local damage (such as burns), nutritional disorders (such as cachexia, vitamin-deficiency-associated glossitis, and zinc deficiency), depression, psychosis, known cancer, and endocrine and metabolic disorders (particularly hypothyroidism, but also diabetes, chronic kidney disease, and hepatic cirrhosis) (McConnell et al., 1975; Catalanotto, 1978; Frank et al., 1992; Heckmann and Lang, 2006; Reiter et al., 2006; Doty et al., 2008). Oral examination should exclude obvious local pathology, such as candidiasis (thrush), gingivitis, xerostomia, glossitis, burns (thermal, chemical, or radiation induced), and oral cancer. Medications that can alter taste in elderly patients are numerous and varied, and include amitriptyline, baclofen, carbamazepine, phenytoin, levodopa, and propranolol, as well as various lipid-lowering drugs,

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antihistamines, antimicrobials, antineoplastics, antiinflammatories, allopurinol, bronchodilators and other asthma medications, antihypertensives and cardiac medications, lithium, antidepressants, and antipsychotics (Rollin, 1978; Frank et al., 1992; Schiffman, 1997; Spielman, 1998). Possible mechanisms for medication-related dysgeusia include disruption of zinc metabolism (e.g., by impairing absorption or facilitating chelation) and alteration of ion channels, second-messenger systems, and neurotransmitters involved in gustatory perception. Many medications produce a metallic dysgeusia (aliageusia or, more specifically, torquegeusia), including methimazole, captopril, and lithium carbonate, and some (such as iron salts) appear to do this via olfactory mechanisms (Hettinger et al., 1990; Frank et al., 1992). Unfortunately, stopping a medication that may be causing dysgeusia is not always an easy option, particularly when one is dealing with serious disabling or life-threatening conditions such as seizures, cancer, infection, diabetes mellitus, and uncontrolled hypertension. Furthermore, although medication-related dysgeusia terminates quickly after stopping the responsible medication, with captopril and some other medications, dysgeusia may persist for months (Frank et al., 1992). Apart from obvious oral pathology, medicationinduced dysgeusias (metallic taste), hypothyroidism, and depression- or psychosis-related taste complaints, most “taste” complaints in the elderly are usually symptoms of olfactory dysfunction. Altered gustatory thresholds have been identified in groups of patients with various systemic disorders (particularly endocrine, kidney, and hepatic diseases), but as a rule, gustatory complaints are seldom the basis for a separate evaluation in such patients. Gustatory complaints are common in patients with cancer, but toxicity due to chemotherapy or radiation therapy or nutritional deficiencies (such as zinc) can usually be readily identified.

Conductive gustatory disturbances Conditions that impede or alter the contact of tastants with the taste receptors produce conductive (or “transport”) hypogeusia or dysgeusia. Such conditions can include poor oral hygiene, dental caries, periodontal disease, denture use, gastroesophageal reflux, upper respiratory infections, oral candidiasis (thrush), and oral cancer. With oral candidiasis, for example, the growth of yeast produces a barrier that precludes contact of the tastants with the gustatory receptors. Similarly, elderly patients not infrequently develop a thick, whitish mucoid coating on the tongue (“tongue plaque”), which is evident on arising and which can interfere with taste acuity. This can be removed easily with a soft toothbrush, with a dry gauze pad, or by eating so-called “detergent” foods (hard bread, dry cereal, uncooked vegetables, or fibrous meats). Tongue brushing should be encouraged twice a day, upon

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rising and before bed, especially in elderly patients with oral prostheses. Conditions that interfere with chewing or salivation are also likely to produce conductive hypogeusia. During mastication, food is crushed and ground by the teeth (chewed), warmed, and mixed with liquid saliva. These actions release tastants from the food and also facilitate conveyance of tastants in a liquid or semiliquid state to the gustatory receptors (among other actions such as facilitating enzymatic breakdown of food components). Therefore, conditions that interfere with chewing or movement of the food bolus (such as lack of teeth, poorly fitting dentures, temporomandibular joint dysfunction, jaw claudication, and dysphagia) can lessen the experience of taste. Because saliva is necessary to help soften the masticated food and to convey tastants in a liquid state to the gustatory receptors, disorders that interfere with saliva production result in hypogeusia and/or dysgeusia. In addition, saliva helps to prevent pathologic growth of bacteria and fungi and to maintain oral pH and ionic composition at proper levels; disruption of any of these can alter taste sensation (Spielman, 1998). Saliva also has another role in taste, which has only recently been elucidated and which is also impaired by xerostomia—saliva modulates some long-lasting flavors by trapping free thiols produced by oral anaerobic bacteria (Starkenmann et al., 2008). Bacteria convert odorless sulfur compounds in some fruits and vegetables (grapes, onions, and bell peppers) into odoriferous thiols after the foods had been swallowed (the socalled “retroaromatic effect”). The odoriferous thiols can be perceived after 20–30 seconds and persist for several minutes. Xerostomia (dry mouth due to a lack of saliva, sometimes colloquially called “cotton mouth” or “dough mouth”) is a common cause of conductive hypogeusia in the elderly. Xerostomia can occur with the use of various medications (such as anticholinergic medications and diuretics) and with tobacco smoking, diabetes mellitus, radiation therapy for head and neck cancers, and Sjögren’s syndrome (Spielman, 1998). Breath mints, sugarless chewing gum or lozenges, artificial saliva products, citric acid mouthwashes, and systemic pilocarpine can each be of modest symptomatic benefit in patients with xerostomia.

Sensorineural and central gustatory disturbances Taste sensations are mediated by polarized neuroepithelial cells that are clustered into taste buds scattered across the dorsal surface of the tongue and are present to a lesser degree on the soft palate, pharynx, epiglottis, larynx, and the first third of the esophagus. The facial (via the chorda tympani), glossopharyngeal, and vagus nerves transmit taste signals from the taste receptor cells to the rostral

portion of the nucleus of the solitary tract in the dorsal medulla. Chemesthetic (pungent) sensations in the oral cavity are mediated separately via the trigeminal nerve and also via free nerve endings in the chorda tympani, glossopharyngeal, and vagus nerves. Such sensations are considered to be a form of nociception distinct from taste (Schiffman, 1997). From the nucleus of the solitary tract, taste-responsive axons project through the ipsilateral central tegmental tract in the pons, decussate at a higher level (probably in the midbrain), and project to the ventroposteromedial nucleus of the thalamus and to other sites, including the lateral hypothalamus and the amygdala (Lee et al., 1998; Sánchez-Juan and Combarros, 2001). In the elderly, interruption of the central gustatory pathway in the brainstem most commonly results from lateral pontine strokes (Sánchez-Juan and Combarros, 2001; Landis et al., 2006). Gustatory neurons in the thalamus project to the primary gustatory cortex, which in humans has been tentatively localized to the transition area between the posterior insula and parietal operculum and the central sulcus (Kobayakawa et al., 2005). Cortical areas involved in processing gustatory stimuli are located in the insula, the frontal and parietal opercula, and the orbitofrontal cortex (Small et al., 1999). In right-handed individuals, the left cerebral hemisphere contains a gustatory representation of both hemitongues, whereas only the right hemitongue is represented in the right hemisphere (Sánchez-Juan and Combarros, 2001; Mathy et al., 2003). Severe symptomatic neural or central hypogeusia rarely occurs as a clinical entity, particularly in isolation. Nevertheless, sensorineural or central gustatory disorders can potentially result from damage to any part of the gustatory neural pathway from the tastebuds via the cranial nerves conveying gustatory sensation (the facial, glossopharyngeal, and vagal nerves), through the brainstem and thalamus to the cerebral cortex (Heckmann and Lang, 2006). Sensorineural and central gustatory disorders in the elderly may be caused by drugs, toxins, and physical agents; damage to the cranial nerves conveying gustatory sensation (for example, isolated cranial mononeuropathy as with Bell’s palsy, or cranial polyneuropathy); spaceoccupying processes (particularly with tumors involving the cerebellopontine angle or the jugular foramen); degenerative disorders (such as PD or AD); seizures; and depression.

Presbygeusia Presbygeusia (literally “elderly taste” or “old age taste”) is the gradual loss of taste that occurs in most people as they grow older. The elderly have higher detection and recognition thresholds for taste than younger individuals, and taste sensitivity is further compromised by medications and comorbid medical problems (Schiffman, 1997; Spielman, 1998). Healthy elderly people have higher

Disorders of the Special Senses in the Elderly

thresholds for each taste category (sweet, sour, salty, bitter, and umami/savory), particularly for bitter substances, with the average threshold for taste rising fourfold in the elderly (Frank et al., 1992; Schiffman, 1997; Spielman, 1998). The changes in taste sensitivity make food seem relatively tasteless and contribute to difficulties complying with dietary regimens (such as a low-salt diet for management of hypertension) (Schiffman, 1997). Chemosensory deficits reduce the pleasure obtained from eating, and represent risk factors for nutritional deficiencies and for nonadherence to dietary regimens (Duffy et al., 1995; Schiffman, 1997). Lower olfactory perception in elderly women is associated with lower interest in food-related activities (such as cooking and eating a varied diet), a lower preference for foods with either a predominantly sour or bitter taste (such as citrus fruits) or pungency (such as horseradish), a higher intake of sweets, and a lower intake of low-fat milk products (Duffy et al., 1995). Nutritional adequacy should be assessed in elderly women with a self-reported or measured difficulty in perceiving odors or flavor (Duffy et al., 1995). Flavorenhanced food can have a positive effect on food intake and can increase enjoyment of food and improve the quality of life for elderly patients with chemosensory deficits (Schiffman, 1997). Flavor enhancements with simulated flavors can be used to amplify odor intensity, to improve the enjoyment of eating, and to facilitate adequate nutrition in the elderly with hyposmia (but not anosmia) (Schiffman, 1997). Simulated flavors are mixtures of odoriferous substances that are either extracted from natural substances (as with concentrated orange juice or vanilla) or synthesized de novo (as with vanillin in artificial vanilla).

Burning mouth syndrome Burning mouth syndrome is an uncommon painful intraoral disorder affecting mostly postmenopausal women (Spielman, 1998). The pain is described as an uncomfortable constant burning sensation in the mouth affecting particularly the anterior tongue, palate, and lips. This may be associated with paresthesias or a numb sensation in the mouth or on the tip of the tongue, as well as a sensation of dry mouth and increased thirst, without associated mucosal lesions. Approximately two-thirds of affected individuals report dysgeusia or persistent abnormal taste sensations (which might be termed “palingeusia”) (Spielman, 1998). Most have alterations in sensations of saltiness, and some have alterations in sweet, sour, and bitter tastes (Spielman, 1998). The persistent taste sensations are most often described as bitter or metallic (torqugeusia) (Spielman, 1998). Risk factors include older age, female gender, menopausal status, status as a “supertaster” (with a high-density of lingual papillae), upper respiratory infection, previous dental procedures, medications, traumatic life events, and stress (Brailo et al., 2006). The

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etiology of burning mouth syndrome appears to be multifactorial; various conditions have been associated with it, including menopause, endocrine disorders (such as diabetes and hypothyroidism), nutritional disorders (such as deficiencies of iron, zinc, thiamine, riboflavin, pyridoxine, folate, and cobalamin), xerostomia (such as from Sjögren’s syndrome or other causes), medications (especially anticonvulsants and angiotensive-converting enzyme inhibitors), gastroesophageal reflux, postnasal drip, oral candidiasis, tongue plaque, removable dentures, halitosis, and mouth irritation (such as from overbrushing of the tongue, mouthwash, or acidic drinks) (Spielman, 1998; Salort-Llorca et al., 2008). Many cases, however, are idiopathic. Burning mouth syndrome can be disabling and may cause a variety of complications, including anorexia, weight loss, insomnia, irritability, depression, anxiety, and impaired socialization. The treatment depends on the etiology (if it can be identified). For primary (idiopathic) burning mouth syndrome, saliva-replacement products, oral rinses, clonazepam (applied topically or taken orally), gabapentin, selective serotonin reuptake inhibitor antidepressants, alpha-lipoic acid, B vitamins, and capsaicin have all been employed, with variable but limited success (although high-quality trials are lacking) (Mínguez Serra et al., 2007; Buchanan and Zakrzewska, 2008).

Cerebrovascular disease Taste disorders are common, although underrecognized, in acute stroke, with hypogeusia occurring in approximately 30% of cases (Heckmann et al., 2005). Strokerelated hypogeusia is typically unilateral with brainstem strokes (Landis et al., 2006) but is strictly unilateral in only a minority of patients with cerebral infarction (Heckmann et al., 2005). Risk factors for stroke-associated gustatory loss include male gender, greater stroke-related functional impairment, dysphagia, and anterior circulation location, especially involving the periopercular frontal lobe (Heckmann et al., 2005). Interruption of the gustatory pathway in the brainstem usually occurs with lateral pontine stroke (Landis et al., 2006). Thalamic hypogeusia may be associated with a cheiro-oral syndrome (SánchezJuan and Combarros, 2001). Stroke-related damage to the left insula causes an ipsilateral deficit in taste intensity but a bilateral deficit in taste recognition, suggesting that the left insula is dominant for taste recognition (Pritchard et al., 1999; Mathy et al., 2003). Stroke-associated dysgeusia and hypogeusia often persist while other deficits improve and can contribute to unwanted weight loss poststroke (Mathy et al., 2003; Finsterer et al., 2004). Lewy body alpha-synucleinopathies Although less common than olfactory defects, impaired taste appreciation is also present in about a quarter of patients with clinically defined PD, independent of age, disease severity, or olfactory deficits (Shah et al., 2009).

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Given the sparing of the first- and second-order taste neurons in PD, a disorder of taste may indicate involvement of primary or secondary gustatory cortical areas, although confounding by drug effects (such as anticholinergic drugs) and changes in salivary constitution are possible (Shah et al., 2009).

Acknowledgments The author thanks Phyllis Goetz, MLS; Erin McGinnis, BSIR; Debra Alexander-Friet, MLIS; and Tammy Elsing, Tomah VA Medical Center Library, for assistance in obtaining reference materials, as well as Anjela K. Krome, OD, for reading sections of the chapter and for providing constructive suggestions.

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Chapter 18 Nervous System Infections Ronald Ellis1, David Croteau1, and Suzi Hong2 1 2

Department of Neurosciences and HIV Neurobehavioural Research Center, University of California, San Diego, CA, USA Department of Psychiatry, School of Medicine, University of California, San Diego, CA, USA

Summary • Acute bacterial meningitis is among the most important neurologic emergencies and is diagnosed by blood cultures and lumbar punctures (LPs) for cerebrospinal fluid (CSF) analyses. Viral meningitides are self-limited and less serious conditions than bacterial meningitides. Mycobacterial and fungal meningitides are examples of chronic infectious meningitides. • Acute viral encephalitis is mostly caused by viruses such as herpes viruses, arboviruses, and enteroviruses. CSF analysis is essential for diagnosis. • Clinical manifestations of intracranial abscesses are fever, raised intracranial pressure (ICP), and focal neurologic deficit. Brain imaging, particularly MRI and CT, are vital for diagnosis. • Myelitis is diagnosed through spine MRI and CSF analyses. Spine MRIs usually have T2 hyperintense signal abnormality and CSF usually shows lymphocytic pleocytosis with or without hyperproteinorachia, and normoglycorrhachia. • Varicella zoster virus (VZV), septic encephalopathy, human immunodeficiency virus (HIV), and immunosenescence effects in the elderly are further discussed.

Introduction Despite the availability of advanced antimicrobial therapies, infectious diseases remain a major cause of morbidity and mortality in the elderly. Infections of the central and peripheral nervous systems demand special consideration in older individuals, for several reasons. First, age-related changes in immunity particularly impact the central nervous system (CNS). Second, changes in the blood–brain barrier (BBB) and blood–cerebrospinal fluid barriers (BCB), particularly in glycoconjugates that serve as bacterial receptors, may explain increased susceptibility to CNS infection by specific pathogens (Tuomanen, 1994; Shah and Mooradian, 1997). Third, as enumerated in Table 18.1, there are several important ways in which the clinical presentation of CNS infectious diseases in the elderly differs from that of younger individuals. Finally, systemic diseases in the elderly can masquerade as CNS infections, as for example, when fever in the context of pneumonia or urinary tract infection “unmasks” preexisting focal neurologic deficits, leading to a false impression of focal CNS infection. This chapter addresses common neurologic disorders related to specific bacterial, mycobacterial, fungal, and viral pathogens, including human immunodeficiency virus (HIV) infection. Prion diseases are discussed in a separate chapter. An exhaustive review of specific

pathogens is beyond the scope of this chapter, so references for more comprehensive reviews are provided. We describe pathogens to which the elderly patient is more susceptible, along with specific differential diagnostic considerations in this patient population. In addition, this chapter discusses appropriate treatments and toxicities to which the elderly patient is more susceptible. An anatomopathologic approach is employed whenever Table 18.1 Infectious anatomopathologic syndromes and clinical features specific to the elderly Infectious syndrome

Clinical features specific to the elderly

Acute bacterial meningitides

Less acute onset (for example, days versus hours) Predominant encephalopathy with variable (sometimes absent) meningeal irritation and fever

Acute viral meningitides

Encephalopathy present

Chronic infectious meningitides

Predominant personality or cognitive changes, fever that may be minimal or absent

Acute viral encephalitides

Altered consciousness not correlating with overall disease severity, fever may be minimal or absent

Intracranial abscess

Encephalopathy more prominent than focal features

Other spinal canal infections

Minimal or absent fever

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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possible to facilitate syndrome recognition and differential diagnosis generation. Because clinical manifestations of nervous system infections reflect complex interactions between specific pathogens and the immune system, we discuss pathogen-specific immune responses throughout the chapter. Finally, at the end of the chapter, we review immunosenescence (age-related changes in immune function) both generally and in the CNS specifically.

Infectious meningitis Acute bacterial meningitis is among the most important neurologic emergencies because early recognition, prompt diagnosis, and rapid institution of therapy can save lives and prevent permanent disability. Meningitis is defined as any inflammatory process that involves the meninges, including the pia, the arachnoid, and the dura matter. Bacteria can reach the CNS through hematogenous spread (for example, nasopharyngeal colonization and blood stream invasion or bacteremia from any sources), extension from paracranial structures (such as paranasal sinuses, skull osteomyelitis, and mastoiditis, although rare in the elderly), and by direct implantation through intracranial surgeries, ventriculoperitoneal shunt, intracranial hardware (such as deep brain stimulation devices or intracranial electrodes), or, rarely, lumbar puncture (LP). The clinical presentation of bacterial meningitis in older patients differs from that of younger adults in several ways. Whereas symptom onset is typically abrupt in younger adults, symptoms may evolve over several days in older patients. Also, whereas the cardinal clinical manifestations in younger adults include headache, fever, and nuchal rigidity, elderly patients often present with encephalopathy (altered consciousness, behavior, and cognition), less frequently accompanied by fever and signs of meningeal irritation. Indeed, encephalopathy with fever in older individuals should not be ascribed to other causes until bacterial meningitis has been excluded by cerebrospinal fluid (CSF) examination. Encephalopathy may also be the result of raised intracranial pressure (ICP) or ongoing nonconvulsive seizures, both caused by the primary infectious process. Whereas younger patients who develop acute bacterial meningitis exhibit limited neck flexion (nuchal rigidity) that is more specific for meningeal irritation, older patients with or without meningitis frequently have degenerative cervical spine disease that produces limitations also in neck extension, lateral flexion, and rotation. Other clinical findings that may be present, although less frequently in the elderly, include nausea and vomiting; photophobia; Brudzinski (knee and hip flexion associated with passive neck flexion in supine position); and Kernig (back and leg pain elicited by knee extension while hips are flexed in supine position) signs, reflecting spinal

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nerve roots inflammation and reflex muscle spasm and pain; seizures; focal deficits, which are usually the result of an inflammatory or vascular complication such as arteritis, septic venous thrombosis, cerebritis, or subdural empyema; cranial neuropathy, particularly with Listeria monocytogenes meningitis; or cutaneous rash with Neisseria meningitidis. The differential diagnosis of acute bacterial meningitis includes viral meningitis, viral encephalitis, intracranial abscess, and subarachnoid hemorrhage. With less acute meningitis presentations, etiologic considerations include mycobacterial and fungal meningitis, as well as carcinomatous or lymphomatous meningitis. The symptomatic manifestations of bacterial meningitis depend in part on the specific pathogen and the immune responses to it. Extracellullar bacteria, such as Staphylococcus and Streptococcus spp., N. meningitidis, and Escherichia coli (gram-negative bacilli), replicate outside of cells. These pathogens produce toxins and induce innate immunity acutely (for example, phagocytosis by neutrophils and monocytes/macrophages, and cytokine production), followed by adaptive immune responses (such as antibody production) that aim to neutralize bacterial toxins and eliminate the pathogens. These inflammatory responses are often responsible for fever, edema, and tissue damage at the site of the infection and, in severe cases, for septic shock. A polymorphonuclear (PMN) CSF pleocytosis reflects phagocytes recruited to the site of the infection, and this response may be limited in immunocompromised individuals, such as those with HIV infection or transplant recipients. On the other hand, intracellular bacteria such as mycobacteria and L. monocytogenes are capable of surviving and replicating inside phagocytes, partly explaining their propensity to cause more chronic or persistent infections. In the case of intracellular pathogens, adaptive cell-mediated immunity (such as T and B lymphocytes) plays a major role in resolving infection. Such chronic infections caused by intracellular bacteria result in prolonged activation of the immune system and may cause permanent, severe tissue damage. Paradoxically, older individuals demonstrate greater and more prolonged inflammatory responses but diminished immune clearance of bacterial infections. As a result, early diagnosis and treatment are key to obtaining optimal outcomes. The diagnosis of acute bacterial meningitis requires blood cultures and urgent LP for CSF analyses. Antibiotic therapy must be started promptly because delay may result in the formation or progression of purulent exudates in the subarachnoid space and ventricles, with consequent diffuse brain edema. Brain computed tomography (CT) before LP is indicated when clinical evidence of raised ICP or focal findings are present, such as with papilledema (Kastenbauer et al., 2002). Brain imaging also is indicated in patients with new-onset seizures or immunocompromised states, to rule out cerebral mass

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Table 18.2 CSF differential diagnosis in acute and chronic meningitisa Pleocytosis

Protein

Glucose

Meningitis type

Selected investigation

PMN >1000/mm3

↑

↓

Bacterial

Bacterial cultures, antigen testing

PMN <1000/mm

↑

Normal

Early viral

Select viral PCR

Lymphocytes <1000/mm3

↑

Normal

Aseptic (viral or drug induced)

Select virus PCR, acute and convalescent serologies

Lymphocytes <1000/mm3

↑

↓

Partially treated bacterial, fungal, mycobacterial, neoplastic, granulomatous (sarcoidosis)

Bacterial antigen testing, India ink, fungal cultures and antigens, AFB, cytology, ACE

3

PMN, polymorphonuclear; PCR, polymerase chain reaction; AFB, acid fast bacilli; ACE, angiotensin-converting enzyme. aNote that these ranges are general guidelines only. Exceptions may arise in selected cases.

lesions that may precipitate brain herniation after LP. However, because suspected bacterial meningitis is a neurologic emergency, LP should be done immediately in the absence of these risk factors, as a definitive microbiologic diagnosis is important to guide appropriate antibiotic selection. When the need for CT significantly delays LP, blood cultures should be obtained and empiric antibiotic therapy administered based on the clinical setting. Although antibiotic therapy takes a few hours to sterilize CSF, and culture results are often positive for the first several hours after antibiotic administration, every effort should be made to obtain CSF before or within 1–2 hours of antibiotic therapy initiation. CSF analyses are useful in distinguishing bacterial meningitides from other types of meningitis (Table 18.2). For bacterial meningitis, LP and CSF analyses may show elevated opening pressure, hyperproteinorachia (high protein; typically 100–150 mg/dL), and hypoglycorrhachia (low glucose), usually defined as a CSF-to-serum glucose ratio of less than 0.5. However, clinicians should bear in mind that this ratio assumes a normal serum glucose. In diabetes mellitus, a frequent comorbidity in older patients, the rule may be broken. Thus, in hyperglycemic states, a CSF-to-serum glucose ratio substantially lower than 0.5 may be normal, and appropriate adjustments should be made using a nomogram (Skipper and Davis,

1997). Bacterial meningitis usually produces a PMN pleocytosis (increased cell count) greater than 1000/mm3, but if the pleocytosis is less than 1000/mm3, one should suspect partially treated bacterial meningitis, immunosuppression, or a nonbacterial cause, such as an early viral meningitis. As an exception to the rule of PMN pleocytosis, Streptococcus spp. meningitis may occasionally present with a lymphocytic predominance. Finally, paranasal sinuses plain X-ray (or CT, if brain CT was performed) and chest X-ray may be performed to document a primary infectious focus. Table 18.3 summarizes current antimicrobial recommendations for bacterial meningitis in the elderly, by specific bacterial pathogens. Antibiotic selection depends on the clinical setting, with important considerations being drug allergies, comorbid medical conditions, local antibiotic resistance patterns, and laboratory findings, including CSF analyses results. When LP is delayed or the Gram stain is nondiagnostic, empiric therapy is initiated (Fitch and van de Beek, 2007). In the elderly patient, organisms such as Streptococcus pneumoniae, L. monocytogenes, and gram-negative bacilli (for example, E. coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) are the most common offenders and should be covered empirically. Until recently, empiric coverage included ampicillin to cover most S. pneumoniae and L. monocytogenes cases, plus a

Table 18.3 Specific therapy of bacterial meningitis in the elderly Microorganism

Antibiotic

Comments

H. influenzae

Third-generation cephalosporins

Covers ampicillin-resistant H. influenzae; duration 7–10 days

S. pneumoniae

Third-generation cephalosporins + vancomycin (for penicillin-resistant strains)

Normally sensitive to penicillin G and ampicillin; duration 10–14 days

L. monocytogenes

Ampicillin + gentamicin

Ampicillin only bacteriostatic; cephalosporins inactive; gentamicin duration 14–21 days and 6 weeks for cerebritis

Gram-negative bacilli

Third-generation cephalosporins

Ceftazidime or aminoglycoside for P. aeruginosa; duration 21 days

S. aureus

Vancomycin

Covers methicillin-resistant S. aureus

Nervous System Infections

third-generation cephalosporin such as cefotaxime, ceftriaxone, or ceftazidime for gram-negative bacilli. However, local resistance patterns influence empiric antibiotic coverage in adults with community-acquired meningitis. For example, with the emergence of ampicillin-resistant S. pneumoniae in some regions, vancomycin is included empirically until susceptibility is confirmed. Although Haemophilus influenzae is infrequently observed in the elderly, it should be considered and covered if there is any comorbid immunosuppression. In the settings of head trauma, neurosurgery, or ventriculoperitoneal shunt, Staphylococcus spp. (including S. aureus) should be covered with vancomycin and gram-negative bacilli with a thirdgeneration cephalosporin such as cefotaxime, ceftriaxone, or ceftazidime. Ceftazidime, unlike other third-generation cephalosporins, covers Pseudomonas spp. and is reserved for situations in which this organism is suspected as or proven to be the cause of the meningitis. Adjunctive therapy with dexamethasone should be strongly considered to reduce mortality and morbidity, particularly if there is raised ICP or very high bacteria concentration in CSF. In a recent study in the Netherlands, adjunctive treatment of S. pneumoniae meningitis with dexamethasone in 84% of patients from 2006 to 2009 significantly improved favorable outcomes and mortality compared with less widespread use of dexamethasone in 3% of patients from 1998 to 2002 (Brouwer et al., 2010). However, if an infectious agent other than S. pneumoniae or H. influenzae is suspected or proven, dexamethasone should be stopped, as benefit has not been demonstrated for other organisms (de Gans and van de Beek, 2002; Tunkel and Scheld, 2002). Dexamethasone 0.15 mg/kg body weight should be initiated at the same time as or shortly before the first dose of antibiotics and continued every 6 hours for 2–4 days. The rationale for giving dexamethasone before antibiotic therapy is the inhibition of production of tumor necrosis factor alpha (TNF-α) mRNA before macrophages and microglia are activated by bacterial cell wall components. Some authors recommend the use of rifampin with dexamethasone, as the reduction in inflammation with corticosteroids may impair the penetration of vancomycin into CSF. In treating penicillin-resistant S. pneumoniae meningitis, a second CSF study after 24–48 hours is recommended to document bacteriologic improvement because adjuvant dexamethasone may mask clinical signs of poor antibiotic response (Quagliarello and Scheld, 1997). Prophylactic anticonvulsants are not indicated, as they have not been shown to reduce seizure incidence, may cause significant toxicity, and may alter antibiotic metabolism by hepatic enzyme systems induction. However, any seizure should be treated promptly with appropriate agents, including benzodiazepine and fosphenytoin. Worse prognosis in terms of morbidity and mortality can be expected in the following settings: advanced age,

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altered level of consciousness, raised ICP, seizures and focal neurologic deficits, and S. pneumoniae as the causative organism, because of its propensity to cause arteritis. Residual sequelae in the elderly may include behavioral and cognitive impairment, focal neurologic deficits, and seizures. Viral meningitides, also called aseptic meningitides, are self-limited and less serious conditions than bacterial meningitides. However, they have similar clinical manifestations, including fever, headache, nausea, photophobia, and nuchal rigidity. Focal neurologic deficits, raised ICP, and seizures are absent, but some encephalopathy may be present, particularly in the elderly patient. As with acute bacterial meningitides, viral meningitides are diagnosed with CSF examination. Hyperproteinorachia, normoglycorrhachia, and a lymphocytic pleocytosis less than 1000/mm3 are typically observed (Table 18.2). However, in up to one-third of cases, viral meningitis will present with a predominant, often transient PMN pleocytosis. Bacteria will be absent from the CSF gram stain, bacterial cultures and antigen studies will be negative, and no parameningeal infectious foci (such as abscess) will be identified. Enteroviruses (for example, coxsackieviruses and echoviruses) are the most common cause of viral meningitides, followed by herpes simplex virus, HIV, arthropod-borne viruses, also called arboviruses (such as the West Nile virus), more commonly causing encephalitis and, less commonly, lymphocytic choriomeningitis virus (LCMV). Specific virologic diagnosis can be pursued with CSF realtime polymerase chain reaction (PCR) (for DNA viruses) and reverse transcriptase PCR (for RNA viruses) and other methods (such as acute and convalescent specific serum IgG), although the sensitivity and specificity of pathogenspecific PCR vary (Debiasi and Tyler, 2004). Viral cultures are difficult and have been largely replaced by PCR. In patients with suspected viral meningitis, the following differential diagnoses should be considered in addition to acute bacterial meningitis: viral encephalitis (especially herpes simplex virus); chronic meningitides such as those due to mycobacteria, fungi, metastatic neoplasms (carcinomatous or lymphomatous), and sarcoidosis; and drug-induced meningitis. Infectious and neoplastic chronic meningitides are similar to viral meningitis, as they are associated with lymphocytic pleocytosis; they also differ, in that the CSF glucose level is often depressed (Table 18.2). Drug-induced meningitis in older patients may be due to nonsteroidal anti-inflammatory agents (such as ibuprofen) or sulfa-containing antibiotics (such as trimethoprim-sulfamethoxazole). The latter often are used to treat problems that are common in the elderly, such as arthralgia and urinary tract infections (Wambulwa et al., 2005; Periard et al., 2006). Among patients with viral meningitis of undetermined cause, empiric acyclovir therapy is prudent until PCR

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can rule out herpes simplex virus meningoencephalitis. Otherwise, given the self-limited nature of most viral meningitides, treatment is mostly supportive with analgesics and antipyretics. An exception is HIV seroconversion meningitis, in which combination antiretroviral therapy (cART) should be offered. Other antivirals may also be used if a specific microorganism is identified or suspected. Innate immune responses during the early phase of viral meningitis include immediate interferon (IFN) production by virus-infected cells and killing of infected cells by natural killer (NK) cells. These are followed by antibody production to inhibit viral entry into host cells, limiting virus spread (adaptive humoral immunity) and killing of infected cells by virus-specific cytotoxic T lymphocytes (adaptive cellular immunity). Many viruses (such as HIV and rhinovirus) present antigenic variation to evade immune surveillance by virus-specific T lymphocytes, and the presence of varying serotypes results in ineffective immunization against certain viral strains. Decreased ability of the immune system to respond to and resolve viral infections efficiently due to immunosenescence in the elderly can lead to chronic infection and prolonged activation of the immune system and inflammation. Chronic infectious meningitides include mycobacterial (such as Mycobacterium tuberculosis) and fungal meningitides (such as Cryptococcus neoformans and coccidioidomycosis). Like mycobacteria, many fungi can reside inside phagocytes and other cells, accounting for their predilection to produce chronic and persistent infections. Although clinicians frequently associate these disorders with immunosuppressed hosts or those with comorbidities such as diabetes mellitus, they may occur also in immunocompetent older patients. Diagnosis may be delayed in the elderly due to a more indolent presentation, but suspicion should be high because these conditions carry a grave prognosis if left untreated. Chronic meningitis presents with subacute or chronic headache and encephalopathy, including personality change and cognitive impairment. Cranial mononeuropathies (IV, V, VI, VII, VIII) are an important clue suggesting inflammation of cranial nerves in the subarachnoid space at the base of the brain. Chronic meningitis differs from acute meningitidis, in that fever and nuchal rigidity may be absent or mild. In the elderly, encephalopathy can be the major or only presenting clinical feature and may be mistakenly ascribed to a depressive mood disorder or degenerative dementia. If chronic meningitis remains untreated, late neurologic complications can include seizures, focal neurologic deficits due to arteritis and infarction (M.  tuberculosis), raised ICP from space-occupying lesions (such as tuberculoma or cryptococcoma), or hydrocephalus due to impaired subarachnoid CSF flow or CSF reabsorption through arachnoid granulations.

Identification of a systemic infectious focus of disease such as pulmonary tuberculosis or fungal infections or a known cancer in many cases strongly points to a specific pathogen or noninfectious etiology (such as carcinomatous meningitis). M. tuberculosis typically reaches the CNS through hematogenous spread of bacilli to the superficial cortex or to subependymal regions–-sometimes in the setting of a so-called miliary disease–-forming microtubercles that rupture in the CSF. Occasionally, M. tuberculosis meningitis results from a parameningeal abscess or osteomyelitis. Fungal microorganisms such as C. neoformans and Coccidioides spp. typically access the CNS through hematogenous spread from a primary site, such as lung, gastrointestinal or nasopharyngeal mucosa, or skin. Definitive diagnosis of chronic meningitis requires CSF analyses. CSF analyses typically show a lymphocytic pleocytosis with hyperproteinorachia and hypoglycorrhachia. Occasionally, PMN pleocytosis may be observed in early disease or in cases of superficial abscess/granuloma formation, or may represent a hypersensitivity reaction to microbial antigens, particularly those of M. tuberculosis. A specific microbiologic diagnosis may be obtained with the following: specific smear and staining, including acid fast bacilli (AFB), India ink (facilitating cryptococcus membrane polysaccharide capsule visualization), and cryptococcal antigen; cultures; and PCR. In addition, tuberculin testing or IFN-gamma release assays may be useful in low-prevalence areas. Neuroimaging with magnetic resonance imaging (MRI) may show leptomeningeal contrast enhancement, communicating or noncommunicating hydrocephalus, and, uncommonly, space-occupying lesions. The meningeal contrast enhancement tends to be located in the basal meninges. Over time, C. neoformans can form small, gelatinous pseudocysts in Virchow– Robin perivascular spaces in the basal ganglia, giving a Swiss cheese or soap bubbles appearance best observed on T2-weighted images. Systemic evaluation of chronic meningitides should include at least a chest X-ray. The differential diagnosis of chronic infectious meningitides includes partially treated bacterial meningitis, spirochetal meningitis with agents such as Treponema pallidum (secondary syphilis) and Borrelia burgdorferi (Lyme disease), and lymphomatous or carcinomatous leptomeningeal metastases. If risk factors are present or in endemic areas, serum should be tested for rapid plasma reagin (RPR) and B. burgdorferi antibodies, and a CSF venereal disease research laboratory (VDRL) titer should be obtained. CSF should be collected and analyzed for cytology in all patients, and suspicion should be particularly high in cases with a known primary neoplasm. The treatment of tuberculous meningitis is complex and requires consideration of systemic disease, both pulmonary and extrapulmonary. The input of an infectious disease specialist is invaluable. In general, initial treatment should comprise a regimen of three to four drugs until

Nervous System Infections

the patient’s clinical isolate is tested for drug susceptibility (Small and Fujiwara, 2001). Among these, isoniazid and pyrazinamide are recommended, as they reach CSF concentrations similar to plasma when meningeal inflammation is present. Chemotherapy is continued for at least 6 months. Close monitoring should be performed for side effects of antituberculous therapy because isoniazid, ethambutol, and streptomycin can cause neurotoxicity. To protect against sensorimotor axonal peripheral neuropathy with isoniazid, pyridoxine supplements should be given. In some patients, ethambutol causes optic and sensory peripheral neuropathies, while streptomycin can be ototoxic. The cornerstone of cryptococcal meningitis therapy remains amphotericin B with or without flucytosine for CSF sterilization. In immunocompromised individuals who show a clear clinical improvement with amphotericin B, fluconazole may be substituted after 2 weeks. Fluconazole is then continued for 8–10 weeks of consolidation, after which a chronic suppressive/maintenance phase is begun (van der Horst et al., 1997). In immunocompetent individuals, fluconazole may be stopped after 6–10 weeks if symptoms have resolved, CSF glucose has normalized, and repeat CSF cultures for C. neoformans have been negative on at least two consecutive taps. Additional management considerations are treatment of the primary focus–most often the lung–-restoration of immunity if possible, and therapy for neurologic complications such as hydrocephalus and seizures, if present.

Acute viral encephalitides Viral encephalitis is a medical emergency requiring a high index of suspicion to ensure prompt early treatment initiation and the best possible prognosis. The term encephalitis indicates inflammation of brain parenchyma (cerebritis), but because some degree of leptomeningeal inflammation is almost invariably present, meningoencephalitis is usually the most appropriate descriptive term. While many viral infections are asymptomatic in the majority of affected individuals–-a feature known as the “tip of the iceberg” phenomenon–-individuals who express neurologic disease are likely to be older. Thus, in one study, older individuals (60–79 years) were four to five times more likely to suffer morbid and mortal West Nile virus (WNV) disease than younger ones (30–49 years) Campbell et al., 2002. Viral encephalitis typically causes fever and a rapidly progressive encephalopathy with diffuse brain dysfunction that impairs the level of consciousness and cognitive functions. Additional features overlap with those of viral meningitis and include headache, meningismus, and photophobia. In the elderly, these latter features may be subtle or even absent. Additionally, although the degree

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of encephalopathy often correlates with the severity of the encephalitis in younger patients, this relationship may be less true in the elderly patient. Neuropsychiatric symptoms often predominate, including perceptual disturbances (illusions and hallucinations) and behavioral and personality changes. Seizures, both partial and generalized, are common because of cortical involvement. Focal neurologic deficits also may be present, as in the case of receptive aphasia due to temporal lobe involvement by herpes simplex virus 1 (HSV-1). The frequent occurrence of delirium in elderly patients with systemic infection can make the diagnosis of acute viral encephalitis challenging. Thus, septic encephalopathy (discussed later in a separate section), in which delirium occurs despite the absence of brain parenchymal involvement, is an important differential diagnostic consideration in the elderly. Table 18.4 outlines other differential diagnostic considerations. Viruses responsible for most cases of acute encephalitis in immunocompetent individuals include herpes viruses, arboviruses, and enteroviruses (Redington and Tyler, 2002). An exhaustive list of viral pathogens is beyond the scope of this chapter and has been presented elsewhere (Chaudhuri and Kennedy, 2002). Among the herpes viruses, HSV-1 is the most common cause of severe sporadic viral encephalitis in adults in the United States, followed by Epstein–Barr virus (EBV) and human herpes viruses 6 and 7 (HHV-6 and HHV-7). Herpes simplex virus 2 (HSV-2) is a rare cause of encephalitis in adults. Although cytomegalovirus (CMV) and varicella zoster virus (VZV) can cause encephalitis, they more commonly cause disease in immunocompromised individuals. Arboviruses are arthropod-borne viruses; among them, WNV has been the prototypical agent of epidemic viral Table 18.4 Differential diagnosis of acute viral encephalitis in the elderly Fever and encephalopathy

Encephalopathy without fever

Septic encephalopathy

Metabolic disturbances

Viral or bacterial meningitides

Nutritional deficiencies

Bacterial or fungal brain abscess

Intoxication

Heat stroke

Nonconvulsive status epilepticus

Drugs: anticholinergic intoxication, neuroleptic malignant syndrome, serotoninergic syndrome, and malignant hyperthermia

Cerebrovascular events: certain strategically located ischemic strokes, subarachnoid hemorrhage, CNS vasculitides, hypertensive encephalopathy Neoplasm (such as high-grade supratentorial tumor) Paraneoplastic disorders or autoimmune encephalitides (such as limbic encephalitis) Demyelinating disorders (such as acute disseminated encephalomyelitis

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encephalitis since the outbreak of summer 1999 in the United States. Enteroviruses such as coxsackie- and echovirus can cause viral encephalitis, although they more frequently cause epidemic aseptic meningitis. Several diagnostic studies may help establish the diagnosis of acute viral encephalitis. A complete blood count usually reveals a lymphocytic leukocytosis, although lymphopenia may be seen with some viral infections. Although electroencephalography (EEG) is often regarded as a nonspecific investigation, it may help differentiate focal encephalitis such as HSV-1 from other generalized encephalitides and from noninfectious causes of encephalopathy. Periodic lateralized epileptiform discharges (PLEDs), although seen in up to 50% of patients with HSV-1 encephalitis, are of limited clinical utility because they frequently do not appear until the later stages of the illness. Cranial MRI is the imaging technique of choice in acute encephalitis and may sometimes be diagnostic (as with frontotemporal signal abnormalities in HSV-1 encephalitis; see Figure 18.1). However, CT can be obtained more rapidly and reliably in encephalopathic patients and is useful to rule out other disorders, including a cerebral space-occupying lesion, which would be a contraindication to LP. CSF analysis is an essential part of the investigation. The CSF profile is indistinguishable from acute viral meningitis and includes a lymphocytic pleocytosis, typically less than 500/mm3, normo- or hyperproteinorachia, and normoglycorrhachia. PCR is the most sensitive virologic study and is available for the most common viruses (Debiasi and Tyler, 2004). For certain viruses (such as HSV-1), PCR can provide results within a few hours and may therefore be useful in guiding treatment or deciding whether to continue antivirals. Acute and convalescent (4 weeks) specific serum IgG (more than fourfold

(a)

(b)

Figure 18.1 Herpes simplex encephalitis. Axial T2-weighted image showing hyperintense signal abnormality in the left mesial temporal and basal frontal regions (a). Axial T1-weighted image with gadolinium showing hypointense signal abnormality with faint contrast enhancement in the same regions (b). Courtesy of Dr. John Hesselink, MD, Department of Radiology, University of California, San Diego.

increase) may occasionally be useful but is not commonly used. CSF virus-specific IgM is indicative of intrathecal synthesis and may also be useful. Viral cultures are difficult and have been largely replaced by PCR. Nowadays, brain biopsy is reserved for when the diagnosis of HSV-1 encephalitis is doubtful or there is a need for surgical decompression for raised ICP. Specific therapy for viral encephalitis is limited to a few specific pathogens. Thus, no approved therapy currently exists for enteroviruses or WNV (Diamond, 2009). However, high-throughput screens of small molecules for WNV and in vivo animal studies are ongoing. If HSV-1 encephalitis is suspected, empiric therapy with intravenous acyclovir 10 mg/kg every 8 hours should be initiated as soon as possible, and the need to continue this should be reassessed based on clinical evolution and specific virologic study results (Steiner et al., 2005). In confirmed cases of HSV-1 encephalitis, acyclovir should be continued for at least 14 days. Although acyclovir is relatively safe, it requires dose adjustment for abnormal renal function, a common problem in the elderly. Acyclovir requires phosphorylation by viral thymidine kinase to acyclovir triphosphate in order to inhibit viral DNA polymerase by competing with deoxyguanosine triphosphate. The drug is effective due to the virus’s dependence on a specific thymidine kinase that has high affinity for the drug. The mortality rate for untreated HSV-1 encephalitis is approximately 70%, with less than 3% of the survivors returning to baseline neurologic status. Acyclovir has reduced the mortality to 20–30%, but nearly half of the survivors are left with significant neurologic disability. Advanced age and altered level of consciousness at presentation are poor prognostic factors. Although acyclovir is not effective for the treatment of CMV, HHV-6, and HHV-7, these viruses respond to ganciclovir, a guanosine analog that requires triphosphorylation by three different kinases and that selectively inhibits viral DNA polymerase. Ganciclovir is given 5.0 mg/kg IV every 12 hours with or without foscarnet, a pyrophosphate analog that does not require any phosphorylation and inhibits directly viral DNA polymerase, at a dose of 60 mg/kg every 8 hours (Enting et al., 1992). With the exception of HIV infection (discussed in the later section “HIV and the nervous system in the aging population”), chronic infectious encephalitides are uncommon in the elderly. These conditions include subacute sclerosing panencephalitis (measles virus), progressive rubella panencephalitis (rubella virus), and progressive multifocal leukoencephalopathy (JC virus). Although prion diseases including Creutzfeldt–Jakob disease are often listed in this context, use of the term encephalitis is not technically appropriate in this situation because these disorders are not associated with brain inflammation.

Nervous System Infections

Intracranial abscesses

Table 18.5 Brain abscess microorganisms and portal of entry Portal of entry

Intracranial abscesses are focal suppurative processes that involve brain parenchyma or surround dura matter. Determining the likely source or point of entry is essential, as it narrows the likely pathogens and, therefore, dictates appropriate empiric antimicrobial treatment (Lu et al., 2006). Intracranial abscesses arise from three primary sources: by contiguous spread from a parameningeal focus, by direct contamination, or by hematogenous spread. Contiguous spread likely occurs through valveless emissary veins, from an adjacent infected paracranial structure such as the paranasal sinuses (causing frontal lobe abscess), from the middle ear (causing temporal lobe or cerebellar abscesses), or from teeth, oropharynx, or bone (causing craniofacial osteomyelitis with epidural abscess or subdural empyema). Risk factors for direct contamination are open head trauma and neurosurgical procedures. Abscesses originating from contiguous spread or direct contamination are usually solitary. In contrast, hematogenous brain abscesses are often multiple, found at the gray/white matter interface, and arise from a remote source such as pyogenic lung disease, bacterial endocarditis, intra-abdominal abscess, or urinary tract infections. In addition to brain abscesses, bacterial endocarditis can lead to mycotic aneurysms through infected emboli lodging into the vasa vasorum of the cerebral vasculature distal from the circle of Willis, resulting in vessel wall weakening and aneurysm formation. Twenty percent of brain abscesses remain occult without identifiable sources. A variety of organisms can lead to brain abscess, and mixed infections are present in 30–60%. Table 18.5 outlines specific etiologic considerations in the elderly. Clinical manifestations of brain abscess include a classic triad of fever, raised ICP, and focal neurologic deficit. Specific focal deficits depend on abscess location and may range from aphasia (left temporal or parietal lobes) to hemiparesis (frontal lobe or descending corticospinal tracts), hemiataxia (cerebellar hemisphere), hemianopsia (occipital lobe or temporal isthmus), hemichorea, or hemiballismus (basal ganglia). Manifestations of raised ICP, including headache, emesis, altered level of consciousness, and papilledema, are present in up to 70% of patients. Fever, however, is not uniformly observed, especially in the elderly, as only 30–50% of patients have a temperature higher than 38.5°C. Elderly patients can also exhibit a predominant encephalopathy, in addition to focal neurologic deficit and raised ICP. Focal or generalized seizures occur in up to 50% of patients. When a brain abscess is suspected, neuroimaging is the key diagnostic study. The use of a contrast agent is important, as there is often BBB disruption caused by the accompanying inflammatory process. While MRI is the most sensitive and specific modality, CT frequently can be obtained more rapidly and provides helpful

467

Specific microorganisms

Contiguous spread Paranasal sinus infections

Streptococcus spp., Enterobacteriaceaea, anaerobic organismsb

Odontogenic (oral) infections

Streptococcus spp., anaerobic organismsb

Direct contamination Open head trauma

Staphylococcus spp., Enterobacteriaceaea, anaerobic organismsb, Clostridium spp.

Neurosurgical procedures

Staphylococcus spp., Enterobacteriaceaea, Pseudomonas spp.

Hematogenous spread Pulmonary origin

Streptococcus spp., Nocardia spp., Actinomyces spp., anaerobic organismsb

Endocarditis

S. viridans, S. aureus

Urinary tract origin

Enterobacteriaceaea, Pseudomonas spp.

Intra-abdominal origin

Enterobacteriaceaea, Streptococcus spp.

Special setting with either contiguous or hematogenous spread Relative immunosuppression, M. tuberculosis, L. monocytogenes, including diabetes mellitus Nocardia spp. and advanced age T. gondii Aspergillus spp., Mucormycosis, Candida spp. aIncludes gram-negative bacilli such as E. coli, K. pneumoniae, and others. bIncludes microorganisms such as Bacteroides spp., Peptococcus spp., Propionibacterium spp., and Fusobacterium spp.

diagnostic information. As outlined in Table 18.6, imaging features depend on the stage of the bacterial abscess at the time of imaging (Britt et al., 1981; Erdogan and Cansever, 2008). Although a contrast-enhancing ring is typical, this pattern may be absent during early abscess evolution, and occasional multiloculated enhancement is seen. Thickness, irregularity, and nodularity of the contrast-enhancing ring are suggestive of a neoplastic process or a nonbacterial infectious etiology (such as fungal or parasitic). In addition to T1, T2, and fluid attenuated inversion recovery (FLAIR) sequences, diffusion-weighted imaging (DWI) can help differentiate brain abscesses from other necrotic or cystic lesions, such as neoplasms (Chang et al., 2002). DWI evaluates the movement (diffusion) of water molecules in brain parenchyma. Restricted diffusion, which appears hyperintense on DWI and hypointense on corresponding apparent diffusion coefficient (ADC) maps, suggests a bacterial abscess cavity (Figure  18.2). Exceptions are fungal, tuberculous, and toxoplasmic abscesses, in which restricted diffusion can be absent.

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Neurologic Conditions in the Elderly

Table 18.6 Radiographic and pathologic correlation of bacterial brain abscess Stage

Histopathology

Imaging

Early cerebritis (1–4 days)

Parenchymal softening, early necrosis, edema, vascular congestion, and perivascular inflammation

Low attenuation area on CT; T1 hypointense and T2 hyperintense signal abnormalities on MRI; absent or patchy contrast enhancement

Late cerebritis (4–10 days)

Liquefaction, with necrotic debris (dead neutrophils, proteins) converted to pus

Similar to early cerebritis, with more mass effect and contrast enhancement

Early capsule formation (10–14 days)

Fibroblasts from neovessels produce reticulin, which are converted to collagen in the capsule, which is highly vascular, with a poorly developed BBB

Same as cerebritis, but with formation of a new cavity and a surrounding thin (thicker near cortex), smooth, contrastenhancing ring

Late capsule formation (>14 days)

Abscess encircled by a vascularized, fibrotic capsule and gliosis

Enhancing ring better demarcated

Conversely, restricted diffusion is seen in some necrotic tumors and cystic metastases, limiting the sensitivity and specificity of DWI. Screening investigation to identify the source of infection is based on clinical history and physical findings but should also include blood cultures, chest X-ray, and imaging of

Figure 18.2 Bacterial brain abscess. Axial T1-weighted without (a) and with (b) gadolinium images shows a ring-enhancing lesion in the left parieto-occipital region, with surrounding hypointensity and mass effect. T2-weighted image shows more extensive surrounding hyperintense signal abnormalities reflecting edema (c). Diffusion-weighted image (d) shows a hyperintense signal and the ADC map (e), a hypointense signal indicating restricted diffusion. Reproduced from Bradley et al. (2008), with permission from Elsevier.

paracranial structures, in addition to specific cultures and imaging based on clinical suspicion. Definitive microbiologic diagnosis requires biopsy of the abscess, with evaluation of purulent material by gram and AFB staining, as well as aerobic, anaerobic, and fungal cultures. The differential diagnosis of brain abscess depends on the clinical circumstances and radiographic appearance, including factors such as lesion stage and whether solitary or multiple lesions exist. Etiologic considerations include high-grade glioma, brain metastases, primary CNS lymphoma, cerebral infarction, resolving cerebral contusion or hematoma, cerebral radiation necrosis, and demyelinating disease. Cerebral abscesses are managed by aspirating the purulent cavity or excising the entire abscess, followed by parenteral antibiotic therapy for 6–8 weeks. Empiric medical therapy is best avoided and should be reserved for patients who have a microbiologic diagnosis from a systemic source or who are too ill to undergo any surgical intervention (Moorthy and Rajshekhar, 2008). Small abscesses and lesions at the cerebritis stage respond well to medical therapy alone, however. Multiple abscesses are best treated with aspiration of the largest lesion, followed by antibiotic therapy. Excision may be required if no imaging improvement is observed after aspiration and/or medical treatment, as well as for mass effect relief purposes. Typical empiric therapy, if required, should include metronidazole to cover anaerobic organisms and a third-generation cephalosporin to cover Enterobacteriaceae and Streptococcus spp., with or without vancomycin to cover Staphylococcus spp. (in post-traumatic or neurosurgical settings). Corticosteroids may be used for temporary mass effect relief. Prophylactic anticonvulsants can be considered because up to 50% of patients will have seizures in the acute period and up to 70%, following the acute period (Lu et al., 2006). However, no randomized controlled studies have been performed to study that question. Anticonvulsant toxicities and hepatic enzyme system induction potentially leading to interaction with antimicrobial agents should also be kept in mind when considering seizure prophylaxis and treatment.

Nervous System Infections

Extraparenchymal abscesses are discussed briefly here. Subdural empyema, defined as a suppurative process in the virtual subdural space (between the dura matter and subarachnoid membrane), is commonly the result of paracranial structures infections with contiguous spread, as well as open head trauma and neurosurgical procedures. Microorganisms are similar to those causing intraparenchymal brain abscesses but are less often mixed. Clinical manifestations generally include fever, focal neurologic deficit commensurate to location, and meningismus. The treatment may include aspiration through a burr hole or removal through craniotomy, along with appropriate antibiotics. Intracranial epidural abscess, a suppurative process taking place between the dura and the skull, is similar to subdural empyema in terms of pathogenesis, microorganisms (except for more frequent S. aureus), clinical manifestations (except for meningismus, which is uncommon), and treatment. Intraparenchymal abscess, subdural empyema, and epidural abscess may also occur simultaneously in the same patient.

Myelitides and spinal canal infections Infectious myelitides are uncommon but must be differentiated from other serious disorders. Myelitis is defined as any inflammatory process involving the spinal cord white matter, gray matter, or both. Infectious myelitis is typically subacute, with clinical manifestations evolving over several hours or days, except for HIV vacuolar myelopathy and human T lymphotropic virus (HTLV-1) presenting with a chronic myelopathy. Various microorganisms may cause myelitis, although the most common offenders are viruses. Some viruses have specific tropism for, or preferential involvement of certain anatomic structures, which may help narrow the microbiologic diagnosis, as outlined in Table 18.7. Acute viral myelitis can present as acute flaccid paralysis (also referred as poliomyelitis-like gray matter syndrome), particularly

469

with enteroviruses or neurologic dysfunction due to the involvement of the descending and ascending white matter tracts (also referred as partial or complete white matter syndrome), particularly with herpes viruses. The latter usually affects only part of the transverse plane of the spinal cord and manifests as asymmetric motor and sensory symptoms. When both halves of the spinal cord are affected, the entity is referred to as acute transverse myelitis, and patients exhibit uniformly symmetric weakness, sensory loss, and sphincter disturbances. The presence of back pain should raise the suspicion for a space-occupying lesion with spinal cord compression, although it is also described with myelitides, particularly postinfectious. The diagnosis of infectious myelitis is established by spine MRI and CSF analyses. Spine MRI typically reveals a T2 hyperintense signal abnormality extending over two to three segments or more extensive longitudinal involvement, along with some mass effect from edema, and contrast enhancement. The MRI may be initially normal and should therefore be repeated in suspected cases of acute viral myelitides. CSF is obtained to determine a microbiologic diagnosis. The CSF typically reveals a lymphocytic pleocytosis with or without hyperproteinorachia, and normoglycorrhachia. A PMN pleocytosis may be present with CMV and WNV neuroinvasive infections. CSF real-time PCR (for DNA viruses) and reverse transcriptase PCR (for RNA viruses) for the various viruses outlined earlier and CSF VDRL should be obtained based on clinical features. Viral cultures are difficult and have been largely replaced by PCR. Unfortunately, in most cases of isolated transverse myelitis, a specific viral cause is never determined (Kincaid and Lipton, 2006). The differential diagnosis of acute infectious myelitides includes spinal cord compression, which must be ruled out with an urgent spine imaging; demyelinating process either primary (such as multiple sclerosis) or postinfectious; paraneoplastic; vascular disorders (such as ischemic infarction,

Table 18.7 Myelitides microorganisms and clinical manifestations Microorganism

Anatomic structure tropism

Distinguishing clinical manifestations

VZV

Dorsal root ganglia

Radicular pain, dermatomal skin rash

HSV-2

Sensory roots

Radicular pain, genital rash

T. pallidum (meningovascular syphilis)

No specific tropism

None (isolated transverse myelitis)

Poliovirus, coxsackieviruses, enterovirus-70, 71, WNV

Anterior horn cells

Isolated flaccid paralysis

EBV

No specific tropism

Mononucleosis symptoms or none (isolated transverse myelitis)

CMV

Motor and sensory roots

Polyradiculopathy, cauda equina syndrome

HIV-1

Corticospinal tracts and dorsal columns

Spastic paraparesis with sphincter disturbance and sensory symptoms

HTLV-1

Corticospinal tracts

Spastic paraparesis with sphincter disturbance

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hematomyelia, dural vascular malformation, spinal canal hemorrhage, and connective tissue diseases). The differential diagnosis of chronic infectious myelitides is much broader and encompasses degenerative disorders (such as hereditary spastic paraparesis, spinocerebellar ataxia, and primary lateral sclerosis), nutritional deficiencies (such as vitamin B12 deficiency), and progressive compressive myelopathies (such as spondylosis and low-grade neoplasm). The treatment of acute infectious myelitides is mainly supportive unless there is clinical suspicion (such as genital or skin rash) or microbiologic diagnosis of herpes virus infections or meningovascular syphilis. Chronic myelitides are managed with specific antiretrovirals or immunotherapy. Prognosis is variable, but some degree of recovery usually occurs after acute infectious myelitides. Spinal canal infections are limited to epidural abscesses. Spinal epidural abscesses tend to occur in the posterior aspect of the spinal canal and in the thoracic region in the majority of cases, but also in the lumbar and cervical regions. In one-third of the cases, abscesses result from contiguous spread from vertebral osteomyelitis or soft tissue infection (such as retroperitoneal, mediastinal, or paraspinal tissue), from penetrating trauma, and, rarely, as the result of surgery, LP, or epidural anesthesia. In another one-third, hematogenous spread from skin infection or parenteral drug use is the pathogenic mechanism. The exact origin is unknown in another one-third. S. aureus is the most common pathogen, followed by Streptococcus spp. and gram-negative enteric bacilli. Other pathogens such as M. tuberculosis and fungi may result in more chronic abscesses. Cardinal clinical manifestations include fever, localized back pain and tenderness, radicular pain, and myelopathy symptoms and signs, including Lhermitte phenomenon (paresthesia often described as an electric shock going down the back and limbs following neck flexion). In addition, symptoms of bacteremia are often present. Blood cultures are often positive, and a peripheral PMN leukocytosis may be present. The diagnosis is established by neuroimaging with MRI or myelogram combined with CT in patients unable to undergo MRI. The myelogram should be performed at a different level of the suspected abscess because of risk of infection spread to the CSF and, less commonly, of spinal herniation. Urgent surgical decompression along with antimicrobial agents is the cornerstone of treatment. Microbiologic diagnosis is typically confirmed by material obtained from surgery, but empiric antibiotic treatment covering S. aureus, Streptococcus spp., and gram-negative enteric bacilli with a third-generation cephalosporin and vancomycin may be initiated before surgery. Corticosteroids should be considered if there are myelopathy signs, but empiric antibiotic treatment must be initiated beforehand or simultaneously, and surgical decompression should be scheduled promptly.

Cutaneous herpes zoster and complicated zoster syndromes VZV is an exclusively human neurotropic virus. Primary infection, typically in childhood, causes varicella (“chicken pox”), after which the virus becomes latent in the sensory cranial nerve ganglia, dorsal root ganglia, and autonomic ganglia of the entire neuraxis. As VZV-specific, cellmediated immunity against VZV appears to diminish with age and immunosuppression, VZV may reactivate, spreading distally along the nerve and causing zoster, commonly known as “shingles.” Although the exact mechanisms of how VZV evades innate and adaptive immune responses during reactivation remain to be uncovered, diminished VZV-specific T lymphocyte responses (such as proliferation and IFN production in response to secondary exposure to VZV) are observed in older individuals (Oxman, 2009). Among older individuals with shingles, up to half develop postherpetic neuralgia (PHN), characterized by persistent (more than 3 months) neuropathic pain in the distribution of the affected dermatomes, despite resolution of the skin lesions. Given the ongoing VZV vaccination in children, the incidence of zoster syndromes later in life may decrease over the next few decades. Uncomplicated zoster is characterized by pain in the distribution of the nerve(s) involved and a cutaneous vesicular rash on an erythematous base. Prodromal dysesthesias and paresthesias described as itching, burning, or tingling may be present. Zoster can develop anywhere on the body but tends to be limited to one or, rarely, two or more dermatomes. The most common dermatomes are T5 to T10 and the V1 branch of the trigeminal nerve (zoster ophthalmicus). The latter may be associated with a keratitis that can lead to blindness and, therefore, should be treated aggressively and monitored carefully. In most patients, the resolution of the skin rash, usually within 2 or 3 weeks, is accompanied by pain reduction and, ultimately, resolution within 4–6 weeks. Diagnosis in most patients is based on the typical clinical syndrome, including dermatomal pain and vesicular rash. A Tzanck smear can further support the diagnosis by demonstrating multinucleated giant cells, reflecting virus-infected skin cells. CSF analyses are not usually necessary but, if done, will show mild lymphocytic pleocytosis, hyperproteinorachia, and positive VZV PCR. Occasionally, occult zoster may be suspected clinically based on reports of typical dermatomal pain in the absence of rash, a condition known as zoster sine herpete. Definitive diagnosis of such cases requires CSF analysis. Complicated zoster syndromes include the following: nonsensory cranial neuropathies (such as optic neuropathy or ocular motor neuropathies), which occur due to a meningitic reaction or direct perineural spread along anastomotic pathways; zoster radiculitis, through mixed spinal nerve involvement, causing segmental weakness

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of limbs or abdominal muscles in 5% of cases; myelitis (discussed earlier); encephalitis (discussed earlier); and a thrombotic cerebral vasculopathy, presenting as an ischemic cerebral infarction, 2–10 weeks after zoster ophthalmicus, through either direct viral invasion of arterial walls innervated by V1 or an immune-mediated process (Gilden et al., 2000). Specific antiviral treatment includes oral nucleoside analogs such as acyclovir, famciclovir, or valacyclovir. Intravenous acyclovir should be considered for any immunocompromised patient and for any patients with complicated zoster syndromes. Early treatment within 72 hours of rash appears to reduce the acute pain and accelerate healing, but the effect on postherpetic neuralgia (PHN) is less clear (Wood et al., 1994). Adjunctive treatment with corticosteroids may help reduce the incidence of PHN, although this question has not been addressed in controlled clinical studies. Corticosteroids are contraindicated in immunocompromised patients (Gilden et al., 2000). VZV prevention in patients 60 years and older may be attained by giving live attenuated VZV vaccine, which reduces the subsequent incidence of cutaneous zoster and PHN (Oxman et al., 2005). PHN can occur after zoster in any location, but is particularly common following zoster ophthalmicus. It is characterized by constant pain, along with superimposed lancinating exacerbations and sometimes other sensory disturbances at the site of the rash, including hypesthesia and hyperesthesia. PHN appears to be central in origin, with overactivity of some neurons in the caudal trigeminal nucleus, possibly through impaired segmental inhibition. Therefore, pain management should include centrally active agents such as tricyclic antidepressants (nortriptyline or amitriptyline), gabapentin, or pregabalin (Dubinsky et al., 2004). Temporary opioids are sometimes necessary. Lidocaine patches and topical high-concentration capsaicin patches are also effective. Because the pain is of central origin, surgical denervation is ineffective and should be avoided.

Septic encephalopathy Septic encephalopathy is a relatively common and important but under-recognized disorder in the elderly that is associated with confusion and behavioral disturbances such as agitation and hallucinations. Among critical care patients with sepsis, approximately 25% develop encephalopathy, even after excluding individuals whose encephalopathy is attributable to severe coexisting hepatic or renal dysfunction, endocarditis, pulmonary failure, sedative or opiate medications, or other causes. In a manner analogous to other organ system failures, including cardiac, renal, and pulmonary, so-called “brain failure” independently predicts poorer prognosis among patients admitted to intensive care units (Knaus et al.,

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1991). Under-recognition is perhaps explained by the lack of a specific treatment other than antimicrobial therapy directed at the specific pathogen and by the exclusionary nature of the diagnosis. The clinical manifestations of septic encephalopathy reflect diffuse brain dysfunction consisting of altered level of consciousness ranging from somnolence, stupor, and coma to hypervigilance and psychomotor hyperactivity; cognitive dysfunction and behavioral disturbances ranging from agitation to catatonia; and perceptual disturbances such as hallucinations. In a given patient, these disturbances may fluctuate in severity and type over minutes to hours. Individuals with preexisting CNS lesions, especially dementias, are more vulnerable to septic encephalopathy. Symmetric paratonic rigidity or gegenhalten may be observed in some patients, but focal neurologic functions are absent (Young et al., 1990). The diagnosis of septic encephalopathy is excluded by the presence of any other condition that, in isolation, could reasonably explain the encephalopathy, such as certain CNS infections, structural lesions (such as ischemic stroke or hemorrhage), severe coexisting systemic organ dysfunction, hypotension with reduced cerebral perfusion, hypoxemia or hypercarbia, or other metabolic, endocrine, or toxic derangements. Additional considerations in the differential diagnosis include postictal state or ongoing nonconvulsive status epilepticus. Investigations should include brain imaging without and with contrast to rule out structural lesions. Because the clinical features of meningitis and encephalitis in the elderly can be subtle or atypical, as detailed earlier, clinicians should have a low threshold to perform CSF analyses. In addition to excluding ongoing nonconvulsive status epilepticus or interictal epileptiform activity, EEG may also be useful in identifying patterns consistent with toxic-metabolic disturbances, such as diffuse slowing or triphasic waves. A comprehensive metabolic, endocrine, and toxicologic evaluation should be performed to evaluate, among other things, sepsis-induced hepatic or renal failure, hyper- or hypoglycemia, or hypo-osmolar states, such as the syndrome of inappropriate antidiuretic hormone (SIADH). Potentially offending medications should be discontinued, keeping in mind that even short-acting medications can accumulate due to slower renal and hepatic clearance in patients with sepsis and in the elderly. Management of septic encephalopathy entails identification and specific treatment of the systemic infection. The underlying pathophysiology of septic encephalopathy remains a source of debate. Brief endotoxemia alone does not explain the occurrence of septic encephalopathy, as short-term systemic infusion of bacterial lipopolysaccharides (LPS) to normal individuals results primarily in an inflammation-mediated increase in cortisol and alertness (van den Boogaard et al., 2010). On the other hand, in animal models, administration of LPS increases cerebral

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venous volume and ICP, which, in turn, reduces cerebral perfusion pressure and oxygen extraction (Desai et al., 1995). Other proposed mechanisms for sepsis-induced brain dysfunction are altered hepatic amino acid metabolism, altered serotonin metabolism, formation of endogenous benzodiazepine-like compounds, inflammatory cytokine production, and microabscess formation (Streck et al., 2008; Pytel and Alexander, 2009).

Human immunodeficiency virus and the nervous system in the aging population The worldwide burden of HIV and its tropism for the nervous system makes this one of the largest single infectious causes of neurologic disease worldwide. Across the globe, approximately 36 million people live with HIV-1 infection. The greatest burden is in sub-Saharan Africa, where there are 22 million infected individuals, accounting for two-thirds of the worldwide disease burden (UNAIDS, 2008). In the United States, approximately one million individuals are living with HIV infection, and the epidemic is growing fastest in women, intravenous drug users, and ethnic minorities. Although not commonly viewed as a disease of aging, the CDC estimates that, by 2015, more than half of all HIV-infected individuals in the United States will be 50 years and older (www.cdc.gov/ hiv/topics/over50). HIV is a member of a family of retroviruses having a propensity to cause CNS disease. The virus enters the nervous system via a “Trojan horse” mechanism, piggybacking on trafficking macrophages from the peripheral circulation across the BBB into the CNS. This trafficking occurs within days of initial infection and persists throughout the disease. The virus does not directly infect neurons, instead injuring them through “bystander” mechanisms grouped into three categories: viral factors, host factors, and cofactors. Viral factors include toxic proteins such as gp120 and Tat. Host factors include cellular changes that occur in response to viral infection and secondarily injure neurons. Cytokines, chemical regulators of inflammation and immunity, mediate injury through cell surface receptors on neurons, microglia, astrocytes, and oligodendrocytes. Cofactors include comorbid conditions such as drug use and hepatitis C infection, or social, nutritional, or behavioral characteristics that contribute to or amplify the pathogenicity of HIV. These three mechanisms interact to damage neural networks at the level of dendrites and synapses. Synaptodendritic injury impairs higher-order neural systems involved in information processing, leading to HIVassociated neurocognitive disorders. Injury is diffuse, but often particularly affects the basal ganglia, hippocampus, and fronto-striato-thalamocortical circuits generally (Langford et al., 2003). As with other causes of CNS injury,

neuroprotective and regenerative pathways are upregulated in HIV. Successful protective and repair mechanisms may explain why some HIV-infected individuals are spared from CNS injury and neurocognitive impairment. While the widespread use of cART since the mid1990s has led to a decline in the most severe neurologic complications of HIV, including dementia, HIV-infected individuals continue to experience mild and moderately severe forms of nervous system diseases. Interactions between aging and HIV are important because certain age-related neurologic disorders and/or risk factors for those disorders occur with a higher frequency in cARTtreated individuals, and because the symptoms and signs of HIV-associated neurologic disorders may overlap with those of age-related neurologic disorders. Additionally, HIV and cART are responsible for premature metabolic and atherosclerotic changes likely to contribute to neurologic disorders common in older individuals. The current gold standard for case definition of HIVassociated neurocognitive disorders (HAND) is a recently published, international expert consensus document commissioned by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, often referred to as the Frascati criteria (Antinori et al., 2007). These criteria integrate objective neuropsychological (NP) performance with information about changes in functional status and comorbid conditions, as schematized in Table 18.8. HAND is diagnosed only in the absence of another comorbid condition sufficient to otherwise explain documented neurocognitive dysfunction. NP testing must document impaired performance in at least two domains of cognitive functioning (such as learning and speed of information processing) using appropriate normative comparisons, adjusted for age, education, and other demographic factors. Among those meeting the criteria for global neurocognitive impairment, three severity levels are defined. HIV-associated dementia (HAD) describes individuals with moderate-to-severe deficits in two or more domains and substantial impairment in everyday functioning that renders the individual incapable of employment and frequently unable to live independently. Mild neurocognitive disorder (MND) is diagnosed when there is mild to moderate impairment in at least two domains and at Table 18.8 Summary of diagnostic criteria HIV-associated neurocognitive disorders (HAND) Asymptomatic NP Mild neurocognitive HIV-associated impairment (ANI) disorder (MND) dementia (HAD) NP testing impairment Functional disability

≥ Mild

≥ Mild

≥ Moderate

None

≥ Mild

≥ Moderate

NP, neuropsychological.

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least mild interference in everyday functioning. Asymptomatic NP impairment is assigned to individuals who meet criteria for impairment in at least two domains, but without any clear effect on everyday functioning. Criteria for functional impairment are met when an individual has developed dependence in instrumental activities of daily living after becoming infected by HIV, when there is inability to work or significantly reduced work efficiency attributed to HIV-related cognitive changes, or when there are complaints of increased cognitive difficulties in the everyday life of an individual who does not have clinically significant depression. Impaired functional performance may be demonstrated by objective everyday functioning tasks such as standardized work samples or medication management. A recent study applied the Frascati criteria to classify 1555 HIV-infected individuals at six university clinics across the United States (CNS HIV Antiretroviral Therapy Effects Research (CHARTER)) (Heaton et al., 2009). Most study participants were middle-aged (mean 43 years), nonwhite (61%) men (77%) who had received a diagnosis of AIDS (63%) by CD4+ counts below 200 cells/μL. Most (71%) were on cART and had experienced substantial immune reconstitution. At least mild NP impairment was found in 52% of the cohort, and the most frequently affected domains were learning, executive functioning, recall, and working memory. After excluding individuals for whom diagnoses of HAND were confounded by severe comorbid neurologic conditions such as traumatic brain injury or residual deficit from prior CNS opportunistic infection, 46% of the remaining 1316 individuals were impaired. Rates of specific HAND diagnoses were as follows: ANI, 32.7%; MND, 11.7%; and HAD, 2.4%. Extrapolating these figures to the larger population of HIV-infected individuals, the estimated prevalence of HAND nationwide is comparable to that of multiple sclerosis. Advanced HAD is now quite uncommon, being seen principally among individuals who are severely immunosuppressed due to late HIV diagnosis or because of poor adherence to or resistance to antiretrovirals. Such disabling dementia develops over a period of many weeks or months. A more rapid onset raises suspicions of other diagnostic possibilities. In the more advanced stages, patients may have little insight into their disabilities, requiring a knowledgeable informant to provide history on their functional status. Typical complaints include slowed thinking; loss of spontaneity and initiative; slowness or inability to complete multistep, sequential tasks such as meal preparation; and slowed movements or balance problems. Cognitive examination demonstrates frontal/subcortical cognitive impairments without apraxia, agnosia, or aphasia. Neurologic examination frequently shows frontal release signs, diffuse hyperreflexia, and a slow, unsteady gait. Anecdotally, antiretroviral

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treatment in some such patients can produce a remarkable recovery of cognition and functional abilities that takes place over many weeks to months. Patients with MND, who are less disabled than those with HAD frequently have insight into their difficulties and are able to report slowness or difficulty in performing at work or in other activities at which they were previously adept. Conventional bedside cognitive tests such as the mini–mental state examination (MMSE) are not useful. Even screening instruments designed for use in HIV, such as the HIV Dementia Scale (HDS), are not sufficiently sensitive, although better sensitivity and specificity may be achieved through the use of appropriate normative corrections (Morgan et al., 2008). NP testing is necessary to document impairment in these patients. The neurologic examination is frequently normal or may show an incidental distal sensory polyneuropathy. Because HAND remains a diagnosis of exclusion, cognitive impairment presenting in an older HIV-infected individual represents a true clinical conundrum. Potential contributing factors include reversible endocrine disturbances, nutritional deficiencies, and infectious disorders. These should be evaluated with thyroid function tests, serum vitamin B12, and RPR. CSF analysis, including mycobacterial and fungal cultures, AFB staining, India ink, and cryptococcal antigen, is also warranted to rule out subacute and chronic infections such as M. tuberculosis, C. neoformans, and T. pallidum. Unfortunately, quantitative HIV RNA polymerase chain reaction (PCR) performed on CSF is not sufficiently sensitive or specific to serve as a guide. Detailed NP testing is most useful to differentiate HAND from common degenerative dementias such as Alzheimer’s disease (AD) or pseudodementia associated with depressive mood disorder, a common comorbidity in the elderly. Imaging is quite useful in ruling out other conditions that may be associated with neurocognitive impairment. However, in HAND, conventional anatomic MRI is nonspecific, usually showing only cortical and subcortical atrophy with scattered, punctate T2 hyperintense abnormalities. There is great interest in MR spectroscopy, diffusion tensor imaging, and functional MRI, but at present, these remain research tools that require validation for clinical use (Gongvatana et al., 2009). There is a general consensus based on studies performed in both the United States and Europe that antiretroviral treatment significantly improves neurocognitive function in patients with HAND who start new regimens. However, Cysique et al. demonstrated that reliable cognitive improvement is achieved only in about 40% of patients treated for up to 1 year, with many individuals showing slow improvement over 6–12 months (Cysique et al., 2009). Among the factors considered as possible explanations for limited neurocognitive recovery are irreversible neural injury during severe immunosuppression, persisting

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neural injury due to dysfunctional immune reconstitution (immune recovery disease), reduced penetration of antiretroviral drugs into the CNS, and the presence of comorbid conditions leading to neurocognitive impairment (e.g., opportunistic infections). However, as noted previously, excluding individuals with major comorbidities still leaves a marked excess of neurocognitive impairment. Observational studies have demonstrated better neurocognitive responses among individuals receiving antiretroviral regimens with superior predicted CNS penetration, but not all studies are in agreement (Letendre et al., 2004; Marra et al., 2009; Tozzi et al., 2009). Superior penetration also is related to lower viral loads in CSF. Letendre et al., have developed a clinical scale that can be used to rank the expected relative CNS penetration effectiveness of available antiretroviral medications (Letendre et al., 2008). An ongoing controlled clinical trial is testing the use of this scale as part of a strategy to improve neurocognitive outcomes in HIV-infected individuals with HAND (see www.clinicaltrials.gov). Adjunctive therapies such as central cholinesterase inhibitors, memantine, monoamine oxidase inhibitors, and amphetamine-derived stimulants have not been evaluated in randomized clinical studies or have not shown significant benefit. The exact mechanisms by which the immune system contributes to brain dysfunction in HAND remain elusive. Substantial additive-adverse effects of aging and HIV are anticipated as the epidemic matures and individuals live decades on cART. Aging leads to suppressed immunity despite elevated inflammation, which is compounded by accelerated, virally induced immunosenescence. Immunosenescence is characterized by changes in the composition of immune cell populations, particularly by decreased naïve and central memory cells, with increased terminally differentiated effector cells. Cellular expression of CD28, a marker for naïve or central memory cells, has been shown to be lower, especially on CD8 cells, among HIV-infected individuals (Kalayjian et al., 2003; Cao et al., 2009). With the use of cART, increases in naïve CD4 and CD8 T cell counts are observed, but the degree of naïve cell recovery is significantly smaller in older individuals, who also show lower CD28 expression on CD8 cells compared with younger individuals (unpublished data from ACTG A5015 study). Given the pro-inflammatory nature of terminally differentiated effector cells that readily traffic to target tissues, it is reasonable to hypothesize that an expansion of these cell types coupled with the lack of naïve and central memory cells may contribute importantly to HIV-related CNS pathology in aging. HIV-infected individuals on cART prematurely develop metabolic disorders usually linked to aging, such as arterial hypertension, dyslipidemia (elevated triglycerides and reduced high-density lipoproteins), abdominal obesity, glucose intolerance/insulin resistance, and

a prothrombotic/inflammatory state (Grinspoon and Carr, 2005; Aboud et al., 2007; Ances et al., 2009). Metabolic syndrome has been associated with ischemic stroke in HIV-infected individuals (Ances et al., 2009). Even in the absence of stroke, these risk factors are associated with cognitive impairment in older individuals (Kuusisto et al.,  1997; Valcour et al., 2005; Valcour et al., 2006; Cukierman-Yaffe et al., 2009; McCutchan et al., 2009). Premature atherosclerotic changes have been observed with HIV alone in the absence of other risk factors (Grunfeld et al., 2009; Hsue et al., 2009). Atherosclerotic lesions typically originate at sites such as the common carotid bifurcation and bulb, carotid siphon, and middle cerebral artery stem, where complex flow patterns yield low shear stress and flow reversal that promote monocyte binding to endothelial cells. Increased transmigration of monocytes across the endothelium at these sites results in alterations of the intima and media that may promote lipid deposition and platelet aggregation (Cunningham and Gotlieb, 2005; Bui et al., 2009). These findings suggest that management of HIV infection should include aggressive control of atherogenic risk factors, earlier and more aggressive viral suppression, and use of cART regimens less likely to cause the metabolic syndrome. Sensory neuropathy remains a frequent disorder in HIV, with 38% of those in one study reporting neuropathic pain that often interferes with daily activities, employment, and quality of life (Ellis et al., 2010). Its prevalence increases greatly with age. The polyneuropathy is a symmetric, axonal, length-dependent syndrome, predominantly sensory, affecting small and large fibers and often associated with painful dysesthesias and paresthesias. It can be differentiated from dideoxynucleoside analogueinduced (“d-drug”) neuropathy only by the latter’s temporal relationship with drug initiation and improvement following drug discontinuation. The differential diagnosis includes paraproteinemia (such as monoclonal gammopathy), vitamin B12 deficiency, diabetes mellitus, toxins (such as alcohol, platinum compounds, vincristine, taxanes, thalidomide, and pyridoxine), and inherited sensory and autonomic neuropathies. Investigation including serum protein electrophoresis and immunofixation, serum vitamin B12, and glycosylated hemoglobin is usually sufficient. However, the presence of significant motor involvement warrants a more extensive investigation, including CSF analysis, nerve conduction studies, and electromyography. Management of HIV-associated neuropathy consists of minimizing neurotoxic agent exposure and optimizing pain control (with a tricyclic antidepressant (such as amitriptyline or nortriptyline), a serotonin–norepinephrine reuptake inhibitor (such as duloxetine or venlafaxine), an anticonvulsant (such as gabapentin or pregabalin), or topical capsaicin). Anticonvulsants are particularly useful for pain with shooting or stabbing characteristics.

Nervous System Infections

Age-associated changes in immunity The term immunosenescence refers to the gradual decline and dysregulation of immune function that occurs in the elderly. Immunosenescence is a double-edged sword, in that whereas overall immunity is decreased, inflammatory responses are increased. The nature of immunosenescence has not been thoroughly characterized for all components of the immune system, but several aspects are well established. First, neutrophils demonstrate decreased phagocytic activity, particularly in association with chronic comorbid conditions such as diabetes mellitus. Monocytes and macrophages show attenuated cytokine production upon stimulation by pathogens. T cell clonal expansion is reduced, possibly because of thymic involution. Effector memory T cells are proportionately increased, and NK cell cytotoxic activity and number are decreased (Castle, 2000; Agarwal and Busse, 2010). B cells demonstrate reduced naïve subpopulations, but memory cells with limited diversity are increased. Finally, aging individuals exhibit diminished antibody responses to vaccination, increasing their susceptibility to specific pathogens such as H. influenzae and S. pneumoniae. The relative impact on morbidity and mortality of these distinct, age-related changes in various components of the immunologic armamentarium remains to be fully delineated. • Markers of immunosenescence: Among the betterdescribed markers of immunosenescence are reduced numbers of naïve CD4+ and CD8+ T cells and increased numbers of more terminally differentiated T lymphocytes, such as effector memory cells. The decline in thymic output of naïve T cells diminishes responses to newly encountered pathogens, such as WNV. At the same time, terminally differentiated cells that are not proliferative or immunocompetent, yet are resistant to programmed cell death, accumulate with aging. Such cells demonstrate short telomeres and decreased telomerase activity, another cellular marker of aging. The reduced functionality of these terminally differentiated memory T cells correlates with persistent infection (Derhovanessian et al., 2009). Certain latent viral infections, such as CMV, accelerate immunosenescence by increasing numbers of these cells. Other chronic viral infections, such as EBV and VZV, appear to contribute to a lesser degree to this effect (Pawelec et al., 2005). • Aging and BBB alterations: A large body of literature describes compromised function and permeability of the BBB in aging individuals with and without a variety of CNS pathologies such as AD and multi-infarct dementia. Even among healthy asymptomatic individuals, aging is associated with increased BBB permeability, assessed by CSF/plasma albumin ratios or imaging (Farrall and Wardlaw, 2009). In rodent models of aging, increased BBB permeability is shown to be associated with learning

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or memory impairment and with microglial activation (Popescu et al., 2009). Compromised function of the BBB likely contributes to intraparenchymal deposition of complement, leading to recruitment of pro-inflammatory immune cells into the CNS. • Brain-immune interactions and aging: Traditionally considered as an “immune-privileged” site, it is now clear that brain–immune interactions are part of necessary normal immunosurveillance (Schwartz and Shechter, 2010). In mice rendered immunodeficient by genetic manipulation or other means, impaired learning and memory can be remediated by injection of immunocompetent T cells (Kipnis et al., 2004; Kipnis and Derecki, 2008). Thus, normal T cell immunity contributes to healthy brain function, and T cell dysregulation during aging may impair cognition. Aging-related neuroinflammation is characterized by increased brain expression of IFN-γ, activation of microglia and astrocytes, and elevated glial production of pro-inflammatory cytokines such as interleukin (IL)-1β, TNF-α, and IL-6 (Lynch, 2010). Elevated expression of major histocompatibility complex II (MHC II) suggests increased interactions between microglia and T cells and increased T cell infiltration into the CNS with aging. In animal models, these features contribute to impaired learning and memory. Either peripheral (intraperitoneal) or central (intrahippocampal) administration of inflammatory cytokine IL-1β or viral or bacterial infections leads to poor performance during learning and memory tasks. Elevated levels of pro-inflammatory cytokines in the brain also lead to a reduction in synaptic plasticity in rodents. Aging glial cells express higher levels of activation markers such as MHC II, CD80, and glial fibrillary acidic protein. Peripheral immune activation and inflammation occurring in response to systemic infection can lead to alterations in the brain microenvironment that impair CNS function. Thus, sepsis or injection of an endotoxin (such as bacterial LPS) activates microglia in rodent models. Such activated microglia downregulate expression of neurotrophic mediators and upregulate neurotoxic ones. Aging is associated with amplification of these deleterious responses to peripheral inflammation (Dilger and Johnson, 2008). Accordingly, LPS injection in older mice led to prolonged decreases in social exploratory behavior and locomotor activity, compared with younger mice (Godbout et al., 2005). These behavioral deficits were accompanied by a greater elevation in the tissue expression of inflammatory cytokines such as IL-6 and IL-1β. The greater and prolonged decline in sensorium and cognitive function that occurs in older patients with sepsis compared with those who are younger is consistent with these animal models (Murray et al., 2012). Future research will hopefully bring to light new therapeutic strategies to address these pathophysiologic alterations.

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Chapter 19 Delirium Alan Lerner1, Stefani Parrisbalogun2, and Joseph Locala3 1

Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA Rawson-Neal Psychiatric Hospital, Las Vegas, NV, USA 3 Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA 2

Summary • There is a high prevalence of delirium in hospitals and specialty care units. • Delirium is associated with a variety of causes, presumed to ultimately affect cerebral cortical processing. Hypotheses concerning pathology include acute cholinergic deficiency, alterations in dopaminergic function, and changes in GABA. • Common risk factors include underlying brain diseases, age, and dementia. Chronic medical illness, comorbidity, severity, functional impairment, medication prescription, and polypharmacy can also cause delirium. • Etiologies may be singular or multiple. A variety of laboratory tests can help identify the cause(s). • The Confusion Assessment Method is a tool used to ascertain the presence of delirium. • Clinical symptoms of delirium vary widely and investigators have proposed motoric subtypes including hypoactivity and hyperactivity. • Delirium is considered preventable and reversible. Prevention strategies include avoidance of anticholinergics and inhibition of alcohol withdrawal. Initial treatment of delirium is often nonpharmacologic. Pharmacologic agents can result in sedation. Haloperidol is often used.

Introduction Delirium, also known as acute confusional state (ACS), is best defined as a global disorder of cognition and behavioral disturbance (Lipowski, 1987, 1989). This symptom complex is common and may present in a dramatic fashion, such as extreme postoperative confusion, or as a more insidious process over days and weeks. ACS is of clinical importance because it is, by definition, due to an underlying medical problem that is often treatable. Thus, ACS should often be considered reversible. As discussed here, dementia of various causes is a major risk factor. Therefore, expectations for recovery may need to be tempered by the presence of an underlying irreversible condition, such as Alzheimer’s disease (AD) and other types of dementia. Delirium is a frequent and potentially preventable source of morbidity and mortality for older hospitalized patients. Based on 1994 data, delirium complicates hospital stays for more than 2.3 million older persons per year, occurs during 17.5 million inpatient days, and accounts for more than $4 billion of Medicare expenditures. Substantial additional costs accrue due to need for various levels of post-acute care and treatment directly related to the presence of delirium. Advancing age is an independent risk factor for delirium. Given the demographic

shift of the United States (and other countries) to a larger percentage of geriatric patients, the incidence of delirium will likely increase over time. This chapter reviews the epidemiology, pathophysiology, diagnostic criteria, treatment, and outcomes related to delirium.

Epidemiology Delirium occurs in many age groups, from children to older adults, and in many clinical settings, the community inpatient hospital settings and long-term care facilities. It also has multiple different clinical presentations. Therefore, concisely summarizing the epidemiology of delirium is difficult. The prevalence within mixed community-based populations is estimated at 1–2%, but the overall prevalence in hospitals at any time may be as high as 24% (Inouye, 1998). The incidence of delirium may be as high as 56% in general medical wards, but conceivably higher in specialty care units such as palliative care, hospice, postoperative, or intensive care. Estimates of delirium incidence in intensive care units have ranged as high as 87% (Pisani et al., 2003). Age is a major risk factor for delirium, so the incidence rises with age in all settings. This problem is likely to

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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grow in absolute magnitude with the overall aging of the population, particularly in the United States and other developed countries.

Pathophysiology Delirium has a wide assortment of causes, either alone or in combination. For example, in DSM-IV, delirium may be ascribed to various categories, such as a general medical condition, substance abuse or withdrawal, or other conditions (American Psychiatric Association, 2000). However, diagnostic nomenclature does not begin to cover the myriad etiologic causes or underlying pathophysiology of this complex disorder. Indeed, multiple studies have suggested that, even in individual cases, as many as six possible causes can be identified (Trzepacz et al., 1985; Breitbart et al., 1996; Lang et al., 2006). The underlying final pathophysiologic pathway presumably affects cerebral cortical processing, as indicated by the wide array of effects on behavior and cognition, perception and sleep, and slowing on the EEG (Jacobson and Jerrier, 2000). One hypothesis regarding the neurochemical changes present in delirium suggests that it is a state of acute cholinergic deficiency, possibly with excess dopaminergic tone (Blass and Gibson, 1999; Hshieh et al., 2008). Other transmitter systems are almost certainly involved in many cases. This includes alterations in GABAergic, serotonergic, and glutaminergic systems (Trzepacz, 2000; Hshieh et al., 2008; Furuse and Hashimoto, 2010). Part of the empirical basis for the hypothesis of cholinergic deficiency comes from the wide variety of medications and their metabolites that have anticholinergic activities and are associated with delirium. An animal model of delirium using atropine has also been reported. This low cholinergic tone may be related to the increased risk for delirium in individuals with AD and vascular dementia. Lewy body dementia may also mimic delirium and is associated with a severe loss of cholinergic innervation (Blass and Gibson, 1999; McKeith et al., 2003; Jicha et al., 2010). Alterations in dopaminergic function are also associated with delirium. Many of the medications used to treat parkinsonism and related disorders, including levodopa and dopamine agonists, are associated with delirium. Similarly, bupropion and cocaine usage, both of which increase dopaminergic activity, may be linked with delirium. Genetic polymorphisms in the dopamine transporter gene and serotonin transporter genes have also been associated with delirium, and opiates may mediate increased dopamine release (Murray et al., 2007; Karpyak et al., 2010; van Munster et al., 2010). Dopamine agonists may cause slowing on the EEG, as can many of the neuroleptics and other medications that activate both D1 and

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D2 receptors. Nonspecific blockers of dopamine receptors, such as haloperidol, are frequently used in treating acute delirium. Changes in other neurotransmitters, such as gamma aminobutyric acid (GABA), have resulted in delirium, and Pregabalin has been associated with delirium in patients with multiple sclerosis (Solaro and Tanganelli, 2009). In particular, benzodiazepines and other GABAergic drugs, including several drugs of abuse, such as “liquid ecstasy” drugs, are associated with delirium (Supady et al., 2009; Galldiks et al., 2011). Reduced GABA activity may be secondary to withdrawal from ethanol and sedatives and may present with catatonic symptoms (Hauser et al., 1989; Rosebush and Mazurek, 1996). Both high and low levels of serotonin have been associated with delirium. Hepatic encephalopathy may result in increased serotonin activity, possibly related to increased tryptophan uptake in the brain, but multiple neurotransmitter changes occur in hepatic encephalopathy, raising some doubt about simple, direct connections between clinical symptoms and neurotransmitter changes (Lozeva-Thomas, 2004; Palomero-Gallagher et al., 2009). Polymorphisms in the A9 allele of the dopamine transporter gene may affect the course of delirium in alcohol-dependent women (Limosin et al., 2004). Changes in other neurotransmitters, including histamine, glutamate, and opiates, have also been associated with delirium. However, the complete relationship of changes in these neurotransmitters to the pathophysiology of delirium is not clear at this time.

Risk factors Delirium mostly occurs as a result of multiple etiologies and thus can be thought of as a multifactorial disorder (Inouye and Charpentier, 1996). Risk factors for delirium either increase the patient’s baseline vulnerability to systemic disturbances or contribute directly to the disturbance (Elie et al., 1998). A patient’s vulnerability at hospital admission can include a history of cognitive decline/ impairment, low cognitive reserve, or noxious insults prior to the time of hospitalization. More often than not, factors that contribute to systemic disturbance are more clinically significant, in that they may be treatable and, therefore, preventable risks. Studies have shown that patients with less baseline vulnerability or more cerebral reserve were more resistant to possible systemic disturbances after hospital admission, and an increased likelihood of delirium or an ACS was associated with more baseline vulnerability. The most commonly identified risk factors that increase a patient’s baseline vulnerability are underlying brain diseases as a result of dementia, stroke, Parkinson’s disease, or central nervous system (CNS) injury/trauma; these may be present in nearly half of the older patients with

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Table 19.1 Medical causes of delirium Heart disease Heart failure Hepatic encephalopathy Kidney failure Renal failure, acute Endocrinopathies Pituitary apoplexy Cushing’s syndrome Hyperthyroidism Hypothyroidism Nutritional deficiency Vitamin B12 deficiency Folate deficiency Nicotinic acid deficiency Thiamine deficiency Respiratory failure Hypoxia Hypothermia Electrolyte imbalance Hyponatremia Hypercalcemia

Carbon tetrachloride Transient global amnesia Cerebral edema Infections Urinary tract infection Surgical wound infection Legionnaires’ disease Malaria Brain abscess Meningitis Encephalitis Viral hemorrhagic fevers Plague Neuroleptic malignant syndrome

delirium. Examples of other CNS pathology that may increase a patient’s baseline vulnerability include hypertensive encephalopathy, intracranial hemorrhage, mass lesions, infection, vasculitis, and seizure (see Tables 19.1 and 19.2). Cerebrovascular disease predisposes to delirium in 24–48% of patients (Henon et al., 1999; Caeiro et al., 2004). Subsequently, age becomes the most important risk factor in the development of delirium as the degree of cognitive impairment increases with age over 60 years. The aging brain’s diminished capacity to respond to metabolic

Table 19.2 DSM-IV diagnostic criteria for delirium A. Reduced ability to maintain attention to external stimuli and to appropriately shift attention to new external stimuli B. At least one of the following: Questions had to be repeated because attention wandered Perseverated answers to previous questions Disorganized thinking C. Confusion developed over a short period of time D. Fluctuating level of confusion E. At least 2 out of 6 of the following: Reduced level of consciousness Perceptual disturbances Disturbance of sleep–wake cycle Increased or decreased psychomotor activity Disorientation to time, place, or person Memory impairment F. Either of the following: Evidence that an organic factor initiated and maintained this confusion Confusion cannot be accounted for by any nonorganic mental disorder Source: Adapted from American Psychiatric Association (2000) with permission from APA.

systemic stressors is apparent in cortical hypometabolism markers such as low glucose, blood flow, and oxygen. As mentioned earlier, EEG activity slows, and there is an alteration or imbalance of neurotransmitters (Obrecht et al., 1979). Delirium is often comorbid with dementia (Lerner et al., 1997). The prevalence of delirium superimposed upon dementia documented in the literature ranges from 22% to 89% (Fick et al., 2002). On average, patients with dementia have up to fivefold increased risk for developing a superimposed delirium or ACS. Nearly two-thirds of cases of delirium occur in patients with some form of underlying dementia due to the increased baseline vulnerability or low cerebral reserve (Trzepacz and van der Mast, 2002; Cole, 2004; Inouye, 2006a). The frequency of delirium also increases with severe medical disorders with and without CNS pathology such as cancer (paraneoplastic syndrome or limbic encephalitis); human immunodeficiency virus (HIV); other systemic or non-neurologic infections that can be symptomatic or occult; and serious life-threatening conditions such as renal, hepatic, respiratory, and cardiac organ failure or insufficiency. Clinically, suspicion of an infectious process must remain high, especially in older patients who may not be able to mount the appropriate immunologic response and present with fever or leukocytosis. Cardiovascular events such as acute myocardial infarction, congestive heart failure, cardiac arrest, and cardiogenic shock commonly present with delirium. Low perfusion states, hypoxia, metabolic disorders such as dehydration, hypo- or hyperglycemia, hyper- or hyponatremia, hypercalcemia, and toxic confusional states such as alcohol or drug intoxication or withdrawal can also contribute to the development of delirium (Kolbeinsson and Jónsson, 1993; Fick et al., 2002). Chronic medical illnesses, comorbidity, severity, and functional impairment also serve as predisposing factors to delirium. Thyroid or adrenal dysfunction, alcohol dependence, diabetes mellitus, burns, cancer, malnutrition with reduced plasma binding, vitamin B1 deficiency, vitamin B12 deficiency, and pellagra may also contribute to the development of delirium. Environmental factors that lead to altered sensory perceptions, including sensory impairment (for example, inadequate lighting, increased noise levels, blindness or poor hearing, sleep deprivation, stress, or major environmental factors) contribute to the development of delirium or the worsening of behavioral symptoms in a delirious state. Iatrogenic events such as surgery (notably, emergency hip fracture, gastrointestinal surgery, coronary artery bypass grafting, and lung transplant), anesthesia, medications, ECT, transfusion reactions, and allergic reactions can also cause ACS (Gleason, 2003). Functional impairment such as immobility including physical restraint use and the use of indwelling bladder catheters greatly increases the risk of delirium and functional decline. Psychological states such as depression, anxiety, and pain may also predispose a patient to ACS (Inouye et al., 2003; Inouye, 2006b).

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Table 19.3 Drugs associated with delirium Antipsychotic agents Phenelzine Haloperidol Quetiapine Olanzapine

Cardiovascular Antihypertensives Clonidine Guanethidine Methyldopa Propranolol Reserpine

Antibiotics Quinolones Isoniazid

Anticonvulsants Barbiturates Ethosuximide Phenytoin Primidone Vigabatrin Bromide Levetiracetam Carbamazepine Oxcarbazepine

Digoxin Amiloride Sedative–hypnotics Barbiturates Benzodiazepines Zolpidem

Anticholinergics Atropine Chlorpheniramine Diphenhydramine Hydroxyzine Scopolamine

Anesthetics Bupivicaine General anesthetics Ketamine Lidocaine Procaine

Antidementia drugs Donepezil Galantamine Memantine Rivastigmine

Stimulants Amphetamine salts Methylphenidate Atotmoxetine

Chemotherapeutic and immunosuppresant agents Asparaginase Prednisolone Tacrolimus

Opiates and pain medications Buprenorphine Codeine Fentanyl Diamorphine Hydrocodone Hydromorphone Oxycodone Tramadol Ziconotide

Antispasmodics Baclofen Tizanidine

Antidepressants and mood stabilizers Lithium Tricyclic antidepressants

Miscellaneous agents Aspirin Iron compounds Quinine Chloroquine Aminophylline

Anti-Parkinson’s agents Amantadine Bromocriptine L-DOPA Pramipexole Ropinirole Tolcapone Pergolide Apomorphine

Illegal and substances of abuse Cocaine Phencyclidine Mescaline Lysergic acid diethylamide Tetrahydrocannabinol Gamma hydroxybutyrate

Likewise, a patient with adequate cerebral reserve may develop delirium with singular or multiple exposures to multiple risk factors. One of the most common iatrogenic precipitants of delirium is medication prescription and polypharmacy (see Table 19.3). Although medications across many classes have been noted to precipitate delirium, commonly used psychoactive drugs such as benzodiazepines, sedative-hypnotics, narcotics, histamine H2 blockers, and anticholinergic medications have been shown to increase the risk associated with ACS (Brown and Stoudemire, 1998; Han et al., 2001; Pandharipande et al., 2006).

Causes One of the most characteristic aspects of delirium is the wide differential diagnosis of syndromes contributing to the clinical presentation of delirium (refer to Table 19.1).

Although cerebral disorders are prominent, many other systemic disorders affecting the CNS secondarily, as well as multiple drugs and other exogenous substances, can contribute to delirium. Because of this wide range of causes producing a limited number of clinical subtypes, it is best to focus one’s attention on the identification of delirium (refer to Table 19.2 for diagnostic criteria). A single etiology is causal in fewer than 50% of cases, with as many as six multifactorial etiologies identified in others. Multiple causes occur particularly in the elderly who may have a systemic illness, such as cancer or stroke, and may be on medications affecting systemic organ function or that are psychoactive. Thus, the astute clinician can often recognize a primary cause but should be aware of multiple contributors to the clinical syndrome under consideration in a given patient. Particularly in individuals with underlying dementia, the importance of polypharmacy cannot be overstated.

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Frequently, the differential diagnosis includes progression of dementia, although the time course may suggest more frequent etiologies, such as urinary tract infection or drug-related toxicity. Other causes that are less frequent in older adults but should be considered in the appropriate context include HIV and illicit drug use (Perry, 1990). Appropriate screening tests in delirium of unknown cause should include consideration of these etiologies.

Evaluation Knowledge of the wide differential diagnosis of delirium should help guide the clinician in appropriate evaluation. Typically, this includes comprehensive metabolic evaluation, complete blood count, urine analysis, possible chest X-ray or electrocardiogram, and imaging of selected body parts as indicated. Combined with the history and physical examination findings, these laboratory tests can help identify the singular or multiple causes of the patient’s delirium. More extensive testing may be necessary to rule out more rare causes of confusional states determined on a patient-by-patient basis.

Diagnostic criteria Various diagnostic criteria have been used for delirium over the past 30 years, with varying sensitivity and specificity, and optimized for different populations (inpatients versus outpatients, broad surveys versus well-defined populations). The prevalence and incidence of delirium has been estimated to affect as many as 56% of inpatients on general medical wards (Inouye, 1998). Clearly, this prevalence figure is dependent on the diagnostic criteria and its application to the study population in determining the presence of delirium. A number of studies have compared DSM-III, DSM-IV, and ICD-10 delirium criteria for their sensitivity and specificity. Cole et al. (2003), reported a study of 322 medical inpatients stratified by the presence of delirium and dementia (or neither), using clouding of consciousness only, clouding of consciousness and inattention, clouding of consciousness or inattention as criteria. When the criterion was defined as clouding of consciousness or inattention, the sensitivity and specificity of DSM-IV, DSM-III, and ICD-10 criteria were 100% and 71%; 96% and 91%; and 61% and 91%, respectively, with similar results with or without dementia present. The lower specificity of DSM-IV was felt to be due to inclusion of patients without disorganized thinking. However, DSM-IV has extremely high sensitivity, which is key to delirium recognition and subsequent treatment.

The confusion assessment method Originally developed by Inouye et al. (1990), the Confusion Assessment Method (CAM) is a widely used, reliable, and easy method for ascertaining the presence of delirium. When validated against the reference standard ratings of geriatric psychiatrists’ ratings based on comprehensive psychiatric assessment, the CAM had a sensitivity of 94–100%, specificity of 90–95%, positive predictive value of 91–94%, and a negative predictive value of 90–100%. The interobserver reliability of the CAM was high (Kappa = 0.81–1.0). Because delirium is a fluctuating condition by nature, test–retest reliability cannot be validly assessed. Importantly, the CAM is significantly correlated with the Mini-Mental Status Examination (Folstein et al., 1975), the Visual Analog Scale for Confusion, and the digit span test. Although the CAM tool can be administered in less than 5 minutes and closely correlates with DSM-IV criteria for delirium, studies have shown a false positive rate of 10%, and the instrument has not been widely tested as a bedside tool for nurse raters. The tool identifies the presence or absence of delirium but does not assess the severity of the condition, making it less useful to detect clinical improvement or deterioration. It also does not indicate the etiology of the delirium, which is based on a thorough history, physical examination, and a wide-ranging battery of laboratory tests and imaging results.

Clinical presentations Given the multitude of possible causes of delirium and the multiple age groups affected, it should not be surprising that the clinical symptoms can vary widely. One model for thinking about delirium and clinical presentation is that the wide diversity of etiologies converges on a final common pathway with disruption of brain structures and neurochemical systems to produce the clinical symptomatology (Trzepacz, 1996, 2000). Broad agreement does not appear to exist on what might be “core symptoms” in delirium, although candidates for this include memory impairment, attentional deficits, disturbance of the sleep/wake cycle, thought process changes, alterations in the motor system, and language disturbances. Other associated symptoms include perceptual disturbances such as illusions, hallucinations, delusions, and mood changes. Motoric subtypes have been identified by some investigators as providing a biologic basis for different forms of delirium. Although the motor system may not be involved in an individual patient with delirium, different presentations of motor system dysfunction, both hypoactivity and hyperactivity, have been recognized. Indeed, the word delirious seems to connote a degree of motor hyperactivity.

Delirium

Lipowski (1989) described three variants of delirium based on motor activity termed hyperactive, hypoactive, and mixed. However, no standardized definition exists, and it is unclear what symptoms should be included in each subtype. Meagher and Trzepacz (2000) found that delusions, hallucinations, mood changes, speech disturbances, and sleep disturbances were more frequent in hyperactive patients. It is recognized that the waxing and waning nature of the symptoms and the sleep/wake cycle abnormalities also complicate our understanding and classification of motoric subtypes of delirium. Therefore, it is also not surprising that many patients—in some studies, a majority—are described as having a mixed motoric subtype. It is also not clear that the motoric subtypes have distinct structural or neurochemical bases. Numerous studies have indicated that patients with a hyperactive subtype, however, experience a better outcome, as determined by shorter hospital stays and lower mortality rates and better recovery. The possibility of selection bias in these studies cannot be fully ruled out. It is also possible that hypoactive delirious patients may be overlooked in many surveys.

Treatment Although treatment of an underlying condition is relatively straightforward and can contribute to resolution of an episode of delirium, the multifactorial nature and the need for a possibly offending medication need to be considered. For example, individuals with preexisting agitation due to dementia may develop delirium secondary to benzodiazepine or antipsychotic use. Withdrawal of the drug entails neuropsychiatric risk of returning to the patient’s baseline state that was judged to require the medication in the first place. Treatment of delirium can be roughly divided into prevention strategies as well as symptomatic treatment. Fong et al. (2009), estimate that as many as 40% of the cases of delirium are preventable and that prevention is an effective strategy for minimizing the occurrence of delirium and its negative outcomes. An example of delirium prevention is avoidance of anticholinergic drugs in individuals known to be susceptible to the effects, such as a patient underlying dementia. Strategies for prevention of alcohol withdrawal are another example in which a common cause of delirium may be easily prevented in an inpatient setting. A number of studies have examined the role of pharmacologic agents in delirium prophylaxis. Haloperidol may reduce the incidence of delirium in patients undergoing surgery; however, a larger study did not produce a statistically significant reduction in delirium. A randomized controlled clinical trial of cholinesterase inhibitors has not

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shown benefit for preventing delirium in postoperative patients, but these studies have generally been small case series (Gleason, 2003; Overshott et al., 2008).

Treatment strategies The first-line treatment for delirium in all patients should consider nonpharmacologic interventions. This includes behavioral approaches to improve orientation and behavioral interventions by multiple health-care providers. Attention to sensory impairments such as vision, hearing loss, unilateral hemineglect, or tactile loss should be minimized. Physical restraints should be avoided whenever possible, as they lead to decreased mobility, increased agitation, and risk of injury, sometimes resulting in death. Adequately staffing hospital units and providing optimal patient care settings with frequent human interactions, appropriate lighting, and adequate nutrition may assist in this regard. Minimal noise at night to allow an uninterrupted period of sleep at night is considered of crucial importance in the management of delirium. A recent review of pharmacologic strategies for treatment of delirium indicates that there are few well-performed, randomized, controlled studies; therefore, our evidence base for treatment of delirium is relatively limited to recommendations based on case series and retrospective reports. It needs to be recognized that the majority of medications that help calm agitated patients also can result in sedation. This is true for benzodiazepines, many of the tricyclic antidepressants, and many of the neuroleptics, especially the atypical antipsychotics (Sipahimalani and Masand, 1997). Part of the paradigm of geriatric medicine is that pharmacologic agents be initiated at the lowest starting dose and that the “start low, go slow” heuristic be considered. Modifications to this concept need to be individualized because of the importance of preventing self-injury or injury to staff or family members by the delirious patient. Haloperidol is frequently used to treat delirium, and the effectiveness of this drug has been studied in randomized, controlled clinical trials. Haloperidol is available in parenteral formulations. Haloperidol use is associated with a higher rate of extrapyramidal side effects and acute dystonia, although it is less sedating than many of the newer atypical antipsychotics. The long half-life of haloperidol is frequently underestimated, particularly in older adults. Especially in patients with cardiac issues, use of any of the neuroleptics can result in prolongation of the QT interval. Use of atypical antipsychotics has become common practice, but lack of parenteral forms limits use in ICUs and in seriously agitated patients. In the future, it is possible that large databases such as those maintained by hospitals or other care organizations or insurance companies may provide new methods of

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understanding the relative efficacy of agents used in the setting of delirium, to identify those associated with shorter length of stay, reduced mortality, and better outcomes.

Future directions and research The mediators of ACS are multiple, and additional research is necessary to elucidate whether a “common final pathway” in the brain is present in ACS. That is, despite the panoply of causes, is there a common molecular mechanism, such as acute cholinergic failure, that is present in a majority of ACS cases and represents a therapeutic target for the cognitive and behavioral changes? We also need more robust data on long-term outcomes; although complete recovery is present in the majority of patients, suboptimal responses and incomplete recovery to profound brain changes in delirium might be more common than medical professionals generally assume (Maclullich et al., 2009). Additional research into tools necessary for rapidly identifying delirium beyond staff education and frequent independent assessments would be valuable. Depending on methodology, delirium may be present in as many as 70% of acute hospital inpatients. Tools to assess its importance and to delineate who needs urgent assessment and treatment would be useful in promoting good outcomes and providing timely care in a complex health-care environment.

References American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), 4th edn. Washington, DC: American Psychiatric Association. Blass, J.P. and Gibson, G.E. (1999) Cerebrometabolic aspects of delirium in relationship to dementia. Dement Geriatr Cogn Disord, 10 (5): 335–338. Breitbart, W., Marotta, R., Platt, M.M., et al. (1996) A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry, 153 (2): 231–237. Brown, T.M. and Stoudemire, A. (1998) Psychiatric Side Effects of Prescription and Over-the-Counter Medications. Washington, DC: American Psychiatric Press. Caeiro, L., Ferro, J.M., Albuquerque, R., and Figueira, M.L. (2004) Delirium in the first days of acute stroke. J Neurol, 251 (2): 171–178. Cole, M.G. (2004) Delirium in elderly patients. Am J Geriatr Psychiatry, 12 (1): 7–21. Cole, M., McCusker, J., Dendukuri, N., and Han, L. (2003) The prognostic significance of subsyndromal delirium in elderly medical inpatients. J Am Geriatr Soc, 51 (6): 754–760. Elie, M., Cole, M.G., Primeau, F.J., and Bellavance, F. (1998) Delirium risk factors in elderly hospitalized patients. J Gen Intern Med, 13 (3): 204–212.

Fick, D.M., Agostini, J.V., and Inouye, S.K. (2002) Delirium superimposed on dementia: a systematic review [Review]. J Am Geriatr Soc, 50 (10): 1723–1732. Folstein, M.F., Folstein, S.E., and McGugh, P.R. (1975) Mini-Mental State. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res, 12 (3): 189–198. Fong, T.G., Tulebaev, S.R., and Inouye, S.K. (2009) Delirium in older adults: diagnosis, prevention, and treatment. Nat Rev Neurol, 5: 210–220. Furuse, T. and Hashimoto, K. (2010) Sigma-1 receptor agonist fluvoxamine for postoperative delirium in older adults: report of three cases. Ann Gen Psychiatry, 24: 9–28. Galldiks, N., Kadow, I., Bechdolf, A., et al. (2011) Variety of symptoms after drug use of gamma-hydroxybutyric acid (GHB) [in German]. Fortschr Neurol Psychiatr, 79 (1): 21–25. Gleason, O.C. (2003) Donepezil for postoperative delirium. Psychosomatics, 44 (5): 437–438. Han, L., McCusker, J., Cole, M., et al. (2001) Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med, 161 (8): 1099–1105. Hauser, P., Devinsky, O., De Bellis, M., et al. (1989) Benzodiazepine withdrawal delirium with catatonic features. Occurrence in patients with partial seizure disorders. Arch Neurol, 46 (6): 696–699. Henon, H., Lebert, F., Durieu, I., et al. (1999) Confusional state in stroke: relation to preexisting dementia, patient characteristics, and outcome. Stroke, 30 (4): 773–779. Hshieh, T.T., Fong, T.G., Marcantonio, E.R., and Inouye, S.K. (2008) Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci, 63 (7): 764–772. Inouye, S.K. (1998) Delirium in hospitalized older patients. Clinical Geriatric Medicine, 14: 745–764. Inouye, S.K. (2006a) Current concepts: delirium in older persons. N Engl J Med, 354: 1157–1165. Inouye, S.K. (2006b) Elucidating the pathophysiology of delirium and the interrelationship of delirium and dementia. J Gerontol A Biol Sci Med Sci, 61 (12): 1277–1280. Inouye, S.K. and Charpentier, P.A. (1996) Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. J Am Med Assoc, 275 (11): 852–857. Inouye, S.K., van Dyck, C.H., and Alessi, C.A. (1990) Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med, 113 (12): 941–948. Inouye, S.K., Bogardus, S.T., Jr., Williams, C.S., et al. (2003) The role of adherence on the effectiveness of nonpharmacologic interventions: evidence from the delirium prevention trial. Arch Intern Med, 163 (8): 958–964. Jacobson, S. and Jerrier, H. (2000) EEG in delirium. Semin Clin Neuropsychiatry, 5 (2): 86–92. Jicha, G.A., Schmitt, F.A., Abner, E., et al. (2010) Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease. Neurobiol Aging, 31 (10): 1805–1813. Karpyak, V.M., Biernacka, J.M., Weg, M.W., et al. (2010) Interaction of SLC6A4 and DRD2 polymorphisms is associated with a history of delirium tremens. Addict Biol, 15 (1): 23–34. Kolbeinsson, H. and Jónsson, A. (1993) Delirium and dementia in acute medical admissions of elderly patients in Iceland. Acta Psychiatr Scand, 87 (2): 123–127.

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Lang, P.O., Heitz, D., Hédelin, G., et al. (2006) Early markers of prolonged hospital stays in older people: a prospective, multicenter study of 908 inpatients in French acute hospitals. J Am Geriatr Soc, 54 (7): 1031–1039. Lerner, A.J., Hedera, P., Koss, E., et al. (1997) Delirium in Alzheimer’s disease. Alzheimer’s Dis Assoc Disord, 11 (1): 16–20. Limosin, F., Loze, J.Y., Boni, C., et al. (2004) The A9 allele of the dopamine transporter gene increases the risk of visual hallucinations during alcohol withdrawal in alcohol-dependent women. Neurosci Lett, 362 (2): 91–94. Lipowski, Z.J. (1987) Delirium (acute confusional states). J Am Med Assoc, 258 (13): 1789–1792. Lipowski, Z.J. (1989) Delirium in the elderly patient. N Engl J Med, 320 (9): 578–582. Lozeva-Thomas, V. (2004) Serotonin brain circuits with a focus on hepatic encephalopathy. Metab Brain Dis, 19 (3–4): 413–420. Maclullich, A.M.J., Beaglehole, A., Hall, R.A., and Meagher, D.J. (2009) Delirium and long-term cognitive impairment. Int Rev Psychiatry, 21 (1): 30–42. McKeith, I.G., Burn, D.J., Ballard, C.G., et al. (2003) Dementia with Lewy bodies. Semin Clin Neuropsychiatry, 8 (1): 46–57. Meagher, D.J. and Trzepacz, P.T. (2000) Motoric subtypes of delirium. Semin Clin Neuropsychiatry, 5(2): 75–85. Murray, F., Harrison, N.J., Grimwood, S., et al. (2007) Nucleus accumbens NMDA receptor subunit expression and function is enhanced in morphine-dependent rats. Eur J Pharmacol, 562 (3): 191–197. Obrecht, R., Okhomina, F.O., and Scott, D.F. (1979) Value of EEG in acute confusional states. J Neurol Neurosurg Psychiatry, 42 (1): 75–77. Overshott, R., Karim, S., and Burns, A. (2008) Cholinesterase inhibitors for delirium [Review]. Cochrane Database Syst Rev, (1): CD005317. doi:10.1002/14651858.CD005317.pub2 Palomero-Gallagher, N., Bidmon, H.J., Cremer, M., et al. (2009) Neurotransmitter receptor imbalances in motor cortex and basal ganglia in hepatic encephalopathy. Cell Physiol Biochem, 24 (3–4): 291–306.

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Pandharipande, P., Shintani, A., Peterson, J., et al. (2006) Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology, 104: 21–26. Perry, S.W. (1990) Organic mental disorders caused by HIV: update on early diagnosis and treatment. Am J Psychiatry, 147 (6): 696–710. Pisani, M.A., McNicoll, L., and Inouye, S.K. (2003) Cognitive impairment in the intensive care unit. Clin Chest Med, 24: 727–737. Rosebush, P.I. and Mazurek, M.F. (1996) Catatonia after benzodiazepine withdrawal. J Clin Psychopharmacol, 16 (4): 315–319. Sipahimalani, A. and Masand, P.S. (1997) Use of risperidone in delirium: case reports. Ann Clin Psychiatry, 9 (2): 105–107. Solaro, C. and Tanganelli, P. (2009) Acute delirium in patients with multiple sclerosis treated with pregabalin. Clin Neuropharmacol, 32 (4): 236–237. Supady, A., Schwab, T., and Busch, H.J. (2009) ‘Liquid ecstasy’: gamma-butyrolactone withdrawal delirium with rhabdomyolysis and dialysis dependent renal failure. Dtsch Med Wochenschr, 134 (18): 935–937. Trzepacz, P.T. (1996) Delirium. Advances in diagnosis, pathophysiology, and treatment. Psychiatr Clin North Am, 19 (3): 429–448. Trzepacz, P.T. (2000) Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry, 5 (2): 132–148. Trzepacz, P.T. and van der Mast, R. (2002) The neuropathophysiology of delirium. In: J. Lindesay, K. Rockwood, and A.J. MacDonald (eds), Delirium in Old Age. New York: Oxford University Press. Trzepacz, P.T., Teague, G.B., and Lipowski, Z.J. (1985) Delirium and other organic mental disorders in a general hospital. Gen Hosp Psychiatry, 7 (2): 101–106. van Munster, B.C., de Rooij, S.E., Yazdanpanah, M., et al. (2010) The association of the dopamine transporter gene and the dopamine receptor 2 gene with delirium, a meta-analysis. Am J Med Genet B Neuropsychiatr Genet, 153B (2): 648–655.

Chapter 20 Headache in the Elderly Brian McGeeney Department of Neurology, Boston University School of Medicine, Boston, MA, USA

Summary • Headache is one of the more common pain complaints encountered by practitioners and remains so in the elderly population. • Tension-type headache remains common though somewhat less so in the elderly. • Secondary headaches are a much greater proportion but still a minority of elderly headache. • Migraine is less common beyond the age of 70 and rarely ever has its onset in the elderly, with the possible exception of migraine-type visual aura. • Treatment of headaches is more challenging in elderly.

Introduction • Up to 20% of elderly headache sufferers may have a secondary headache, which is higher than in the general population. PRIMARY HEADACHE DISORDERS • Migraine is less common beyond the age of 70 and rarely ever has its onset in the elderly, with the possible exception of migraine-type visual aura. Triptans are used by most practitioners in its treatment, caution is needed in prescribing acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), β blockers, and antidepressants. • Tension-type headache remains common though somewhat less so in the elderly. It is important to avoid daily analgesic use especially for mild headaches. • Cluster headaches are more common in males (4–10:1), and are characterized by bouts of unilateral short-lived headache usually in the early hours of sleep, accompanied by tearing and nasal discharge. Abortive treatment relies on high-flow oxygen and steroids rather than triptans, and verapamil and lithium are used for prophylaxis. • Hypnic headaches or “alarm clock” headaches occur in those over 50 years of age, mostly women, following the onset of sleep. • Other uncommon headache disorders include paroxysmal hemicranias, hemicrania continua and short-lasting unilateral neuralgias with conjunctival tearing (SUNCT). SECONDARY HEADACHE DISORDERS • Medication overuse headache (MOH), or rebound headache, actually occurs in individuals with primary

headaches taking analgesics, no matter what the indication for the analgesics. Sometimes simply eliminating medication overuse does not solve the problem. • Other medications associated with headache, which again occurs more often in patients already suffering from migraine, are dipyridamole, nitrates, sildenafil, bromocriptine, caffeine, and alcohol. • Giant cell (temporal) arteritis (GCA) or Horton’s disease is the most common systemic vasculitis in the elderly. Involvement of the posterior ciliary artery can cause blindness. Biopsy with empirical commencement of steroid therapy is recommended. • Other vascular causes of headaches include ischemic and more often hemorrhagic strokes, which need to be differentiated from venous sinus thrombosis, reversible cerebral vasoconstriction syndrome, intracranial hypotension, malignant hypertension, cough headache, and extension of sphenoid sinusitis. • Cervicogenic headache may occur in patients with arthritis or cervical trauma. Diagnostic confirmation as well as treatment relies on anesthetic blockade of the cervical sensory nerves involved. • Trigeminal neuralgia (TN) typically presents as paroxysms of severe unilateral shooting facial pain triggered by touch, movement, or cold air. MRI, possibly with magnetic resonance angiography (MRA) is warranted to rule out intracranial pathology. Medical therapy is preferred to nerve decompression or surgical ablation. • Other possible etiologies to consider are acute glaucoma, primary brain tumors and metastases, and controversially, obstructive sleep apnea.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Overview Headache is one of the more common pain complaints encountered by practitioners and remains so in the elderly population. One study of symptom prevalence in the elderly noted that headache is the tenth most common symptom among elderly women and the 14th most common symptom among elderly men (Hale et al., 1986). What is notably different in the elderly headache population compared to younger people is the prevalence of secondary headaches; that is, conditions that are symptomatic with headache, contributing a much greater proportion but still a minority of elderly headache. Published studies suggest that 2.2–20% of elderly headache sufferers have a secondary headache problem (Edmeads and Wang, 2006). Clinicians should approach all new headache problems in the elderly as secondary until satisfied otherwise, in contrast to evaluating young people with headache. In one population study, of those with headache, 16.9% had onset at or older than 65 years of age (Prencipe et al., 2001). The majority of headache problems in the elderly are still primary; however, meaning that they derive from a disturbance in the pain system of the head alone (approximately) and include tension-type, migraine, and cluster headache. As primary headache is largely genetically predetermined, one would expect symptomatic expression before the senior years, hence one does not expect to make a new diagnosis in this age group. Although a few common headache problems constitute the majority of headache in the elderly, the differential diagnosis is wide because many medical disorders are symptomatic with headache (see the following list). Selected Etiologies of Headache in the Elderly, Most of Which Can Manifest As Episodic or Chronic Daily Headache Primary Headache Migraine Tension-type Cluster Hypnic Secondary Headache More Common Medication induced Medication overuse Alcohol induced Cervicogenic Severe hypertension Stroke (including subarachnoid bleed) Intracranial mass lesions Respiratory failure Depression Less Common Temporal arteritis Meningitis

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Acute eye syndromes, such as iritis Vertebral/carotid dissection Experimental studies in the 1930s and later on awake individuals led to our present understanding of what is pain sensitive in the head (Ray and Wolff, 1940). The venous sinuses, larger arteries (especially at the base of the brain), and parts of the dura were pain sensitive, while the brain parenchyma, ependymal ventricular lining, and pia are insensitive to pain. Headache can be experienced with traction of these structures, in addition to local irritation of trigeminal sensory endings. Direct pressure on cranial nerves may also cause head pain. Overall, site of headache has not been particularly useful in diagnosis, less useful than patients might think. A review of the more common primary headache disorders and selected examples of secondary headaches is presented.

Headache classification Practitioners are greatly challenged by a lack of diagnostic markers and pathognomonic features of the various primary headache disorders. Hence, diagnosis and classification is a descriptive approach. The current International Classification of Headache Disorders (ICHD) is based on consensus opinion, which can and does change over time (Headache Classification Subcommittee of the International Headache Society [IHS], 2013). The classification is not based on good scientific evidence, as there is little evidence available that can separate the different headaches. Clinicians are encouraged to visit the website www.i-h-s.org and, under “Guidelines,” download the ICHD-3, which is about 160 pages long. The guidelines are best suited for research purposes, and in clinical practice, one does not have to strictly follow the criteria. Out of necessity, in research, specificity is weighted over sensitivity in an attempt to exclude “non” cases from clinical study. In clinical practice, one does not have to be so strict. The classification is a valuable resource for how headache medicine practitioners approach the diagnosis of headache disorders and is a great reference point.

The clinical approach to headache Evaluation of those with headache clearly requires a comprehensive history and examination. History about the amount of impairment, independent of pain severity, is important to consider, as there may be considerable disparity from one patient to another. A background headache history from the patient can change the level of concern or diagnosis, as can (to a lesser extent) the family history of significant headache problems. Two aspects of the examination require particular mention: measurement of blood pressure and visualization of the optic disks. Severe abnormalities may otherwise show

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no signs, and these cannot be guessed. Neurologic abnormalities, even if transient, often result in brain imaging. Signs on neurologic examination include visual field abnormalities, nystagmus, and a new or worsening gait problem, among other concerning findings. Stigmata of arthritis in the large or small joints may increase the likelihood of significant cervical spinal disease, along with reduced range of motion of the cervical spine. The eyes are examined for signs of acute glaucoma. The threshold for radiologic investigation of the brain is much lower in new-onset headache in the elderly, with either a CT scan or an MRI. In practice, occasional headache presentations warrant cerebrospinal fluid examination, with concern for infection among other problems. Occasionally, occipital predominant headache results in cervical spine imaging, and the normal degenerative disease present at this age presents a challenge to attribute causality. Meningoencephalitis in the elderly is less reliably accompanied by signs of meningism or fever, hence a lumbar puncture and cerebrospinal fluid examination may be warranted using a lower clinical threshold for new headache disorders. Structures other than the brain itself are important to review when imaging the head. Nasopharyngeal carcinoma can present with headache, hence scrutiny of the head imaging for abnormalities in the nasopharynx is advised. The management approach of elderly headache when the etiology of the headache is not clear commonly involves reducing or discontinuing nonessential medications, at least until the headache problem is under control. Finally, somatic symptoms such as headache are more common with depression and may alert the provider to poor mood (Mazzotta et al., 2003).

Primary headache disorders Migraine The propensity to migraine, largely genetically determined, is expressed to a lesser extent in the elderly. The practitioner should not be making a new diagnosis of migraine in the elderly, with the possible exception of migraine-type visual aura, which can present as visual phenomena only, without significant headache, and has been termed late-life migraine accompaniments (Fischer, 1980). A minority of migraineurs continue to have attacks into their 70s and beyond. Such attacks are mostly a lighter version and are easier to treat than their migraine attacks in earlier years. Often migraineurs in their older years have learned how to micromanage their medication doses down to smaller amounts, reflecting an improved responsiveness to smaller doses and possibly an increased concern about medication side effects and tolerability at an older age. By the time they are much older, affected people have developed a deeper understanding of their symptoms and lack the exasperated, frustrated, and helpless feelings that younger migraineurs may experience.

Migraine is mostly an episodic disorder, with at times impairing headache and associated symptoms that can include nausea, photophobia, and phonophobia (Goadsby et al., 2002). Migraine can transform into a daily or neardaily variety called chronic migraine, and this continues to be seen in the elderly, although much less than in younger years. Many conditions can worsen or expose migraine/ migrainous-type headache again, from medications to severe hypertension. It is a matter of debate whether less severe hypertension can worsen migraine, but this may be the case. As mentioned earlier, aura may occur for the first time in older individuals. This is typically visual, such as scintillating scotomas, or “seeing stars,” but it can also be accompanied by sensory symptoms. Such visual symptoms often result in a workup for possible transient ischemic attack (TIA) or even a focal seizure. Fischer used the term “late-life migrainous accompaniments” to describe such visual experiences (Fischer, 1980). Despite this, the overall burden of aura in migraine is generally reduced when compared to younger years in the minority of migraineurs who experience aura.

Therapy of migraine in the elderly Medical conditions common to the elderly often make managing migraine more challenging. In addition, therapy is rather individual, balancing the suffering and frequency of the headache with the patient’s expectations and appropriateness of various medications. Use of standard nonsteroidal anti-inflammatory drugs (NSAIDs), a gold standard in headache treatment, may be inadvisable due to peptic ulcer disease, renal failure, anticoagulation, or just poor tolerability. Ergotamines are often avoided in the elderly, due to their considerable vascular effects, and triptans are used much less frequently for similar reasons. Sumatriptan has been available since the early 1990s (the first triptan), and many people continue to take this (and other triptans) as they get older. In the absence of new vascular concerns, clinicians commonly continue to prescribe triptans to older individuals at an age when they would not initiate new triptan therapy. Typical migraine prophylactic agents such as β blockers and tricyclic antidepressants (TCAs) are more often accompanied by bothersome side effects in the elderly. In particular, TCAs are generally avoided in this age group. The elderly are particularly susceptible to the cognitive side effects of medications, such as but not limited to topiramate and gabapentin, which are also used in migraine prophylaxis. Renal impairment may necessitate a reduction in the dose of gabapentin also. Acetaminophen- or butalbital-containing compounds continue to be used successfully in the elderly. Isometheptene-containing compounds have also been used, although this medication has recently become unavailable in the United States. Dopamine antagonists such as promethazine remain useful when used with caution in the elderly.

Headache in the Elderly

Tension-type headache Tension-type headache remains common, although less so, in the elderly. This type of headache, the “common” headache, is defined more by the absence of migrainous features and is a mild or, at most, moderate, generally global headache, with a sensation of tightness around the head. Tension-type headache has a chronic form, is present on most days, and contributes to the more benign chronic daily headache population (IHS, 2013). As with headache in general in the elderly, the practitioner should reach this diagnosis by exclusion and then decide whether the suffering element warrants medication use or whether reassurance and an explanation are sufficient. As this type of headache may be frequent, the provider is alerted not to encourage daily analgesic use, especially for mild and unimpairing headache. Cluster headache Cluster headache is a primary headache disorder with a prevalence estimated at 2–6 per 10,000, and characterized by attacks of strictly unilateral short-lived headache, mostly with autonomic features such as tearing and unilateral nasal discharge. For most patients, the disorder is characterized by periods of weeks (cluster periods) when the patient is vulnerable to one or more attacks a day, followed by longer quiescent periods that are cluster free. Cluster headache is clearly a distinct entity of short-lived, strictly unilateral pain, and generally there is not much difficulty in making the diagnosis when the practitioner is familiar with the symptoms and signs. Cluster periods appear more likely in the spring and fall seasons. There is an estimated male:female ratio of 4–10:1 from available data, hence cluster is much more common in men. Patients can be quiescent for 10 years or more, with attacks recurring when older. Seidler and colleagues describe a 91-year-old patient with new-onset cluster headache, the oldest new presentation of cluster headache (Seidler et al., 2006). It is common for cluster headache to disappear in older age, but for those afflicted, it is known for the severity of the pain and remains intense in those afflicted. The headache can last from 20 to 150 minutes, hence a headache that lasts all day is not a cluster headache. Up to 10% of new cluster headache may occur in those over 60 years of age (Silberstein and Young, 1998). The attacks are most commonly experienced at night in the first 1–2 hours after falling asleep. Treatment involves abortive agents for the actual attack and daily prophylaxis to induce and maintain a remission. Sumatriptan, administered subcutaneously for a cluster headache attack, is a treatment of choice and is often avoided due to vascular risk factors in the elderly. With avoidance of vasoactive agents, abortive treatment relies on high-flow oxygen (10 L) administered with a nonrebreather mask for about 20 minutes or intranasal lidocaine. Oral agents for a short-lived headache attack are generally slow to

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act. The quickest way to induce a remission of cluster headache is to use steroids such as prednisone 60–80 mg daily, tapering over 10 days to 3 weeks (Shapiro, 2005). Steroids are usually well tolerated but carry a small risk of osteonecrosis. The prophylactic agent of choice is verapamil and has demonstrated efficacy, tolerability, and safety in chronic prophylaxis (Leone et al., 2000). The starting dose is 240 mg slow-release tablet daily or 80 mg three times daily. Up to 720 mg daily are used. An electrocardiogram is suggested at doses above 240 mg daily, due to slowed conduction across the atrioventricular node. Constipation, hypotension, and dizziness are other side effects. The other prophylactic agent with reasonable literature support is lithium (Stiener et al., 1997). Lithium may be used in combination with verapamil. Monitoring of blood levels of lithium is necessary along with assessment of renal, liver, and thyroid status. Lithium is administered three times daily or as a daily slow-release preparation. Starting doses are 300 mg twice daily, with a maintenance of 600–1200 mg daily in divided doses. Other prophylactic options include the pineal hormone melatonin, valproic acid, topiramate, and baclofen.

Paroxysmal hemicranias, short-lasting unilateral neuralgias with conjunctival tearing, and hemicrania continua Paroxysmal hemicranias are different from cluster attacks only by being of shorter duration and more frequent, lasting 2–30 minutes and occurring 10–30 times a day. In addition, they are less common than cluster headache. Paroxysmal hemicrania is termed episodic when there are remissions of at least a month and is chronic with a year of no remission. The short-lasting unilateral neuralgias with conjunctival tearing (SUNCT) syndrome is an uncommon disorder, with attacks lasting 5–240 seconds, but is otherwise similar to cluster. Attack frequency is up to 200 a day. Hemicrania continua is a continuous headache that is otherwise similar to cluster, in being strictly unilateral and generally accompanied by unilateral autonomic features. This headache type is thought to be under-recognized and a considerable cause of refractory, unilateral, chronic daily headache in the population. It is important to note that, despite the continuous pain, there are clear exacerbations of variable length. These disorders all share common features of unilateral headache and autonomic features. The autonomic features seen include unilateral lacrimation, nasal discharge, and a blocked nasal passage. Good studies are not available from which to guide treatment decisions on these less common headaches. As currently defined by the International Headache Classification, paroxysmal hemicranias should respond to prophylaxis with indomethacin. In practice, some patients fulfill criteria except for response to indomethacin. Otherwise, consideration should be given to verapamil, celecoxib, acetylsalicylic acid, and topiramate. The treatment of SUNCT

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syndrome is suggested to be lamotrigine, gabapentin, or valproic acid. By definition, hemicrania continua is completely responsive to indomethacin. Failing that, verapamil, valproic acid, or β blockers may be considered. All these uncommon headache syndromes should be considered after head imaging, to rule out secondary cause.

Medication-associated Headache Vasodilators

Histamine release Dompamine agonist

Serotonergic agents TNF inhibitors

Hypnic headache Hypnic headache, sometimes called “alarm clock” headache, is a rare headache syndrome first described in the literature in 1988 and occurs by definition in those over 50 years of age upon awaking from sleep. It can be unilateral or bilateral (Raskin, 1988). Hypnic headache is a dull headache lasting from 15 to 180 minutes. About twothirds of the cases are women. Secondary causes must be excluded, and most cases are mild to moderate in severity. Typical attacks awaken the patient between 1 am and 3 am, and there are generally no associated features, such as photophobia or nausea. The pathophysiology of hypnic headache is unknown. It has been suggested that this is a rapid eye movement (REM) sleep-related disorder, but recent evidence demonstrates that the onset of hypnic headache was not associated with sleep stage (Holle et al., 2011). There is no consensus on treatment. Aspirin or caffeine is suggested as initial nightly treatment, followed by lithium 300–600 mg, melatonin 3 mg, or indomethacin 25–75 mg, all administered at night (Holle et al., 2010).

Secondary headache disorders Medication-related headache Overuse of analgesic medications in those with primary headache disorders occurs commonly and can itself induce headache. This type of headache is typically termed medication overuse headache (MOH), sometimes called rebound headache. The pathophysiology of this problem is not well understood and can occur no matter what the indication for the analgesics. MOH is a common secondary headache, typically seen in the young and early middle-aged migraineur. However, it can also occur in the elderly, although the prevalence is much less than those under 50 years of age. It is important to note that this phenomenon occurs in individuals with primary headache, especially with a big burden of a headache, and should not occur in people taking daily analgesics without a headache history. Sometimes eliminating medication overuse, after sufficient time for mechanisms to reset, does not improve the headache problem. In addition to MOH, medications by themselves cause headache separate from analgesic overuse (Figure 20.1). A critical point to recognize is that the propensity to do so is much more common in those with a background of migraine. The elderly patient with a background of migraine during the younger years is more likely to

Hormones Immunomodulators Raised ICP Others

Figure 20.1 Medications capable of inducing headache, independent of analgesic overuse.

present with medication-induced headache. Both caffeine and alcohol remain a common cause of headache in the elderly, and one may miss the nightly alcohol intake without a careful history. Medications commonly associated with headache include dipyridamole, cyclosporine, vasodilators like nitrates, and sildenafil. Dopamine antagonists such as bromocriptine and tumor necrosis factor (TNF) inhibitors such as etanercept also may cause headache. Consideration should be given to stopping as much medication as possible when working to improve a headache problem.

Giant cell arteritis Giant cell arteritis (GCA), otherwise known as temporal arteritis or Horton’s disease, is the most common systemic vasculitis in the elderly (Ward and Levin, 2005). (See the following list for diagnostic criteria.) International Headache Society Diagnostic Criteria for Giant Cell Arteritis A. Any new persistent headache fulfilling criteria C and D B. At least one of the following: swollen, tender scalp artery with elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) temporal artery biopsy demonstrating GCA C. Headache develops in close temporal relation to other symptoms and signs of GCA D. Headache resolves or greatly improves within 3 days of high-dose steroid treatment GCA presents with headache that is often daily; other symptoms may be present, including jaw claudication (which significantly increases the chance that headache is from GCA), proximal limb pain characterizing polymyalgia rheumatica, cranial neuropathies including optic

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nerve ischemia, and less commonly, oculomotor palsy. Examination can demonstrate tenderness and induration of the temporal arteries (Ward and Levin, 2005). The headache has no particular features, and the feared complication is involvement of the posterior ciliary arteries that can easily result in blindness without recovery from optic nerve ischemia. The gold standard of diagnosis is temporal artery biopsy, and some clinicians advise bilateral biopsies to increase the likelihood of pathology. Treatment involves steroid use and, much less commonly, immunosuppressants for months. Starting doses are often 60 mg of prednisone daily, which is tapered gradually over the next 4 weeks, then continued around 40 mg daily, and reduced much more gradually over many months. After initiation of steroids, the headache typically disappears within a few days (helpful for diagnosis); this generally commits patients to a few months of steroids. Laboratory testing reveals ESR elevation in 97% of those with GCA, often with an ESR over 100, an elevated CRP, a platelet count of >375,000, and sometimes a normochromic microcytic anemia. GCA may also affect the vertebral and carotid arteries. Patients with GCA have a greater proportion of vertebrobasilar territory infarcts and TIAs, compared with carotid circulation events (Caselli et al., 1988).

Other vascular diseases Both ischemic and hemorrhagic stroke may be accompanied by headache, and generally other symptoms and signs point to the diagnosis of stroke. A sudden-onset severe headache is helpful in identifying a vascular catastrophe and is termed a “thunderclap” headache, with pain maximal at onset. It is commonly associated with subarachnoid hemorrhage from a cerebral aneurysm. The patient should be questioned carefully, as severe headache may also have onset in 5–10  minutes from more benign etiologies instead of being true thunderclap. The differential diagnosis of thunderclap headache is firstly primary and secondary. There are people with apparent primary headache which can result in thunderclap headache, a diagnosis made after excluding other disorders. Thunderclap headache can also occur secondary to intracranial hemorrhage, central vein/venous sinus thrombosis, reversible cerebral vasoconstriction syndrome, intracranial hypotension, acute hypertension, and sphenoid sinusitis with extension. A sudden-onset headache may occur with cough headache, a primary headache syndrome triggered by a cough or the Valsalva maneuver, and this headache can last 30 minutes or more. Unruptured cerebral aneurysms are frequently found on noninvasive imaging such as magnetic resonance angiography (MRA) and are, for the most part, asymptomatic; thus, their discovery on a workup for

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headache is incidental. Subdural hematomas often have a more subtle presentation and are not invariably associated with a trauma history, making the diagnosis more difficult. As the blood pushes the brain aside, one may find only subtle neurologic signs, if any. Small vessel disease that involves cranial nerves can result in dysfunction, such as ischemic optic neuropathy or oculomotor neuropathy, particularly in diabetes. Such syndromes can be associated with headache. Although there is consensus that severe or “malignant” hypertension is invariably accompanied by some headache, most of the available studies suggest that lesser degrees of hypertension are not associated with headache (Gus et al., 2001; Hagen et al., 2002). Many medications used to control hypertension have independent effects on headache control, making the assessment more difficult. The author’s opinion is that, in those with migraine, the onset of essential hypertension or a significant worsening of blood pressure control may be accompanied by more headache.

Cervicogenic headache Neck pain is well known to result in headache, and the neck is often injured alone–-for example, in whiplash or in conjunction with head injury (Packard, 2002; Bogduk, 2004). Many structures in the neck can produce referred pain to the head, including the atlanto-occipital joint, atlanto-axial joints, zygapophyseal joints, cervical and vertebral ligaments, vertebral disks, and neck muscles. Pain from neck structures often refers pain to the occipital region, which also carries cervical root sensory innervation. Neck pain causing headache should be separated from the common experience of neck pain in those with migraine/headache, as trigeminal activation tends to sensitize the upper cervical sensory system, at least intermittently. Migraineurs often have considerable neck pain–this is not cervicogenic headache. The same concept applies to any headache that can sensitize the upper cervical system. Admittedly, the cervical pain so generated can then act as an irritant to headache. Those at risk for cervicogenic headache are older individuals with arthritis and those with post-traumatic headache (PTH). Younger headache patients should be suspected of having cervicogenic headache only if they suffered trauma, such as a flexion–extension injury. Patients with rheumatoid arthritis commonly have headache, thought to be associated with extensive involvement of the upper cervical spine in the arthritis. Cervicogenic headache is best demonstrated by abolition of headache following diagnostic blockade of a cervical structure or its nerve supply. A variety of peripheral procedures have been employed to treat cervicogenic headache and PTH. Most rely on anesthetizing structures thought to be etiologic in the subject’s head and neck pain. Chronic zygapophyseal joint pain is thought to

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contribute to chronic neck pain post whiplash-associated injury, in particular and has been the focus of interventional treatments. An occipital nerve block may merely change sensory input, which has a modulating effect centrally and can result in benefit. Benefit obtained likely will be short lived. Interventional procedures to anesthetize neck structures may work in a similar way. A prolonged positive outcome is likely due to successfully identifying the source of nociception. Unfortunately, tenderness in the neck is not a reliable or valid feature for the source of neck or head pain, as this finding is extremely common with head and neck pain. Primary headache is often associated with an allodynic or hyperalgesic state via peripheral and central mechanisms that results in abnormal tenderness, as noted earlier. The most compelling explanation for cervicogenic headache is pain from the upper cervical joints. Convergence of spinal afferents and occipital afferents easily explains referred pain from the spine to the occipital region, but there is also anatomic convergence between the cervical system and the trigeminal system. Pain in the spine thus can be referred not just to the occipital region, but to all regions of the head. The term cervicogenic headache is frequently used and relies entirely on clinical criteria, by standard definition. This is controversial. The features are not specific, and similar presentations may be seen with migraine. Complete response to diagnostic blockage of cervical nerves or structures is stronger evidence of true cervicogenic headache. Post-traumatic neck pain with headache, in particular, is thought to be caused by irritation of upper cervical joints, particularly the C2–3 zygapophyseal joint. This joint is innervated by the third occipital nerve, anesthetic blockage of which may result in the resolution of headache. More long-term treatment is available with radiofrequency neurotomy.

Other secondary headaches Any intracranial mass lesion, which is common in the elderly, can produce headache by raised intracranial pressure and traction on blood vessels and meninges, among other mechanisms, as noted earlier. Primary brain tumors and metastatic disease to the brain are common in the elderly and often, but not always, have headache as a presenting complaint. Acute angle closure glaucoma, more common in the elderly, can present with headache, eye pain, blurry vision in the affected eye, and nausea. Disease and disorders in the thoracic cavity may less commonly present with facial or head pain, including cardiac ischemia, and, via the vagal nerve, lung carcinoma. Some evidence suggests that those with obstructive sleep apnea may experience morning headaches, although the literature is mixed.

Trigeminal neuralgia Although not a headache, it is useful to review this facial pain problem in the headache chapter. Trigeminal neuralgia (TN) is a severe unilateral neuropathic pain syndrome, resulting in brief (seconds), repeated paroxysms of unilateral facial pain, often described as sharp and shooting from the back of the face forward (Rozen, 2004). TN affects predominantly older age groups and, for the most part, is idiopathic. Attacks are often spontaneous but may be triggered by touching certain areas of the face or even talking. A cold breeze on the face is a common trigger. Mostly there is no sensory loss or neurologic findings on examination. Eliciting neurologic deficits should trigger a search for secondary causes of neuralgia in the distribution of the trigeminal nerve. The clinical presentation of apparent TN may be secondary to intracranial lesions, and all patients warrant MRI imaging, generally with an MRA as well. An MRA is performed, as it is thought that some patients have TN due to compression of the trigeminal nerve by an arterial vascular loop (microvascular compression). Most patients are managed medically, although there are surgical options. Older treatments such as carbamazepine, clonazepam, and baclofen provide reasonable relief for most patients, but there are still many refractory patients. The use of carbamazepine is most commonly used for this purpose (for more than 40 years). Other medications that are used for TN include oxcarbazepine, valproic acid, lamotrigine, and gabapentin. A variety of denervation procedures has been advocated, with variable acceptance in the medical community. Side effects include problems with pain in the area of anesthesia– anesthesia dolorosa. Radiofrequency thermocoagulation of the trigeminal nerve is the most common surgical treatment in the United States for TN. This option requires an appropriately trained surgeon and still leaves the patient open to denervation-related complications such as pain. Often patients regain their pain eventually. Microvascular decompression has been advocated by Jannetta (Jannetta and Bissonette, 1985). This requires a craniotomy and placement of synthetic material between the trigeminal nerve and an abutting arterial vessel. Initial outcomes are good, although pain returns in some patients. The main advantage of surgical decompression is that there is no destruction of nervous tissue.

References Bogduk, N. (2004) The neck and headaches. Neurol Clin N Am, 22: 151–171. Caselli, R.J., Hunder, G.G., and Whisnant, J.P. (1988) Neurologic disease in giant cell (temporal) arteritis. Neurology, 38: 352–359. Edmeads, J.G. and Wang, S.J. (2006) Headaches in the elderly. In:  J. Olesen, P.J. Goadsby, and N.M. Ramadan (eds), The Headaches, 3rd edn. Philadelphia: Lippincott Williams & Wilkins.

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Fischer, C.M. (1980) Late-life migraine accompaniments as a cause of unexplained transient ischemic attacks. Can J Neurol Sci, 7: 9–17. Goadsby, P., Lipton, R.B., and Ferrari, M.F. (2002) Migrainecurrent understanding and treatment. N Engl J Med, 346 (4): 257–270. Gus, M., Fuchs, F.D., Pimentel, M., et al. (2001) Behavior of ambulatory blood pressure surrounding episodes of headache in mildly hypertensive patients. Arch Int Med, 161: 252–255. Hagen, K., et al. (2002) Blood pressure and risk of headache: a prospective study of 22 685 adults in Norway. J Neurol Neurosurg Psychiatry, 72: 463–466. Hale, W.E., Perkins, L.L., May, F.E., et al. (1986) Symptom prevalence in the elderly. An evaluation of age, sex, disease, and medication use. J Am Geriatr Soc, 34: 333–340. Holle, D., Naegel, S., Krebs, S., et al. (2010) Clinical characteristics and therapeutic options in hypnic headache. Cephalalgia, 30 (12): 1435–1442. Holle, D., Wessendorf, T.E., Zaremba, S., et al. (2011) Serial polysomnography in hypnic headache. Cephalalgia, 31(3): 286–290. Headache Classification Committee of the International Headache Society (IHS). (2013) The Internatiional Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia, 33: 629–808. Jannetta, P.J. and Bissonette, D.J. (1985) Management of the failed patient with trigeminal neuralgia. Clin Neurosurg, 32: 334–347. Leone, M., D’Amico, D., Fredian, F., et al. (2000) Verapamil in the prophylaxis of episodic cluster headache: a double blind study versus placebo. Neurology, 54: 1382–1385.

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Mazzotta, G., Gallai, V., Alberti, A., et al. (2003) Characteristics of migraine in an outpatient population over 60 years of age. Cephalalgia, 23: 953–960. Packard, R.C. (2002) The relationship of neck injury and posttraumatic headache. Curr Pain Headache Rep, 6: 301–307. Prencipe, M., Casini, A.R., Ferrentti, C., et al. (2001) Prevalence of headache in an elderly population: attack frequency, disability, and use of medications. J Neurol Neurosurg Psychiatr, 70: 377–381. Raskin, N.H. (1988) The hypnic headache syndrome. Headache, 28: 534–536. Ray, B.S. and Wolff, H.G. (1940) Experimental studies on headache: pain-sensitive structures of the head and their significance. Arch Surg, 41: 813–856. Rozen, T.D. (2004) Trigeminal neuralgia and glossopharyngeal neuralgia. Neurol Clin N Am, 22: 185–206. Seidler, S., Marthol, H., Pawlowski, M., et al. (2006) Cluster headache in a ninety-one-year-old woman. Headache, 46: 179–180. Shapiro, R.E. (2005) Corticosteroid treatment in cluster headache: evidence, rationale, and practice. Curr Pain Headache Rep, 9: 126–131. Silberstein, S.D. and Young, W.B. (1998) Headache. In: M.S.J. Pathy (ed.), Principles and Practice of Geriatric Medicine, 3rd edn. New York: John Wiley & Sons, Inc. Stiener, T.J., Hering, R., and Couturier, E.C.M. (1997) Double-blind placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia, 17: 673–675. Ward, T. and Levin, M. (2005) Headache in giant cell arteritis and other arteritides. Neurol Sci, 26 (Suppl. 2): 134–137.

Chapter 21 Neuromuscular Disorders Heber Varela and Clifton Gooch Department of Neurology, University of South Florida College of Medicine, Tampa, FL, USA

Summary • Motor neuron diseases (MNDs) are the result of degeneration of anterior horn cells in the spinal cord, motor neurons of the brainstem, and the motor cortex. Mechanisms of motor neuron injury may be sporadic or hereditary. • Amyotrophic lateral sclerosis (ALS) is the most common form of MND and is an incurable paralyzing disorder. It is a clinical diagnosis and diagnosis of exclusion. Symptoms screened for is upper and lower motor neuron dysfunction. Treatment is mainly supportive. Other MND include primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), focal MND, and post-polio syndrome. • Nerve root diseases affect the peripheral nervous system, inflictions include radicular pain, dermatomal sensory loss, decreased deep tendon reflexes. Lumbosacral radiculopathies more common than cervical. Assessments of nerve root include MRI and CT myelography. Treatment of cervical radiculopathies through conservative approach to relieve pain, and surgical approach if patient is unresponsive to other interventions. • Diseases of brachial and lumbosacral plexus are very rare, and can be caused by plexus injury or metastatic tumors and radiation treatment. Patients experience severe arm pain, weakness, and atrophy of muscles. MRI and EMG/NCS are the diagnostic tools of choice. Radiation plexopathy is treated symptomatically, with pharmacologic and physical therapy. Surgery is sometimes performed for neurolysis and removal of scar tissue. • Neuropathy affects the peripheral sensory, motor, or autonomic nerves. it can occur symmetrically in the body or in irregular distribution. A major diagnosis tool is a lumbar puncture, for autoimmune neuropathies. • Guillain–Barré syndrome is an acquired neuropathy, that targets the peripheral nerves. The most common form is the acute inflammatory demyelinating polyradiculoneuropathy (AIDP). • Neuromuscular disorders include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), paraproteinemic polyneuropathy, paraneoplastic neuropathy, toxic neuropathies, diabetic neuropathies, idiopathic polyneuropathy, hereditary motor and sensory neuropathy (HMSN), neuromuscular junction disorders, and disorders of muscle.

Introduction The prevalence of most neuromuscular diseases increases with advancing age, and many of these disorders are particularly common in the elderly. Any level of the peripheral nervous system may be affected, including the anterior horn cell, the nerve roots, the plexi, the peripheral nerves, the neuromuscular junction, and the muscle. This chapter discusses the most common of these disorders, including their history, physical examination, diagnostic evaluation, and therapy.

The motor neuron diseases Diseases of the anterior horn cell, or motor neuron diseases (MNDs), encompass a group of chronic, progressive degenerative disorders affecting primarily the anterior horn cells in the spinal cord, the motor neurons of the

brain stem, and the motor cortex. The clinical manifestations are those of amyotrophic weakness, atrophy, and fasciculations and signs of corticospinal tract dysfunction (weakness, spasticity) in various combinations. Amyotrophic lateral sclerosis (ALS) is the most common form of MND. As it damages both the corticospinal tracts and the anterior horn cells, it presents with progressive weakness in concert with amyotrophy, spasticity, and upper motor neuron (UMN) signs. Other forms of MND include primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA), which selectively affect the corticospinal tracts and the lower motor neurons, respectively.

Pathophysiology MNDs are marked by pathologic loss of motor neurons in either the UMN pathway (the corticospinal tract from the cortex through the spinal cord), the lower motor neuron pathway (the anterior horn cells), or both. Typically, these disorders spare the sensory system. Mechanisms of motor

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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neuron injury may be sporadic or hereditary and include excitotoxic and oxidative injury, inflammatory mediators, disorders of cellular transport, mitochondrial dysfunction, support cell dysfunction (such as glial abnormalities), and neurofilament dysfunction, among others. Most cases of ALS are sporadic, and no specific trigger has been found to date, although much has been learned about the pathophysiology underlying its progression, once established. About 10–20% of the cases are hereditary and typically transmitted as an autosomal dominant trait (familial ALS), usually with younger onset than the sporadic form. In some of these cases, disordered processing of superoxide dismutase (SOD) results in a toxic gain of function, which causes the motor neuron injury.

Amyotrophic lateral sclerosis ALS is the most common form of MND and presents, with progressive weakness, in concert with amyotrophy, spasticity, and UMN signs, due to damage to the corticospinal tracts and the anterior horn cells.

Epidemiology and clinical features ALS is a lethal, paralyzing disorder that most commonly affects adults in the fifth to seventh decades of life, although it can impact both younger and older patients. It affects men twice as often as women and is relatively rare, with an incidence of 1 in 50,000 to 1 in 100,000. The disease most commonly begins with distal, focal limb weakness, and atrophy, often accompanied by muscle cramps and fasciculations, which then progresses to involve all voluntary muscles, ultimately affecting the muscles of respiration. Bulbar symptoms, such as dysarthria and dysphagia, develop during the course of the disease, but they may be a presenting feature. Bulbar-onset ALS has a poorer prognosis, with earlier respiratory compromise. Involvement of the corticospinal tracts is marked by spasticity, hyperreflexia, and Babinski signs. Clinically, ALS is a relatively selective motor neuron syndrome, with no sensory symptoms. However, approximately one-third of patients will have a mild frontotemporal dementia.

Diagnosis ALS is a clinical diagnosis and a diagnosis of exclusion; no single test is diagnostic of ALS. A careful history and physical examination is crucial and should focus on symptoms and signs of combined upper and lower motor neuron dysfunction. A series of serum studies should also be performed to exclude disorders of the nerve and muscle that might mimic ALS. Electrodiagnostic testing (EDX) with electromyography and nerve conduction studies (EMG/NCS) is the single most important diagnostic test, as it provides detailed and sensitive information regarding motor neuron injury and also excludes potential mimics. NCS demonstrates only motor axon loss with normal sensory responses,

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while EMG reveals widespread denervation of muscles throughout the body, ultimately including all extremities; the cervical, thoracic, and lumbosacral paraspinal muscles; and the cranial muscles. EMG/NCS can also help classify the level of diagnostic certainty at different stages of the disease in a given patient (suspected, possible, probable, or definite ALS; Hammad et al., 2007). Imaging studies of the brain and spine are also typically indicated to rule out other lesions that might cause UMN injury. Because ALS is a lethal disease, it is extremely important to exclude mimics that are potentially treatable, particularly intercurrent cervical and lumbosacral spondylotic myelopathy and polyradiculopathy, motor neuropathies such as multifocal motor neuropathy with conduction block (MMNCB), bulbar myasthenia gravis, and inclusion body myositis.

Treatment There is no cure for ALS, and treatment is primarily supportive. Riluzole, an antiglutamatergic agent, has a modest but definite therapeutic effect and prolongs survival by 10–30% (an average of 2–3 months) when given in a dose of 50 mg by mouth twice a day (Miller et al., 2009). Other medications, such as gabapentin, have not shown consistent benefit and are not approved for the treatment of ALS. Stretching and range of motion exercises guided by a physical therapist help improve mobility and avoid contractures, with the appropriate use of mobility aids and orthotic devices. Maintaining nutrition is of paramount importance and has been shown to clearly and significantly prolong survival; it should be emphasized from the beginning, with early assessment by a nutritionist. As patients will eventually develop progressive dysphagia, percutaneous endoscopic gastrostomy (PEG) tube placement should be considered early, to maintain nutrition and prevent weight loss and catabolic muscle deterioration (Miller et al., 2009). Dysarthria will also eventually develop in most patients, and augmentative and alternative communication devices should be prescribed for patients with severe dysarthria. Respiratory function should be carefully followed (typically by serial forced vital capacity measurements). Before respiratory compromise begins to approach critical levels, noninvasive ventilation should be offered. Tracheostomy and mechanical ventilation should also be discussed with patients, with the understanding that, although this will prolong life, it will not prevent the progression of weakness, which will ultimately lead to total quadriparesis and loss of cranial nerve functions. The care of the ALS patient in a multidisciplinary clinic optimizes health-care delivery and has also been shown to prolong survival. In this setting, patients are evaluated by different health-care professionals, including a neurologist; physical, occupational, respiratory, and speech therapists; and a social worker on a single visit.

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The mean duration of the disease is 3–5 years. Approximately one-third of patients die in less than 3 years and onethird live longer than 5 years. About 10% of patients survive more than 10 years. Younger age at onset and limb weakness at onset correlate with slower disease progression (Magnus et al., 2002). Bulbar-onset ALS has the poorest prognosis.

Primary lateral sclerosis

Epidemiology and clinical features PLS is a form of MND characterized by the degeneration of the corticospinal tracts, with sparing of the anterior horn cells of the spinal cord and the brain stem. Whether PLS and ALS are distinct disorders or simply part of a broader spectrum of the same disorder remains a matter of debate, as some patients with an initial diagnosis of PLS eventually progress to ALS. There is also a well-recognized UMN–onset form of ALS, but patients in this category develop lower motor neuron symptoms and signs within a year of their UMN symptoms, whereas true PLS remains restricted to the UMNs. Gordon and colleagues (2006) proposed that the definition of PLS includes the stipulation that pure upper motor signs remain restricted for at least 4 years after symptom onset. The clinical syndrome of PLS is rare, accounting perhaps for 1–3% of all patients with MND, which extrapolates to a prevalence rate of 1 in 500,000 to 1 in 1,000,000 (Mitsumoto et al., 1998). The age of onset is most commonly between 50 and 55 years. The disease begins with a pure spastic paraparesis, typically manifested as slowing of gait, with spasticity predominating over weakness. Over the years, the arms become involved, along with the bulbar muscles, causing pseudobulbar palsy (emotional incontinence), dysarthria, and dysphagia. About half the patients develop spastic bladder. Sensory symptoms are rare and should raise the question of another disorder.

Diagnosis As with ALS, PLS is a clinical diagnosis and a diagnosis of exclusion. The workup and evaluation parallels that of ALS. Mimics include any disorder that can affect the UMN anywhere along its path, as well as the myriad causes of progressive paraparesis.

Treatment As in the other types of MND, there is no cure for PLS. Treatment is supportive, including physical therapy, with particular emphasis on ambulation and spasticity management. Unlike ALS, true PLS is a syndrome of slow progression, with long maintenance of function and survival up to several decades.

Progressive muscular atrophy

Epidemiology and clinical features PMA is a pure lower motor neuron disorder seen more commonly in men than in women. PMA comprises from

1% to 19% of motor neuron cases, with an estimated prevalence of 1 in 250,000 to 1 in 1,000,000. Onset is in the distal upper extremities and often asymmetric, with atrophy of the intrinsic hand muscles and ultimate progression to the proximal arms and the legs. Fasciculations, cramping, and bulbar dysfunction are variably present, and deep tendon reflexes are decreased or absent. It can occur at almost any age but commonly manifests in the fifth and sixth decades. There is also a lower motor neuron form of ALS, with the later appearance of UMN signs, which may be initially confused with PMA. A study of 962 patients found UMN signs developed in 22% of patients with PMA within 61 months after diagnosis (Kim et al., 2009). Some patients with the clinical features of PMA frequently have UMN pathology detected only with autopsy, and most have ubiquitinated inclusions typical of ALS (Ince et al., 2003), leading some to classify PMA as a variant of ALS.

Diagnosis PMA, as with other forms of MND, is a clinical diagnosis, and the workup is similar to that of ALS, including EMG/NCS, serum screens, and imaging studies to exclude other disorders. Numerous emerging imaging modalities, including diffusion tensor imaging, positron emission tomography (PET), and transcranial magnetic stimulation, have been used to determine which patients with PMA actually have UMN dysfunction. However, no method has proven to be sensitive or specific enough for diagnosis.

Treatment Treatment is supportive and focuses on physical therapy and orthoses to maintain function. PMA is characterized by slower progression and longer survival than ALS, ranging from 3 to 30 years, with a mean of 13 years (Norris, 1992).

Focal motor neuron disease

Epidemiology and clinical features Although most forms of MND initially present with focal findings, the vast majority of them then follow a course of inexorable progression and generalization. However, a rare subset of the MNDs begin and progress regionally but never generalize to other areas of the body. True focal MND typically involves only the lower motor neuron, and patients virtually never demonstrate UMN signs on examination. The presence of UMN signs in a patient with focal-onset MND is strongly predictive of future generalization. Focal MND can begin at any age, but the average age of onset, as with ALS, is in the fifth and sixth decades. Some forms of focal MND have been characterized as specific syndromes, such as brachial amyotrophic diplegia. This syndrome begins with bilateral upper-extremity

Neuromuscular Disorders

weakness, but unlike ALS, it remains largely confined to the arms, with no UMN signs. The age of onset is similar to that in ALS patients, but the male-to-female ratio is 9:1 in the brachial amyotrophic diplegia group, compared with 1.5:1 in ALS. Bilateral arm weakness is a presenting symptom in 5–10% of ALS cases (Mulder, 1957; Katz et al., 1999), but these patients develop both UMN signs and more generalized weakness as the disease progresses.

Diagnosis As with other forms of MND, focal MND is a clinical diagnosis, after excluding the many other disorders causing regional denervation (such as radiculopathy, plexopathy, and focal neuropathy). Although it is clinically supported by evidence of denervation and reinnervation restricted to one region on EMG examination, this diagnosis can be confirmed only over time, with a lack of significant generalization and a lack of UMN signs over at least 1–2 years.

Treatment Management is supportive. Generally, these patients live much longer than patients with typical ALS, and some have a normal lifespan. However, in a minority of patients with focal MND of the arms, respiratory involvement may ensue. In the syndrome of brachial amyotrophic diplegia, median survival is 57 months, compared with a median survival of 39 months in ALS.

Post-polio syndrome

Epidemiology and clinical features Polio is an enterovirus that causes focal injury to the spinal cord and anterior horn cells, often in a segmental pattern. Typically, the disorder causes acute-onset weakness or paralysis with gradual recovery of strength over 1–2  years, but some patients with more severe infection can be left with degrees of permanent weakness, ranging from mild to complete paralysis. Poliomyelitis epidemics in the United States ended with the introduction of the polio vaccine in 1955. Some of these survivors develop recurrent weakness after the age of 60 years, many decades after the initial attack, due to a unique disorder known as the “post-polio syndrome.” This disorder is primarily a disease of the elderly. The most prominent neurologic manifestation of postpolio syndrome is a new slowly progressive weakness, sometimes accompanied by atrophy, typically in a region previously affected by poliomyelitis. However, post-polio syndrome can also affect muscles not previously symptomatic, including the respiratory and bulbar muscles. Mulder et al., 1972 codified the diagnosis, identifying four major criteria: (1) A prior episode of paralytic poliomyelitis with residual motor neuron loss; (2) a period of neurologic recovery followed by an interval (usually 15 years or more) of neurologic and functional stability; (3) a gradual

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or abrupt onset of new weakness or abnormal muscle fatigue, decreased endurance, muscle atrophy, or generalized fatigue; and (4) exclusion of medical, orthopedic, and neurologic conditions that could be causing the symptoms. Generalized fatigue is also common, as is pain from joint instability, and these symptoms can sometimes appear without the development of a new weakness. Several mechanisms have been proposed to explain the post-polio syndrome. The prevalence of post-polio syndrome varies in different studies from 22% (Codd et al., 1985) to 64% (Windebank et al., 1991).

Pathophysiology After the acute attack of polio, the remaining motor neurons send out sprouts to take over degenerated muscle fibers (collateral sprouting), creating enlarged motor units five to ten times larger than normal. Some of these new synapses may never fully stabilize (Wiechers and Hubbell, 1981), ultimately resulting in the degeneration of axonal branches, drop-out of motor neurons, and the inability to fully activate muscles. However, most cases of post-polio syndrome likely result from the normal loss of motor neurons with aging. In healthy subjects without a history of polio, this loss does not typically cause significant functional weakness (though it can be quantitated electrophysiologically and with quantitative strength testing), but in patients with a substantially reduced pool of motor neurons due to polio, this additional loss may drive strength below a functionally significant threshold, with continuing declines as aging progresses.

Diagnosis The diagnosis of post-polio syndrome is a clinical one. Electrodiagnostic studies cannot differentiate patients with post-polio syndrome from asymptomatic post-polio patients. However, these studies are important to exclude other neuromuscular diseases, such as ALS, radiculopathies, and myopathies. The needle examination demonstrates diffuse neurogenic motor unit potentials indicative of reinnervation, with little or no evidence of active denervation (which helps to exclude severe and progressive disorders such as ALS). Because of aggressive and maximal collateral reinnervation, polio survivors typically demonstrate extremely large (“giant”) motor units in previously affected myotomes, sometimes as large as 10–20 millivolts in amplitude, much larger and in greater abundance than most other neurogenic disorders. Imaging studies (MRI) are needed to exclude spine problems such as spondylosis and stenosis.

Treatment Most patients experience noticeable but mild additional weakness and do not require specific intervention. For those with more significant weakness, treatment is

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supportive, including the institution of a nonfatiguing strengthening exercise program, avoiding the overuse of weakened muscles. Dysphagia can be treated with swallowing techniques; respiratory dysfuncion, if present, may be ameliorated by the use of noninvasive positivepressure ventilation. Most patients do not develop respiratory symptoms, and in those who do, more invasive ventilation is rarely required. Musculoskeletal pain and joint instability are managed conservatively, with physical therapy, lifestyle changes, and the use of assistive orthotic devices. The natural course of post-polio syndrome is characterized by slow progression with plateaus and is not ultimately disabling in the majority of patients. One study reported continuous progression of weakness over 12 years of follow-up (Mulder et al., 1972). A more recent study demonstrated progression when patients were followed for 15 years (Sorenson et al., 2005). Mechanical complications from arthritis are common, and additional bulbar weakness, though rare, may lead to aspiration pneumonia.

Nerve root diseases Epidemiology and clinical features Diseases of the nerve root (radiculopathies) are among the most common disorders affecting the peripheral nervous system. With advanced age, degenerative disease of the spine becomes an extremely common cause of cervical and lumbar radiculopathy. Spondylosis is characterized by osteoarthritic changes in the spine and osteophyte formation, leading to compromise of the nerve root. In the cervical region, nerve root compression in patients older than 50 years is often caused by disc herniation superimposed on chronic spondylotic changes (Bradley et al., 2003). Epidural spinal tumors, particularly metastasis, can also compromise the nerve roots at any level but are more common in the thoracic spine. Other less common causes of radiculopathy include infections such as herpes zoster, cytomegalovirus (CMV), HIV, Lyme disease, tuberculosis, and syphilis. Diffuse root involvement can occur in inflammatory conditions, such as Guillain–Barré and chronic inflammatory polyradiculoneuropathies and carcinomatous meningitis. Radicular pain is described as knifelike or aching and typically is aggravated by coughing, sneezing, and straining. Dermatomal sensory loss or paresthesias referred to the specific dermatome, weakness in the affected myotome, and decreased or absent deep tendon reflexes subserved by the affected root are characteristic clinical features, which can present in varying combinations, depending on the severity. Lumbosacral radiculopathies are more common than cervical radiculopathies. Disc herniations occur at the

L4–L5 or L5–S1 levels in 95% of lumbar radiculopathies, typically compressing the L5 and/or S1 roots (Bradley et al., 2003). At the cervical level, C7 radiculopathies are the most common, followed by C6 (Yoss et al., 1957). In S1 radiculopathy, pain radiates to the buttock and down the posterior leg, and paresthesias may be felt in the lateral ankle and foot. The ankle jerk is frequently diminished or absent, and weakness in the gluteus maximus (hip extension), knee flexors, and foot dorsiflexors may be present. In L5 radiculopathy, the distribution of pain is similar, but with paresthesias on the dorsum of the foot and the lateral aspect of the calf. Weakness can occur in the L5 root innervated muscles, including the gluteus medius (hip abduction), tibialis anterior (dorsiflexion), extensor hallucis longus (extension of the first toe) tibialis posterior (inversion), and peroneus longus (eversion). The ankle reflex is spared in L5 radiculopathy. The straight-leg raising test, in which the examiner has the patient lie in the supine position and then gently raise the leg at the hip while keeping the knee straight to reproduce the symptoms of pain, paresthesias, or numbness, can be a sensitive supportive sign of L5 or S1 radiculopathy (Bradley et al., 2003). Lumbar spinal stenosis deserves special consideration here, as it is relatively common in the elderly population. Spinal stenosis is associated with multilevel degenerative spine disease, which narrows both the foramen through which the nerve roots pass and the interior diameter of the spinal column itself. Such narrowing of the spinal canal is asymptomatic in 21% of cases (Boden et al., 1990) but is frequently associated with low-back pain and can cause symptoms and signs of focal nerve root injury. In addition, it can give rise to the syndrome of neurogenic claudication, in which prolonged walking reliably reproduces symptoms of pain and cramping in the legs, mimicking peripheral vascular disease. Patients may alter their gait to help prevent the onset of symptoms, and one study found that a wide-based gait among patients with low-back pain had specificity exceeding 90% for lumbar spinal stenosis (Katz et al., 1995). Cervical radiculopathies typically cause symptoms in the arms and hands. In C7 radiculopathy, pain radiates to the shoulder, chest, forearm, and hand, and paresthesias involve the middle finger. The triceps reflex is generally reduced or absent. Weakness may be found in the triceps (elbow extension), extensor carpi radialis (extension of the wrist), and extensor digitorium communis (finger extension). In C6 radiculopathy, pain radiates to the shoulder, lateral forearm, and thumb. Paresthesias are felt in the thumb and the index finger. Weakness may occur in the biceps (elbow flexion and supination), pronator teres (forearm pronation), and flexor carpi radialis (wrist flexion). Biceps and brachioradialis reflexes are diminished or absent. Radiculopathies rarely occur in the thoracic spine. However, conditions such as herpes zoster infections, as

Neuromuscular Disorders

well as its sequelae, postherpetic neuralgia, most commonly affect the thoracic region, and diabetes mellitus can involve the thoracic roots as well. Discogenic pain in the thoracic spine is relatively rare compared to the cervical and lumbosacral areas. Symptoms of thoracic radiculopathy may include chronic intermittent anterior thoracic pain, acute nontraumatic thoracic radicular pain, and tenderness in the medial scapular region. In diabetics, the pain of thoracic radiculopathy is generally intense, burning, or shooting pain that radiates to one side of the chest or abdomen from the thoracic nerve root. The symptoms of thoracic radiculopathy can sometimes be confused with cardiac pain, and a cardiac workup may sometimes be indicated. Herpes zoster radiculitis presents with burning pain, itching, hyperesthesia, or paresthesias. The pain may be mild to extreme in the affected thoracic dermatome, often described as stinging, tingling, aching, or throbbing, and can be interspersed with quick stabs of agonizing pain. In most cases, after a few days, the initial phase is followed by the appearance of the characteristic erythematous and vesicular skin rash, limited to one or two thoracic dermatomes on one side of the body without crossing the midline.

Etiology and pathophysiology Spondylosis is characterized by osteoarthritic changes in the spine and osteophyte formation, leading to compromise of the nerve root. In the cervical region, nerve root compression in patients older than 50 years is often caused by disc herniation superimposed on chronic spondylotic changes (Bradley et al., 2003). Epidural spinal tumors, particularly metastasis, can also compromise the nerve roots at any level but are more common in the thoracic spine. Other, less common causes of radiculopathy include infections such as herpes zoster, CMV, HIV, Lyme disease, tuberculosis, and syphilis. Diffuse root involvement can occur in inflammatory conditions, such as Guillain–Barré and chronic inflammatory polyradiculoneuropathies and carcinomatous meningitis. As mentioned previously, lumbar spinal stenosis is caused by degenerative spine disease, leading to narrowing of the intervertebral foramina and the diameter of the spinal canal. Diagnosis The best methods for visually assessing the nerve root and surrounding structures for mechanical compromise are MRI and CT myelography. MRI is preferred because it has equivalent diagnostic capacity to CT myelography, high resolution, and the absence of ionic radiation. However, EMG and NCS may detect damage when no specific structural cause of nerve compression is visualized by radiologic studies (as with diabetic radiculopathy, polyradiculitis, and intermittent positional compression not visualized in the supine position). In addition, EMG/ NCS provides localization of the root affected, as well as

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the severity and evolution of the process, and also helps to exclude other disorders. Sensory nerve conduction studies (NCS) are generally normal in radiculopathies because most radiculopathies occur at the level of the intervertebral foramen, which is proximal to the dorsal root ganglia, allowing integrity between the cell body and the sensory axons to be maintained and precluding detectable distal degeneration. Needle EMG examination is the most important tool in the diagnosis of suspected radiculopathy. Active denervation, manifested as fibrillation potentials or positive sharp waves (spontaneous activity) in two or more muscles innervated by a given root, identifies an active radiculopathy. As fibrillation potentials typically do not appear until 2–3 weeks after the onset of the nerve root compromise, information regarding the timing of the lesion can also sometimes be obtained. Chronic denervation–reinnervation change, identified on needle EMG as motor unit remodeling due to reinnervation (long duration, high amplitude, polyphasic motor unit potentials), typically does not appear until 2 months after the initial injury.

Treatment The treatment of cervical radiculopathies is divided into conservative (nonsurgical) and surgical approaches. Traditionally, physicians have used a number of conservative measures with the intention of relieving the pain, improving neurologic function, and preventing recurrences (Wolff and Levine, 2002). These include analgesics such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), short courses of prednisone, epidural injections of corticosteroids, immobilization with a hard or soft collar, cervical traction, and exercise therapy. However, none of the commonly recommended nonsurgical therapies has been tested in randomized placebo-controlled trials (Wolff and Levine, 2002). Thus, recommendations derive largely from case series and anecdotal experience. The preferences of patients should be taken into account in decision making. As most cervical radiculopathies will improve gradually over several months without surgical intervention, conservative management is indicated as an initial approach in most patients. However, if symptomatic weakness appears; if the patient is in severe, intractable pain and is unresponsive to other interventions; or if there is evidence of intercurrent myelopathy, then surgery may be indicated, provided that a clearly source of mechanical compression can be identified and targeted with the appropriate techniques. Category 1 data regarding the efficacy or timing of surgery for cervical radiculopathy is highly limited (Sampath et al., 1999; Heckmann et al., 1999). Management of lumbar radiculopathy is similar. In the absence of the cauda equina syndrome or progressive neurologic deficit, patients with acute lumbar radiculopathy should be treated nonsurgically with conservative

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measures such as analgesics, physical therapy, and light traction. Prolonged bed rest is ineffective and may make worsen symptoms. Epidural corticosteroid injections may offer temporary symptomatic relief for some patients (Carette et al., 1997). In cases of spinal stenosis, nonsurgical therapy, including exercise bicycle or walking, is recommended, with brief rest when pain occurs (Hilibrand and Rand, 1999). Analgesics, NSAIDs, physical therapy, and epidural corticosteroids may be useful. Decompressive laminectomy may be indicated in some patients with severe intractable pain or progressive motor deficits.

present, should also raise suspicion of an apical tumor of the lung.

Pathophysiology The brachial plexus is a vulnerable structure because of its relationship to surrounding structures, such as the lung apex, lymph nodes, bones (clavicle and ribs), and major vessels. In addition, the plexus is susceptible to traction caused by the mobility of the neighboring shoulder joint and neck.

Diagnosis

Diseases of the brachial and lumbosacral plexus Brachial plexopathy

Epidemiology and clinical features Disorders affecting the brachial or lumbar plexus (plexopathies) are much rarer than neuropathies and radiculopathies. In younger patients, trauma is a common cause of plexus injury. In the elderly, however, metastatic tumors (such as those in the lung, breast, colon, and prostate) involving the plexus may be the first indicator of a larger cancer, and trauma can still occur, particularly with surgical intervention such as cardiac bypass, which requires thoracotomy. Brachial plexopathies are frequently caused by trauma such as traction, compression, or stretch. Other etiologies include ischemia, inflammatory disorders (spontaneous or hereditary), neoplastic infiltration, and radiation-induced and structural causes (such as neurogenic thoracic outlet syndrome). Diseases involving the plexus typically produce severe arm pain, weakness, and atrophy of the involved muscles, with loss of deep tendon reflexes and sensory loss. The pattern of weakness and sensory loss does not follow the territory of a specific nerve or root, and plexopathy should be suspected when the clinical findings cannot be solely explained by the involvement of a particular root or nerve. The upper trunk of the brachial plexus is particularly susceptible to stretch and other traumatic injury, in addition to being a common site for metastatic disease. Injury to the upper trunk of the brachial plexus may produce weakness of upper arm abduction, external rotation of the shoulder, and elbow flexion, and supination with loss of biceps and brachioradialis reflexes. Sensory loss in upper trunk lesions, when present, may involve the lateral aspect of the arm and forearm. Injury to the lower trunk causes weakness of the wrist and finger flexors, as well as the intrinsic hand muscles, with loss of the finger flexor reflex. Sensory loss may affect the medial arm and forearm and the ulnar aspect of the hand. Horner’s syndrome (ptosis, miosis, and anhidrosis) can be superimposed if the sympathetic fibers are involved and, when

Evaluation includes careful history and physical examination, often followed by imaging studies of the plexus (typically MRI with contrast) and, most importantly, comprehensive EMG/NCS. As electrophysiologic assessment of the brachial plexus is highly complex, it is best performed in an academic electromyography laboratory that is experienced in this area and capable of performing advanced techniques such as Erb’s point stimulation.

Specific syndromes and treatment Idiopathic brachial plexitis (neuralgic amyotrophy or Parsonage–Turner syndrome) is an idiopathic, presumably inflammatory, attack on the brachial plexus, often in a multifocal distribution. An autoimmune mechanism is likely. Patients typically present with acute shoulder pain, followed within hours to days by numbness and weakness of the arm or hand. These symptoms rapidly plateau and are usually followed by gradual recovery over months. Most patients recover completely, and recurrence is rare, although some patients may have permanent deficits. Electrophysiologic studies are of critical importance, but nerve conduction abnormalities may not appear for up to several days after onset, and needle EMG may not become abnormal for 2–3 weeks. Imaging studies of the neck and shoulder may be indicated, and serum studies to assess for a broader autoimmune process may be needed. The differential diagnosis includes stroke, acute radiculopathy, and traumatic injury to the shoulder or plexus, such as shoulder dislocation or rotator cuff injury. Most patients recover without treatment. Physical therapy is helpful for aiding recovery and preventing complications. Within days of onset, a tapering course of corticosteroids may be given, although the efficacy of this intervention remains uncertain. Tumors, such as breast cancer and lymphoma, usually reach the brachial plexus by direct extension from axillary or supraclavicular lymph nodes, whereas superior sulcus bronchogenic carcinomas (Pancoast tumors) spread directly to the adjacent plexus. Patients typically present with pain that is relentlessly progressive and is followed after a variable interval by weakness and sensory loss in a pattern reflecting involvement of more than one nerve root (Kori et al., 1981; Lederman and Wil-

Neuromuscular Disorders

bourn, 1984) The weakness affects mainly the muscles innervated by the lower trunk of the plexus and can be associated with Horner’s syndrome. Electrodiagnostic studies in patients with brachial plexus tumors usually demonstrate evidence of severe axonal loss, either diffuse or predominantly affecting the lower trunk (Lederman and Wilbourn, 1984). MRI appears to be more sensitive than CT scanning in detecting a mass in or near the brachial plexus (Thyagarajan et al., 1995). Radiotherapy produces significant pain relief in 40–70% of patients with brachial plexus metastases from lung or breast carcinoma (Kori et al., 1981). Fewer than one-third of patients have improvement in focal motor or sensory deficits following radiotherapy. In patients who received prior radiation exposure to the brachial plexus and later develop metastases, surgical neurolysis may improve pain but does not improve neurologic deficit (Lusk et al., 1987). Patients with cancer who have received radiotherapy to the neck and chest may develop brachial plexopathy due to radiation injury either acutely (rare) or, more commonly, delayed by several months or years. The most common presenting symptoms of radiation plexopathy are numbness and paresthesias of the hand and fingers, with weakness tending to develop later in the course. Most patients do not have pain at the outset, and approximately one-third of patients have minimal or no pain throughout their entire course (Thomas and Colby, 1972; Kori et al., 1981). Kori et al. (1981) reviewed 100 cases of brachial plexopathy in patients with cancer and found that severe pain occurred in 80% of tumor patients but in only 19% of patients with radiation injury. In the majority of cases, the radiation injuries affected the upper plexus (C5–C6 roots), in keeping with the field of radiation. The electrophysiologic abnormality that helps to best distinguish radiation injury from primary neoplastic brachial plexopathy is myokymia, a specific electrical discharge recorded during needle electromyography, consisting of spontaneous, semirhythmic groups of motor unit potentials, discharging in irregular bursts. Treatment of radiation plexopathy is generally symptomatic, with pharmacologic therapy for neuropathic pain and physical therapy to improve strength and function and to reduce contractures. Occasionally, surgery for decompression of the epineural sheath (neurolysis) and removal of scar tissue may be tried to reduce the otherwise intractable pain. However, neurolysis rarely relieves motor or sensory deficits, and it is not clear whether surgery can halt the progression of deficits.

Lumbosacral plexopathy

Epidemiology and clinical features Lumbosacral plexopathies are less common than brachial plexopathies, mainly because traumatic lesions are infrequent in this area. Surgical procedures on the abdominal

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and pelvic organs and pelvic tumors, such as ovarian, uterine, testicular, colon, and retroperitoneal lymphomas, can implicate various parts of the lumbosacral plexus. As in the case of the brachial plexus, it is sometimes difficult to differentiate tumor infiltration from radiation injury. Diabetes mellitus (described shortly), retroperitoneal hematomas (often associated with anticoagulation), and aortic aneurysms extending into the pelvis are other causes of lumbosacral plexopathy. Insidious onset of pelvic or radicular leg pain, followed weeks to months later by sensory symptoms and weakness is characteristic. The main effect of upper lumbar plexus lesions is weakness of flexion and adduction of the thigh and extension of the leg, with sensory loss over the anterior thigh and leg. Weakness of thigh adduction distinguishes this condition from femoral neuropathy. Lower plexus lesions weaken the posterior thigh (hip extension), leg, and foot muscles, and cause loss of the ankle reflex and sensory loss over the posterior thigh and leg and the entire foot. Weakness of hip extension differentiates lower plexus lesions from sciatic neuropathy.

Diagnosis As with brachial plexopathy, diagnosis rests upon history, physical examination, imaging studies, and electrophysiologic evaluation.

Specific syndromes and treatment Treatment of lumbosacral plexopathy in general depends upon successfully addressing the underlying etiology, as neural regeneration cannot yet be facilitated beyond the peripheral nerves’ natural mechanisms for recovery from injury. Diabetic lumbosacral plexopathy, also known as diabetic amyotrophy, is a syndrome of subacute, painful unilateral or asymmetric multiple mononeuropathies, which typically affects older patients with mild or clinical unrecognized diabetes mellitus. The discomfort begins in the lower back or hip radiating to the thigh and knee, has a deep aching quality, and is more severe at night. Weakness and later atrophy are more evident in the pelvic girdle and the thigh muscles, focally at first and then more generally as the disease progresses. The patellar reflex is lost on the affected side. Sensation is intact or mildly impaired. The EMG demonstrates a multifocal axonal neuropathy with denervation typically in the L2 and L3 myotomes. An ischemic vascular mechanism has been suggested, affecting the vasa nervorum. Complete recovery is the rule, but it often requires months or years and it may recur. Treatment is centered initially on pain control with anti-inflammatory medications, tricyclic antidepressants, anticonvulsants, and narcotics in severe cases, along with physical therapy and assistive devices. Immunomodulatory therapy, such as IVIG and steroids, has been used experimentally, with reported successes in

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some case series, but controlled trials are required (Dyck et al., 2005). Good glycemic control is of paramount importance, and physical therapy can improve functional recovery.

Disorders of the peripheral nerve Epidemiology and clinical features Neuropathy is a disease of the peripheral sensory, motor, or autonomic nerves. Neuropathy may be pure motor, pure sensory, or mixed sensorimotor. It may occur symmetrically throughout the body (polyneuropathy), individually in single nerves (mononeuropathy), or in multiple, scattered nerves in an irregular distribution (multifocal neuropathy). Autonomic neuropathy may accompany a larger neuropathic process or occur independently. Polyneuropathy has hundreds of potential etiologies. Diabetes mellitus is the most common cause of polyneuropathy in the United States, as it is in most of the Western world, affecting at least 1–2% of the population. The prevalence of polyneuropathy progressively increases and is particularly common in patients over the age of 60, at approximately 3.5% in the outpatient elderly population. In geriatric patients, the incidence of idiopathic distal symmetric polyneuropathy is high and accounts for at least 25–30% of cases. Diagnosis Evaluation of a patient with suspected neuropathy begins with a careful history, to provide information about the symptoms, distribution, and course of the neuropathy. The medical and social history and review of systems may alert the examiner to a possible systemic cause, such as diabetes, inflammation, or cancer, or to a toxic or nutritional etiology. A positive family history is suggestive of hereditary neuropathy. A detailed neurologic examination is required to confirm the presence of neuropathy and to provide information regarding the functional impairment, distribution, and severity of the disease. Potentially treatable conditions such as vitamin B12 deficiency, glucose intolerance, liver and renal disease, vasculitis, and paraproteinemias are easily tested in the blood. Other blood studies may also be indicated, including assays for antibodies directed against specific nerve or myelin components, some of which may be associated with specific clinical syndromes, such as anti-GM1 antibody (acute motor axonal neuropathy (AMAN)), antiGQ1b (Miller Fisher variant of Guillain–Barré syndrome), anti-Hu antibody (paraneoplastic sensory neuronopathy), and antimyelin-associated glycoprotein (MAG) antibody (multiple myeloma). Searches for other infectious processes, particularly HIV and hepatitis, may also be indicated. More rarely, serum cryoglobulins and serum and urine heavy metal screening may be needed.

Lumbar puncture is especially important for the diagnosis of autoimmune neuropathies, such as acute inflammatory demyelinating polyradiculopathy and chronic inflammatory demyelinating polyneuropathy, and may provide additional information regarding infectious and neoplastic diseases as well; however, it is not needed for most neuropathy evaluations. EMG and nerve conduction studies are the single most important diagnostic test for the evaluation of neuropathy. The indications for nerve biopsy are highly limited, and it should be used sparingly, as harvesting of the sural nerve at the ankle (the most common procedure) carries a 10–15% risk of chronic neuropathic pain at the biopsy site. Biopsy can help to establish the diagnosis in suspected vasculitis, amyloidosis, sarcoidosis, giant axonal neuropathy, and leprosy. More refined diagnostic tools include quantitative sensory testing, autonomic studies, and skin biopsy with staining and quantitation of intraepidermal small sensory nerve fibers.

Acquired neuropathies Guillain–Barré syndrome

Epidemiology and clinical features Guillain–Barré syndrome refers to a group of immunemediated disorders targeting the peripheral nerves, having an annual incidence ranging from 1 to 2 cases per 100,000 people and affecting all ages. The most common form of Guillain–Barré syndrome, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), accounts for 85–90% of cases. Less common variants of Guillain– Barré syndrome include AMAN, also associated with Campylobacter jejuni infection, and acute motor sensory axonal neuropathy (AMSAN), which together account for approximately 10% of Guillain–Barré cases. AIDP often begins 1–3 weeks after an infection or inciting event, such as surgery. Seventy percent of patients initially have paresthesias or vague numbness in their hands and feet. Symmetric weakness appears a few days later and progresses over days to a few weeks. Paralysis is maximal by about 2 weeks in more than 50% of patients and by 1 month in more than 90%. If the disease progresses longer, it is considered subacute or chronic inflammatory polyradiculoneuropathy. Ascending weakness beginning in the legs is typical, although descending paralysis with predominant proximal muscle weakness rarely appears. Facial weakness occurs in half of patients with AIDP, and ophthalmoparesis and lower cranial neuropathies can cause dysarthria and dysphagia. Life-threatening respiratory paralysis may rapidly appear as the disease progresses, necessitating intubation and mechanical ventilation. All patients with AIDP must be identified as quickly as possible and carefully monitored until the disease has stabilized. One quarter

Neuromuscular Disorders

of patients with AIDP require mechanical ventilation. Another serious complication, more common in patients with severe quadriparesis and often difficult to control, is autonomic nervous system involvement, which can cause dangerous fluctuations in blood pressure or precipitate cardiac arrhythmia. Significant autonomic dysfunction in AIDP carries a high mortality. On examination, weakness is symmetric and ranges from mild-to-severe flaccid quadriparesis. Sensation is usually normal, despite sensory symptoms, although mild distal vibratory loss may be found. Reflexes are diminished or absent, but sphincter tone is normal. Bedside pulmonary function testing (forced vital capacity and negative inspiratory force) may reveal impending respiratory failure. Patients with autonomic involvement may demonstrate cardiac arrhythmia, fluctuations in blood pressure, flushing and sweating, and abnormalities of gastrointestinal motility.

Etiology and pathophysiology Upper respiratory and gastrointestinal infections or nonspecific febrile illness precedes neurologic symptoms in about 60% of Guillain–Barré syndrome patients, usually by 1–3 weeks, and there is considerable evidence for autoimmune-mediated demyelination as the cause of this disorder. CMV, Epstein–Barr virus, Mycoplasma pneumoniae, HIV, and hepatitis A and B infection have all been associated with AIDP. Several other antecedent events, including surgery, cancer, pregnancy, autoimmune disease, and vaccinations (such as the swine flu vaccine of 1976), have also been linked to AIDP. In this disorder, there is significant segmental demyelination, disproportionately affecting the roots and proximal nerve segments at onset. AIDP demonstrates both humoral and cell-mediated mechanisms of nerve injury. Pathologically, demyelination begins in the proximal nerves and then extends distally as the disease progresses. However, as in the cases of AMAN and AMSAN, the primary immune-mediated attack is not against the myelin, but rather against a component of the axon, leading rapidly to axonal degeneration and subsequent poor recovery. Although respiratory infections are the most common precedent in AIDP, C. jejuni (a cause of gastroenteritis) is the most frequently identified organism in cases of axonal GBS (AMAN). There is growing evidence that cross-reactivity of C. jejuni epitopes and peripheral nerve gangliosides may play a role in AMAN via inducing autoimmune axonal attack.

Diagnosis Imaging studies of the spinal cord may be necessary to rule out a myelopathy. All patients with acute to subacute onset of symmetric weakness and areflexia should have a lumbar puncture after spinal cord disease has been excluded. CSF protein concentration

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begins to rise a few days after onset of symptoms and peaks in 4–6 weeks. The cell count typically remains normal or shows only mild lymphocytic pleocytosis (more common in patients with HIV infection). Appropriate evaluations for infection should be performed, and electrocardiogram and chest radiographs should be obtained. In AIDP, nerve conduction studies demonstrate demyelination with slowed motor conduction velocities and prolonged distal motor latencies within 3–5 days of symptom onset, but they may be normal if performed within the first few days of onset. Studies assessing proximal demyelination (F-wave responses), an early feature of Guillain–Barré syndrome, may be diffusely abnormal at the time of clinical presentation. Sensory conduction studies are often normal at presentation but may be slowed. In early Guillain–Barré syndrome, needle EMG may show a reduction in motor unit recruitment. Evidence of axonal injury (denervation change with fibrillations potentials), if present, usually does not appear on EMG for 2–3 weeks. Prominent axonal change on needle EMG supports significant axonal injury and suggests a worse prognosis for complete recovery (AMAN or AMSAN).

Treatment Both intravenous immunoglobulin (IVIG; 0.4 g/kg/day for 5 days) and plasmapheresis (five to six exchanges over 1–2 weeks) appear equally effective when given within the first 2 weeks after onset. Combination therapy consisting of both does not seem to confer additional benefit. Plasmapheresis may be precluded in hemodynamically unstable patients. These measures generally increase the pace of recovery, although their effects on the severity of the disease, the risk of respiratory and autonomic dysfunction, and ultimate disability are less clear. Randomized trials of oral and intravenous corticosteroids (methylprednisolone and prednisolone) have failed to show benefit in Guillain–Barré syndrome.

Prognosis Most patients with Guillain–Barré syndrome return to normal function. After disease progression stops, symptoms usually plateau for 2–4 weeks, followed by gradual recovery. About 20–25% of patients require mechanical ventilation, and 5% die, usually from the complications of respiratory failure or autonomic dysfunction. Residual motor weakness is present in 25% of patients after 1 year. Older age (60 years or older), ventilatory support, rapid progression (<7 days), and low motor amplitudes (suggesting axonal injury) on early nerve conduction studies are poor prognostic factors associated with a less than 20% probability of walking independently at 6 months.

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Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Epidemiology and clinical features The prevalence of CIDP is estimated to range from 1.0 to 7.7 cases per 100,000 people. CIDP disproportionately affects men and those older than 50 years of age. CIDP can present in a stepwise progression with periods of plateau, a steadily declining course, or a course with recurrent episodes. Most patients initially have predominately motor symptoms, although examination typically reveals both motor and sensory signs. Weakness may begin focally but usually becomes bilateral or multifocal within a few months of onset. As with Guillain–Barré syndrome, CIDP is usually symmetric, and both proximal and distal muscles are affected. Some degree of proximal hip flexor weakness on examination (often unnoticed by the patient at presentation) is considered by some authorities to be an essential feature. Cranial neuropathies and respiratory muscle weakness are rare. Pathophysiology The etiology of CIDP is unknown, and it is unclear whether preceding vaccinations, infections, surgeries, or other insults are implicated. A study of 92 patients with CIDP found a history of preceding infection or some other precipitating event in 32% of the cases, and there was a significantly higher titer for CMV antibodies in the serum of patients with CIDP than in controls (McCombe et al., 1987).The presence of inflammatory infiltrates in peripheral nerves and much other experimental data supports an autoimmune etiology. Epineurial and endoneurial infiltrates consist mainly of T lymphocytes and macrophages expressing MHC class II molecules and chemokine receptors (Schmidt et al., 1996). Diagnosis Nerve conduction studies typically reveal significant demyelination with slowed conduction velocities, prolonged distal latencies, conduction block, and abnormal late responses (such as F waves). Both motor and sensory nerves may be affected. In severe cases, evidence of secondary axonal injury may be seen. Lumbar puncture reveals an elevated protein concentration, but the cell count typically remains normal or shows only mild lymphocytic pleocytosis. Nerve biopsy, which carries a substantial risk of permanent focal neuralgia (10–15%), is no longer routinely recommended. Treatment Most patients improve with immunomodulatory therapy. Long-term therapy is often required, and complete remission is rare. The goals of treatment are to restore patients to a level of function sufficient to enable them to go about their daily activities while minimizing the adverse effects

associated with therapy. Some patients have persistent symptoms despite aggressive combination therapy. Oral prednisone therapy is effective in most patients. Dosage is 1 to 1.5 mg/kg/day, titrated according to clinical response after several weeks. Alternate-day therapy (in equivalent weekly doses) may be instituted after 2–3  months in patients who improve, with subsequent taper by 5–10 mg every 2–4 weeks thereafter. The side effects of long-term corticosteroid administration may limit their use, particularly in older patients. Some patients respond incompletely to corticosteroids and require adjunctive therapy or a switch to an alternate modality. IVIG and plasmapheresis are both effective but often must be continued indefinitely. The evidence shows that IVIG, prednisone, and plasma exchange (PE) have similarly efficacy. Disease severity, long-term side effects, concurrent illness, cost of treatment, venous access, and age should all be taken into consideration when selecting therapy. A large trial of CIDP treatment demonstrated short-term and long-term efficacy and safety of IVIG, supporting use of IVIG as a therapy for CIDP (Hughes et al., 2008). If IVIG and corticosteroids are ineffective, PE should be considered. Two double-blind, randomized, controlled trials showed that PE produces significant improvements in about two-thirds of patients (Dyck et al., 1986; Hahn et al., 1996). Other adjunctive immunosuppressive therapies, such as azathioprine or mycophenolate, are often considered in patients with persistent symptoms, although there is limited evidence of their benefit in CIDP. In patients with disease that is refractory to all other modalities, cyclophosphamide (oral or intravenous) may be of benefit.

Paraproteinemic polyneuropathy Epidemiology and clinical features Abnormally elevated serum immunoglobulin levels can cause a paraproteinemic neuropathy, sometimes because of the production of antibodies targeted to myelin components. Paraproteinemias typically affect men older than 50 years of age, with an increasing prevalence with each decade thereafter. Paraproteinemic neuropathies are also associated with lymphoma, leukemia, amyloidosis, cryoglobulinemia, multiple myeloma, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, Monoclonal protein (M-protein), and skin changes), and Waldenström macroglobulinemia. In about two-thirds of patients, no underlying neoplasm or other cause for the monoclonal spike is found (such as MGUS). However, 20% of patients with MGUS ultimately develop a malignant plasma cell disorder. IgG is the most common paraprotein found in patients with MGUS, but IgM is the most common in patients with neuropathy, followed by IgG and, rarely, IgA. Patients with IgM gammopathy often present with large-fiber sensory loss, prominent

Neuromuscular Disorders

tremor, and sensory ataxia. Distal weakness and atrophy can occur as the disease progresses. IgM gammopathy is predominantly a demyelinating neuropathy, although axonal loss may occur. Fifty percent of patients with IgM neuropathy have antibodies to MAG, a protein found in the periaxonal Schwann cell membranes. Anti-MAG antibodies are associated with a discrete clinical syndrome consisting of a slowly progressive, large-fiber neuropathy with late distal weakness. IgG gammopathy can be either axonal or demyelinating. Its clinical presentation is usually similar to that of IgM gammopathy.

Pathophysiology The excess serum protein in these disorders (paraprotein or M-spike) is usually a monoclonal immunoglobulin. It may be an isolated abnormality or a by-product of a plasma cell malignancy. The M-proteins are thought to cause neuropathy through autoimmune demyelination and axonal attack, corresponding to the antigenic specificity of the autoantibodies. Deposits of anti-MAG M-proteins and compliment are found on the affected myelin sheaths (Latov, 1995). Diagnosis Serum and urine protein electrophoresis may detect the M-protein and are frequently used as a screening tool during the initial evaluation of polyneuropathies. However, immunofixation is a more sensitive technique in detecting the M protein in some cases when protein electrophoresis is unrevealing. Therefore immunofixation has become the screening test of choice in cases of suspected monoclonal gammopathy. EMG usually demonstrates demyelination and axonal loss. Treatment One-third of patients with MGUS neuropathy improve within days to weeks of IVIG therapy (0.4 g/kg/day for 5 days), plasmapheresis (220 mL/kg in four to five treatments), or oral corticosteroids, often in combination with other immunosuppressants. Patients with IgG or IgA monoclonal gammopathy–associated neuropathies respond better than those with IgM monoclonal gammopathy. In patients with osteoscherotic myeloma, including patients with POEMS syndrome, the neuropathy usually improves with resection of solitary bone lesions, focused radiation, or chemotherapy with melphalan, cyclophosphamide, or prednisone. Primary systemic amyloid neuropathy (nonfamilial) responds poorly to melphalan and prednisone, despite improvement in survival with these medications.

Paraneoplastic neuropathy Epidemiology and clinical features Paraneoplastic neuropathy may appear as the first manifestation of an occult neoplasm or may not appear until

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after a cancer is diagnosed. As cancer is more common with advancing age, these neuropathies are seen most commonly in patients over the age of 60. Several different paraneoplastic neuropathy syndromes exist. Paraneoplastic sensory neuropathy is the most common and is often associated with anti-Hu antibodies (type 1 antineuronal nuclear autoantibodies, or ANNA-1). It is strongly associated with small cell lung cancer, but it is also seen in liver, bladder, breast, and pancreatic cancers, as well as lymphoma and sarcoma. Antiamphiphysin antibody may also be present in paraneoplastic sensory neuropathy, although it is not as specific as anti-Hu for a sensory neuropathy. Antiamphiphysin antibodies are also associated Lambert–Eaton myasthenic syndrome (LEMS) and stiff-person syndrome. Autonomic neuropathy is also sometimes seen with anti-Hu-associated sensory neuropathy and may cause gastroparesis, achalasia, dysphagia, and pseudoobstruction. Other paraneoplastic syndromes include subacute sensory neuronopathy, demyelinating neuropathy (usually a feature of paraproteinemic malignancies; see the preceding discussion in Paraproteinemic polyneuropathy), mononeuropathy multiplex, MND, and motor neuropathy. Paraneoplastic sensory neuropathy is characterized by numbness, painful paresthesias, and lancinating pain. It may begin in one limb and then spread to the remaining limbs, but it is usually generalized by the time of presentation. All sensory modalities are lost, and proprioception is most severely affected. Strength is normal or only minimally decreased, and tendon reflexes are reduced or absent. Frequently, there is concurrent involvement of the myenteric plexus, autonomic ganglia, spinal cord, brainstem, cerebellum, or limbic cortex. Subacute sensory neuronopathy (Denny-Brown syndrome or dorsal root ganglionitis) appears to be distinct from paraneoplastic sensory neuropathy; the dorsal root ganglion is the site of primary injury. Women are affected twice as often as men, and small cell lung cancer is, again, the most common underlying tumor. Breast carcinoma, ovarian cancer, and lymphoma are also frequently associated with this neuronopathy. Paraneoplastic demyelinating neuropathy can mimic either Guillain–Barré syndrome (usually associated with Hodgkin disease) or a CIDP (non-Hodgkin lymphoma). Multiple myeloma is also associated with a demyelinating neuropathy and can be associated with POEMS syndrome. Vasculitic neuropathy is associated with hematologic malignancy, and these patients typically present with mononeuropathy multiplex. A form of MND has been described as part of paraneoplastic encephalomyelitis and may respond to treatment of an underlying associated tumor; subacute motor neuropathy has also been associated with malignancy. Finally, subacute paraneoplastic autonomic neuropathy may be associated with neuronal nicotinic acetylcholine receptor (AChR) antibodies.

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Pathophysiology Peripheral neuropathies may develop in cancer patients from one or more of three distinct pathogenic processes: (1) Direct invasion of nerve roots by neoplastic cells; (2) a remote effect of cancer on the peripheral nervous system— that is, a paraneoplastic process; and (3) toxic side effects from chemotherapy. Paraneoplastic sensory neuropathy with associated autoantibodies is perhaps the best-defined peripheral nerve disorder related to cancer. The role of the autoantibodies in the pathogenesis of the neuropathy is unclear. One hypothesis suggests that antibodies directed toward tumor cell antigens cross-react with identical neuronal nuclear proteins, resulting in cell damage and neuronal death. Another possibility is that autoantibodies may simply be generated during the evolution of the neuropathy but not be related pathogenetically to the clinical syndrome; some evidence suggests that an immune response mediated by T cells may be important in mediating the nervous system injury (Dalmau et al., 1991). Diagnosis Anti-Hu antibodies are often associated with paraneoplastic sensory neuropathy, but their absence does not rule it out. Nerve conduction studies show low-amplitude or absent sensory nerve action potentials with preserved motor amplitudes. Nerve biopsy is not usually needed unless amyloidosis is suspected and cannot otherwise be confirmed. CSF analysis may reveal elevated protein concentration and mild pleocytosis, especially in patients with associated lymphoma. Patients with subacute sensory neuropathy in whom no underlying cause is found should be screened for the presence of a malignancy. Neoplastic screening may be indicated as well in other instances of “idiopathic” neuropathy, depending on the patient’s age, history, and risk factors. True paraneoplastic neuropathies must be distinguished from other forms of nerve injury associated with cancer and its treatments, especially tumor invasion of the peripheral nerves and the toxic effects of chemotherapy and radiation. Treatment Treatment of the underlying neoplasm is the mainstay of therapy and offers the best chance of improvement, although neuropathic symptoms may persist if the nerve injury is well established. Treatment with corticosteroids, immunosuppressants, and plasmapheresis is of questionable benefit, although IVIG has been reported to be effective in some patients.

Toxic neuropathies A wide range of toxins may cause neuropathies. Nerves can be injured by industrial and environmental toxins (such as aromatic hydrocarbons), heavy metals (such as

lead and arsenic), and medications. Antineoplastic drugs are common offenders, causing a length-dependent sensorimotor axonal neuropathy, pure sensory neuropathy, or ganglionopathy. A symmetric stocking-glove distribution neuropathy is most often found with distal weakness and hyporeflexia. Treatment consists of discontinuing the offending agent.

The diabetic neuropathies Epidemiology and clinical features Diabetes mellitus is the most common cause of neuropathy in the United States, and neuropathy is identified by objective testing in two-thirds of diabetic patients. As with cancer, the prevalence of diabetes increases with each decade over 40 and is particularly common in patients over the age of 60. Diabetic nerve injury produces many clinical syndromes. Distal symmetric sensorimotor neuropathy is most common and may appear in isolation as the first manifestation of diabetes. Different syndromes, however, can appear in virtually any combination. Distal symmetric neuropathy begins with numbness, paresthesias, or dysesthesias (alone or in combination) in the feet. Over months or years, symptoms ascend up the leg and eventually affect the upper extremities. Painful diabetic neuropathy may also develop at this early stage. Loss of foot sensation in diabetic patients greatly increases the chance of unrecognized cutaneous ulceration, which, along with impaired cutaneous healing, can result in gangrene and limb amputation. Loss of light touch, pain, and temperature typically occurs early, followed by loss of proprioception, which may cause gait ataxia. Distal weakness and atrophy follow, with gradual subsequent ascension. Pure small fiber diabetic neuropathy is also relatively common. The small cutaneous nerve fibers that sense pain and temperature are often damaged in diabetic patients, resulting in loss of distal pinprick and temperature sensation, sometimes accompanied by the development of burning, electric, aching, stabbing, and pins-and-needles dysesthesias and pain, which can be incapacitating. Patients may have allodynia (the perception of a nonpainful stimulation as painful), especially at night, and foot contact with bed sheets may interfere with sleep. Painful neuropathy spontaneously improves over months to years in some patients, but becomes a chronic symptom in others. Pure small fiber neuropathy may be reversible if good control of serum glucose is achieved and maintained, but it often is followed by large fiber injury if the diabetes is not adequately treated. Autonomic neuropathy affects nearly 50% of diabetic patients, commonly causing genitourinary dysfunction (erectile dysfunction and neurogenic bladder), postural hypotension, and gastrointestinal dysmotility. Autonomic

Neuromuscular Disorders

derangement can contribute to silent cardiac ischemia and cardiac arrhythmia, the most common causes of death in diabetic patients. In addition to these neuropathies, patients with diabetes are prone to many mononeuropathies resulting from the occlusion of the vasa nervorum in individual nerves secondary to diabetic small vessel disease. These mononeuropathies can occur in the cranial nerves (especially the sixth and seventh) or in any peripheral nerve, creating acute pain, weakness, and numbness. These syndromes are often thought to be due to stroke on presentation, and a full acute evaluation is often indicated. Some degree of recovery may occur, though permanent deficit, ranging from mild to severe, may persist.

Pathophysiology The pathophysiology of the diabetic neuropathies is complex and includes a combination of deleterious events. Ischemic injury, due to disease of the small arterioles supplying the peripheral nerves (the vasa nervorum), plays a substantial role in human and animal models, but oxidative injury, deficiency of nerve growth factors, activation of deleterious alternative metabolic pathways due to insulin deficiency (the polyol hypothesis), nitric oxide deficiency, and deficiency of insulin itself (as insulin has important nerve growth factor properties) have all been implicated. Maintenance of normal serum glucose levels through insulin and antiglycemic measures can ameliorate most, if not all, of these problems in many patients and in animal models. Diagnosis No single test can prove that the primary cause of nerve injury is diabetes, as diabetic neuropathy is a clinical diagnosis and a diagnosis of exclusion. Careful history and physical examination may define patterns conforming to a single diabetic syndrome or some combination. Diabetic patients may develop neuropathy from a cause other than diabetes, and at least one careful evaluation for other potential causes is warranted. In patients who present with neuropathy but no prior history of diabetes, a 3-hour glucose tolerance test may be useful when fasting glucose measures or glycosylated hemoglobin are normal or borderline. EMG and nerve conduction studies define the type of nerve injury and are also critical for identifying superimposed conditions such as carpal tunnel syndrome and lumbosacral radiculopathy, to which patients with diabetes are more susceptible than the general population. Distal symmetric diabetic neuropathy begins as an axonal disorder, with decreased sensory and motor amplitudes. Demyelinating change causing nerve conduction slowing often follows, and patients frequently have both axonal and demyelinative features at EDX. Pure small fiber neuropathy, which does not produce nerve conduction or

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EMG abnormalities, can be diagnosed through quantitative sensory testing and quantitation of small nerve fiber density via epidermal skin biopsies. When autonomic symptoms are present, specific tests of autonomic function may be indicated. Cardiac symptoms require more detailed cardiologic evaluation.

Treatment Optimal glucose control is the most effective method of preventing the development of diabetic neuropathy and limiting its progression if it does develop. Intensive control is less likely to reverse existing neuropathy. Diabetic foot care is of critical importance, and patients should undergo diabetic foot care education. If other foot abnormalities (such as bony deformities, ingrown nails, or corns) are present, referral to a podiatrist may be necessary. Autonomic dysfunction may necessitate assistance from the following specialists: urologist, gastroenterologist, and, especially, cardiologist. Physical therapy, gait training, occupational therapy, and orthotics are also important and should be appropriately utilized.

Idiopathic polyneuropathy The term idiopathic polyneuropathy is used in the 25% of patients with distal polyneuropathy for whom no cause is identified after extensive diagnostic evaluation. Patients with idiopathic polyneuropathy are typically in their sixth decade and have a slow progression of symptoms over years. Distal sensory or sensorimotor symptoms and signs are most common, and legs are affected more significantly than the arms. Electrophysiologic testing shows axonal polyneuropathy, and nerve biopsy reveals degeneration and regeneration of axons without inflammatory changes. Rarely, vasculitic changes may be found on biopsy examination in patients with idiopathic neuropathy. Immunomodulatory treatment with corticosteroids, IVIG, or plasmapheresis has not shown clear benefit. (Vrancken et al., 2004).

Hereditary motor and sensory neuropathy Epidemiology and clinical features Hereditary motor and sensory neuropathy (HMSN), or Charcot–Marie–Tooth (CMT) syndrome, is one of the most common neurogenetic disorders, with a prevalence of 30 cases per 100,000. Genetically, it is divided into autosomal dominant, autosomal recessive, and X-linked types. Phenotypically, it is traditionally divided into those types with very slow nerve conduction velocities; such as CMT1 and demyelinating) and those with normal or

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near-normal conduction velocities and low amplitudes (such as CMT2 and axonal). For all types, onset is usually in childhood, adolescence, or young adulthood. However, though onset after the age of 40 years is unusual, symptomatic onset in CMT2 may appear from midadulthood to as late as the seventh decade (Bennett et al., 2008). Distal muscle weakness and atrophy, with predilection for the peroneal myotome, loss of distal muscle stretch reflexes, and severe large fiber sensory loss, are characteristic. Pes cavus and hammer toes are common, as are foot sores and poorly healing ulcers.

Pathophysiology The pathophysiology of the HMSNs varies according to the specific mutation causing the variant. The most common varieties (such as CMT1) are associated with defects resulting in disordered myelin formation and maintenance, but the specific molecular mechanisms for most of these diseases have yet to been worked out. Diagnosis History, family history, and physical examination are highly important. Electrodiagnostic studies show axonal injury in CMT2 and predominately demyelinative change in CMT1. Genetic testing is available for many of the HMSNs and is confirmatory when positive. Treatment Management is supportive and rehabilitation measures are advised. Many patients with foot drop will benefit from using ankle-foot orthoses to ameliorate foot drop. Drugs that cause peripheral neuropathy should be avoided. Genetic counseling is based on the inheritance pattern of the disease. Occupational therapy is recommended for strategies to assist with a variety of manual activities, such as writing and eating.

Neuromuscular junction disorders Myasthenia gravis Myasthenia gravis is an autoimmune postsynaptic disorder of the neuromuscular junction characterized by fluctuating weakness and fatigability. Most cases are caused by autoantibodies directed against the nicotinic AChR in the skeletal muscle membrane. Blocking of neuromuscular transmission due to interference with AChR function produces the clinical weakness that is the hallmark of the disease.

Epidemiology and clinical features The disease onset has a bimodal distribution, appearing in patients from 15 and 30 years old and also those between 60 and 75. Females predominate in the younger group, whereas males comprise more of the older patients.

Though myasthenia has been eminently treatable since the 1970s, natural history data from the years preceding effective therapy demonstrated a mortality rate of 20–30% due to respiratory failure (Oosterhuis, 1981). The principal clinical manifestations of myasthenia gravis are fluctuating weakness and premature fatigue, affecting the ocular, bulbar, and peripheral muscles. Prominent fatigability with diplopia and ptosis, worsening with sustained gaze and improving with rest, are characteristic. With generalized disease, proximal weakness of the arms and legs, as well as neck flexion and extension weakness, are common and more severe after physical activity, especially toward the end of the day. Dysarthria with nasal speech can occur with sustained conversation. Dysfunction of the swallowing muscles and respiration is particularly dangerous because of the risk of aspiration or respiratory failure. Diplopia and ptosis are early primary features in 50–60% of patients. Isolated extraocular and palpebral muscle weakness may be the only initial manifestations in some patients (ocular myasthenia gravis). However, 85–90% of patients presenting with ocular symptoms will eventually develop more generalized weakness (Oosterhuis, 1988; Beekman et al., 1991). However, those patients with pure ocular disease for at least 2 years have only a 10% chance of further progression to generalized disease (Grob et al., 1987). A higher prevalence of this form of the disease has been reported in male patients older than 40 years (Grob et al., 1987). The most serious complication of myasthenia gravis, however, is respiratory muscle weakness, which may progress to hypoventilation and respiratory failure. Dyspnea on exertion may be the initial manifestation, followed by dyspnea at rest. Fatal respiratory dysfunction may develop rapidly, over a matter of hours. Myasthenia has been associated with a number of other disorders. The best-known association is with thymoma, and approximately 10–15% of myasthenics have a thymoma. The mean age of thymoma patients is 50 years. Of thymomas, 90% are benign and easily treatable with resection, whereas 10% are malignant and will spread to local tissue, the lymphatic system, or the blood. The frequency of autoimmune diseases is also increased in myasthenics. Hyperthyroidism is the most prevalent. Connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as sarcoidosis, have also been described.

Pathophysiology Myasthenia gravis is one of the best understood of all autoimmune diseases. It is caused by autoantibodies directed against epitopes on or around the AChR in the postsynaptic membrane of the neuromuscular junction. These antibodies can block the binding of acetylcholine (ACh) to its receptors or cause receptor malfunction through other mechanisms and may initiate immune-mediated

Neuromuscular Disorders

degradation of the receptors, reducing receptor numbers and damaging the postsynaptic membrane. Decreased number and malfunction of the ACh receptors results in fewer miniature end plate potentials (MEPPs) and a lower end plate potential (EPP), reducing the likelihood of reaching the depolarization threshold necessary for muscle contraction.

Diagnosis Three ACh antibody assays are available for diagnostic evaluation: the AChR binding, modulating, and blocking antibodies. Binding antibody assays are widely available and have an average sensitivity of 60–70%. Blocking antibodies are found in only 1% of myasthenic patients without binding antibodies. Although the modulating antibody assay may also be more sensitive in patients with early, mild, or pure ocular disease, it is nonspecific and prone to false positive results due to its technical complexity. Some patients with symptomatic disease do not have detectable AChR antibodies by theses assays and have been traditionally termed seronegative myasthenia gravis. However, between 40% and 70% of patients who are seronegative for anti-AChR antibodies have antibodies to muscle-specific tyrosine kinase (MuSK). Anti-MuSK myasthenia gravis affects predominantly women and involves mainly the neck, shoulder, and respiratory muscles, with less limb weakness and rare ocular symptoms. The molecular mechanisms underlying the interactions of the anti-MuSK antibody in MG are not well understood. Antistriated muscle antibodies are another class of antibodies and can be found in up to 90% of patients with myasthenia gravis and concurrent thymoma (Limburg et al., 1983). Progressive rises in antistriational antibody titers can be the first indication of thymic tumor recurrence following resection. Two major electrodiagnostic tests are available to assess neuromuscular junction function. Repetitive nerve stimulation (RNS) studies of the peripheral nerve are widely available and demonstrate significant decrements in the CMAP amplitude in myasthenics, but have a sensitivity of 60–70%. A second, more sophisticated test of neuromuscular junction function is single fiber electromyography, a technique measuring the variability in the time required for neuromuscular transmission at the level of the single muscle fiber. Though technically complex and not widely available, single fiber electromyography has a sensitivity of 95% or greater in generalized and 90% or greater in ocular myasthenia gravis when appropriate muscles are tested (Howard et al., 1994). Because of its high sensitivity, single fiber electromyography is mainly indicated when the diagnosis of myasthenia is still suspected and other confirmatory tests such as AChR antibodies and RNS are unrevealing. This test is particularly useful in cases of mild generalized, ocular, or seronegative myasthenia gravis.

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Intravenous administration of edrophonium (tensilon), an acetylcholinesterase inhibitor, to a suspected myasthenia gravis patient may transiently improve certain symptoms, providing supporting evidence for the diagnosis. This test, known as the tensilon test, may be up to 90% sensitive if an appropriate muscle is available for testing. However, it can be technically challenging and carries a risk of life-threatening cardiac arrhythmia, and it is rarely performed in contemporary assessment of MG.

Treatment Myasthenia gravis can be adequately controlled in the vast majority of patients with appropriate immunomodulatory therapies, and most patients lead normal lives. Well-controlled MG should not decrease life expectancy. However, if not properly treated, it can be disabling or fatal. Acetylcholinesterase inhibitors inhibit the enzyme that metabolizes acetylcholine and, therefore, increase the availability of acetylcholine at the neuromuscular junction. Acetylcholinesterase inhibitors do not effect lasting changes in the primary disease process and are purely symptomatic therapy. They have greatest utility in pure ocular disease, in mild generalized disease, or as adjunctive therapy in stable but symptomatic disease after an appropriate course of immunosuppressive therapy. Pyridostigmine is the most commonly used agent in the United States and is typically started at 30 mg orally every 4–6 hours and titrated by clinical response. It takes effect within 20–30 minutes and peaks at approximately 2 hours in most patients. The main side effects are abdominal cramps and diarrhea, although it is well tolerated by most patients. Because the myasthenic thymus demonstrates an increased percentage of mature T-lymphocytes and thymic B-cells, with active AChR antibody production, removal of the thymus (thymectomy) may be of benefit. Thymectomy should be considered in most patients with new-onset myasthenia and is usually recommended in all patients with thymoma or in myasthenics younger than age 60 with generalized weakness. Patients with pure ocular disease have not traditionally been treated with thymectomy, and its benefits in this group remain questionable. The procedure has been discouraged in patients older than 60 because of increased surgical risk, as well the fact that the thymus significantly atrophies with advancing age. Corticosteroids have been particularly effective in generalized and ocular myasthenia when symptoms are disabling and not controlled with acetylcholinesterase inhibitors. Patients should be started at high doses (60–80  mg) in severe cases, but lower doses, gradually increasing over time, can be employed in particular clinical circumstances. Some patients may experience a brief, steroid-induced exacerbation within the first week

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of high-dose therapy, lasting for 1–2 days, after which improvement begins. After high-dose therapy is initiated, sustained improvement appears in most patients within 2  weeks, with substantial improvement within 4–12 weeks; after that time, patients on daily therapy may be switched to alternate-day therapy. Maximal improvement appears within 6 months in most patients, after which the alternate dose is further reduced slowly until the minimal effective dose is reached. If steroids cannot be reduced to an acceptable level due to worsening symptoms, alternative immunosuppressive therapies should be considered. Complications of steroid therapy include weight gain, Cushingoid features, osteoporosis, cataracts, GI symptoms, hypertension, diabetes, and increased susceptibility to infections. Other immunosuppressive therapies are typically used when steroid therapy fails or is contraindicated, or when excessive steroid maintenance doses are required and a steroid-sparing agent is needed as add-on therapy. Such medications include azathioprine, cyclosporine A, cyclophosphamide, and mycophenolate mofetil. Cyclophosphamide is effective but carries the risks of chemotherapy and is poorly tolerated as long-term maintenance therapy, as is cyclosporine. Azathioprine and mycophenolate are typically considered first under these circumstances but are slow acting; a response to these agents may not begin for 3–12 months, and a maximal response may not appear for 1–2 years. Consequently, they are not used as monotherapy in severe MG when a rapid response is critical. PE and high-dose IVIG are temporizing therapies with rapid onset of action and duration of action of 4–6 weeks. They are particularly helpful in acute exacerbations, severe myasthenia that is refractory to other immunosuppressive therapy, or as booster therapy prior to thymectomy. Myasthenic crisis is defined as a rapid and severe deterioration with worsening oropharyngeal weakness and respiratory distress. Patients with rapidly worsening symptoms should be hospitalized and monitored closely with serial measures of the forced vital capacity. If impending respiratory failure is evident, endotracheal intubation and mechanical ventilation are required. In these instances, IVIG or PE hastens improvement and aid in weaning from the ventilator.

Lambert–Eaton myasthenic syndrome

Epidemiology and clinical features LEMS is an autoimmune disorder of the neuromuscular junction caused by antibodies directed against the voltage-gated calcium channels (VGCCs) at the presynaptic nerve terminal. Blockade of these antibodies inhibits release of acetylcholine from the presynaptic terminal, resulting in failure of neuromuscular transmission and clinical weakness. It is a rare disorder, with a prevalence of between 1 in 500,000 and 1 in 1,000,000. Nearly 60% of

LEMS cases are paraneoplastic, and are most commonly associated with small cell lung cancer (Gutmann et al., 1992; Tim et al., 2000); occasionally, LEMS may be the first manifestation of the malignancy. Because of this association with lung cancer, it is more common in patients over the age of 60. Patients develop fluctuating proximal limb weakness that begins in the legs and spreads to the arms. Symptoms of sympathetic or parasympathetic autonomic dysfunction are common, including dry mouth, impotence, blurred vision, constipation, difficulty with micturition, and reduced sweating. Sensory loss may be seen if there is concurrent paraneoplastic sensory neuropathy. Deep tendon reflexes are typically reduced but may transiently normalize following brief (15-second) exercise of the attached muscle (reflex facilitation or reflex augmentation). Strength testing usually demonstrates mild proximal weakness, most commonly affecting the hip flexor muscles. Mild improvement in strength after exercise (the warm-up phenomenon), which wanes with more continuous activity, is characteristic. Though oculobulbar symptoms may be subtle, careful cranial nerve examination reveals ptosis and/or diplopia, usually mild, in 25% of patients. If a cancer patient has prolonged paralysis following the use of neuromuscular blocking agents following surgery, LEMS should be strongly considered and evaluated, with neurologic consultation and appropriate diagnostic testing.

Pathophysiology The primary pathophysiologic abnormality in Lambert– Eaton syndrome is a reduction of the calcium-dependent quantal release of acetylcholine triggered by a nerve impulse. In paraneoplastic LEMS, it is believed that an autoimmune response initially directed against tumor cell antigens subsequently targets the same or antigenically related proteins at the presynaptic nerve terminal of the neuromuscular junction. Eighty-five percent to 95% of patients with LEMS are seropositive for antibodies directed at the P/Q type of VGCC in the presynaptic neuronal membrane. Anti-VGCC antibodies reduce numbers of VGCC in motor nerve terminals. By decreasing the influx of calcium triggered by each arriving action potential, anti-VGCC antibodies ultimately impair the calcium-dependent release of acetylcholine into the neuromuscular junction, causing clinical muscle weakness. Parasympathetic, sympathetic, and enteric neurons are all affected.

Diagnosis History and physical examination are important, with attention to reflexes, tests for reflex facilitation and also proximal strength. Nerve conduction studies in LEMS demonstrate low motor amplitudes due to neuromuscular blockade, in contrast to MG, in which motor amplitudes

Neuromuscular Disorders

are usually normal on routine testing. RNS produces decrement similar to that seen in MG when low-frequency stimulation is used. However, brief exercise in LEMS patients classically produces dramatic increases in CMAP size (postexercise facilitation), typically exceeding 100%. However, RNS has a sensitivity of around 70% when one muscle is tested. Sensory nerve conductions are normal. Needle EMG examination may reveal motor unit instability and subtle myopathic change in the proximal muscles. Neuromuscular junction function is typically abnormal by single-fiber EMG, which has a high sensitivity of 90% in LEMS. Antibodies directed at the P/Q type of VGCC are also a sensitive indicator of disease and are seen in 85–95% of patients with LEMS. In patients with confirmed Lambert–Eaton syndrome, a neoplastic workup is indicated, with a special emphasis on the search for small cell lung cancer. Chest CT or MR scanning with contrast should be performed and, in some cases, FDG-PET scanning can detect the tumor despite normal chest CT or MR (Linke et al., 2004; YounesMhenni et al., 2004). Patients over 50 with a history of chronic smoking and LEMS have a high probability of an underlying lung cancer, and bronchoscopy should be considered in these cases if chest CT or MRI is unrevealing. It is not uncommon for initial evaluation for an occult lung tumor to be unrevealing; in these cases, the workup should be repeated at regular intervals. The diagnosis of LEMS may be the presenting feature of cancer and precedes its diagnosis by two years or more. As LEMS may also be associated with other tumors, the patient should be brought up-to-date on all routine cancer screens, and additional screens should be considered, depending upon the specifics of the history.

Treatment Paraneoplastic LEMS typically responds to successful treatment of the underlying cancer, though symptoms may return if the tumor comes back. In SCLC, chemotherapy is the first choice and will have an additional immunosuppressive effect. The presence of LEMS in a patient with SCLC is associated with improved patient survival from the cancer, perhaps because of earlier detection. 3,4-diaminopyridine (DAP) is a drug that blocks potassium channel efflux in nerve terminals so that action potential duration is increased, causing Ca2+ channels to be open for a longer time, facilitating greater acetylcholine release and partially overcoming the VGCC blockade. 3,4DAP in doses from 5 mg three times a day up to 25 mg four times a day or more produces some degree of symptomatic improvement in nearly all patients with Lambert– Eaton syndrome, with or without an associated neoplasm. Immunotherapy has little effect in improving strength in patients with paraneoplastic LEMS if the underlying tumor is not successfully treated. In patients with LEMS who do not have cancer, aggressive immunotherapy may

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be tried but is generally minimally effective. Case reports suggest temporary benefit from PE and IGIV, but no controlled trials have been performed and our experience with these approaches has not suggested effectiveness (Dau and Denys, 1982; Rich et al., 1997). Lambert–Eaton syndrome is generally a chronic disorder in patients without tumor, although some patients may experience clinical remissions. About 40% of patients with LEMS will never develop a cancer.

Disorders of muscle Dermatomyositis

Epidemiology and clinical features Dermatomyositis is a common autoimmune disease affecting the striated (voluntary) muscle, the skin, and connective tissues. The exact incidence of dermatomyositis is unknown, but the inflammatory myopathies as a group affect approximately 1 in 100,000 adults. Most often, the skin changes precede the muscle weakness and include a heliotrope rash (blue–purple discoloration) on the upper eyelids with edema, a flat red rash on the face and upper trunk, erythema of the knuckles with a raised violaceous scaly eruption (Gottron’s papules), and subcutaneous calcium deposits (subcutaneous calcinosis), especially at the elbows. The erythematous rash can also occur on other body areas, including extensor surfaces such as the knees, elbows and malleoli, the neck and anterior chest (often in a V-shaped configuration), or along the back and shoulders (shawl sign). Dilated capillary loops at the base of the fingernails are also characteristic of dermatomyositis and suggestive of its pathophysiology as a primarily vasculitic disorder. The cuticles may be irregular, thickened, and distorted, and the lateral and palmar areas of the fingers may become rough and cracked, with irregular, “dirty” horizontal lines, resembling a mechanic’s hands. When the weakness develops, it takes the form of a myopathy, with proximal leg and arm weakness, developing over weeks to months. Dermatomyositis can be seen in concert with connective tissue disorders such as systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, and also mixed connective tissue disease. Cardiac arrhythmias and interstitial lung disease, particularly pulmonary fibrosis, can also accompany the disease. The incidence of malignancies is increased in patients with dermatomyositis (Buckbinder et al., 2001; Hill et al., 2001). Ovarian cancer is most frequent, followed by intestinal, breast, lung, and liver cancer. A complete annual physical examination, with breast, pelvic, and rectal examinations (including colonoscopy in high-risk patients); urinalysis; complete blood-cell count; blood chemistry tests; and chest X-ray, is usually sufficient and

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is highly recommended, especially within the first 3 years after diagnosis.

Etiology and pathophysiology No clear causative agent has been demonstrated in dermatomyositis. An autoimmune mechanism is supported by the association of dermatomyositis with other autoimmune disorders, such as lupus and systemic sclerosis. Various autoantibodies against nuclear and cytoplasmic antigens are found in patients with inflammatory myopathies (Dalakas, 2001). In addition, 80% of dermatomyositis patients with the anticytoplasmic antibody anti-Jo-1 develop interstitial lung disease. The primary antigenic targets in dermatomyositis are components of the endothelium of the endomysial blood vessels. The antibody-triggered complement activation attacks the endomysial microvasculature, leading to muscle fiber destruction and inflammation. The endofascicular hypoperfusion is prominent distally and causes the perifascicular atrophy typically seen in pathology sections. The histologic picture of skin lesions in DM is characterized by dermal perivascular infiltrates consisting mainly of CD4+ cells, followed by macrophages (Hausmann et al., 1991).

Diagnosis The clinical diagnosis of dermatomyositis is suggested by history and physical examination and confirmed by serum muscle enzymes, electrophysiologic findings, and muscle biopsy. Creatine kinase (CK) levels are typically elevated, sometimes up to 50 times the normal level, and frequently parallel disease activity. Needle EMG demonstrates abundant spontaneous activity with fibrillations, positive sharp waves, and complex repetitive discharges reflecting the muscle membrane instability associated with the inflammation in this disease. Myopathic motor unit potentials are also abnormal, reflecting loss of muscle fibers (characterized by short-duration, low-amplitude and polyphasia), most clearly seen in the proximal muscles. Electromyographic and nerve conduction studies are also useful to exclude neuromuscular disorders. Muscle biopsy is a definitive test to confirm the diagnosis. In contrast to necrosis of single fibers and endomysial infiltrates seen in polymyositis, the classic histologic features of dermatomyositis are perimysial and perivascular inflammatory infiltrates, as well as perifascicular atrophy. Skin biopsy, performed in the vicinity of a characteristic rash, may also confirm the diagnosis.

Treatment Prednisone is the first-line therapy. A high dose of 80–100  mg/day as a single daily morning dose for an initial period of 3–4 weeks is preferable. In patients with aggressive disease, methylprednisolone 1 gm IV every day for 3 days may be considered first, followed by the oral steroid dose. Prednisone taper must be undertaken

cautiously, and high daily doses often must be continued for 2–3 months, after which gradual taper is undertaken over several months to low doses. If the patient develops intolerable side effects from prednisone or develops repeated relapses during ongoing attempts at taper, a steroid-sparing agent should be added. Azathioprine (1.5–3 mg/kg/day) is usually effective after 3–6 months of treatment. Methotrexate is also used and may be effective as a sole agent. It can be given orally starting at 7.5 mg weekly for the first 3 weeks (given in a total of three doses, 2.5 mg every 12 hours), increasing gradually by 2.5 mg per week up to a total of 25 mg per week. An important side effect is methotrexate pneumonitis. Cyclophosphamide, an alkylating agent, is also effective as monotherapy and can be given intravenously at doses of 0.5–1 gm/m2, but has significant deleterious side effects, especially with prolonged usage. Cyclosporine has been used with limited success. A case series found mycophenolate effective at controlling skin lesions, resulting in decreased steroid dose required (Gelber et al., 2000). Plasmapheresis has not been helpful, but IVIG has been shown to be effective in a small double-blind study, improving strength and dermatologic lesions and also clearing the underlying immunopathology (Dalakas et al., 1993). The natural history of dermatomyositis is unknown, as no natural history studies were performed prior to the advent of steroid therapy. Dermatomyositis typically responds to immunotherapy more readily than polymyositis, but patients with interstitial lung disease (typically a late complication) may have a high mortality rate, requiring aggressive treatment with cyclophosphamide. Some patients do not respond adequately to therapies and become disabled.

Polymyositis

Epidemiology and clinical features Polymyositis is an inflammatory disorder of muscles, cause unknown, characterized by progressive proximal and symmetrical weakness of the arms, legs, and neck muscles appearing over weeks to months. Typically, patients’ complaints are related to proximal weakness and include difficulty combing their hair, climbing stairs, and getting up from a low seated position. Deep tendon reflexes are usually normal and sensation is intact. The disease spares the ocular muscles, and the facial muscles are rarely affected. Patients frequently complain of myalgias, muscle tenderness, and fatigue, though pain is absent in a significant minority of patients. Dysphagia can also occur, and systemic complications can include dilated cardiomyopathy and interstitial lung disease. It may be associated with other connective tissue diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren’s syndrome. As mentioned previously, the inflammatory myopathies as a group have an incidence

Neuromuscular Disorders

of approximately 1 in 100,000 adults, with peak incidence in the fifth and sixth decades.

Pathophysiology The cause of polymyositis remains unknown, but there is ample pathologic evidence of autoimmune mediated attack on the muscle fibers as the primary insult. It may occur alone but may also be associated with a wide variety of more systemic autoimmune diseases, and it responds extremely well to aggressive immunomodulatory therapy.

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As with dermatomyositis, the natural history of polymyositis is largely unknown, as no natural history studies were performed prior to the advent of steroid therapy. In general, older age, interstitial lung disease, and frequent pneumonias due to esophageal dysfunction are associated with poor prognosis. A minority of patients still does not adequately respond to immunotherapy and become disabled. However, if there is no response to aggressive immunotherapy, the diagnosis should be reconsidered, with review of the history, neurologic examination, electrophysiologic and biopsy data, and consideration should be given to repeat and/or additional evaluations.

Diagnostic tests Polymyositis is a clinical diagnosis based upon history and physical examination and supported by serum studies, electrophysiologic testing, and muscle biopsy. The differential diagnosis includes muscular dystrophies; dermatomyositis; metabolic myopathies; endocrinopathies; electrolyte disturbances; mitochondriopathies; systemic medical illnesses such as malabsorption syndromes, cancer, vasculitis, systemic infections, sarcoidosis, and granulomatous disease; or toxic myopathies. Serum CK levels may be increased up to 50 times the upper limit of normal. Other enzymes, including ALT, AST, and LDH, may also be increased and may sometimes lead to a diagnosis of primary hepatic disease, particularly if the CK level is not concurrently checked. As with dermatomyositis, needle electromyography demonstrates abundant spontaneous activity with fibrillations, positive sharp waves, and complex repetitive discharges reflecting the muscle membrane instability associated with the inflammation in this disease. Myopathic motor unit potentials are also abnormal, reflecting loss of muscle fibers and characterized by short duration, low amplitude, and polyphasia, most clearly in the proximal muscles. Electromyographic and nerve conduction studies are also useful to exclude neuromuscular disorders. Muscle biopsy should be taken from an affected muscle (most often the vastus lateralis) and may demonstrate necrosis of single fibers and endomysial inflammatory infiltrates. However, a normal muscle biopsy does not exclude the diagnosis, as inflammation and necrosis can be patchy and may be missed in the small tissue sample taken. Consequently, EMG is a more sensitive test for polymyositis because of its ability to assay large areas of multiple muscles and also because of the typically widespread changes wrought by muscle membrane instability in this disorder.

Treatment Polymyositis typically responds extremely well to aggressive immunomodulatory therapy, with significant improvement beginning within 1–2 months in most patients. Treatment options are typically the same as those for dermatomyositis.

Inclusion body myositis

Epidemiology and clinical features Inclusion body myositis is the most frequent myopathy in patients over the age of 50, with a prevalence of over 50 per 1,000,000 (Needham et al., 2008; Mastaglia et al., 2009). It affects males more often than females (3:1 ratio) and is rare in people of African descent. There is also a rare hereditary form, with onset in the second and third decades. Sporadic IBM produces painless muscular weakness and atrophy, progressing gradually over many years. Onset is often asymmetric, and the wrist and finger flexors muscles are classically affected first and most severely, with secondary progression to the quadriceps and foot dorsiflexors. Hand weakness is an early manifestation in most patients, producing difficulty with fine motor movements such as grasping, pinching, or buttoning, followed by falling and tripping due to leg weakness. Significant dysphagia is a late feature in some patients, but some degree of dysphagia may be present in up to 40% of the patients by the time of diagnosis (Lotz et al., 1989). Mild facial weakness and neck extensor weakness may also be seen, but the extraocular muscles are spared. Tendon reflexes may be normal, but patellar and ankle reflexes are typically depressed early in the course of the disease. Sensory examination is generally normal. The extremely slow rates of progression, as well as the absence of fasciculations, hyperreflexia, and UMN signs, helps distinguish inclusion body myositis from ALS.

Diagnosis CK is usually mildly elevated (two- to threefold) but may be significantly increased (up to tenfold) or normal in some patients. Electromyography can exclude important mimics. Classic IBM patients demonstrate a pattern of predominately myopathic motor unit potential alteration with early recruitment in clinically affected muscles (especially the forearm flexor compartment and the distal legs, as opposed to a primarily proximal distribution of myopathic change in most acquired myopathies) on EMG examination, with an intermixed subset of neurogenic motor units.

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Spontaneous activity may sometimes be present, though it is typically mild (Joy et al., 1990). Muscle biopsy may be definitive. Characteristic findings seen in IBM include rimmed vacuoles, endomysial inflammation, and eosinophilic cytoplasmic inclusions. By electron microscopy, these eosinophilic inclusions appear to correspond to collections of 12–18 nm intranuclear or cytoplasmic filaments. However, the pathognomonic feature for IBM on muscle biopsy is the presence of congophilic deposits of amyloidlike material, which give apple-green birefringence on polarized light microscopy after Congo red staining.

Pathophysiology The trigger for this slowly progressive disorder is unknown, but there is pathologic and other evidence of combined mitochondrial, degenerative, and autoimmune dysfunction as significant contributors to muscle fiber injury and degeneration. However, the amyloid accumulation so characteristic for this disorder appears to be a marker of the degenerative process rather than a toxic contributor to it (unlike the rare myopathy sometimes seen in systemic amyloidosis).

Treatment There is no effective therapy for inclusion-body myositis at present. The disease is steroid resistant, and other immunosuppressive agents, such as azathioprine, methotrexate, cyclophosphamide, and total lymphoid irradiation, have proven unsuccessful. The weakness progresses slowly over years, and it is associated with worsening atrophy of the weak muscles. Progression to disability appears to occur more rapidly when symptoms begin after 60 years of age (Peng et al., 2000). Both supportive and symptomatic therapies are essential in inclusion-body myositis patients, including physical therapy, occupational therapy, and the judicious application of assistive devices. Close monitoring of dysphagia is important.

Toxic myopathies

Epidemiology and clinical features A vast number of drugs and other chemicals are myotoxic and can produce muscle injury through a number of mechanisms, including local trauma (intramuscular injections), electrolyte disturbances (hypokalemia), increased metabolic demands (malignant hyperthermia), and toxic effects on the muscle membrane and the internal apparatus of the cell. Several clinical features suggest a potential toxic etiology for myopathic injury, including temporal link between exposure to the toxin and the onset of symptoms, a lack of preexisting muscular symptoms, no other identifiable cause, and complete or partial resolution of the symptoms after withdrawal of the putative agent. Toxic myopathies can appear at any age, but those due to cumulative toxins and medication-induced injury are more prevalent with advancing age.

Many drugs have been associated with myopathy, but only a small number have been well documented as clearly causative, including alcohol, amiodarone, chloroquine, cholesterol-lowering agents, colchicine, corticosteroids, d-penicillamine, and zidovudine. Each of these drugs acts through a different mechanism. Autophagic degeneration and phospholipid accumulation in muscles is seen in chloroquine-induced myopathy, while colchicine causes disruption of the microtubule-dependent cytoskeletal network. Zidovudine inhibits mitochondrial function in the muscle, and D-penicillamine can produce a syndrome that is clinically and pathologically indistinguishable from polymyositis. Rhabdomyolysis has now been associated with statin therapy and is a feature of at least two other drug-induced disorders: neuroleptic malignant syndrome and malignant hyperthermia (typically triggered by anesthetic agents).

Diagnosis History and physical examination remain paramount in the evaluation of toxic myopathies, with particular attention to known and potential exposures, including detailed occupational, recreational and geographic history, current and prior medication and recreational drug use, and any similar illnesses in fellow employees, neighbors, or family members. Serum CK is one of the most sensitive indicators of acute muscle damage. EMG may show myopathic change and is more likely to be abnormal in moderate to severe, acute or subacute cases. However, some toxins such as steroids produce minimal electrophysiologic alterations. Muscle biopsy may be helpful in some cases to confirm the presence and degree of muscle damage, but rarely provides data allowing identification of a specific toxic agent.

Specific toxins Cholesterol-lowering agents (“Statins”)

Epidemiology and clinical features The incidence of myopathy is similar for all lipid-lowering drugs and is in the range of 0.1–0.5% with monotherapy, increasing to 0.5–2.5% with combination therapy (Hodel, 2002). However, the incidence of myopathy increases dramatically when statins are given in combination with fibrates such as gemfibrozil. Approximately one case of rhabdomyolysis is reported for every 100,000 treatmentyears. The first-generation statins (lovastatin, pravastatin, and simvastatin) are rarely associated with myopathy, but the new synthetic drugs (atorvastatin, Fluvastatin, and cerivastatin) are more frequently toxic. Cerivastatin was the most commonly implicated statin and has been removed from the market.

Neuromuscular Disorders

Symptoms range from mild muscular aches to severe weakness and fatal rhabdomyolysis. Most patients with this myopathy complain of muscle cramps and proximal weakness. Myotonia is a common finding. Statin-associated necrotizing myopathy is a different and recently recognized disorder, likely immune mediated, characterized by proximal muscle weakness occurring during or after treatment with statins, which persists despite discontinuation of the statin and improves with immunosuppressive agents. The muscle biopsy shows necrotizing myopathy without significant inflammation. In addition to these clearly identified disorders, we have anecdotally recognized at least mild proximal leg weakness, often subclinical, in up to 50% of our patients on chronic statin therapy, usually after many years of treatment, which has no other apparent cause. This condition appears to be nonprogressive and is often clinically insignificant, but it can be problematic as a cause of additional weakness in patients with another cause of proximal weakness.

Pathophysiology The mechanisms through which statins cause muscle damage are poorly understood. An increase in “cell membrane fluidity,” high blood lactate-to-pyruvate ratio (suggestive of mitochondrial dysfunction), and depletion of metabolites of geranylgeranyl pyrophosphate could be potential causes.

Diagnostic tests The diagnosis of statin myopathy is a diagnosis of exclusion and is based upon history, physical examination, CK measurements, and electromyographic and histologic assessment. Drug challenge/dechallenge and rechallenge may be confirmatory. EMG and nerve conduction studies demonstrate classic myopathic findings, including fibrillation potentials, early recruitment, and short-duration, low amplitude polyphasic motor unit potentials. Muscle biopsy demonstrates atrophy and, in severe cases, necrosis of type I and II fibers.

Treatment The elderly and female patients, as well as those already on other potentially myotoxic medications or those with impaired metabolism may be at particular risk for statin myopathy and should be given extra consideration before cholesterol-lowering therapy is initiated. Genetic analysis for mutations identified as risk factors for statin myopathy may also provide predisposition testing and is becoming commercially available. Because myotoxic events are more frequent at higher doses, statins more likely to be effective at lower doses should be used, if possible. If symptoms develop, immediate discontinuation of statins usually results in reversal of symptoms over days to weeks. Controlled trials of

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coenzyme Q supplementation in statin myopathy have yielded contradictory results. If CK is elevated but the patient has no symptoms (hyperCKemia) or signs, the medication can be continued as long as the CK elevation remains in the low range (less than two times the upper limit of normal) and does not progressively increase.

Steroid myopathy

Epidemiology and clinical features At least mild myopathy (as manifested by at least some degree of detectable proximal muscle weakness on exam) may be seen in up to 60% of patients receiving steroids on a chronic basis (Batchelor et al., 1997). However, this figure may be confounded by the fact that muscle injury is caused by many chronic diseases for which steroids are the treatment of choice, including systemic lupus erythematosus, rheumatoid arthritis, bronchial asthma, chronic obstructive pulmonary disease (COPD), and polymyositis. The prolonged use of corticosteroids can induce a painless myopathy, manifested by a slowly evolving proximal leg weakness. Although typically caused by oral steroid therapy, other routes of administration, including inhaled steroids, can induce myopathy in some cases. A specific syndrome of acute myopathic injury and prolonged paralysis can occur in the setting of high-dose steroid therapy in critically ill patients, particularly those in whom depolarizing neuromuscular blocking agents are used to facilitate ventilation.

Pathophysiology Corticosteroids seem to inhibit messenger RNA synthesis that, in turn, influences the translation and synthesis of muscle-specific proteins. Fast-twitching glycolytic (type 2b) fibers are more susceptible to injury in steroidinduced myopathy.

Diagnosis Steroid-induced myopathy is a diagnosis of exclusion and rests primarily on history and physical examination, as there are no pathognomonic findings on diagnostic workup. CK may be normal and EMG is frequently normal. Muscle biopsy may demonstrate atrophy of type 2b fibers or may be normal. EMG in steroid myopathy associated with critical illness may demonstrate fibrillation potentials and myopathic motor units. Muscle biopsy in these cases often demonstrates muscle fiber necrosis, vacuolation, and a striking loss of myosin filaments.

Treatment Corticosteroid myopathy is usually reversible if the drug is withdrawn or the dose is reduced. Corticosteroidinduced muscle atrophy and weakness can often be

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partially prevented or reversed by a program of physical exercise. The prognosis of steroid-induced myopathy is generally good and the symptoms subside after discontinuation of the offending drug. In more advanced cases of necrotic myopathy, residual muscle weakness, or paralysis of the involved muscle may persist.

Late-onset hereditary myopathies Most inherited muscle diseases typically manifest early in life. However, a few hereditary muscle disorders may present with onset late in life. Welander distal myopathy (late-onset distal myopathy) has an autosomal dominant inheritance pattern and presents with weakness predominantly affecting the long extensors of the hands and, later, the feet. Onset is usually in the fourth and fifth decades. CK values are normal or slightly elevated. Electromyography reveals both myopathic and neuropathic motor unit change. Muscle biopsy demonstrates myopathic change, often including rimmed vacuoles. Makesbery and colleagues reported a late-onset distal myopathy in which weakness begins in the distal muscles (tibialis anterior) and later spreads to the hands, with late cardiac involvement. Tibial muscular dystrophy is a similar disorder, but with no cardiac involvement and symptom onset ranging from the fourth to the eighth decades. Few case reports of late-onset McArdle’s disease have been described, manifesting as exercise-induced cramps and exercise intolerance, with at least one late case with onset as late as 60 years (Felice et al., 1992).

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Dalakas, M.C. (2001) The molecular and cellular pathology of inflammatory muscle diseases. Curr Opin Pharmacology, 1: 300–306. Dalakas, M.C., Illa, I., Dambrosia, J.M,, et al. (1993) A controlled trial of high-dose intravenous immunoglobulin infusions as treatment for dermatomyositis. N Engl J Med, 329: 1993–2000. Dalmau, J., Forneaux, H.M., Gralla, R.J., et al. (1991) Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer—a quantitative Western blot analysis. Ann Neurol, 27: 544–552. Dau, P.C. and Denys, E.H. (1982) Plasmapheresis and immunosuppressive drug therapy in the Eaton–Lambert syndrome. Ann Neurol, 11: 570–575. Dyck PJ, Daube J, O’Brien P, et al. (1986) Plasma exchane in chronic inflammatory demyelinating polyradiculoneuropathy. N Engl J Med, 314: 461–465. Dyck, P.J., O’Brien, P.C., Bosch, E.P., et al. (2005) Results of a controlled trial of IV methyprednisolone in diabetic lumbosacral radiculplexus neuropathy (DLRPN): A preliminary indication of efficacy. J Periph Nerv Syst, 10 (Suppl. 1): 21. Felice, K.J., Schneebaum, A.B., and Jones Jr., H.R. (1992) McArdle’s disease with late-onset symptoms: Case report and review of the literature. J Neurol Neurosurg Psychiatry, 55: 407–408. Gelber, A.C., Nousari, H.C., and Wigley, F.M. (2000) Mycophenolate mofetil in the treatment of severe skin manifestations of dermatomyositis: A series of 4 cases. J Rheumatol, 27: 1542–1545. Gordon, P.H., Cheng, B., Katz, I.B., et al. (2006) The natural history of primary lateral sclerosis. Neurology, 66: 647–653. Grob, D., Arsura, E.L., Brunner, N.G., and Namba, T. (1987) The course of myasthenia gravis and therapies affecting outcome. Ann NY Acad Sci, 505: 472–499. Gutmann, L., Phillips, L.H., and Gutmann, L. (1992) Trends in the association of Lambert–Eaton myasthenic syndrome with carcinoma. Neurology, 42: 848–850. Hahn, A.F., Bolton, C.F., Pillay. N., et al. (1996) Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy. A double blind, sham-controlled, crossover study. Brain, 119: 1055–1066. Hammad, M., Silva, A., Glass, J., et al. (2007) Clinical, electrophysiologic, and pathologic evidence for sensory abnormalities in ALS. Neurology, 69 (24): 2236–2242. Hausmann, G., Herrero, C., Cid, M.C., et al. (1991) Immunopathologic study of skin lesions in dermatomyositis. J Am Acad Dermatol, 25: 225–230. Heckmann, J.G., Lang, C.J.G., Zobelein, I., et al. (1999) Herniated cervical intervertebral discs with radiculopathy: An outcome study of conservatively or surgically treated patients. J Spinal Disord, 12: 396–401. Hilibrand, A.S. and Rand, N. (1999) Degenerative lumbar stenosis: Diagnosis and management. J Am Acad Orthop Surg, 7: 239–249. Hill, C. L., Zhang, Y., Sigurgeirsson, B., et al. (2001) Frequency of specific cancer types in dermatomyositis and polymyositis: A population-based study. Lancet, 357: 96–100. Hodel, C. (2002) Myopathy and rhabdomyolysis with lipid-lowering drugs. Toxicol Lett, 128 (1–3): 159–168. Howard, J.F., Sanders, D.B., and Massey, J.M. (1994) The electrodiagnosis of myasthenia gravis and the Lambert–Eaton myasthenic syndrome. In: D. B. Sanders (ed.), Myasthenia Gravis and Myasthenic Syndromes. Neurologic Clinics of North America. Vol. 12, no. 2. Philadelphia: WB Saunders Company.

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Part 4 Therapeutics for the Geriatric Neurology Patient

Chapter 22 Neurosurgical Care of the Geriatric Patient David Fusco, Rasha Germain, and Peter Nakaji Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

Summary • Chronic subdural hematomas (SDHs): • An accumulation of blood between the dura and brain as a result of trauma or brain atrophy. • Large SDHs may mimic brain disorders such as dementia. • Some chronic SDHs may resolve on their own, however, blood must be evacuated should enlargement occur. Liquefied chronic SDHs are treated with drainage through one or two bur holes, twist-drill craniotomy, or a Subdural Evacuating Port System. • Aneurysms: • An abnormal local dilation in the blood vessel wall due to defect, disease, or injury. • Age considerations must be made when deciding whether the aneurysm should be treated and how it should be treated. • Computed tomography (CT) angiography, magnetic resonance angiography (MRA), and catheter-based digital subtraction angiography (DSA) are used to study size, location, and morphology of the aneurysm. • Treatment options include observation, craniotomy and clipping with or without bypass, and endovascular coil embolization with or without stent assistance. • Stroke: • A sudden loss of blood circulation to an area of the brain resulting in loss of neurologic function. • A noncontrast head CT distinguishes between ischemic and hemorrhagic infarction. An MRI with diffusion-weighted imaging (DWI) may be used as well for improved sensitivity. • Treatments for carotid occlusive disease, acute intracranial thrombotic stroke, spontaneous intracerebral hematoma, and normal pressure hydrocephalus (NPH) are also reviewed. • Neurooncology: • Brain tumor diagnosis is based on clinical presentation, neuroimaging, and histology. • Surgery to remove the tumor and obtain tissue for diagnosis is the initial treatment. Radiation therapy (RT) is also a component of treatment, followed by chemotherapy. • Odontoid fractures: • A fracture through the second cervical vertebra resulting in neck pain. Injury is assessed with CT, magnetic resonance imaging (MRI) and treated according to fracture classification (I, II, III). • Nonoperative management (nonOP) includes rigid cervical orthosis or rigid immobilization in a halo vest; however, prolonged immobilization may risk edema and other physical challenges. • Surgical treatment includes either anterior or posterior fixation. • Compression fracture: • Often related to osteoporosis but may involve tumor infiltration or infection. • Conservative management includes pain management, bracing, and rehabilitation. • Surgery includes vertebroplasty and kyphoplasty. • Pain: trigeminal neuralgia (TGN) • Facial pain involving the trigeminal nerve. Pain is managed most commonly through carbamazepine. • Surgical treatment options include percutaneous injury to the Gasserian ganglion, stereotactic radiosurgery, and microvascular decompression (MVD). • Parkinson’s disease (PD): • Levodopa and carbidopa relieve symptoms by working to replenish dopamine in the brain. • Deep brain stimulation (DBS) is a relatively safe option to treat movement disorders. The optimal target for DBS is the subthalamic nucleus (STN). The globus pallidus interna may also be targeted.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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As an organ system, the central nervous system (CNS) holds up fairly well to the effects of aging. Only a few diseases of neurosurgical importance that specifically affect older populations cannot also be found in younger individuals. However, the impact of these diseases changes as patients age. Furthermore, with aging, the decision about not only how to treat but whether to treat becomes important because the relative risks of some conditions change as patients grow older. For neurosurgical diseases, we must consider both the absolute age of the patient and the remaining life expectancy. For example, an unruptured aneurysm with a 1% risk of rupture per year has a different implication for a 20-year-old patient with a 5% surgical risk when compared with a 75-year-old patient with a 15% surgical risk. That the former patient has a longer life expectancy and 60 years of risk without treatment puts him in a very different status than the latter patient, with only a 13-year life expectancy. Actuarial analysis is often necessary to provide optimal counseling. Complete treatment of the entire range of neurosurgical conditions affecting the geriatric population is impractical in this chapter. Therefore, we concentrate on selected highlights of the most common conditions and those most often overlooked in geriatric patients.

Chronic subdural hematoma Chronic subdural hematomas (SDHs) are common in the elderly. In its simplest form, an SDH is an accumulation of blood between the dura and the brain. These liquefied clots most often occur in patients of age 60 years and older who have brain atrophy and a loss of cerebral parenchymal volume due to age or disease. As the brain shrinks inside the skull over time, a potential space is created between the brain and the dura. Minor head trauma can cause tearing of blood vessels over the brain surface, resulting in a slow accumulation of blood over several days to weeks. Because of the space made available by the brain atrophy, these liquefied blood clots can become quite large before they cause symptoms. Chronic SDH is a very different entity than blood that occurs in a similar location on an acute basis as a result of direct major head trauma. These latter patients are most often affected by increased intracranial pressure (ICP) and the damage caused by shear forces on the brain, whereas chronic SDH patients often do not recall any trauma and are more affected by the mass effect of the blood clot than by increased ICP. In fact, fewer than half of chronic SDH patients remember the traumatic event itself because even relatively trivial trauma, such as a minor bump on the head, can produce these slow hemorrhages. Other risk factors include alcohol

abuse, seizures, shunts that drain excess cerebrospinal fluid (CSF) from the brain, bleeding diatheses such as those due to hepatic or platelet dysfunction, and bloodthinning medications such as warfarin. The most common complaint of chronic SDH is headache, seen in up to 80% of patients. Other symptoms may include lethargy, memory impairment, confusion, weakness, imbalance, nausea, vomiting, impaired vision, and seizures. Patients with large hematomas may develop varying degrees of paresis and coma. A chronic SDH may mimic a number of other brain diseases and disorders, including dementia, stroke, transient ischemic attack (TIA), encephalitis, and brain lesions such as tumors or abscesses. An initial misdiagnosis of dementia is particularly common in elderly patients when symptoms involve a steady decline in the overall mental function. An errant diagnosis at the time of hospital admission occurs in up to 40% of cases. Ultimate diagnosis of these lesions involves computed tomography (CT) and magnetic resonance imaging (MRI). Chronic SDHs are often mixed density (CT) and intensity (MRI) due to the presence of blood components of varying ages. They may extend over a large portion of the surface of the brain and often have multiple membranes and septations (Figure 22.1). When they are in their subacute phase, they may be isodense to the brain and difficult to visualize. Chronic SDHs may begin as a subdural hygroma, a separation in the dura–arachnoid interface that fills with CSF. Dural border cells proliferate around this CSF collection to produce a neomembrane. Fragile new vessels grow into the membrane. These vessels can hemorrhage with minor trauma and become the

Figure 22.1 Axial CT scan of the head demonstrating mixeddensity, chronic subdural hematoma (SDH). There is layering of hemosiderin (arrow), effacement of the lateral ventricles, effacement of the sulcal–gyral pattern, and significant midline shift. © Barrow Neurological Institute.

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(a)

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(b)

Figure 22.2 Axial CT scans of the head showing evolution and liquefaction of an acute chronic subdural hematomas (SDHs) 1 week (a) and 3 weeks (b) after the initial injury. © Barrow Neurological Institute.

source of acute blood into the space, resulting in the growth of the chronic SDH (Kawakami et al., 1989). Chronic SDHs also may evolve from liquefaction of an acute SDH, particularly one that is relatively asymptomatic. Liquefaction usually occurs after 1–3 weeks, with the hematoma appearing hypodense on a CT scan (Figure 22.2). Patients with chronic SDHs that produce symptoms can be treated effectively and safely by multiple means. In patients who have no significant mass effect on imaging studies and no neurologic symptoms or signs except mild headache, chronic SDHs have been observed on serial scans and have been seen to remain stable or to resolve in many cases. In some cases, however, enlargement occurs, mandating evacuation of the blood. Liquefaction of an acute SDH produces a mass that has a thinner consistency but an unpredictable volume. Furthermore, although spontaneous hematoma resolution is well described, it cannot be forecast reliably. No medical therapy has been shown to be effective in expediting the resolution of acute or chronic SDHs. Consequently, diligent surveillance of all chronic SDH with serial imaging is essential. In general, collections that cause neurologic signs or are thicker than 1 cm and/or cause 5 mm or more of midline shift are evacuated. Various surgical techniques for the treatment of chronic SDH have been described. Liquefied chronic SDHs are commonly treated with drainage through one or two bur holes in the skull overlying the hematoma. The bur holes are placed so that conversion to a craniotomy is possible, if needed. (Mori and Maeda, 2001) A closed drainage system is sometimes left in the subdural space 24–72 hours after surgery. Drainage via twist–drill craniotomy at the bedside with placement of a drain to a closed bag system has also been used frequently (Horn et al., 2006). Recently,

a new system, the Subdural Evacuating Port System (Medtronic, Inc., Minneapolis, MN), has been introduced, with encouraging results. This system involves screwing a hollow bolt to the skull overlying the hematoma, entering the hematoma, and placing the bolt-to-bulb suction (Lollis et al., 2006). Under certain circumstances, craniotomy is recommended for chronic SDH, depending on factors such as recurrence, a thick consistency of the hematoma, and the presence of membranes. Bilateral chronic hematomas may require drainage from both sides, usually during the same operation by means of bur holes placed on each side of the head. Recovery after treatment varies widely. Overall, 80–90% of patients have significant brain function improvement after drainage of a chronic SDH. However, the course of such patients is not uniformly smooth. Despite its apparent simplicity, chronic SDH is a complicated condition that can confound neurosurgeons. Complications of treatment can include seizures, acute SDH formation, infection, empyema, and pneumocephalus. Complication rates tend to increase with age and medical comorbidities. Residual fluid may collect after treatment, and reoperation rates have been reported to range between 10% and 25% (Stroobandt et al., 1995). Importantly, the fluid does not have to be removed completely for symptoms to improve and the clot may resolve eventually through resorption.

Aneurysms Aneurysms affect older patients just as they do younger ones. As patients age, the risk of treatment typically increases, leading to careful consideration of whether to treat. For low-risk unruptured aneurysms, observation is

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often recommended. This is not because there is no risk of rupture, but because the risk of treatment can be greater. Nonetheless, with modern techniques, unruptured aneurysms are often treatable, with excellent morbidity and mortality rates. With ruptured aneurysms, the risk of no treatment is so high that treatment is usually undertaken despite the risks. Below we discuss the nature of cerebral aneurysms and the role of age in treatment decisionmaking. An aneurysm is an abnormal local dilation in the wall of a blood vessel, usually an artery, due to a defect, disease, or injury. The three major types of true intracranial (IC) aneurysms are saccular, fusiform, and dissecting. The common causes of IC aneurysms include hemodynamically induced vascular injury, degenerative vascular injury (for example, from hypertension, tobacco use, or arthrosclerosis), underlying vasculopathy (such as from fibromuscular dysplasia), and high-flow states, such as seen in association with an arteriovenous malformation (AVM) or arteriovenous fistula. Uncommon causes include trauma, infection mycotic aneurysms, drug use, and primary or metastatic neoplasms. The classic cerebral aneurysm is the saccular or berry type. Saccular aneurysms are rounded, balloon-like outpouchings that arise from arterial bifurcation points, most commonly in the circle of Willis. The initiation, growth, thrombosis, and even rupture of IC saccular aneurysms can often be explained by abnormal hemodynamic shear stresses at these bifurcation points. In the aneurysm, wall shear stress caused by rapid changes in the direction of blood flow (the result of systole and diastole) continually damages the intima at the neck of an aneurysm. These hemodynamic stresses work synergistically with the degenerative insults noted previously to produce aneurysm progression and ultimately rupture. Congenital and developmental factors such as autosomal dominant polycystic kidney disease (ADPKD), connective tissue disease, and fibromuscular dysplasia contribute to aneurysm development as well. The true incidence of IC aneurysms is unknown but is estimated at 1–6% of the population, with a 5–40% incidence in ADPKD patients (Wiebers et al., 2003; Yanaka et al., 2004). IC aneurysms are multiple in 10–30% of cases, with a strong female predilection for multiple lesions (between 5:1 and 11:1; Brisman et al., 2006). Aneurysms typically become symptomatic in people aged 40–60 years, with the peak incidence of subarachnoid hemorrhage (SAH) occurring in people aged 55–60 years (Greenberg, 2011). A substantial proportion of aneurysms afflicts the elderly over 60 as well. Age is an important consideration in the evaluation and treatment of all cerebral aneurysms, whether ruptured or unruptured. Whether to treat depends on both life expectancy and the changing response of the aging brain to the available surgical treatments. How to treat is also influenced strongly

by age because of the varying durability of the potential treatments and the decreasing tolerance of the aging brain to the neurologic impact of open surgery. Approximately 86% of all IC aneurysms arise on the anterior (carotid) circulation. Common locations include the anterior communicating artery (30%), the internal carotid artery (ICA) at the posterior communicating artery origin (25%), and the middle cerebral artery (MCA) bifurcation (20%). The ICA bifurcation (7.5%) and the pericallosal/callosomarginal artery bifurcation (4%) account for the remainder. About 14% of all IC aneurysms arise on the posterior (vertebrobasilar) circulation. Seven percent arise from the basilar artery bifurcation, and 3% arise at the origin of the posterior inferior cerebellar artery (PICA) where it exits the vertebral artery. Fusiform aneurysms are arterial ectasias that occur because of a severe and unusual form of atherosclerosis. Because they are often sequelae of atherosclerosis, fusiform aneurysms more often occur in the middle-aged and elderly. These ectatic vessels may have more focal areas of fusiform or even saccular enlargement. Intraluminal clots are common, and perforating branches often arise from the entire length of the involved parent vessel. The vertebrobasilar system is commonly affected. Fusiform aneurysms may thrombose, producing brainstem infarction as small ostia of perforating vessels that emanate from the aneurysm become occluded. They can also compress the adjacent brain structures or cause cranial nerve palsies. Dissecting aneurysms are the product of dissection of arterial blood through the arterial wall to the level of the subadventitial plane. They do not represent encapsulated hematomas and thus must be distinguished from pseudoaneurysms. Most commonly, significant head trauma or an underlying vasculopathy such as fibromuscular dysplasia is implicated in the origin of a dissecting aneurysm. Extracranial (EC) vascular segments such as V2, V3, and the mid- and terminal cervical ICA are most commonly affected. Additional aneurysm subtypes that can fall into any of the three major categories include traumatic pseudoaneurysms, mycotic aneurysms, oncotic aneurysms, flow-related aneurysms, and vasculitic (true) aneurysms. These aneurysm types are less common, and their treatment is similar in geriatric and nongeriatric populations. Most aneurysms do not cause symptoms until they rupture; when they rupture, they most frequently cause SAH and are associated with significant morbidity and mortality. In North America, 80–90% of nontraumatic SAHs are caused by the rupture of an IC aneurysm. Another 5% are associated with bleeding from an AVM or tumor, and the remaining 5–15% are idiopathic. However, as the overwhelming cause of SAH is trauma, it is critical to obtain a good history. On presentation, patients with nontraumatic SAH typically report experiencing the worst headache of their lives. The association of meningeal signs should increase suspicion for this event. The

Neurosurgical Care of the Geriatric Patient

most widely used clinical method for grading the clinical severity of SAH is the Hunt and Hess scale, which measures the clinical severity of the hemorrhage on admission and correlates swell with outcome (Hunt and Hess, 1968): Grade 0: Unruptured aneurysm Grade 1: Asymptomatic or minimal headache and slight nuchal rigidity Grade 2: Moderate-to-severe headache, nuchal rigidity, no neurologic deficit other than cranial nerve palsy Grade 3: Drowsiness, confusion, or mild focal deficit Grade 4: Stupor, moderate-to-severe hemiparesis, possible early decerebrate rigidity, and vegetative disturbances Grade 5: Deep coma, decerebrate rigidity, and moribund appearance The Fisher grade, which describes the amount of blood seen on noncontrast head CT, is also useful in correlating the likelihood of developing vasospasm, the most common cause of death and disability from SAH. Vasospasm is overwhelmingly most common in Fisher grade 3 and rarely found in patients with no blood on CT (Fisher et al., 1980): Fisher 1: No blood detected Fisher 2: Diffuse or vertical layers less than 1 mm thick Fisher 3: Localized clot or vertical layer greater than or equal to 1 mm Fisher 4: Intracerebral or intraventricular clot with diffuse or no SAH Of patients with SAH, 10% die before reaching medical attention and another 50% die within 1 month. Fifty percent of survivors have neurologic deficits. Ruptured aneurysms are most likely to rebleed within the first day (2–4%), and this risk remains very high for the first 2 weeks (20–25%) if left untreated. Vasospasm, the leading cause of disability and death from aneurysm rupture, is thought to be secondary to a toxic relationship between subarachnoid blood products and the vessel wall. Vasospasm typically occurs 3–14 days after rupture, leads to neurologic decline via ischemia and stroke if left untreated, and correlates with the severity of the Fisher grade. Early referral to a hospital with physicians experienced in treating IC aneurysms, early treatment (open surgery and clipping or endovascular coiling), and aggressive treatment of vasospasm are three factors that have been correlated with improved outcomes over the last 20 years. Signs and symptoms of aneurysms other than those associated with SAH are relatively uncommon. Selected IC aneurysms can produce cranial neuropathies. A common example is the third cranial nerve palsy related to posterior communicating artery aneurysms. This condition is typically a pupil-involving, painless third cranial nerve palsy. Other less common symptoms include visual loss caused by an ophthalmic artery aneurysm that compresses the optic nerve, ophthalmoplegia from a large cavernous sinus aneurysm, and seizures, headaches, TIAs, or cerebral infarction related to emboli associated

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with a large or giant partially thrombosed MCA aneurysm. Giant aneurysms (diameter >2.5 cm) tend to be symptomatic because of their mass effect. The risk of rupture among aneurysms that have not bled is unknown and, for many years, has been believed to be 1–2% per year. The International Study of Unruptured Intracranial Aneurysms (ISUIA)), published in 1998 (retrospective component) and 2003 (prospective component), examined 2621 and 1692 subjects, respectively, with IC aneurysms without intervention (The International Study of Unruptured Intracranial Aneurysms Investigators, 1998). Its objective was to determine the natural history of unruptured aneurysms and has since challenged our understanding of aneurysm rupture risk. Surprisingly, the study found that, for aneurysms smaller than 7  mm and located in selected parts of the anterior circulation in patients who had not had a prior aneurysmal SAH, the risk of subsequent rupture was extremely small (0.05%  per year in the retrospective arm and a 5-year cumulative risk of rupture of 0% in the prospective arm). Aneurysms at other locations (such as the basilar tip and the posterior communicating artery), aneurysms larger than 10 mm, and aneurysms found in patients who had bled from a prior aneurysm had a higher risk (about 0.5% per year). The cumulative risk for aneurysms greater than 7 mm in size was 0.8% (1998). Critics of the ISUIA study emphasized that the selection was biased because surgeons who entered patients into the study thought that these aneurysms were less likely to bleed. In fact, about 15,000 aneurysms that are 7 mm in size or less rupture every year in the United States. Specifically, smaller aneurysms that have not ruptured but have manifested with other symptoms, such as a new-onset third cranial nerve palsy or visual loss (caused by an ophthalmic artery aneurysm), should be treated because the natural history risk of rupture is believed to be significantly higher (6% per year) than that of incidentally discovered lesions. The three primary modalities used to study the size, location, and morphology of IC aneurysms are CT angiography (CTA), magnetic resonance angiography (MRA), and catheter-based digital subtraction angiography (DSA). On noncontrast CT, the typical nonthrombosed aneurysm appears as a well-delineated isodense to slightly hyperdense mass located somewhat eccentrically in the suprasellar subarachnoid space or sylvian fissure. Enhanced images of the cerebral vasculature can be obtained using rapid contrast infusion and thin-section dynamic CT scanning. Various threedimensional (3D) display techniques, including shaded surface display, volume rendering, and maximal intensity projection complement the conventional transaxial images. Such studies provide multiple projections of anatomically complex vascular lesions and delineate their relationships to adjacent structures. The accuracy

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of high-resolution axial CTA in the diagnosis of cerebral aneurysms 3 mm and larger has been reported to be about 97%. The reported ability of CTs to reveal SAH caused by ruptured cerebral aneurysms in the acute phase is about 95%. This sensitivity decreases over time. Acute SAH appears as high attenuation within the subarachnoid cisterns. Aneurysm appearance on MRI is highly variable and may be quite complex. The signal depends on the presence, direction, and rate of flow, as well as on the presence of clot, fibrosis, and calcification within the aneurysm itself. Fortunately, MRA technology can overcome many of the imaging challenges while precisely rendering the pathology. MRA relies on the macroscopic motion of the moving spins in flowing blood, together with background suppression of stationary tissue to create images of the cerebral vasculature. The images can be viewed as individual thin sections (source images) or can be reprojected in the form of flow maps. DSA continues to be the standard for delineating the features of an IC aneurysm. Recent advances in technology, most notably 3D rotational angiography, have increased the ability of catheter-based angiography to define aneurysm anatomy. Infundibuli and vascular loops are now well distinguished from aneurysms with such techniques. Technically adequate cerebral angiography is considered an important and indicated test in the assessment of nontraumatic SAH, although some groups have reported success with CTA as the only diagnostic test before treatment. When angiography is performed, visualizing the entire IC circulation, including the anterior and posterior communicating arteries and both PICAs is important. Multiple oblique, submental vertex, anteroposterior, and lateral projections, as well as subtraction studies, are integral parts of the complete angiographic evaluation. If an aneurysm is found, endovascular intervention to secure the aneurysm can be performed in the same setting, if appropriate. Treatment decisions for ruptured aneurysms differ significantly from those for unruptured aneurysms. Ruptured aneurysms should be treated urgently (within 72 hours of hemorrhage, and preferably within 24 hours) to prevent rebleeding and to permit aggressive management of vasospasm. Untreated ruptured aneurysms have a very high risk of rebleeding after the initial hemorrhage. The risk is estimated at over 20% in the first 2 weeks and 50% over the first 6 months, and such rebleeding carries a mortality rate of nearly 85%. Unruptured aneurysms may be treated electively. There are three major options for treating IC aneurysms: observation, craniotomy and clipping with or without bypass, and endovascular coil embolization with or without stent assistance. In the earlier days of aneurysm treatment, surgery was delayed until the second or third week after hemorrhage to avoid difficulty related

to brain swelling during surgery. Although this strategy lowered surgical morbidity and mortality rates, management results were not always good because of a high incidence of rebleeding and morbidity from vasospasm. The use of nimodipine and “triple-H” therapy (hypertensive hypervolemic hemodilution) for prevention and treatment of vasospasm, and ventriculostomy or lumbar drain for treatment of SAH, intraventricular hemorrhage, and hydrocephalus have become standard of care (Barker and Ogilvy, 1996; Elliott et al., 1998). The goal of open surgical treatment is usually to place a clip across the neck of the aneurysm to exclude the aneurysm from the circulation without occluding normal vessels (Figure 22.3). Microsurgical techniques are used to dissect the aneurysm neck free from the feeding vessels without rupturing the aneurysm. For aneurysms that cannot be primarily clipped, wrapping with cotton, muslin, or a synthetic patch and proximal occlusion with bypass are additional surgical options. Intraoperative angiography is now frequently used as an adjunct to clipping and permits confirmation of aneurysm occlusion and patency of nearby vessels. Recently, a new technique called near-infrared indocyanine green (ICG) videoangiography has become popular as a less invasive way to assess aneurysm and blood-vessel patency during aneurysm surgery. After intravenous injection of the ICG, an operating microscope equipped with appropriate software can detect blood flow within the vasculature within seconds using near-infrared video technology (Raabe et al., 2005). The operative morbidity and mortality associated with clipping depends on whether the aneurysm has ruptured: ruptured aneurysms are more treacherous, and morbidity is higher than that of unruptured aneurysms. The risk of surgery for unruptured aneurysms is estimated to be 4–10.9% morbidity and 1–3% mortality (Solomon et al., 1994; Cloft and Kallmes, 2004). Many factors affect the morbidity rates, with larger aneurysms in certain locations and in older, less medically healthy patients faring less well. Surgeons’ experience likely plays a role, with high-volume surgeons working in high-volume institutions having lower morbidity rates. In general, life expectancy influences the decision strongly. An older patient with a short life expectancy may not be a candidate for surgery for an unruptured aneurysm because the remaining lifetime risk is low. Conversely, due to the high mortality associated with a ruptured aneurysm, treatment is usually considered at any age if the patient is in good neurologic condition. After successful obliteration of a ruptured aneurysm, the patient remains at significant risk for vasospasm, hydrocephalus, and medical complications (including hyponatremia, venous thromboembolism, infections, and cardiac stun) and remains in an intensive care setting for at least 7–10 days (Zaroff et al., 1999). Operative

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(d) Figure 22.3 Multiple CT scans of a 57-yearold woman with Fisher 3 subarachnoid hemorrhage (SAH) secondary to rupture of a 6 mm, right-sided middle cerebral artery (MCA) aneurysm. (a) Axial CT slice shows SAH, acute hematoma within the right sylvian fissure, and right-to-left midline shift. An external ventricular drain is in place. (b) Axial and (c) coronal CT angiogram slices show an MCA bifurcation aneurysm (arrow) within a focus of SAH. (d) Coronal CT angiogram slice demonstrating clip occlusion of the aneurysm via ipsilateral pterional craniotomy. © Barrow Neurological Institute.

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complications represent only a small portion of the morbidity and mortality rates associated with a ruptured IC aneurysm. The major causes of morbidity and mortality include hydrocephalus, seizure, infection, and vasospasm. As noted earlier, vasospasm refers to narrowing of the IC vasculature in response to SAH. Management protocols for vasospasm include daily nimodipine, transcranial Doppler (TCD) trending, and balloon angioplasty with intra-arterial calcium-channel blocking agents. Over the past 15 years, endovascular methods to treat IC aneurysms have been developed and refined. The use of detachable platinum coils to embolize aneurysms has become the primary treatment modality of aneurysms at some centers. The purpose of the coil is to induce thrombosis at the site of deployment. Early limitations, such as an inability to coil aneurysms with wide necks or complex morphologies and high rates of recurrence secondary to coil compaction, are increasingly being addressed with complex-shaped coils, balloon and stent technology, and biologically active coils (Figure 22.4). In particular, stent-assisted coiling for the treatment of wide-neck aneurysms is increasing, although the complication rates

associated with this technique remain high. Two selfexpandable stents specifically designed for IC use (Neuroform and Enterprise) are approved by the Food and Drug Administration for use in the United States. More recently, both experimental and clinical evidence suggests that stent placement across the neck of an aneurysm causes a hemodynamic flow diversion that can occasionally cause aneurysmal occlusion/thrombosis without the need to introduce coils. A new stent with a more tightly constructed mesh, known as the Pipeline Embolization Device, designed to cause increased hemodynamic diversion relative to the Neuroform or Enterprise, is undergoing experimental investigation (Fiorella et al., 2006). The use of stent technology requires adjuvant antiplatelet therapy with aspirin and clopidogrel for 6–12 weeks to prevent in-stent stenosis (incidence ~6%). These additional medications carry their own set of risks (Lylyk et al., 2009). Obliteration of an aneurysm (ruptured or unruptured) with coiling or clipping is a matter of significant controversy. Currently, data suggest that whereas coiling is somewhat safer than clipping for both ruptured and unruptured aneurysms in the acute perioperative period,

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Therapeutics for the Geriatric Neurology Patient

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Figure 22.4 Multiple angiographic images of a 65-year-old woman with an 11 mm, unruptured, right-sided V4 aneurysm. (a) Oblique view

demonstrating a wide-necked, irregular aneurysm. The aneurysm arises directly from V4, at about the level of the exit (arrow) of the ipsilateral posterior inferior cerebellar artery (PICA). There is atherosclerotic dolichoectasia present in the ipsilateral proximal V4 as well. (b) Intraoperative “roadmap” view demonstrating dual microcatheter technique. One catheter deploys an inflatable balloon (arrow) as a buttress across the aneurysm neck, while a second catheter deploys coils into the aneurysm. (c) Unsubtracted lateral view demonstrating partial coil occlusion of the aneurysm with residual at the neck. Final (d) lateral and (e) Townes views of the aneurysm showing complete coil embolization and preservation of ipsilateral PICA. © Barrow Neurological Institute.

aneurysm obliterating via clipping is more durable and more often complete. The well-publicized International Subarachnoid Aneurysm Trial (ISAT) demonstrated increased safety of coiling over clipping for the subset of aneurysms considered suitable for either treatment (Molyneux et al., 2002). In that study, 2143 patients who presented with SAH and were deemed to have an aneurysm that was considered treatable with coiling or clipping were prospectively randomized to one of the two treatments. The study was stopped prematurely after a planned interim analysis found a 23.7% rate of

dependency or death in the coiling cohort versus a 30.6% rate in the clipping cohort. The main criticism of the study was that most of the aneurysms were thought to be better treated by one modality over the other, and thus only 22.4% of all aneurysms screened were randomized. Of those, the overwhelming majority were small and located in the anterior circulation. Therefore, although the study is important, generalizing the results to all ruptured aneurysms is inappropriate. Ultimately, the decision to clip or coil should be made on an individual basis and may often involve difficult-to-quantify variables such as a patient’s

Neurosurgical Care of the Geriatric Patient

interest in one technique over the other or the experience or availability of the physician operators. Cerebral aneurysms are increasingly revealed before rupture because of the ready availability of noninvasive neuroimaging techniques. With our increased ability to discover aneurysms comes the need to identify which incidentally discovered aneurysms should be treated and with what modality. A decision to treat is individualized and should be made by a physician or group of physicians who are capable of offering both modalities of treatment, clipping or coiling, without bias. The risks of any proposed treatment must outweigh the natural history risks or risk associated with no treatment. Risks of treatment and no treatment depend on many patientspecific and aneurysm-specific factors, including aneurysm size, location, and morphology and the patient’s age and medical comorbidities. In general, life expectancy of 12 years or more would warrant treatment of all incidentally discovered aneurysms, with the exception of very small aneurysms in elderly patients. Some patients will choose conservative observation and forego surgery and its risks (death and disability) in favor of the risk of future rupture. On the other hand, some patients are so frightened by knowing that they have an aneurysm that they cannot function until it is repaired. This psychological burden can be overcome in some patients with good counseling. In other patients, only definitive treatment of the aneurysm can provide relief. In the end, physicians should review all the relevant data from trials and natural history studies to help patients make their decision. Final decisions take time, patience, and experience, and may require repeated visits with patients.

Neurosurgical considerations for stroke Stroke is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. Also previously called cerebrovascular accident (CVA) or stroke syndrome, stroke is a nonspecific term encompassing a heterogeneous group of pathophysiologic causes, including thrombosis, embolism, and hemorrhage. The neurosurgical options for patients with stroke vary widely and are based on the etiology of the stroke, as well as its severity. While most patients with stroke will not benefit from surgery, many need neurosurgical evaluation. Carotid endarterectomy (CEA), carotid artery stenting, evacuation of intracerebral hematoma, endovascular revascularization, external ventricular drainage, and decompressive craniectomy are a few of the neurosurgical interventions that may benefit these patients. Strokes are broadly classified as either hemorrhagic or ischemic. Acute ischemic stroke refers to stroke caused by thrombosis or embolism and is more common than

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hemorrhagic stroke. A recent retrospective review found that 40.9% of 757 strokes were hemorrhagic. The increased percentage of hemorrhagic stroke may be due to improvement of CT availability and implementation, unmasking a previous underestimation of the actual percentage, or it may be due to an increase in therapeutic use of antiplatelet agents and warfarin causing an increase in the incidence of hemorrhage (Shiber et al., 2010). In recent years, significant advances have been made in stroke prevention, nonsurgical supportive care, and rehabilitation. Nonetheless, when the direct costs (care and treatment) and the indirect costs (lost productivity) of strokes are considered together, the cost to US society is $43.3 billion per year (Roger et al., 2011). On the macroscopic level, ischemic stroke is most often caused by extra-cranial (EC) embolism or IC thrombosis, but it may also be caused by decreased cerebral blood flow. The risk of both types of stroke increases with age. Embolic strokes are seldom of neurosurgical concern, except for the possibility of endovascular lysis or hemicraniectomy. Thrombotic stroke can be divided into large vessel, including the carotid artery system, and small vessel, comprising the branches of the circle of Willis and the posterior circulation. The most common sites of thrombotic occlusion are cerebral artery branch points, especially in the distribution of the ICA. Arterial stenosis can cause turbulent blood flow, which can increase the risk for thrombus formation, atherosclerosis (for example, ulcerated plaques), and platelet adherence. Each of these then causes the formation of blood clots that either embolize or occlude the artery. The open microsurgical as well as endovascular management of thromboembolic large vessel stenosis or occlusion is discussed in the next two subsections. Less common causes of thrombosis include polycythemia, sickle cell anemia, protein C or S deficiency, Factor V Leiden, fibromuscular dysplasia of the cerebral arteries, moyamoya disease, and prolonged vasoconstriction from migraine headache disorders. Any process that causes dissection of the cerebral arteries also can cause thrombotic stroke (such as trauma or thoracic aortic dissection). Occasionally, hypoperfusion distal to a stenotic or occluded artery or hypoperfusion of a vulnerable watershed region between two cerebral arterial territories can cause ischemic stroke. Some of these processes (such as arteritis, dissection, and hypercoagulability) are more likely to have an initial presentation in elderly patients, while others (such as moyamoya disease and sickle cell anemia) are more likely in younger patients. Neurosurgical intervention for stroke of these etiologies is usually limited to temporal artery biopsy (giant cell arteritis) or superficial temporal artery to MCA anastomosis for moyamoya disease. The acute presentation of a potential stroke is a medical emergency. Emergent noncontrast head CT is mandatory for rapidly distinguishing ischemic from hemorrhagic

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infarction and may help determine the anatomic distribution of stroke. Head CT is a fundamental branch point in the evaluation of stroke because patients with acute ischemic stroke may be triaged to receive thrombolytic therapy, whereas patients with hemorrhagic stroke are best served via a completely different diagnostic and therapeutic pathway. CT may also rule out other lifethreatening processes, such as other forms of hematoma, neoplasm, and brain abscess. The changes on CT over the course of acute cerebral infarction must be understood. The sensitivity of standard noncontrast head CT increases 24 hours after an ischemic event (Adams et al., 2007). After 6–12 hours, sufficient edema is recruited into the stroke area to produce a regional hypodensity on CT (Wardlaw and Mielke, 2005). A large hypodense area present on CT within the first 3 hours of reported symptom onset should prompt careful review regarding the time of stroke symptom onset (for example, determining when the patient was last seen in usual health). The presence of CT evidence of infarction early in presentation has also been associated with poor outcome and increased propensity for hemorrhagic transformation after thrombolytics (Hacke et al., 1995; The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group 1995; Von et al., 1997). Other radiologic clues to acute ischemic infarction include the insular ribbon sign, the hyperdense MCA sign (MCA occlusion), obscuration of the lentiform nucleus, sulcal asymmetry, and loss of gray–white matter differentiation (Adams et al., 2007). Noncontrast CT may be followed by a CTA in certain centers. CTA may identify a filling defect in a cerebral artery, thus localizing the lesion to a specific portion of the causative vessel. In addition, CTA can provide an estimation of perfusion because poorly perfused cerebral tissue appears as hypodense areas of tissue. Noncontrast head CT in combination with CTA and CT perfusion imaging is more sensitive for detecting small ischemic lesions, compared with any of the individual imaging modalities alone. CT perfusion imaging is a relatively new modality potentially useful in identifying early areas of ischemia. By continuing to scan through the brain after an initial bolus of intravenous contrast dye, perfusion of different brain regions can be measured. Areas of hypoattenuation on CT perfusion imaging correspond well with ischemia and allow some determination of viability and the ischemic penumbra (Klotz and Konig, 1999; Wintermark et al., 2002). Various MRI protocols have utility in acute stroke. Standard T1-weighted and T2-weighted MRI sequences may be combined with other imaging protocols, such as diffusion-weighted imaging (DWI) and perfusionweighted imaging, to yield improved sensitivity for the detection of acute ischemic and hemorrhagic strokes over standard noncontrast CT. Furthermore, subacute intracerebral hemorrhage, while difficult to diagnose

via standard noncontrast CT, can be detected using MRI with reliability approaching 100%. DWI can detect ischemia much earlier than standard CT or MRI sequences and provides useful data in stroke and TIA patients outside of the initial management window (Sorensen et al., 1996; Gonzalez et al., 1999; Adams et al., 2007). DWI can detect small areas of ischemia, particularly in regions poorly visualized by noncontrast CT, such as the cerebellum and the brainstem (Adams et al., 2007). Acute stroke volume, as measured on DWI, correlates well with final lesion volume and clinical stroke severity scales, suggesting a possible role in prognostication (Lovblad et al., 1997; Barber et al., 1999). Carotid duplex ultrasonographic scanning is indicated for patients with acute ischemic stroke in whom carotid artery stenosis or occlusion is suspected. TCD ultrasonography is useful for evaluating more proximal vascular anatomy, including the MCA, intracranial ICA, and vertebrobasilar artery (Camerlingo et al., 1993). The central goal of therapy in acute ischemic stroke is to preserve the area of oligemia in the ischemic penumbra (Roger et al., 2011). The area of oligemia can be preserved by limiting the severity of ischemic injury (neuronal protection) or by reducing the duration of ischemia (restoring blood flow to the compromised area). The ischemic cascade offers many points at which such interventions can be attempted, and multiple strategies and interventions for blocking this cascade are currently under investigation. Several neurosurgical interventions have a defined role in flow restoration, in the acute, subacute, and even chronic phases of stroke.

Neurosurgical management of carotid occlusive disease As noted earlier, stenosis due to atherosclerotic disease at the carotid bifurcation in the neck is a common cause of stroke. Most are due to embolism, with a much smaller proportion causing acute ischemia. Characteristically, plaque forms in the lumen of the Y-shaped junction of the internal and external carotid arteries. As the stenosis becomes more severe, the risk of fracture of the plaque and subsequent embolization and stroke increases commensurately. Asymptomatic disease is often diagnosed through physical examination or diagnostic imaging. If mild, it is usually treated medically. If severe, it is often treated surgically via CEA (carotid bifurcation plaque removal; Figure 22.5). Symptomatic disease presents with stroke, visual loss, or TIA. The degree of stenosis determines whether treatment or best medical therapy is employed. Age also plays an important role in determining what treatment, if any, is required. Patients with any degree of identifiable stenosis should be considered for treatment at a minimum with a single full-dose aspirin per day. Patients with a higher degree of stenosis who are not surgical

Neurosurgical Care of the Geriatric Patient

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Figure 22.5 CT angiogram of the neck in an asymptomatic patient shows severe calcified stenosis of the right ICA bifurcation in (a) sagittal (arrow) and (b) axial planes (arrow). CT angiogram of the neck is repeated after a right-sided carotid endarterectomy (CEA) confirms restoration of flow in (c) sagittal and (d) axial planes. © Barrow Neurological Institute.

candidates should be considered for stronger antiplatelet agents, such as clopidogrel. A number of high-quality prospective randomized trials have compared CEA with best medical care. The North American Symptomatic Carotid Endarterectomy Trials (NASCET) I and II compared symptomatic patients and conclusively showed improved benefit with endarterectomy, as well as a very low procedural and periprocedural complication rate. Symptomatic patients with stenosis as low as 50% were seen to benefit from CEA (North American Symptomatic Carotid Endarterectomy Trial Collaborators, 1991). Other trials, such as the VA Cooperative

Trial and European Carotid Surgery Trial (ECST), confirmed these results (European Carotid Surgery Trialists’ Collaborative Group, 1991; Hobson et al., 1993). In addition, asymptomatic patients have been similarly studied, with a statistically significant benefit found for surgery for patients with greater than 60% stenosis in trials such as the Asymptomatic Carotid Atherosclerosis Study (ACAS) (Executive Committee for Asymptomatic Carotid Atherosclerosis, 1995). Because the benefit of endarterectomy is much greater for symptomatic patients than asymptomatic patients and for patients with high degrees of stenosis versus mild stenosis, there is some debate

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about how strongly treatment should be recommended for asymptomatic patients with lower degrees of stenosis. Therefore, recommendation for surgery for asymptomatic patients can be made for all degrees of stenosis over 60% but should be made more strongly as the degree of stenosis rises from 60% to 99%. Although counterintuitive, the older a patient is, the more likely he or she is to benefit from CEA, because the risk of stroke rises faster than the surgical risk. Carotid angioplasty and stenting (CAS) has emerged more recently as an endovascular treatment option for carotid stenosis. Carotid stenting is an alternative treatment for carotid stenosis in which the femoral artery is catheterized, a catheter is passed up to the carotid artery, a balloon is inflated to open the stenosis, and a metal stent is placed. Although intrinsically appealing as a minimally invasive option, data to support its use over CEA has mostly been lacking. The SAPPHIRE trial, a comparative noninferiority study of patients with a high cardiopulmonary risk, showed no difference in the outcome of CAS versus CEA (Yadav et al., 2004; Gurm et al., 2008). This result has been interpreted to mean that patients with high medical (cardiopulmonary) risk for surgery can be considered for CAS as a first choice. It is important that age not be conflated with high medical risk, as CEA has been shown to have a better risk profile than CAS for patients over the age of 70 (Bonati et al., 2010). Furthermore, because there is only a weak association between medical risk and age, it is crucial to assess risk factors independently of age when evaluating a patient’s global medical risk profile. A number of other recent trials have compared stenting and endarterectomy. At present, all of these have shown a very low risk for CEA. None of these large trials have shown advantage for CAS, including SPACE and EVA-3S in Europe and, most recently, the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) in North America (Mas et al., 2006; Ringleb et al., 2006; Mas et al., 2008; Mantese et al., 2010; Silver et al., 2011). A number of criticisms have been raised by the endovascular community about these trials, including concerns that distal antiembolism protection devices were not used in enough patients and that the enrolling endovascular surgeons were not skilled enough. Nonetheless, no current trial has shown more benefit for CAS in terms of the major endpoints of stroke and myocardial infarction. Therefore, patients who have a low or moderate cardiopulmonary risk should undergo endarterectomy as a first choice. Patients who have a higher risk can be considered for CAS or CEA, depending on the degree of that risk. Table 22.1 summarize the indications and other factors that may influence decision making. Complete closure (occlusion) of the carotid is typically managed conservatively. For any chronic complete clo-

Table 22.1 Indications for carotid endarterectomy (CEA) or carotid artery stenting (CAS) Symptomatic stenosis >60%—high benefit Low or moderate medical risk—CEA High risk—CAS Asymptomatic stenosis >60%—moderate benefit Low or moderate risk—CEA High risk—CAS CEA favored Age >80 Calcified plaque CAS favored Recurrent (postendarterectomy) stenosis Postradiation therapy to neck Contralateral carotid occlusion (relative) Contralateral laryngeal nerve palsy High (to C1 level) carotid stenosis

sure of the carotid, surgery to reopen the carotid artery has shown no benefit. This is likely because the major risk for stroke is at the time of closure, and thus surgical recanalization provides no reduction of stroke risk. However, patients with ongoing stroke or TIA may be considered for thromboendarterectomy if they are identified and treated soon after the time of closure. This option may be considered for patients with: (1) a zone of hypoperfusion on MR or CT perfusion larger than the area of completed diffusion change on MRI and (2) a luminal thrombus that does not extend beyond the petrous carotid artery. EC–IC bypass in the form of an STA-to-MCA anastomosis was evaluated for carotid occlusion in the International EC–IC Bypass Trial in the 1980s (EC/IC Bypass Study Group, 1985) and, more recently, in the Carotid Occlusion Surgery Study (COSS). In both trials, patients treated with surgery did worse than those treated with best medical care. While STA-to-MCA still has a place in the treatment of moyamoya disease and complex aneurysms, its benefit for ischemia seems doubtful.

Endovascular treatment for acute intracranial thrombotic stroke The endovascular treatment of acute IC thrombosis is advancing rapidly. The major barrier to success in this area appears to be the rapidity with which treatment can be instituted. Endovascular options include direct intraarterial thrombolysis with enzymatic thrombolytics (streptokinase, urokinase, tissue plasminogen activator (rt-PA)) and direct mechanical thrombectomy. A number of trials with new thrombectomy devices are ongoing. In general, endovascular thrombolysis or thrombectomy should be attempted if it can be achieved within 3 hours of the onset of stroke in patients without evidence of IC hemorrhage. There is equivocal evidence of a time window up to 6 hours. Beyond this time window, such procedures should be performed only as part of a clinical trial.

Neurosurgical Care of the Geriatric Patient

Neurosurgical management of spontaneous intracerebral hematoma As noted earlier, a significant number of patients presenting with acute stroke will be found to have suffered from intracerebral hemorrhage. This group is not a candidate for thrombolytic therapy, unless the hemorrhage is predominantly intraventricular. Most patients will be managed conservatively. However, for some patients with larger hemorrhages, surgical evacuation may be considered. Typically, those patients who do best with surgical evacuation have superficially located hematomas in noneloquent areas of the brain. The natural history of patients with substantial intraventricular hemorrhage is much worse than that of other patients with intracerebral hemorrhage. This seems to be due largely to the sequelae of hydrocephalus. External ventricular drainage and treatment with intraventricular thrombolytics provide a gratifying improvement in outcomes (Torres et al., 2008; Staykov et al., 2009). Decompressive hemicraniectomy Decompressive hemicraniectomy in the treatment of stroke has a controversial history. The purpose of the treatment is to open the cranium ipsilateral to an ischemic or hemorrhagic stroke to provide room for the brain to swell. This mitigates the effect of the swelling tissue on the surrounding brain, thereby reducing brain shift and reducing the potential for increased ICP (Figure 22.6). The benefit for elderly patients seems to be less than for younger patients, for reasons that are not immediately clear. If practiced, it should be done before herniation occurs and only as a life-saving measure.

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Normal pressure hydrocephalus Normal pressure hydrocephalus (NPH) is a clinical symptom complex characterized by abnormal gait, urinary incontinence, and dementia and is described in more detail in Chapter 20. It is an important clinical diagnosis because it is a potentially reversible cause of dementia. First described by Hakim in 1965, NPH describes hydrocephalus in the absence of papilledema and with normal CSF opening pressure on lumbar puncture (Hakim and Adams, 1965). Clinical symptoms result from distortion of the central portion of the corona radiata by the distended ventricles. This distention may also lead to interstitial edema of the white matter and impaired blood flow, as suggested in nuclear imaging studies. Hakim first described the mechanism by which a normal or high– normal CSF pressure exerts its effects—increased CSF pressure over an enlarged ependymal surface applies considerably more force against the brain than the same pressure in normal-sized ventricles. It is thought that NPH may begin with a transient high-pressure hydrocephalus that produces subsequent ventricular enlargement, which persists despite ultimate pressure normalization. NPH is predominantly a disease of the elderly. Patients present with a gradually progressive disorder. Although the classic triad is noted, gait disturbance is typically the earliest feature and considered to be the most responsive to treatment. Furthermore, this is an apraxia of gait—it is characteristically bradykinetic, magnetic, and shuffling. True weakness or ataxia is typically not observed. The dementia of NPH is characterized by prominent memory loss and bradyphrenia. Frontal and subcortical deficits are particularly pronounced. Such deficits include forgetfulness, decreased attention, inertia, and

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Figure 22.6 (a) Axial CT angiogram of the head demonstrating contrast block in the right distal M1 segment in a patient with acute onset of left-sided weakness (arrow). (b) Noncontrast CT scan of head obtained hours later demonstrates edema within the right middle cerebral artery (MCA) territory suggestive of infarction, as well as midline shift and ventricular effacement. (c) A decompressive hemicraniectomy was performed to mitigate brain shift and prevent herniation. © Barrow Neurological Institute.

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generalized cognitive slowing. The presence of cortical signs such as aphasia or agnosia should raise suspicion for an alternate pathology such as Alzheimer’s disease (AD) or vascular dementia (Bech-Azeddine et al., 2007). However, comorbid pathology is not uncommon with advancing age. The index of suspicion for NPH should remain high, given its better response to treatment compared with other forms of senile dementia (Golomb et al., 2000). NPH may occur due to a variety of secondary causes but may be idiopathic in approximately 50% of patients. Secondary causes of NPH include head injury, SAH, meningitis, and CNS tumors. Another potential cause may be previously compensated congenital hydrocephalus. Multiple other illnesses, including Alzheimer’s dementia, Pick’s disease, Lewy body dementia, Wilson’s disease, and vascular dementia, may present similarly to NPH and should be considered in the differential diagnosis. In particular, Parkinson’s disease (PD) and NPH may present in a similar, yet subtly distinct manner. Start hesitation and freezing episodes can occur in NPH, often mimicking the gait in PD. In contrast to PD, however, rigidity and unilateral rest tremor are less commonly observed. CT and MRI findings in NPH include the following: ventricular enlargement out of proportion to sulcal atrophy, prominent periventricular hyperintensity consistent with transependymal flow of CSF, and a prominent flow void in the aqueduct and third ventricle. This last finding represents the so-called “jet sign,” a dark aqueduct and third ventricle on a T2-weighted image where the remainder of CSF is bright. A specific MRI cineradiographic study can be ordered to assess flow through the aqueduct. A value

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of >100 μL per cardiac cycle is thought to correlate with shunt responsiveness, though the correlation is not strong. Absence of flow through the aqueduct, especially in the setting of enlarged lateral and third ventricles and a small fourth ventricle, should prompt consideration of the diagnosis of aqueductal stenosis. This condition is responsive to endoscopic third ventriculostomy. Prominent medial temporal cortical atrophy favors a diagnosis of hydrocephalus ex vacuo and is often related to AD or vascular dementia. Radionuclide cisternography has been used in the diagnosis of NPH. A radionuclide such as 99-Technicium diethylene triamine pentaacetic acid (99Tm-DTPA) is introduced into the lumbar spinal fluid, and the neuraxis is imaged at intervals over the first 24–48 hours. A normal study demonstrates flow of spinal fluid over the cerebral convexities and absorption of most of the dose within 24 hours. A study consistent with NPH shows reflux of the fluid back into the ventricles. The use of this test is controversial, as some patients without hydrocephalus show similar findings. However, a clearly positive radionuclide cisternogram has predicted a response to shunting in some studies as high as 75%. All patients with suspected NPH should undergo diagnostic CSF removal (either large-volume lumbar puncture and/or external lumbar drainage (ELD)), which has both diagnostic and prognostic values (Williams et al., 1998). When the CSF opening pressure is greatly elevated, other causes of hydrocephalus should be considered, although CSF pressures may be transiently elevated in NPH. Surgical CSF ventricular shunting remains the main treatment modality (Figure 22.7). Detailed testing is performed before and after CSF drainage. Initially, patients are given a baseline

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Figure 22.7 (a) Axial CT scan of the head showing typical ventriculomegaly out of proportion to volume loss in a patient with normal

pressure hydrocephalus (NPH). (b) Ventriculoperitoneal shunting can use either a right frontal or right parietal approach. (c) Bone windows demonstrate intraventricular drainage sites (black arrow) and flow-regulating valve (white arrow). © Barrow Neurological Institute.

Neurosurgical Care of the Geriatric Patient

neuropsychological evaluation (such as the Folstein test or more formal neuropsychological testing) and a timed walking test/fall risk assessment, such as is included in the Tinetti Gait and Balance Scale (Tinetti et al., 1986). Patients then undergo a lumbar puncture with removal of approximately 25–50 mL of CSF. Testing is repeated 3 hours later. A clear-cut improvement in mental status and/or gait predicts a favorable response to shunt surgery. The effect of the lumbar puncture does not persist beyond 48 hours. While large-volume lumbar puncture was the earliest invasive diagnostic test in predicting response to shunt surgery, ELD is being used with increased frequency. In this method, clinicians use an indwelling CSF catheter in lieu of repeated lumbar punctures (Hebb and Cusimano, 2001). Patients with a good response to predictive testing should be considered for ventriculoperitoneal shunting. The best results are reported in patients who have no adverse surgical risk factors, have responded favorably to a large-volume lumbar puncture, have predominantly gait disturbance with mild dementia, and have appropriate CT or MRI findings and a normal CSF cellular and chemical profile at lumbar puncture. While a significant proportion of patients will achieve substantial functional benefit from shunting, the overall prognosis of NPH remains poor, due to both a lack of improvement in some patients following surgery and a significant complication rate related to shunting (Pujari et al., 2008). In patients who develop recurrent symptoms after initial improvement, shunt malfunction should be suspected and an evaluation for mechanical failure should be pursued. The incidence of shunt complications of all degrees of severity is estimated in 30–40% of patients (Vanneste et al., 1992). These include anesthetic complications, IC hemorrhage from placement of the ventricular catheter, infection, CSF hypotensive headaches, SDHs, shunt occlusion, and catheter breakage. Rapid reduction in ventricular size following the shunt favors complications such as subdural hematoma, which may occur in 2–17% of patients. Shunt valves, which prevent siphoning of CSF from the head, and programmable valves, which can adjust the pressure at which fluid drains, may reduce the incidence of this complication.

Neurooncology Brain tumors, whether benign or malignant, affect the elderly at a higher rate in the general population. Malignant brain tumors, both primary and metastatic, are associated with considerable morbidity and mortality. The overall incidence of brain tumors continues to increase, with the highest increase noted in patients over 60 years of age. The attitude of the medical community toward

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offering treatments to elderly patients with malignancies is changing, and more elderly patients with brain tumors are now treated aggressively. Advances in understanding the molecular biology of brain tumors and the genetics of brain tumors in older patients have resulted in treatments that are more effective or better tolerated in this age group (Nayak and Iwamoto, 2010). The overall prognosis for malignant tumors remains poor, and the search for more effective therapies is ongoing. Malignant brain tumors can be primary or metastatic. Metastatic tumors to the brain are most common, accounting for greater than 50% of all brain tumors in the elderly. Adenocarcinoma of the lung and breast most frequently metastasize to the brain, followed by melanoma and carcinoma of the kidney and thyroid. Among primary brain tumors, malignant gliomas, particularly glioblastomas multiforme (GBMs), are most commonly seen in the elderly. Age is a strong prognostic factor affecting survival for all brain tumor patients (Davis et al., 1999). The 5-year survival rate for patients with a GBM is about 20% in patients younger than 35 years, 10% in patients aged 35–54, and only 1% in patients 55 years and older. This is now known to at least partially reflect fundamental differences in tumor biology (Burger and Green, 1987; Roa et al., 2009). The age-based survival data parallel the survival rates based on performance status, as measured by the Karnofsky performance scale, indicating the importance of this preoperative variable. Additional tumor types commonly seen in older patients are meningioma, acoustic neuroma, and CNS lymphoma. Meningiomas are the most common benign tumor and are often seen in the elderly (mean age 59), with a female predominance. The 5-year survival rate is 92% for patients aged 45–74 and 70% for patients aged 75 and older (Nayak and Iwamoto, 2010). Acoustic neuromas are predominantly benign tumors of the vestibular division of the eighth cranial nerve. They should be suspected in patients with unilateral hearing loss or vertigo that does not resolve with medical treatment. Depending on the age of the patient, the severity of symptoms, and the size of the tumor, management of meningioma and acoustic neuroma can be conservative (with symptomatic treatment and follow-up with serial scans) or more definitive (with surgery or stereotactic radiosurgery). CNS lymphoma is a primary CNS malignancy with poor overall prognosis. The median survival is about a year. These tumors can be multifocal, are associated with immune compromise, and are most commonly treated with a combination of intravenous and intrathecal chemotherapy. The diagnosis of brain tumors is based on clinical presentation, imaging studies, and histology. In the older population, intellectual decline over a brief period, gait disturbances, and short-term memory deficits are clinical signs that may indicate the presence of a brain tumor and must be differentiated from “normal” aging signs

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and cerebrovascular disease. The symptoms and signs are dependent on tumor location. The majority of malignant glioma and metastatic lesions in the elderly occur in the cerebral hemispheres. Headaches and seizures are the most common symptoms at presentation. The presence of focal neurologic deficits helps to localize the lesion (Mahaley Jr. et al., 1989). Tumors in the anterior frontal lobes, the anterior temporal lobes, or the base of the skull can grow to a large size with few or no symptoms or with nonspecific symptoms often ascribed to the aging process (such as memory loss, personality changes, or some gait difficulties). The diagnosis of tumor can be suspected if the symptoms develop over a short period of time (less than 6 months). The presence of any history of cancer, however remote, must greatly raise the index of suspicion for metastatic lesions. Neuroimaging studies are valuable tools in localizing tumors and may suggest the diagnosis and malignant character of a tumor. Contrast-enhanced MRI of the brain is now the most utilized imaging modality. It allows visualization of the tumor in axial, coronal, and sagittal planes, thereby providing a 3D view of the tumor and its relationship with the surrounding structures. MR spectroscopy and MR perfusion can help differentiate recurrent tumor from treatment effect in patients who have received prior radiation therapy (RT). Stereotactic MRI scans can be coregistered with high-resolution microscopes, allowing for intraoperative navigation around a tumor and its surrounding structures as seen on the MRI. Neuroimaging studies such as DWI sequences can differentiate between tumor and stroke when the lesion does not respect a vascular distribution. They can also help to differentiate between hemorrhage due to hypertension and hemorrhage into a tumor. When the scan reveals peripherally enhancing lesions, the differential diagnosis is often primary malignant tumor, metastatic tumor, or abscess. If the chest radiograph is normal, the highestyield procedure will be a biopsy of one of the lesions for tissue diagnosis. In this age group, infectious or vasculitic lesions are less common than in younger patients. The pathologic examination of the tumor specimen on frozen section and fixated material defines the type of tumor and the histologic grade. Primary brain tumors are classified histologically based on the World Health Organization (WHO) classification. The grade of malignancy is based on the cellularity, presence of mitoses, vascular endothelial proliferation, and necrosis. For an accurate grading, the pathologist needs to know whether the patient received RT or chemotherapy prior to the surgical procedure. Tissue necrosis can be caused by RT and chemotherapy, as well as by some malignant tumors, particularly GBM (Roa et al., 2009). On the subcellular level, recent research has focused on defining the genetic alterations and interactions among tumor-suppressor genes, oncogenes and their products, growth factors, and

enzyme systems. The goal of this research is to determine the mechanisms of oncogenesis, cell resistance, and repair mechanisms and to develop new treatment modalities based on the molecular biology data. The p53 tumor suppressor gene, found on chromosome 17p, is frequently altered in gliomas, as it is in systemic cancers. The PTEN gene, located on 10q23, has also been identified as a putative tumor suppressor gene and is often mutated in gliomas. The treatment of brain tumors is determined by the histologic type and the location in the cranial cavity, as well as the patient’s performance status, neurologic status, age, coexisting medical problems and life expectancy. In the elderly, treatment of brain tumors raises particular challenges. Benign tumors such as meningiomas, acoustic neuromas, or pituitary adenomas can often be managed conservatively in older patients unless the symptoms and tumor size warrant a more aggressive approach. For gliomas and metastatic tumors, the conventional therapy involves surgery, RT, and chemotherapy. Most primary brain tumors and metastatic tumors have surrounding vasogenic edema, which contributes to the neurologic symptoms (Figure 22.8). Vasogenic edema is controlled most often with corticosteroids. Dexamethasone is commonly used, and it may need to be tapered slowly following tumor resection to treat persistent edema. Side effects with long-term corticosteroid use include gastric irritation, corticosteroid myopathy, Cushingoid appearance, and, in some patients, osteoporosis, depression, and corticosteroid psychosis. Hence, an effort is made to taper the steroids as quickly as the clinical situation allows. Surgery is the first therapeutic intervention for most brain tumors, with the goal of obtaining tissue for diagnosis and, whenever possible, debulking the tumor to relieve mass effect and bring about rapid clinical improvement. In the elderly, surgery is considered to carry a higher risk of morbidity and mortality compared with younger patients. When feasible, complete resection of malignant glioma (WHO grade III and IV) has been shown to significantly increase the rate of survival by providing cytoreduction, with a better chance of response to subsequent therapy. Outcome studies further show that patients who undergo resection have a better quality of life and are less likely to become depressed than patients who undergo only biopsy (Pietila et al., 1999). For patients with unresectable lesions (most often due to the anatomic location being associated with an unacceptable risk of neurologic deficit) or with associated significant medical comorbidities, a stereotactic biopsy for tissue diagnosis is sufficient. At present, the most important prognostic factors for overall survival are preoperative performance status for malignant glioma and the extent of resection for low-grade glioma (WHO grade II; Nayak and Iwamoto, 2010). For metastatic lesions, surgical resection for patients with one to three lesions has been shown

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Figure 22.8 (a) Sagittal T1-weighted MRI with gadolinium and (b) axial T2-weighted MRI of the brain demonstrate a large right frontal dural-based tumor consistent with a meningioma. The T2-weighted image also shows a large component of surrounding vasogenic edema, visible as a bright signal within the white matter. © Barrow Neurological Institute.

to improve both clinical performance status and overall survival, with most patients ultimately succumbing to systemic disease burden rather than their CNS disease (Suh, 2010). All malignant brain tumors, whether they are primary or metastatic, single or multiple, benefit from RT as a component of standard treatment. RT can also be used as an alternative to surgery in low-grade glioma patients with multiple medical comorbidities. Most intensitymodulated radiation treatment (IMRT) schedules deliver the total radiation dose over a series of weeks. Hyperfractionation schedules allow the RT dose to be delivered in two or three daily treatments, while hypofractionation schedules use a once-weekly treatment (Roa et al., 2009). While hyperfractionation allows for larger total radiation dose with less toxicity to the normal brain, hypofractionation helps to reduce acute RT side effects. Stereotactic radiosurgery is a noninvasive technique that allows delivery of high-dose single fractions of radiation to small, well-circumscribed tumors; it is often used in patients with meningioma, acoustic neuroma, and some cerebral metastases such as nonsmall cell lung cancer. It is occasionally used as a primary tumor treatment or to treat a surgical resection bed as a means of preventing local recurrence. The treatment is low risk and effective, and because it is done in one single dose or a few fractionated doses in an outpatient setting, stereotactic radiosurgery is convenient for the patient and cost-effective. The morbidity associated with this approach is primarily related to increased peritumoral edema, which can be controlled with corticosteroids (Patil et al., 2010). Regardless of the radiation modality used, RT may cause side effects in the elderly patient that need to be discussed and monitored. The reactions to RT are more significant when RT is administered to a large portion of the brain. The effects can be acute or delayed. Acute effects occur during treatment or shortly after completion of

RT. Some patients experience headaches, likely related to edema, or a worsening of the neurologic deficits. Fatigue is another complaint. Depending on the tumor location, patients may experience nausea, sore throat, hearing loss, or blurred vision. These symptoms are transient and can be controlled with corticosteroids and reassurance. Early delayed effects, which appear in the first 3 months after completion of RT, include somnolence, loss of appetite, and apathy. These effects are self-limiting and seem to be more severe in older patients (Roa et al., 2009). Latedelayed radiation injury occurs months or even years after completion of radiation. Patients experience shortterm memory loss and cognitive decline. CT or MRI shows white matter changes bilaterally or may show focal radiation necrosis (Figure 22.9). Chemotherapy has been established as an accepted adjuvant treatment for malignant primary brain tumors.

Figure 22.9 Axial FLAIR MRI of the brain demonstrating profound postradiation changes in a patient who previously underwent both IMRT and stereotactic radiotherapy for cerebral metastases from breast carcinoma. © Barrow Neurological Institute.

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It is traditionally used after completion of RT. The addition of chemotherapy to RT in malignant glioma has been shown to prolong survival by up to 6 months. Temozolomide (Temodar), an alkylating agent, is currently the most effective chemotherapy for treatment of malignant glioma. Clinical trials are currently underway to assess the adjunctive use of other chemotherapy agents such as bevacizumab (Avastin), although the efficacy of this use has not yet been established. Primary CNS lymphoma is another malignant primary brain tumor whose management combines systemic and intrathecal chemotherapy with RT. Methotrexate is often employed. In some cases, an Ommaya reservoir may be of benefit. Clinical studies show that elderly patients tolerate intensive chemotherapy well, although prognosis remains poor, with an average survival of only 1 year (Nayak and Iwamoto, 2010). Chemotherapy can also be considered for control of both CNS and active systemic metastatic disease. The decision to initiate treatment for a brain tumor in an elderly person should be based not only on age, but also on life-expectancy, performance status, the presence or absence of neurologic deficits, the extent of systemic disease, if any, and coexistent chronic illnesses. These factors determine the surgical risk in deciding for resection or biopsy, as well as whether to consider radiosurgery in addition to standard external beam RT. Given the impact of the brain tumor and its treatment on both the cognitive and physical abilities of the patient, the goals of therapy must always include improving performance status and minimizing treatment side effects. For elderly patients with malignant glioma who have a poor long-term prognosis, conventional fractionation or hypofractionation RT provides palliation and can improve the quality of life over the short term. Furthermore, physical therapy and occupational therapy can be utilized to help support a patient’s ability to perform activities of daily living. At all stages, the nature of the tumor and the prognosis must be

discussed with the patient and the family in a manner that would neither discourage therapy nor raise false hope. The involvement of the patient and family in the management decision process creates a support system for the patient. After options are discussed, the patient should be allowed to make the informed choice whenever possible.

Odontoid fractures Odontoid fractures are the most common cervical fractures in the elderly. Gait and balance problems, as well as decreased bone density predispose older patients to these types of fractures. An odontoid fracture is a fracture through the second cervical vertebra (also known as C2 or the axis). In younger patients, this type of injury is usually sustained in a motor vehicle accident or other high-force mechanism. In the elderly, however, a simple fall in which the patient strikes the forehead and sustains a hyperextension injury may produce this type of fracture. Patients often present with neck pain and, barring other injuries, are neurologically intact. Odontoid, or dens, fractures are classified into three types, with Type I fractures occurring through the tip of the dens, Type II fractures occurring at the base of the dens, and Type III fractures occurring through the body of the axis (Figure 22.10) (Anderson and D’Alonzo, 1974). Type IIA fractures, described by Hadley and colleagues (1988) involve a comminution at the base of the odontoid process. Type II fractures are by far the most common and represent 8–15% of all cervical fractures. Type IIA fractures represent 5% of all Type II fractures, are considered highly unstable, and are usually managed with early posterior surgical fixation. CT and plain radiographs are standard in the initial diagnosis of bony injuries such as odontoid fractures (Figure 22.11a). For the complete diagnostic work-up, as well as for treatment planning, MRI is essential in

Figure 22.10 The classification system of Anderson and D’Alonzo. Type I: Fracture through the tip, above the transverse ligament. Rare;

represents less than 5% of cases. Type II: Fracture through the base of the neck. Most common; occurs in >60% of cases. Type III: Fracture through the body of C2. Occurs in 30% of cases. © Barrow Neurological Institute.

Neurosurgical Care of the Geriatric Patient

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Figure 22.11 (a) CT of cervical spine, sagittal view, demonstrating a Type II fracture through the dens with posterior displacement. (b) MRI of cervical spine, gradient echo sequence, axial view, demonstrating the transverse atlantal ligament (TAL). It appears as a homogenous, thick, low-signal intensity structure (arrow) that extends between the medial portions of the lateral masses of C1. © Barrow Neurological Institute.

assessing the spinal cord, as well as for evaluating the status of ligamentous structures such as the transverse atlantal ligament (TAL) (Figure 22.11b). TAL disruption occurs in 10% of patients with odontoid fractures (Greene et al., 1994) and the integrity of this structure is important in selecting the appropriate treatment. For example, anterior odontoid screw fixation will not provide stability if the TAL is disrupted. In addition, odontoid fractures have been seen in association with occipitoatlantal dislocation, and MRI will assist in evaluating for this type of injury. Finally, when a C2 fracture is identified, it is important to evaluate the subaxial spine, as 16% of patients will have a noncontiguous fracture. Type I and III dens fractures are stable injuries that can be treated with a hard collar. Treatment paradigms for Type II fractures, however, remain controversial. Nonoperative management (nonOP) options include rigid cervical orthosis (hard collar) or rigid immobilization after reduction in a halo vest. Studies, however, have revealed a nonunion rate of 35% with nonOP of Type II fractures. Risk factors for nonunion include increasing age, subluxation greater than 5 mm, and any significant posterior subluxation. Elderly patients are uniquely susceptible to the complications of conservative management because of the morbidities associated with prolonged immobilization in a halo vest, as well as the physiologic hurdles associated with the injury. These include edema of the upper cervical region, resulting in difficulties with swallowing and airway protection, and subsequent pulmonary compromise or aspiration. Risks also are associated with prolonged bed rest, pin site care, personal hygiene, pressure sores under the vest, balance and gait impairment, and increased falls (Tashjian et al., 2006). Finally, halo vest usage can significantly limit respiratory function by impairing total vital capacity (Lind et al., 1987). Recent studies revealed higher rates of pneumonia, cardiac arrest, and death in patients treated with a halo vest, as compared to patients treated with cervical orthosis or operative fixation (Tashjian et al.,

2006). In addition, halo vest-treated patients had morbidity and mortality rates of 66% and 42% versus rates of 36% and 20% in nonhalo vest-treated patients (Tashjian et al., 2006). External immobilization is considered as a treatment option in the initial management of all odontoid fractures. Next, consideration is given to the factors involved in determining whether a patient will benefit from operative management. Advanced age and significant comorbidities usually deem a patient as too high risk for operative intervention. Hence, conservative management is selected. After discharge, patients are evaluated on an outpatient basis for evidence of fusion and are maintained in either a rigid cervical orthosis or a halo vest until successful fusion is achieved. If there is no radiographic evidence of fusion after a period of several months (average 3–4 months), operative fixation is considered. For patients with dens displacement of greater than 5 mm, comminution of the odontoid fracture (Type IIa), disruption of the TAL, or inability to achieve or maintain fracture alignment with external immobilization, conservation management is unlikely to be successful. Surgical management must be considered instead (Greene et al., 1997). Surgical fixation can be performed through either an anterior or posterior approach. Options for posterior fixation include C1–2 wiring, C1–2 transarticular fixation, or C1 lateral mass–C2 pars/pedicle screw fixation. Though extremely effective in the treatment of odontoid fractures, posterior fixation also leads to loss of C1–2 axial rotation. For this reason, many surgeons use the posterior approach only when the anterior approach is contraindicated. Anterior odontoid screw fixation has several advantages over posterior fixation. Immediate stabilization is achieved with single screw placement (Figure 22.12). No bone graft is required and there is no need for postoperative halo immobilization. Contraindications to the procedure include osteoporosis or osteopenia, barrel

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Figure 22.12 Schematic of a Type II odontoid fracture repaired

through anterior odontoid screw placement. © Barrow Neurological Institute.

chest from severe chronic obstructive pulmonary disease or emphysema, and cervicothoracic kyphosis. It is not recommended in patients with nonreducible fractures, nonunion longer than 3 months, fractures associated with transverse ligament rupture, fractures that require flexion for reduction, and oblique fractures oriented from anterior–inferior to posterior–superior. After discharge from the hospital, patients are seen in clinic on a regular basis and assessed for progress of fusion with radiographic imaging. A recent study reported a fusion rate of 77% with anterior screw fixation in the

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elderly; mean time to fusion was noted at 17.1  weeks (Collins and Min, 2008). Complications of anterior odontoid screw fixation include tracheal or esophageal injury, vascular injury, hemorrhage, infection, significant dysphagia, and the operative morbidity and mortality related to general anesthesia and surgery in an elderly and compromised population. In one study, up to 25% of patients required feeding-tube placement, and 19% developed aspiration pneumonia in the immediate postoperative period (Dailey et al., 2010). Furthermore, there are the possibilities of nonfusion, suboptimal screw placement, inadequate fracture reduction, poor capture of the distal fracture fragment, and screw breakout (due to poor bone density, the screw fractures through the cortex of the dens). In these cases, a posterior fusion is required. In a systematic review of the literature, the most commonly reported medical complications following odontoid fracture surgery in the elderly included cardiac failure (6.8%), deep venous thrombosis (3.2%), stroke (3.2%), pneumonia (9.9%), respiratory failure (7.7%), liver failure (6.7%), and severe infection (3.2%) (White et al., 2010). The overall mortality rate after surgery was noted at 10.1% (in hospital 6.2%; postdischarge 3.8%). Similar mortality rates and rates of airway complications were reported following both anterior and posterior surgery. Notably, however, there were higher rates of site-specific complications, including nonunion, technical failure, and need for revision surgery, following anterior surgery as compared with posterior surgery. For posterior fixation, several procedures can be employed successfully, depending on the patient’s anatomy. Options, as mentioned previously, include C1–2 wiring, C1–2 transarticular fixation, and C1 lateral mass–C2 pars/pedicle screw fixation (Figure 22.13). These techniques require the harvest of bone graft, either from the iliac crest or a posterior rib, and each leads to the loss of C1–2 axial rotation. Considerations prior to posterior fixation include evaluation for aberrant or ectatic vertebral arteries, dysmorphic C1–2 anatomy, or previous vertebral

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Figure 22.13 Various constructs for posterior fixation. (a) C1–2 interspinous wiring. (b) C1–2 transarticular fixation with wiring. (c) C1 lateral

mass–C2 pars/pedicle screw fixation. © Barrow Neurological Institute.

Neurosurgical Care of the Geriatric Patient

artery injury or occlusion. Studies in elderly patients 65 years and older report an 86% rate of successful fusion after posterior C1–2 arthrodesis (Campanelli et al., 1999; Andersson et al., 2000). Complications with posterior fixation include malalignment, poor screw position, vertebral artery injury, spinal cord or nerve root injury, infection, hemorrhage, and the risks associated with anesthesia and surgery in an elderly and compromised population. Several studies have analyzed the different properties and outcomes between patients who underwent surgical fixation versus those who received conservative treatment, to establish a definitive treatment paradigm for odontoid fractures in the elderly. One recent study reviewed the management of 108 elderly odontoid fracture patients (Fagin et al., 2010). The patients were classified as either “early operative management” (<3 days, early OP), “late operative management” (>3 days, late OP), or “nonOP”. The nonOP patients were predominantly treated with cervical orthosis (64 of 68). These patients were found to be significantly older than the patients within the OP groups (mean 82.4 years vs. 77 years) and had shorter hospital lengths of stay and fewer ventilator days than their operated counterparts. This was thought to be related to (1) increased edema around the airway and esophagus following surgery, resulting in longer ventilator times and problems with dysphagia after extubation, and (2) longer periods of time before mobilization. Furthermore, both operative groups underwent tracheostomy and percutaneous endoscopic gastrostomy (PEG) two times more frequently than the nonOP patients and had an increased risk of deep vein thrombosis (DVT). Otherwise, there were no differences between the two groups in the development of urinary tract infection or pneumonia, or percentage of patients discharged to skilled nursing facility after treatment. Drawing conclusions on the proper management of the elderly with odontoid fractures is difficult because study findings across the board have been extremely variable, with some groups actually reporting increased mortality with nonOP treatment of odontoid fractures (Muller et al., 1999; Smith et al., 2008; Pal et al., 2010). In addition, the study groups tend to be small and the follow-up in most studies has been lacking. As an example, in the study reviewed, clinical or radiographic follow-up was available on only 50% of the patients (Fagin et al., 2010). Although complication profiles for nonOP patients appeared better than for OP patients, the outcomes for nonOP patients were often not ideal. In Fagin et al. (2010), two (2.9%) nonOP patients subsequently required posterior fixation for fracture instability, 16 (23.5%) patients had increasing angulation and narrowing of the spinal canal on follow-up, and four (5.9%) patients had persistent nonunion. This is compared with three (7.5%) OP patients whose surgeries were not

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completed and who continued with nonOP management and one (2.5%) OP patient who required a halo vest after surgical fixation. Thus, the jury is still out on the appropriate management of odontoid fractures in the elderly. A reasonable treatment algorithm is for placement in a collar for (1) fragile patients with numerous comorbidities for whom surgery would pose a grave risk, and (2) patients with adequate alignment and intact ligamentous structures. If the fracture is unstable or unlikely to fuse in proper alignment, surgical management is preferred. Halo vest placement should be approached with caution in the elderly population, given the risks noted earlier.

Compression fracture Along with odontoid fractures, vertebral body compression fractures are extremely common in the elderly population. Because the vast majority are associated with osteoporosis, often very little force is required to generate these painful fractures. Collapse of the vertebral body can lead to loss of height, progressive kyphotic deformity, and, if a fragment of bone is dislodged posteriorly, spinal cord or nerve root compromise. With progressive kyphotic deformity, patients can develop a “dowager’s hump” and impaired respiratory function in the form of decreased vital capacity. Osteoporotic compression fractures most commonly involve the lower thoracic or upper lumbar vertebral levels. Occasionally, they are asymptomatic and incidentally discovered on routine imaging. At other times, the pain has been present for years and is disabling. Most often, however, patients report an acute onset of pain that is localized at the midline within the thoracolumbar region; the pain is exacerbated by standing, sitting, or walking; and is relieved by lying down. The pain is aching or stabbing in quality and very severe. On physical examination, patients may also complain of moderate point tenderness to palpation along the spinous process. In addition to those related to osteoporosis, vertebral compression fractures in the elderly can be due to tumor infiltration. Most commonly, metastatic disease from the breast, lung, kidney, or prostate is responsible. Melanoma, multiple myeloma, or lymphoma can also manifest as spinal pathologic fractures. In the event that the primary tumor is unknown, a biopsy is often required before definitive treatment is undertaken. Lastly, vertebral compression fractures can result from infection. Systemic infection can seed the intervertebral disc and then spread to the bone, leading to osteomyelitis. Severe pain is the hallmark symptom. With spinal tuberculosis, or Pott’s disease, the disc spaces are usually spared and a compression fracture can be the initial presentation.

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With regard to the diagnostic workup, most thoracolumbar pain is initially evaluated with either plain radiographs or CT of the spine (Figure 22.14a). CT can reveal the degree of cortical bony disruption and deformity due to the fracture and is useful in treatment planning. In many patients, imaging can reveal several compression fractures. It is important to elucidate exactly which compression fracture is the source of the pain—or, rather, which fracture is “most acute.” For this purpose, MRI is very valuable, and either T2-weighted images or shorttau inversion recovery sequences (STIR) may be used (Figure 22.14b). In these sequences, the unhealed or acute fractures appear hyperintense. In addition, MRI provides the best visualization of the neural and ligamentous structures. In the case of suspected pathologic fracture (tumor involvement) or possible infection, postcontrast sequences are important for the complete workup. For patients with pacemakers who cannot undergo MRI, the test of choice is the bone scan. Acute fractures will show increased uptake of the tracer as compared with healed fractures. The physical examination is essential in formulating the treatment plan. It is important to determine the degree of disability that the fracture confers on patients and their ability to perform activities of daily living. The interview should aim to address these concerns, as well as assess the patient’s level of pain. Next, a thorough assessment of the patient’s lower extremity, bowel, and bladder function must be made. Lastly, in the case of osteoporotic fractures, it is important to confirm that the patient is on

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Figure 22.14 (a) CT of the thoracic spine, sagittal view. T7 compression fracture with loss of height. (b) MRI, STIR sequence, sagittal view. T7 compression fracture. STIR demonstrates edema within the vertebral body, suggesting an acute fracture. © Barrow Neurological Institute.

appropriate medical treatment for the osteoporosis. Medications can include bisphosphonates, selective estrogen modulators, antiosteoporotic agents such as calcitonin, and recombinant parathyroid hormone. Several options exist for the management of acute, painful compression fractures. Surgical treatment is necessary in the case of neurologic compromise, instability, or severe deformity. Surgery is also indicated if conservative management has failed and there is continued disabling pain or progressive kyphotic deformity on serial imaging. The goals of treatment are pain control and restoration of mobility. Nonoperative treatment consists of pain management, bracing, and rehabilitation. Pain management can be achieved with a variety of medications. Though pain control is essential, in the elderly, it is important to avoid overmedicating patients, as this can result in sedation, respiratory depression, severe disorientation, and constipation. Patients are frequently placed into customized thoracic–lumbar–sacral orthoses (TLSO) to help with pain control during mobilization. If pain control is adequate, some patients can be treated in less restrictive corsets or abdominal binders. Lastly, and most importantly, patients are mobilized as quickly as possible. Physical and occupational therapists are heavily involved in treatment; if necessary, patients undergo a course of therapy in an acute inpatient rehabilitation center before transitioning to outpatient therapy. Weight-bearing exercises are the main types of exercises involved and are believed to slow the progression of osteoporosis. A strong focus is made on keeping the patient as mobile and independent as possible, to avoid the complications associated with immobility. These complications include pneumonia, DVT, pulmonary embolism, skin breakdown, and gastric ulceration. The brace is worn for 1–3 months, and follow-up plain radiographs are obtained during this period. If progressive kyphotic deformity is noted in comparison with prior images, or if the patient continues to have uncontrolled pain and impaired quality of life, surgical intervention is indicated. Vertebroplasty and kyphoplasty are minimally invasive, percutaneous procedures in which a biologic cement is injected into a pathologic vertebral body to relieve pain and disability. Vertebroplasty was first introduced in France in 1984 and used as a technique to treat symptomatic vertebral hemangiomas (Galibert et al., 1987). It was found that the support provided by the hardened polymethylmethacrylate (PMMA) resulted in substantial pain relief. Surgeons expanded the use of this technology to include the treatment of pain from myeloma and metastatic neoplasms of the spine. Today in the United States, the primary use of vertebroplasty is the treatment of pain from osteoporotic compression fractures. Kyphoplasty was introduced in 1999 by Kyphon, Inc. It involves introducing an inflatable balloon into the collapsed vertebral

Neurosurgical Care of the Geriatric Patient

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Figure 22.15 (a) AP and (b) lateral

fluoroscopic views during L1 vertebroplasty. The needle has been introduced through the right pedicle into the vertebral body for injection of the cement. © Barrow Neurological Institute.

body. After inflation of the balloon, the cement is injected directly into the balloon, with the goal of restoring vertebral body height and spinal alignment. The indications for either procedure are for the treatment of painful, unhealed compression fractures. Contraindications to treatment include systemic or spinal infection, uncorrected bleeding disorder, inability to tolerate sedation or general anesthesia, inability to tolerate the prone position, and fracture instability. Spinal canal compromise due to the fracture is also a contraindication to the procedures. Even if there is no clinical evidence of radiculopathy or myelopathy, the risk is increased that even a small leakage of cement posteriorly during injection will lead to neurologic compromise. For either procedure, medical clearance is necessary to ensure that the patient can tolerate sedation and/or general anesthesia. The patient is placed in the prone position on a padded operating table. The correct vertebral level is identified, and a needle is used to pierce the skin and enter through the pedicle into the vertebral body. Next, the PMMA cement is mixed with sterile barium sulfate powder so that it is radio-opaque, and is injected under continuous visualization (Figure 22.15). Posterior leakage of cement is to be avoided, as is intradiscal or venous leakage. The endpoints for injection are (1) leakage of cement beyond the marrow space, (2) cement reaching the posterior quarter of the vertebral body, and (3) the cement filling the vertical height of the vertebral body and extending across midline. The patient is monitored in the recovery room for 2–3 hours and then allowed to attempt ambulation. If there is no increased pain or disability, the patient is discharged home with instructions to limit activity for 3 days. The kyphoplasty procedure is similar, although, due to its longer duration, it is almost always performed under general anesthesia. A large cannula is introduced into the pedicle, and a small hand-operated drill bit is used to drill into the vertebral body. A deflated balloon is then advanced into the created cavity and slowly inflated with iodinated contrast. Usually this procedure is performed bilaterally, and both balloons are inflated simultaneously.

Inflation continues until (1) the kyphotic deformity is corrected, (2) the balloons reach the cortical margins, or (3) the system reaches a maximum pressure of 300 psi or maximum balloon volume. The balloons are then deflated, and the cement is carefully injected under fluoroscopic imaging. Prognosis is very good with both procedures, with many patients reporting excellent relief of pain in the recovery room (Gill et al., 2007; Tang et al., 2010). Both procedures have very low risks of mortality and morbidity. Careful attention to bony landmarks is essential, as one is working near the spinal cord and aorta. Cement leakage is common and must be monitored carefully (Figure 22.16). If the leakage results in nerve root compromise, patients can initially be treated with a short course of steroids or nerve root block. If symptoms do not abate, surgical decompression is necessary. If leakage results in spinal cord compromise, decompression is mandatory. If the cement leaks into perivertebral veins, there is a very small risk of pulmonary embolus (Radcliff et al., 2010).

Figure 22.16 Lateral fluoroscopic view demonstrating anterior

leakage of cement after L4 vertebroplasty. © Barrow Neurological Institute.

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Other procedure risks include infection, hematoma, and pedicle fracture. An analysis of the natural history of vertebral compression fractures has revealed that the majority will heal within 6–12 months with conservative management. Klazen et al. found that, with bracing and pain management, 63% and 69% of patients had significant pain relief at 6 and 23 months, respectively. However, nearly one-third of patients still had severe pain at 23 months. In studies comparing vertebroplasty with conservative management, vertebroplasty-treated patients consistently had significantly reduced pain scores, decreased use of analgesics, more rapid return to normal function, and lower rates of hospitalization, as compared with conservatively treated patients (Diamond et al., 2006; Klazen et al., 2010; Wang et al., 2010). However, the differences in status between the two treatment groups were lost by 12 months of follow-up. These findings are logical in light of the natural history of compression fractures. Nonetheless, many clinicians are moving away from the initially published guidelines recommending 3–6 weeks of conservative therapy in favor of early intervention. For patients in severe, disabling pain, vertebroplasty and kyphoplasty are safe treatment modalities that can be used to immediately reduce pain, facilitate early mobilization, and minimize the risks of immobility in the elderly population afflicted with these fractures.

the mid-1900s provided the first effective medical treatment for TGN. Patients with TGN tend to present with the following symptoms: (1) paroxysmal, “electric” pain in the trigeminal distribution on one side of the face; (2) trigger points on the face that, when stimulated, initiate this type of pain; (3) periods of remission and exacerbation; (4) pain that is worse in the mornings and absent during sleep; and (5) temporary pain relief when treated with an adequate dose of carbamazepine. Wind on the face, talking, eating, brushing of the teeth, and shaving often precipitate symptoms along one or more divisions of the trigeminal distribution. TGN predominantly occurs in people over the age of 50, although the younger population can also be affected. Some reports suggest a female predominance as high as 2:1. The condition can affect either side of the face and any division of the trigeminal nerve, though most often the V2 (maxillary) or V3 (mandibular) division, or both, are involved (Figure 22.17). Findings on the neurologic examination and imaging studies are usually unremarkable. However, vascular anomalies, multiple sclerosis, and tumors of the cerebellopontine angle can also produce TGN. Therefore, MRI of the brain, with and without contrast, is an essential part of the diagnostic workup for facial pain. The exact mechanism underlying TGN is unclear. Autopsy studies reveal demyelination of the large-diameter

Pain: trigeminal neuralgia Facial pain can be a challenging problem to both diagnose and treat. The most common and treatable form is trigeminal neuralgia (TGN). Although facial pain syndromes are prevalent in both younger and geriatric populations, the medical comorbidities of older patients often lead to greater consideration of the full spectrum of conservative treatment options before surgical management is proposed.

Natural history Facial pain syndromes have been described throughout history. One of the earliest descriptions was written in the eleventh century by the Arab physician Jurjani (Ameli, 1965). In 1829, Bell delineated the anatomy of the fifth cranial nerve which was recognized as responsible for facial sensation and innervation of the muscles of mastication. Treatment options for facial pain were limited and ranged from various ointments to cleansing of the gastrointestinal tract. In 1853, Trousseau noted the paroxysmal nature of a particular kind of facial pain, which he likened to a seizure of the trigeminal nerve. Thus, for a time, the disorder was known as neuralgia epileptiform. The introduction of antiepileptic medications in

Trigeminal (Gasserian) ganglion

Figure 22.17 Schematic of the trigeminal nerve and its three

divisions, V1, V2, and V3, and their respective sensory territories. Ophthalmic (blue V1); maxillary (red V2); mandibular (pink V3). © Barrow Neurological Institute. (For a color version, see the color plate section.)

Neurosurgical Care of the Geriatric Patient

A fibers found at the root entry zone of the fifth cranial nerve into the brainstem. One hypothesis is that demyelination leads to erratic signal transduction to poorly myelinated A delta and unmyelinated C fibers, which results in paroxysmal facial pain. It is thought that the demyelination is most often related to compression at the root entry zone by a vascular structure, either an artery or a vein. Nonetheless, autopsy studies have demonstrated both the absence of compression in patients with TGN and instances of obvious compression in patients without TGN. Diagnosing TGN can be difficult, especially when it manifests with atypical features that do not conform to the usual presentation. The differential diagnosis of facial pain includes entities that range from postherpetic neuralgia, to multiple sclerosis, to head and neck cancers, to giant cell arteritis. Hence, it is important to secure a clear description of the pain from the patient before initiating any form of treatment. After the diagnosis of TGN is made, several options are available for treatment.

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medications. The drugs should be titrated until pain relief is achieved or until side effects become intolerable. If medication therapy is ineffective or poorly tolerated, neurosurgical referral should be considered.

Surgical treatment A range of surgical options must be tailored to the individual patient. These options include direct percutaneous injury to the Gasserian ganglion (such as thermal rhizotomy, glycerol rhizolysis, or balloon compression), stereotactic radiosurgery, and microvascular decompression (MVD). Percutaneous rhizolysis and stereotactic radiosurgery are the treatments most often offered to older patients for whom medical therapy has failed. However, for patients with good life expectancy and low medical risk for surgery, retrosigmoid craniotomy for MVD remains the preferred option.

Percutaneous procedures Medical therapy Carbamazepine, a tricyclic drug related to the antidepressant imipramine, is currently the drug of choice for managing TGN. The initial response of TGN to carbamazepine is fairly universal; hence, a lack of response to the drug should lead to a reassessment of the diagnosis. Initially, most patients respond well to carbamazepine. Some patients, however, are unable to tolerate the side effects, which include somnolence, dizziness, nausea, impaired memory, peripheral neuropathy, and nystagmus. These side effects occur most commonly in the elderly and with increases in dosage. Dermatologic reactions occur in 5–10% of patients and include rash, erythema multiforme, and Stevens–Johnson syndrome. Hematologic side effects of carbamazepine are rare but include aplastic anemia. Hence, regular hematologic studies are recommended for monitoring while on this medication. Very rare side effects include hyponatremia, hepatotoxicity, and congestive heart failure. Long-term studies have shown a gradual decline in the efficacy of carbamazepine over time. The initial response rate is almost 80%; however, 10 years after the start of therapy, only about 50% of patients note any relief with treatment. After carbamazepine is ingested, peak blood levels are achieved within 2–8 hours. At first, there is a linear relationship between dose and plasma level; with chronic treatment, however, there is auto-induction of the hepatic metabolic system. Hence, the elimination halflife reduces from 20 to 40 hours to as short as 11 hours in the blood stream. This leads to fluctuations in the serum concentration of the drug, which, in turn, influences drug efficacy and side effects. If carbamazepine therapy fails, other options include phenytoin, baclofen, clonazepam, sodium valproate, oxcarbazepine, pregabalin, and a combination of these

In 1965, the first modern percutaneous modality for the treatment of TGN was developed. It involved using a probe to thermocoagulate the trigeminal nerve rootlets to differentially injure the pain fibers. In this manner, the overall sensory input to the demyelinated root entry zone is reduced, resulting in pain relief. For the procedure, patients lie supine on the operating table and are sedated only to a degree such that they can awaken rapidly during the procedure. A spinal needle is placed through the cheek using standard landmarks and directed toward the foramen ovale (Figure 22.18). Once engaged, the fibers are stimulated with the patient awake to determine the exact area to be targeted. The patient is then resedated and a series of lesions are made with the thermocoagulation probe. The goal of the procedure is not complete analgesia, but rather dense hypalgesia. Patients should still be able to feel that a safety pin is sharp against their skin, but the sensation should be dulled. During the procedure, the presence of the blink reflex, both direct and consensual, is assessed repeatedly. Loss of the blink reflex is associated with a risk of corneal ulceration. Complications or problems with the procedure include confusion and difficulty in communicating with the elderly, sedated patients, and loss of the airway. In addition, complete facial sensory loss, diminished corneal reflex, keratitis, and, rarely, visual loss, are also risks of the procedure. In general, the success of the procedure is related to the level of analgesia achieved. The rate of initial and immediate pain relief is high—almost 99%. However, several large studies have shown that the durability of pain relief is highly variable, with results as good as 90% or as poor as 40% at 5 years of follow-up (Broggi et al., 1990; Taha and Tew Jr., 1996; Kanpolat et al., 2001; Tatli et al., 2008). Glycerol rhizotomy is now regarded by many

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Trigeminal (Gasserian) ganglion V2

V1

Foramen ovale V3

Stylet entry into the cheek

Figure 22.18 For the percutaneous procedures, a spinal needle

or cannula is introduced through the cheek using standard landmarks: 2.5 cm lateral to the angle of the lip, 3 cm anterior to the external auditory meatus, and just below the medial aspect of the pupil. When the foramen ovale is engaged, the patient usually winces, and the surgeon can feel the cannula enter the foramen. © Barrow Neurological Institute.

as the first-line percutaneous treatment modality after failure of medical therapy in the elderly. For this procedure, a spinal needle is introduced through the cheek into the foramen ovale. A mixture of sterile glycerol and tantalum (for permanent marking of the cistern) is injected. The patient is kept seated upright with the head slightly flexed for 1 hour. Afterward, the glycerol is evacuated. The rates of early pain relief are high, at nearly 90%, with 50% of patients achieving immediate pain relief and the other 50% achieving pain relief within 2 weeks. Nonetheless, the median time to recurrence of pain is noted at 16–36 months. Finally, percutaneous balloon compression is considered a secondary treatment option for those who have failed both medical treatment and other percutaneous modalities. The procedure is performed under general endotracheal anesthesia or, rarely, with intravenous anesthesia as well as local anesthesia at the level of the ganglion. A cannula is advanced through the cheek toward the foramen ovale. The cannula stylet is then removed and replaced with a balloon catheter. The balloon is inflated to 1.3–1.5 atmospheres for 60–120 seconds. The balloon is then deflated, and the needle and catheter are removed simultaneously. The entire procedure takes less

than 20 minutes and is usually performed on an outpatient basis. After the procedure, patients must be warned of the risk of herpetic eruptions, be instructed on eye care, and be tapered off the anticonvulsant medications for their TGN. The initial success rate ranges from 78% to 100%, with a mean time to recurrence of 3.5 years (Lichtor and Mullan, 1990; Skirving and Dan, 2001). In the older population, many factors must be considered, such as anticoagulation for atrial fibrillation, coronary disease, and stroke prevention. For these percutaneous procedures, the risk of hemorrhage is very low. Thus, patients may not need to be reversed off their medications for very long periods of time. These considerations must be made in conjunction with the patient’s cardiologist or internist.

Stereotactic radiosurgery Stereotactic radiosurgery is an excellent, noninvasive alternative treatment for elderly patients, especially for those with cardiovascular disease that necessitates anticoagulation, as they may continue taking their medications. First described by Lars Leksell in 1951, radiosurgery is now a major modality for treating TGN, targeting the root entry zone of the fifth cranial nerve adjacent to the pons and minimizing irradiation of the brainstem. The most established modality is gamma knife radiosurgery, which delivers precise radiation using intersecting beams from multiple radioactive cobalt sources. A number of other commercially available linear accelerator-based systems are available. Treatment planning is performed jointly by a radiation oncologist, neurosurgeon, and medical physicist. For the procedure, the patient’s head is placed into a stereotactic coordinate frame, and contrast-enhanced T1- and T2-weighted MRIs of the brain are obtained. The trigeminal nerve root entry zone is visualized, and a single 4-mm isocenter is placed adjacent to it, usually 2–4 mm anterior to the junction of the root and the pons (Figure  22.19). A median prescription dose of 75 Gy (range 70–85 Gy, 35–42.5  GY at the 50% isodose line) is then delivered to the nerve root entry zone. The brainstem receives less than 20% of the dose delivered. Patients are discharged the same day and informed that pain relief may take up to 10 weeks. Tapering of pain medications begins once adequate pain relief is achieved. The best results for stereotactic radiosurgery are obtained with continued use of pharmacotherapy; consequently, it may not be the best option for patients who cannot tolerate their medication. Few publications have reported the long-term follow-up (average 5 years) of patients who have undergone gamma knife treatment for TGN. Urgosik et al., presented their outcomes in 107 treated patients (Urgosik et al., 2005). Initial pain relief was achieved in 80% of patients after a median latency of 3 months. However, pain recurred in 25% of

Neurosurgical Care of the Geriatric Patient

(a)

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(b)

Figure 22.19 (a) Axial and (b) coronal MRIs of the brain delineate the location (circle) of the trigeminal nerve entry zone at the level of the pons. © Barrow Neurological Institute.

patients after a median latency interval of 3 years. In 2009, Dhople et al., analyzed their long-term results with gamma knife surgery for TGN (Dhople et al., 2009). Of 95 patients, initial pain relief was achieved in 81%, with a median time to pain relief of 2 weeks (range 0–12 weeks). Initial response rates for patients with no prior surgeries were the same as those for patients who had undergone prior invasive procedures (81% vs. 77%, p = 0.42). With long-term follow-up, however, the authors noted that the rates of freedom from treatment failure at 1, 3, 5, and 7 years were 60%, 41%, 34%, and 22%, respectively. Furthermore, response duration was significantly better for patients with no prior invasive treatment than for those with prior treatment (32 vs. 21 months, p < 0.02). The major complication from this procedure is bothersome facial numbness, which is reported in 6–20% of patients. Patients with recurrences may be offered repeat gamma knife radiosurgery, MVD, or a percutaneous treatment option.

adhesions, and then pieces of shredded Teflon are used to elevate compressive vascular structures away from the trigeminal nerve. The most common offending vessel is the superior cerebellar artery. The complications of MVD include cerebral or cerebellar infarction, hearing loss, facial paresis, facial dysesthesia, CSF leakage, and pseudomeningocele formation. Usual complication rates are in the middle single digits. Success rates are very high, with 90% of patients reporting excellent pain relief at 1 year and with 70% remaining painfree at 10-year follow-up. Success rates seem to be greater for patients who have their disease treated earlier in its course (Barker et al., 1996; McLaughlin et al., 1999; Sindou et al., 2006).

Microvascular decompression Posterior fossa exploration with MVD of the trigeminal nerve is generally considered the best operation for medically fit patients with TGN. Advantages of MVD include consistently higher long-term success rates and significantly lower rates of facial dysesthesias. Preoperative testing includes audiometry and otologic examination, as well as MRI. For the procedure, a small craniotomy is performed at the junction of the transverse and sigmoid sinuses, in the retrosigmoid region (Figure 22.20). The dura is incised and, under direct microscopic visualization, the cerebellopontine angle is explored (Figure 22.21). The trigeminal nerve is visualized and inspected for any evidence of structural compression. The nerve is freed of arachnoid

Figure 22.20 Left retrosigmoid craniotomy performed at the junction of the transverse and sigmoid sinuses. © Barrow Neurological Institute.

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Figure 22.21 Left retrosigmoid approach. View of neurovascular structures after the dura has been opened. Once the compressive vessel is identified, a Teflon pledget is placed between the nerve and offending vessel to achieve decompression. TS, transverse sinus; SS, sigmoid sinus; SCA, superior cerebellar artery; AICA, anterior inferior cerebellar artery. © Barrow Neurological Institute.

Atypical pain Patients who have progressed to the point at which they have constant pain that is less “shock-like,” but rather more burning in character, with associated sensory changes, have developed atypical facial pain. Some patients begin with pain in this fashion. Whether chronic or de novo, this type of pain is less likely to respond to medical or surgical therapy. Atypical facial pain can be an endpoint for a small number of patients who have resistant TGN that requires multiple treatments. A final complication of TGN is anesthesia dolorosa, a condition in which the patient is both numb and subject to constant pain. This condition is highly resistant to treatment of any kind. Motor cortex stimulation is being explored on an experimental basis for the treatment of this kind of pain; early results appear mixed, at best. Many factors must be considered in the care of elderly patients with TGN. Most importantly, the treatment modality selected must afford the highest success rate at the lowest overall risk to the patient. In the absence of significant medical comorbidities, MVD is an excellent, durable option. Alternatively, the percutaneous treatment modalities offer high rates of pain relief with relatively lower risks, minimal hospital time, and significantly lower cost. Neurosurgical referral for patients who are not easily managed with medication alone should be considered, as many good and effective surgical options are available.

Neurosurgical treatment of Parkinson’s disease Movement disorders, including Parkinson’s Disease (PD) and tremor, have physiologic underpinnings that are increasingly understood. They frequently affect the elderly and are amenable to surgical treatment in many cases. A variety of surgical targets can ameliorate or abolish symptoms with either lesion placement or deep brain stimulation (DBS). Patient and procedure selection are the key factors in achieving success. PD is a motor disorder caused by the loss of dopaminergic cells in the substantia nigra pars compacta. Generally, PD affects people over the age of 50. Symptoms are initially subtle and progress gradually. Most people present with tremor that worsens and begins to affect daily activities. The four primary symptoms of PD include (1)  tremor of the hands, arms, legs, jaw, and/or face; (2) rigidity, or stiffness of the limbs and trunk; (3) bradykinesia, or slowness of movement; and (4) postural instability, or impaired balance or coordination. With progressive disease, patients can develop difficulty with swallowing, chewing, and speaking; urinary problems or constipation; skin problems; sleep disturbances; and depression or emotional changes. Patients are treated with a variety of medications that work to either replenish or mimic dopamine in the brain, often providing dramatic relief from symptoms. Levodopa and carbidopa help relieve symptoms in 75%

Neurosurgical Care of the Geriatric Patient

of cases, although not all symptoms respond equally to treatment. In general, bradykinesia and rigidity are well controlled with medications; on the other hand, tremor is often only mildly reduced, and balance issues may not be affected at all. Other common medications include anticholinergics, bromocriptine, pramipexole, ropinirole, amantadine, and rasagiline. PD is progressive, with symptoms that worsen as more dopaminergic cells are lost. Medications are often initially effective. However, as dosages increase to control symptoms, so do associated adverse effects. Problems include dyskinesias, or involuntary excessive movements; sleepiness; nausea; hallucinations; confusion; cognition problems; lightheadedness; and behavioral/personality changes. At some point, when adequate management with medication is no longer possible, patients consider surgical options. The neurosurgical treatment of movement disorders has been a strong focus of research and effort for more than a century. Early attempts achieved some success at symptom control, but at the cost of significant permanent morbidity and mortality. Over the last several decades, the techniques for surgical treatment of movement disorders have continued to evolve. Surgeons have discovered that (1) bilateral thalamic lesions are associated with significant complications and (2) electrical stimulation, which is frequently used for target localization, can itself be used to arrest tremor and treat bradykinesia and rigidity. With the introduction of CT and MRI, target localization has become very precise. Finally, with continued advancements in research and microelectrode recordings, the targets for stimulation have become more defined. Although much about how DBS helps to control movement disorders remains unknown, it is now an accepted and relatively safe treatment option for patients who are failing medical therapy for their disease. The single most important factor in ensuring the success of DBS is patient selection. To this end, the neurosurgeon, neurologist, and neuropsychologist must work together to ensure that all criteria are met. The ideal candidate is a patient with levodopa-responsive idiopathic PD. Patients should have disabling symptoms, including bradykinesia, rigidity, and tremor, as well as significant side effects from medications, such as dyskinesias and on/off fluctuations. In the early stages of the disease, it is relatively easy to achieve periods of good symptom control and mobility (“on” periods) with medication. However, as the disease progresses, patients must increase their medication dosages to maintain control over their symptoms, as well as take additional medications. At some point, complications such as increased “off” periods (periods of poor symptom control), dyskinesias, and troubling side effects such as sleepiness, nausea, hallucinations, confusion,

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lightheadedness, and behavioral or personality changes become overbearing. A neurologist with experience in treating movement disorders must ensure that a patient has undergone appropriate medical management before considering surgical intervention. Patients are asked to keep a diary of their “on/off” periods during the day and must chart the relationship of these symptoms to the timing of their medications. The following patient selection criteria are generally accepted by most movement disorder treatment centers: • Patients should have significant disability despite maximal medical therapy. • Patients should be in generally good health without significant cardiac, pulmonary, or renal risk factors. In addition, some centers use the age of 70 years as a cutoff. • Patients must not be demented or have significant cognitive impairment. They also may not have uncontrolled psychiatric illness, anxiety, or mood disorders. • Patients must be able to comprehend the risks of surgery and have reasonable expectations regarding outcome from surgery. • Patients should not have severe atrophy or white matter disease on preoperative imaging, as these findings may indicate increased risk of intracerebral hemorrhage or postoperative cognitive impairment. • Patients who are no longer levodopa-responsive or who have Parkinson plus syndromes (progressive supranuclear palsy, multisystem atrophy) are poor candidates for surgery. Last, with the exception of tremor, symptoms that do not respond to levodopa are not likely to improve with DBS. After patients are accepted as candidates for surgery, they must undergo medical clearance for the procedure. Once cleared, the surgery can be scheduled. At many institutions, a neurosurgeon, a neuroelectrophysiologist, and a neuroanesthesiologist are present for the entire procedure. On the day of surgery, a stereotactic head frame and base ring and localizer are affixed to the patient’s head using local anesthetic (Figure 22.22). Next, an MRI is obtained and targeting is performed using a stereotactic targeting system and software. The anterior commissure (AC) and posterior commissure (PC) are identified on axial images, as well as several other midline structures. The target coordinates are calculated based on fixed relationships to these structures. The software then superimposes the target onto the corresponding axial, sagittal, and coronal image slices. Modifications are made if the target appears too close to critical structures such as the internal capsule. When target planning is completed, the surgery commences. Lead implantation is performed under local anesthetic, with light sedation administered by the anesthesiologist (Figure 22.23). Following the cranial procedure,

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Therapeutics for the Geriatric Neurology Patient

Figure 22.22 Patient with head secured in Leksell stereotactic head frame/base ring and localizer. © Barrow Neurological Institute.

patients remain in the hospital overnight and are released the following day if they meet discharge criteria. Operative mortality is less than 1%; overall incidence of complications is 30%, but most are minor. Complications include IC hemorrhage, infection, hardware fracture or malfunction,

hardware migration, or erosion of hardware through the scalp or skin. The incidence of IC hemorrhage ranges from 1% to 5%, although, fortunately, most are small and cause minimal symptoms. Infection rates range from 3% to 13%. Superficial infections can often be treated with antibiotics. Deep infections involving the hardware, however, must often be treated with debridement and explantation of the system. Rare complications include death, coma, paralysis, and medical problems involving the cardiac, respiratory, or circulatory systems. A separate operative procedure is usually scheduled for implantation of the internal pulse generator(s), which is performed under general anesthesia (Figure 22.24). Most patients are discharged directly from the recovery room within a few hours of surgery completion. Patients are seen in clinic for a wound inspection by the neurosurgeon 2 weeks following surgery, and by the neurologist thereafter for programming of the DBS system. Optimal programming of the DBS system can be time consuming, as both stimulation parameters and medication dosage adjustments must be performed concurrently. Hence, at most institutions, programming is solely performed by the neurologist. This allows for a single physician to be in control of all adjustments and reduces the number of office visits for the patient. For the initial programming session, patients are asked to hold their medications for at least 12 hours. A baseline motor assessment is then performed, evaluating the patient for tremor, rigidity, bradykinesia, gait, and postural stability. The

Figure 22.23 The deep brain stimulation (DBS) lead is inserted

into position using the Leksell stereotactic head frame and the preoperatively determined coordinates. The final position is confirmed using microelectrode recordings and intraoperative patient assessment. © Barrow Neurological Institute.

Figure 22.24 Schematic of the DBS system, including the intracranial stimulation lead, connector cable, and internal pulse generator. © Barrow Neurological Institute.

Neurosurgical Care of the Geriatric Patient

electrodes are then evaluated and programmed. When an effective program is established, patients are given a dose of levodopa and observed for dyskinesias. Further adjustments are then made to treat drug-induced dyskinesias. The goal of programming is to provide maximal therapeutic benefit with minimal side effects and with the least amount of power drain on the battery possible. A wide range of stimulus parameters is possible, and the device is externally programmable. Generally, battery life ranges from 3 to 5 years. Consideration of battery life is important, as replacement of the generator requires surgery, and with each surgery there is risk of infecting the system. The targets for DBS are continually evolving (Figure  22.25). Ablation of the ventral intermediate nucleus (VIM) of the thalamus has been used as a treatment for both essential tremor and parkinsonian tremor for more than 50 years. As high-frequency stimulation (>100 Hz) in the same location can also effectively suppress tremor without creating many of the deficits associated with thalamotomy, VIM DBS is now the preferred treatment for tremor. Long-term results of VIM DBS for essential tremor reveal an 80% improvement in tremor and nearly 70% improvement in handwriting (mean follow-up 56.9 months) (Zhang et al., 2010). Studies also reveal a slight decrease in effect over time (Blomstedt et al., 2007), as well as a gradual increase in stimulation parameters to maintain efficacy of treatment (Zhang et al., 2010). In general, resting tremor is better controlled with DBS than action tremor, distal better than proximal/axial tremor, and upper-extremity tremor better than lowerextremity tremor. VIM DBS does little to improve rigidity or bradykinesia in PD patients.

Figure 22.25 Schematic of the commonly used targets for DBS, including the globus pallidus interna, subthalamic nucleus, and ventral intermediate nucleus of the thalamus and adjacent structures. © Barrow Neurological Institute. (For a color version, see the color plate section.)

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The target of choice for PD is the subthalamic nucleus (STN). STN stimulation can potentially improve all the motor symptoms of PD, including rigidity, bradykinesia, postural instability, and gait. Studies have revealed a 70–80% reduction in tremor in the off state as well. Improvements in overall motor function in the off medication state range from 50% to 74% in most series, but improvements in the on medication state show little change (0–26%; Rodriguez-Oroz et al., 2000; Deep Brain Stimulation for Parkinson’s Disease Study Group, 2001). Hence, it is important to counsel patients that the results of DBS will likely be equivalent to their best on conditions, as most of the benefit from STN DBS comes from reductions in off states and on/off fluctuations. Finally, STN DBS significantly increases on time without dyskinesias, an effect that may be related to the reductions in levodopa requirements after STN stimulation. Studies cite a reduction in daily levodopa dose by 40–60% after DBS placement (Rodriguez-Oroz et al., 2000; Deep Brain Stimulation for Parkinson’s Disease Study Group, 2001; Liang et al., 2006). Parent et al., recently evaluated the relevance of age and disease duration in the treatment of PD with STN DBS (Parent et al., 2010). Forty-six patients were evaluated prior to surgery and at 1-year follow-up. At one year, patients with both short and long duration of disease showed significant reductions in dyskinesias: 64% and 70%, respectively. However, patients with shorter disease duration (<10 years) demonstrated a significant reduction in rigidity, whereas those with longer disease duration (>10 years) failed to show significant improvement (45% vs. 31%, respectively). Both younger and older patients showed significant improvements in dyskinesias,

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but those older than age 70 failed to show any significant change in rigidity at one year follow-up. Hence, in regard to rigidity, performing early DBS in younger patients may maximize the benefits of this technology. Another commonly used target for PD, as well as for dystonia, is the globus pallidus interna (GPI). With stimulation, improvements in the off state range from 33% to 50% (Ghika et al., 1998; Deep Brain Stimulation for Parkinson’s Disease Study Group, 2001). The length of the on period without dyskinesias increases and on/off fluctuations decrease. Improvements are significant for tremor, rigidity, bradykinesia, gait, and postural instability. In regard to comparisons between STN versus GPI DBS for PD, most studies find both modalities to be effective in improving motor scores, although anti-PD medications are reduced only in the STN groups (Anderson et al., 2005; Moro et al., 2010). Cognitive and behavioral complications, however, are noted only with STN stimulation. DBS is an accepted, safe treatment for PD, as well as for essential tremor and some forms of dystonia. To determine whether a patient is a good candidate for surgery, a full evaluation by a neurologist who specializes in movement disorders, a neurosurgeon, and a neuropsychologist must be performed. If all the criteria are met, patients stand to gain many years of improved function and better quality of life through this treatment modality.

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Chapter 23 Treatment of Dementia 23.1 Evidence-Based Pharmacologic Treatment of Dementia

Jasmeet Singh1, Marwan N. Sabbagh2, and Anil K. Nair1 23.2 Immunotherapy for Alzheimer’s Disease

Michael Grundman3, Gene G. Kinney4, Eric Yuen5, and Ronald Black6 1

Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA Banner Sun Health Research Institute, Sun City, AZ, USA 3 Global R&D Partners, LLC, San Diego, CA, USA 4 Prothena Biosciences, Inc., South San Francisco, CA, USA 5 Janssen Alzheimer Immunotherapy Research & Development, South San Francisco, CA, USA 6 Probiodrug AG, Halle, Germany 2

Summary Evidence-Based Pharmacologic Treatment of Dementia • There are few preventative treatments available in geriatric neurology due to a lack of ability to predict risk and time frames for each individual. • Symptomatic treatment is typically effective for a few years. • Drug treatments for dementia: • Alzheimer’s disease: Tacrine, donepezil, rivastigmine, galantamine, and memantine. • Frontotemporal dementia (FTD): No FDA-approved medications currently available. FTD patients are more likely to use antipsychotics, antidepressants, and sedatives/anxiolytics. • Dementia with Lewy bodies: No FDA-approved medications currently available. Treatment focuses on hallucination and agitation management. • Vascular dementia: No FDA-approved treatments currently available. Prevention of risk factors such as hypertension is important. • Parkinson’s disease dementia (PDD): Rivastigmine and donepezil are the widely accepted medications for treatment of PDD. • Pseudobulbar affect (PBA): Nuedexta. Immunotherapy for Alzheimer’s Disease • Alzheimer’s disease (AD) may be due to a disrupted balance between Aβ production and clearance. Anti-Aβ immunotherapy may help facilitate clearance using either active or passive immunization. • Studies show that AD mice treated with anti-Aβ antibodies shown greater cognitive performance compared to control AD mice. Antibodies against both soluble and insoluble Aβ have been generated and studied. • AN1792, a full-length Aβ, has been used for active vaccination in clinical studies (phase 1 and phase 2 trials). Subjects who developed sufficient antibody responses showed a slowing of decline; however, there was an occurrence of meningoencephalitis (ME). Follow-up studies showed that despite a high degree of plaque clearance in some subjects at autopsy, progressive dementia still continued. There is also evidence of potential long-term benefits from sustained, low levels of anti-Aβ antibodies. • Immunotherapy may be active or passive, each with relative advantages and disadvantages. • Proposed mechanisms of anti-Aβ immunotherapy include microglial activation, catalytic disaggregation, and the “peripheral sink.” • Bapineuzumab is a passive immunotherapy that has completed clinical trials. Many other immunotherapies are also currently in clinical trials and in development. • Vasogenic edema (VE) was observed as a side effect. Immunotherapy may be more effective when started earlier during the preclinical and prodromal phases of AD.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Chapter 23.1 Evidence-Based Pharmacologic Treatment of Dementia Jasmeet Singh, Marwan N. Sabbagh, and Anil K. Nair

Introduction Lack of effective therapy for geriatric neurologic diseases such as Alzheimer’s disease (AD) may bankrupt the US health-care system. Age is a major risk factor for dementia, with risk doubling approximately every 5 years after age 65—by the age of 85, one’s chances of having dementia due to AD range from 25% to 50% (Alzheimer’s Association, 2010). Prevalence of AD may double every 20 years, due the increase in the average expected life span. Thirty-five million people worldwide have AD today, and more than 100 million individuals will have AD by 2050 (Alzheimer’s Disease International, 2010). For all practical purposes, diagnosing AD is achieved using clinical criteria, as pathologic criteria cannot be confirmed in vivo and brain biopsy to achieve diagnosis is impractical (Dekosky et al., 1992) due to lack of FDA-approved biomarkers. Moreover, preclinical AD criteria defined in 2011 are not yet applicable for clinical treatment. The DSM clinical criteria focus on the requirement for multiple cognitive deficits, including memory loss, aphasia, apraxia, agnosia, and impaired executive functioning (Cummings and Benson, 1983). In addition, functional impairment is a mandatory criterion for the diagnosis of probable DAT. The positive predictive value of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDSADRDA) probable AD category and that of the AD diagnosis by DSM-III-R is very high and ranges from 89% to 100% when validated against an autopsy diagnosis (Nagy et al., 1998). This makes these tools suitable for research purposes. The combination of the NINCDSADRDA categories for possible and probable dementia of the Alzheimer type has a high sensitivity (91–98%) but lower specificity (40–61%; Knopman, 2002). NINCDSADRDA and DSM criteria incorporate a differential diagnosis to exclude other conditions presenting similar clinical symptoms. Computerized tomography (CT) or magnetic resonance imaging (MRI) scans are used to aid the physician in assessing the presence or risk of vascular disease (Richter and Richter, 2002). The Hachinsky Ischemic Scale (HIS) and Geriatric Depression Scale (GDS) have been used in key dementia trials to exclude

patients with dementia caused by or complicated by vascular lesions and depression, respectively (Rosen et al., 1980). The medical history from the patient (when possible) and caregiver, laboratory assessments (chemistry, hematology, and urinalysis panels), and physical examination aid the physician in both the diagnosis and the differential diagnosis. Shorter screening instruments such as the Mini–Mental Status Exam (MMSE) and the Montreal Cognitive Assessment (MOCA) are also useful in a clinical diagnosis of dementia but may lack rigor for use in research (Olson et al., 2011). Several key aspects of the pathogenesis of a disease such as AD remain unknown, but scientific advances over the last 25 years have provided a growing rationale for potentially disease-modifying therapies that target the suspected pathology of the disease. Multiple agents using cholinergic agonism and partial antagonism of N-methyl-d-aspartate (NMDA) receptors have gained FDA approval. Novel strategies with agents addressing the initiating role of amyloid β–protein (Aβ) aggregates, tau protein modification, histamine receptor antagonism, and nicotinic receptor agonism are in clinical trials presently. Current trial design involves treatment of clinically symptomatic patients, a setting in which failure to show efficacy may be even more likely, given the advanced pathologic state of the disease. Moreover, unclear rationale for drug therapy, preclinical testing, and the actual testing of the drug in human clinical trials have been barriers to effective new drug development over the last decade.

Types of treatments Treatments can be divided into primary (preventive therapy used before onset of clinical symptoms or in the preclinical stage), secondary (after onset of clinical symptoms, subdivided into symptomatic, disease modifying, or curative), and tertiary (palliative, used to contain the ravages of the disease and to improve quality of life). In geriatric neurology in general and dementias in particular, curative and disease-modifying treatments have been rare, with most available secondary treatments in the symptomatic realm.

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Primary prevention or treatment in the preclinical state Few preventive treatments are available in geriatric neurology. Moreover, identifying precise disease onset is problematic using current clinical information, which may preclude the development of effective preventive agents. For example, using anti-Aβ therapy in patients with clinically diagnosed AD may be comparable to treating patients with myocardial infarction and heart failure with a statin to lower cholesterol and expecting the current cardiac function to noticeably improve. In these late clinical settings when end organs have already been damaged, treating the pathophysiologic process that is protracted or triggering the disease is not likely to demonstrate efficacy. Such a treatment trial design would be akin to measuring mortality as the endpoint for a statin drug to show efficacy. We now know that statins clearly lower cholesterol, but it is still challenging to demonstrate improvement in cardiovascular morbidity and mortality with these agents. Primary treatments targets in geriatric neurology face a similar dilemma. For instance, in AD, despite advances in the ability to diagnose preclinical AD (Natrini, 2010), a move toward primary prevention depends on advancing our ability to predict who is at very high risk for AD and in what time frame they might develop observable pathology and,

subsequently, clinical symptoms. Age, cardiovascular risk factors, diabetes, African American race, history of head injury, APOE E4 genotype, low cerebrospinal fluid (CSF) Aβ42, and increased positron emission tomography (PET) amyloid tracer binding in the brain may all increase risk for the progression of preclinical AD to mild cognitive impairment (MCI) and MCI to AD (Romas et al., 1999; Blennow, 2004; Storandt et al., 2009; De Meyer et al., 2010). But these risk markers do not provide information regarding onset of disease pathology, which makes timing of preventive treatments difficult. Not surprisingly, multiple preventive interventions in the past have failed in AD (Table 23.1). Phase 2 and phase 3 trials in geriatric neurology are complicated and resource intensive and have low probabilities for success. They consume an estimated 48% of the costs for each drug launched (Paul et al., 2010). Prevention trials are even more expensive. Due to the prohibitive cost of an AD prevention trial, only one such industry trial has been sponsored: a ginkgo biloba extract study in France involving about 2800 patients over 5 years (Vellas et al., 2006). Most of the prevention trials (Table 23.1) were sponsored by the NIH or similar government bodies, leading to the comparably large ADAPT (Leoutsakos et al., 2012; Breitner, 2007) and ginkgo biloba extract (GEM) study (DeKosky et al., 2008) studies that have received approximately $44 million and $28 million, respectively, of total funding.

Table 23.1 Alzheimer’s disease prevention studies Age (years)

Sample size

Length (years)

First degree relative with AD

≥70

2,528

GEM/ginkgo biloba (Snitz et al., 2009)

Asymptomatic 60%, MCI 40%

≥75

GUIDAGE/ginkgo biloba (Vellas et al., 2006)

Memory complaints

Physicians Health Study-II/vitamin E, folate, β-carotene (Christen et al., 2000)

Study

Inclusion criteria

Outcomes

Status

ADAPT/naproxen, celecoxib (Meinert et al., 2009)

5–7

AD, cognitive decline

Early termination

3,072

5

AD, cognitive decline, cardiovascular

No significant effects

>70

2,854

4

AD

No significant effects

Asymptomatic

>65

10,000

9

Telephone cognitive testing

Ongoing

Heart Protection Study/vitamins E, C, β-carotene, simvastatin (Heart Protection Study Collaborative Group, 2002)

Asymptomatic with cardiovascular risk factors

40–80

20,536

5

AD, telephone interview for cognitive status (TICS)

No differences

PreAdvise/selenium, vitamin E (Kryscio et al., 2004)

Asymptomatic, males only

≥60

10,400

9–12

Dementia onset, cognitive tests

Terminated

HERS/estrogen medroxyprogesterone (MPA) (Grady et al., 2002)

Asymptomatic, females

Mean = 67

1,060

4.2

Cognitive tests

Improvement on one test

WHIMS/estrogen and MPA (Craig et al., 2005)

Asymptomatic, female

65–80

4,532

4–5

AD and MCI, cognitive scores (add-on)

Increased risk for MCI/AD, worse scores with hormone replacement therapy (HRT)

WHIMS/estrogen alone (Craig et al., 2005)

Asymptomatic, female

65–80

2,497

4–5

AD and MCI, cognitive scores (add-on)

Increased risk for MCI/AD, worse scores with HRT

Source: Adapted from Golde et al. (2011) with permission from Elsevier.

Evidence-Based Pharmacologic Treatment of Dementia

Despite the cost, primary prevention for most geriatric neurologic conditions, including dementias, is developing into an exciting new field in which we can expect rapid advances. Recent advances in amyloid imaging may allow smaller clinical trials, decreasing the cost. The Alzheimer’s Disease Neuroimaging Initiative has allowed investigators to identify which markers best track change over time, thus allowing for developing clinical trials that are more efficient with lower cost, shorter durations, and smaller sample sizes. Increased knowledge of the mechanisms of neural injury, the best targets for neuroprotection, and improved animal models (such as transgenic mice that exhibit more neurodegeneration and the full spectrum of AD pathologies) may all lead to more successful translation of neuroprotective drugs, from the preclinical to the clinical phase in the near future. The second generation of prevention trials are underway or in development. The Alzheimer’s Prevention Initiative (API) targets the use of the monoclonal antibody crenezumab in subjects that are PS1 carriers (Reiman et al., 2011). The Dominantly Inherited Alzheimer’s Network (DIAN) study will investigate multiple different drugs as a secondary prevention in subjects with autosomal dominantly inherit AD risk (Morris, 2012). Other prevention studies will deploy metabolic-based targets in at-risk people (e.g., TOMM40) or will select subjects for immunotherapy treatment on the basis of the presence of amyloid by PET imaging.

Secondary prevention or treatment after clinical symptom onset The current annual worldwide costs of care for those with AD are approximately 1% of the world’s GDP, or $604 billion. However, regulators across the world are ill prepared to meet the growing need for early stage treatments. For example, the Food and Drug Administration (FDA) regulatory guidelines require that a drug “show benefit for patients with dementia on cognition and a clinical benefit demonstrated either by global or staging assessment or in activities of daily living (ADL).” Almost all trials for mild or for mild-to-moderate AD used the Alzheimer’s Disease Assessment Scale-cognitive subscale ([ADAS-cog] cognitive measure) and the Clinical Dementia Rating or an ADL scale (clinical benefit) (Schneider and Sano, 2009). The trials for MCI used the onset of AD as the primary outcome (Raschetti et al., 2007). These cognitive and functional measures as required now lead to expensive and long trials that may be inadequately powered and add significant costs. Changes in regulatory point of view from these measures to biomarker-based measures that show “delay in the onset of clinical AD or attenuate the course of cognitive impairment” may be possible once regulators recognize and validate at-risk state or markers and accept them as legitimate outcomes. In the absence of such regulatory vision, we are left with symptomatic therapy for most geriatric neurologic conditions.

559

Symptomatic therapy Currently in geriatric neurology, the norm is symptomatic treatment that lasts for a few years in effectiveness. For example, in the typical AD patient, current symptomatic therapies (acetylcholinesterase inhibitors and memantine) demonstrate only modest symptomatic benefit that is sustained for a period of 6 months to a few years. Moreover, there is no clear evidence that these treatments significantly alter disease progression (Schneider et al., 2011). Although there is renewed effort to develop novel cognitive-enhancing agents that target different pathways, only a few, such as the mitochondrial agent dimebon (Doody et al., 2008) and histamine receptor antagonists, have entered phase 3 efficacy studies in humans. Results from the several phase 3 studies of dimebon, unfortunately, showed conflicting evidence of efficacy (Jones, 2010). Studies of the drug in subjects using donepezil as an add-on agent are ongoing. Symptomatic effect is measured in two domains: worsening on a cognitive measure (such as ADAS-cog) and a clinical (or global) measure (such as Clinical Dementia Rating [CDR], Clinician’s Interview-Based Impression of Change [CIBIC], or CIBIC with caregiver input [CIBICplus]). Experience based on longitudinal studies of ambulatory patients with mild-to-moderate AD suggests that scores on the ADAS-cog increase (worsen) by 6–12 points per year. However, smaller changes may be seen in patients with very mild or very advanced disease because the ADAS-cog is not uniformly sensitive to change over the course of the disease. The annualized rate of decline in the placebo patients participating in donepezil trials was approximately two to four points per year. Overall clinical effect is measured using CIBIC or CIBIC-plus. The CIBICplus is not a single instrument and is not a standardized instrument like the ADAS-cog; therefore, it captures the clinical variability. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. The FDA presently requires effectiveness on both domain scales (cognitive as well as improvement in function) to approve a drug for AD. In a meta-analysis of the treatment trials in AD using ADAScog, the pooled analysis showed a diagnostic odds ratio (DAR) of 0.56 (95% CI 0.42–0.74). However, significant heterogeneity was seen. ADAS-cog variability in each study accounted for 89.6% of the treatment effect. Stratifying by treatment class (choline esterase inhibitors vs. others) or by the disease state (MCI vs. AD) did not eliminate the heterogeneity of reported treatment effects using ADAS-cog. Similar DAR was seen with CIBIC, without significant heterogeneity (Figures 23.1 and 23.2). In the last 20 years, the FDA has approved five drugs for the treatment of dementia, and all have been approved specifically for AD: tacrine, donepezil, rivastigmine, galantamine, and memantine. Tacrine, donepezil, rivastigmine, and galantamine have been approved for an

560

Therapeutics for the Geriatric Neurology Patient

Diagnostic OR (95%) Tacrine_160 mg Rivastigmine—high dose Rivastigmine—low dose Galantamine_AD_24 mg Galantamine_AD_32 mg Galantamine_AD_8 mg Galantamine_AD_16 mg Galantamine_AD_24 mg Galantamine_AD_18 mg Galantamine_AD_24 mg Galantamine_AD_36 mg Donepezil_AD Galantamine_24–32 mg

0.001

1 Diagnostic Odds Ratio

0.30 0.43 0.58 0.46 0.50 0.85 0.49 0.54 0.47 0.53 0.38 0.43 0.45

(0.19–0.48) (0.28–0.64) (0.38–0.89) (0.30–0.70) (0.33–0.76) (0.56–1.29) (0.35–0.71) (0.38–0.77) (0.22–0.99) (0.23–1.24) (0.15–0.97) (0.27–0.68) (0.28–0.72)

Random Effects Model Pooled Diagnostic Odds Ratio = 0.49 (0.43–0.56) Cochran-Q = 13.27; df = 12 (p = 0.3500) 100.0 Inconsistency (I-square) = 9.5 % Tau-squared = 0.0058

identical indication: the treatment of mild-to-moderate dementia of the Alzheimer’s type. Memantine has been approved for the treatment of moderate-to-severe dementia of the Alzheimer’s type (MMSE < 14).

Figure 23.1 Changes from baseline in mean

ADAS-cog score in studies of galantamine, donepezil, tacrine, and rivastigmine. Positive changes from baseline on the MMSE indicate improvement; negative values indicate deterioration. Data based on various randomized clinical trials (RCTs) conducted through 2004–2010 after applying the CONSORT quality criteria.

occurred and no serious adverse effects (SAE) attributable to THA were observed, but significant adverse effects (AE) (up to 55% withdrawal rates) limited its use. GI and elevated hepatic transaminase occurred in approximately 25% of patients.

Tacrine The first drug the FDA approved to treat AD was tacrine, or tetrahydroaminoacridine (THA), a centrally active anticholinesterase (Summers et al., 1986). In six studies with 994 subjects with mild-to-moderate AD, significant improvement occurred in one trial with the largest sample size. Two other trials were not blinded and had an additional 425 subjects. Significant improvement was seen among subjects who received the drug, on the global assessment (p = 0.003), the Orientation Test (p = 0.004), the Alzheimer’s Deficit Scale (p = 0.003), and the Names Learning Test (p = 0.001). Symptomatic improvements

Donepezil The next drug approved (1993) for AD was donepezil hydrochloride (Aricept) (Rogers and Friedhoff, 1996), a reversible inhibitor of acetylcholinesterase, which did not have the hepatic toxicity of tacrine. It is available for oral administration in film-coated tablets containing 5, 10, or 23 mg of donepezil hydrochloride and in ODT (orally dissolving tablet) formulation that contains 5 or 10 mg of donepezil administered once daily usually in the evening (if patients recall dreams, it may be switched to morning). Donepezil is postulated to exert its therapeutic effect

Diagonostic OR (95%) Tacrine_AD_160 mg 0.50 (0.33–0.76) Physostigmine_AD 0.56 (0.36–0.88) Rivastigmine_AD_high dose 0.60 (0.38–0.95) Galantamine_AD_24 mg 0.11 (0.06–0.19) Galantamine_AD_32 mg 0.11 (0.06–0.19) Galantamine_AD 0.45 (0.28–0.72) Choline Alfoscerate_AD 0.13 (0.07–0.26) Galantamine–11_MCI 0.86 (0.64–1.15) Donepezil_MCI 0.86 (0.58–1.27) Donepezil_MCI 1.0.2 (0.53–1.96) Galantamine–18_MCI 0.86 (0.65–1.13) Vit.E_MCI 0.96 (0.65–1.40) Rofecoxib_MCI 1.38 (1.01–1.87) Rivastigmine_MCI 0.86 (0.65–1.13) Trifusal_MCI 0.58 (0.30–1.16) Galantamine_MCI 0.54 (0.37–0.79) Donepezil_MCI 0.47 (0.23–0.93) Ginkgo Giloba_MCI 1.03 (0.85–1.25) Figure 23.2 Existing dementia treatments

0.01

1 Diagnostic Odds Ratio

Random Effects Model Pooled Diagnostic Odds Ratio = 0.56 (0.42–0.7) Cochran-Q = 163.96; df = 17 (p = 0.0000) 100.0 Inconsistency (l-square) = 89.6 % Tau-squared = 0.3252

show effectiveness in a meta-analysis of multiple treatments in mild cognitive impairment and Alzheimer’s dementia, using clinical trials meeting the CONSORT 2010 quality criteria (CIBIC).

Evidence-Based Pharmacologic Treatment of Dementia

by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. No evidence indicates that donepezil alters the course of the underlying pathologic process. Pharmacokinetics of donepezil is linear over a dose range of 1–10 mg given once daily. The rate and extent of absorption of donepezil tablets are not influenced by food. The elimination half-life of donepezil is about 70 hours, and a steady state is reached within 15 days. It is 96% bound to human plasma proteins, mainly to albumins. Other protein-bound agents, such as furosemide, digoxin, and warfarin, do not affect donepezil binding to albumin. It is excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active by glucuronidation using CYP 450 isoenzymes 2D6 and 3A4. CYP2D6 genotype affects elimination, with poor metabolizers having a 31.5% slower clearance and rapid metabolizers a 24% faster clearance. Liver impairment can reduce elimination, while renal impairment does not seem to affect clearance. In addition, advancing age reduces clearance. When compared with 65-year-old subjects, 90-year-old subjects have a 17% decrease in clearance. The effectiveness of donepezil as a treatment for mildto-moderate AD is demonstrated by 10 randomized, double-blind, placebo-controlled trials in 3239 patients with AD (diagnosed by NINCDS and DSM III-R criteria; Farlow et al., 2010). The mean age of patients participating in donepezil trials was 73 years; 62% were women. The racial distribution was white 95%, black 3%, and other races 2%. After 24 weeks of treatment, the mean differences in the ADAS-cog change scores for donepezil-treated patients compared to the patients on placebo were 2.8 and 3.1 points for the 5 mg/day and 10 mg/day treatments, respectively. The beneficial effects of donepezil wash out over 6 weeks following discontinuation of treatment. There was no rebound effect after abrupt discontinuation of therapy. Similarly, on the CIBIC, the mean drug–placebo differences for these groups of patients were 0.35 points and 0.39 points for 5 mg/day and 10 mg/day, respectively, once again significantly different from placebo. Each treatment arm was significantly different from placebo on both tests, but there was no between-dose significance. The significant treatment effects continued into moderate and severe disease states while using donepezil. Withdrawal due to adverse events ranged from 0–11% for placebo to 0–18% for donepezil. The most common side effects of donepezil are diarrhea, nausea, vomiting, insomnia, muscle cramps, fatigue, and anorexia. Donepezil can also rarely increase the chance of ulcers and GI bleeding. In people with heart problems, it can rarely cause slow heartbeat and fainting, especially when used with beta-blockers. Very unusual side effects include urinary retention, worsening asthma, and seizures.

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Galantamine Galantamine hydrobromide (Razadyne), a tertiary alkaloid, is a competitive and reversible inhibitor of acetylcholinesterase that the FDA approved in 2000 for mild-tomoderate AD. As with donepezil, the precise mechanism of galantamine’s action of improving memory in dementia is unknown. It is postulated to exert its therapeutic effect by enhancing cholinergic function. The oral bioavailability is 90%, with an elimination half-life of 7 hours and linear pharmacokinetics. It is also glucuronidated by hepatic CYP 450 enzymes 2D6 and 3A4 and excreted unchanged in the urine (Ago et al., 2011). Unlike donepezil, this agent accumulates in subjects with renal impairment. Accumulation can also occur with advancing age and inhibitors of 2D6, such as paroxetine, erythromycin, amitriptyline, fluoxetine, fluvoxamine, and quinidine; it does not affect the levels of other drugs. The FDA approved the drug after reviewing the results of six randomized, double-blind, placebo-controlled trials in 3530 patients with probable AD (NINCDS-ADRDA criteria, with MMSE 10–24 and mean participant age 75 years), with doses of 8–32 mg/day given as twice-daily doses (immediate-release tablets). On the ADAS-cog at 21 weeks of treatment, galantamine-treated patients were better by 1.7, 3.3, and 3.6 units for the 8, 16, and 24 mg/ day treatments, respectively. On CIBIC-plus, the galantamine–placebo differences for these groups of patients in mean rating were 0.15, 0.41, and 0.44 units for the 8, 16, and 24 mg/day treatments, respectively. The 16 mg/day and 24 mg/day treatments were statistically significantly superior to placebo and 8 mg/day treatment in both outcome measures. The AE profile is similar to donepezil, except that is has more GI side effects (Table 23.2). The most common side effects were diarrhea, nausea, vomiting, insomnia, muscle cramps, fatigue, and anorexia.

Velnacrine Two of the three studies evaluating 774 AD subjects with this medication showed benefit. However, hematologic and hepatic adverse events (up to 40%) kept the FDA from approving it (Birks and Wilcock, 2004).

Rivastigmine Six studies evaluated 2071 subjects (three limited to AD) on rivastigmine before the FDA approved it in 2000. Doses varied from 1 to 12 mg given for 14–26 weeks. Evidence indicates that cognitive function improves with rivastigmine at the 12-mg dose, but efficacy results were mixed at lower doses. In two trials, results were inconsistent (between cognitive measures). However, there is consistent benefit for global function—but the effective dose to achieve benefit was variable among the trials. Caregiver burden outcomes were not evaluated.

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Therapeutics for the Geriatric Neurology Patient

Table 23.2 Summary of the adverse events observed with various medications used in the treatment of Alzheimer’s disease Adverse effects (Percentage/ranges indicate multiple trials)

Placebo (N = 3819) (%)

Bradycardia Fatigue Syncope Confusion Dizziness Headache Tremor Constipation Nausea Vomiting Diarrhea Abdominal pain Dyspepsia Weight decrease Anorexia Depression Insomnia Somnolence Anemia Rhinitis Urinary infection Hematuria

0–1 0.6–3 0.2–1 0.3–5 0.3–6 0.8–5 0.1–2 0.5–3 0.5–9 0.7–4 0.4–7 0.6–4 0.5–2 0.3–2 0.4–3 0.4–5 0.8–4 0–3 0–2 0–3 0–7 0–2

Donepezil (Aricept) (N = 2682) (%)

Galantamine (Razadyne) (N = 1040) (%)

0–1 0–1

2 5 2

0.4–1 0.6–1

9 8 3

0.6–1.5 0.6–1.6 0.8–2

24 13 9 5 5 7 9 7 5 4 3 4 8 3

0–1 0.4–1.6 0–1 0.3–1.2 0–1

Withdrawal rates were 4–11% for placebo and 11–27% for the rivastigmine group, with side effects of dizziness, nausea, vomiting, anorexia, and headache (Birks et al., 2000).

Memantine Memantine has been available since 1982 in Germany (originally approved for the treatment of organic brain syndrome) and was available outside the United States in 42 countries before its FDA approval in 2003. In 2013, an extended release formulation was approved by the FDA, which allows a dosing of 28 mg once daily. Even though the precise mechanism of action in AD is uncertain, memantine is thought to be a low-to-moderate affinity, uncompetitive NMDA receptor antagonist with strong voltage dependency and rapid blocking/unblocking kinetics. These pharmacologic features “appear to allow memantine to block the sustained activation of the receptor by glutamate that may occur under pathologic conditions and to rapidly leave the NMDA receptor channel during normal physiologic activation” (McKeage, 2009). In humans, memantine is 100% bioavailable after an oral dose, undergoes minimal metabolism, and exhibits a terminal elimination half-life of 60–80 hours (75% or more of the dose is eliminated intact in the urine). It rapidly crosses the blood–brain barrier with a CSF/serum ratio of 0.52. Memantine does not inhibit cytochrome P-450 (CYP 450) isoenzymes in vitro, and its pharmacokinetics are not affected by food, sex, or age (Micuda et al., 2004).

Rivastigmine (Exelon) (N = 2439) (%)

Memantine (Namenda) (N = 940) (%)

0.8–2 0–1 0–1 1.7–7 1.1–6 0.4–2.8 0–1 4–23 2.6–19 1.6–10 1–4 0–1 0.3–8 1.4–9 0.5–4 0.8–4 0.4–1.1

2 6 7 6 5 3

3

0–1 0–2

Memantine demonstrated efficacy in the treatment of moderate-to-severe AD (MMSE 3–14) using a dose of up to 20 mg/day in two key double-blind, placebo-controlled trials of 6-month duration. As the patients were more advanced, Severe Impairment Battery (SIB) and the 19-item version of the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCSADL19), which is modified for more advanced AD patients, were used as the indices of cognitive and functional change. The clinician made a global clinical assessment of change using CIBIC-plus (Schmitt et al., 1997; Orgogozo, 2002; Reisberg et al., 2003). AE reported frequently (>5%, memantine greater than placebo) were dizziness, confusion, headache, and constipation. This agent did not get FDA approval for use in mild dementia or vascular dementia due to inconsistent effects on cognitive and global measures.

Medical foods Medical foods undergo a different approval process than drugs. As these agents are considered to be derived from or parts of food already consumed widely, the expectation is they are not harmful. Currently these agents can be brought to market with much less oversight by the FDA. The first medical food for Alzheimer treatment approved by the FDA in 2012 was Axona. It is derived from triglycerides moieties in coconut milk. As coconut milk is consumed extensively, the general expectation is that of low side effect profile.

Evidence-Based Pharmacologic Treatment of Dementia

Frontotemporal dementia No FDA-approved medications for frontotemporal dementia (FTD) exist, and the pharmacologic treatment of clinical symptoms is mostly based on clinical judgment. Large-scale, placebo-controlled clinical trials of treatments are not available to determine effectiveness on measures of clinical progression. Psychiatric drugs are more commonly used in FTD than AD. See Table 23.3 for a summary of all studies. See Chapter 9.5 for additional details. Compared to AD, FTD patients are generally younger, with higher MMSE and neuropsychiatric inventory (NPI) scores (p < 0.001). FTD patients are less likely to be prescribed dementia medications, donepezil (27% vs. 53%), and memantine (35% vs. 42%, p < 0.001). FTD patients are more likely to use antipsychotics (10% vs. 5%, p = 0.013), antidepressants (59% vs. 39%, p < 0.001), and sedative/ anxiolytics (17% vs. 8%, p < 0.001), adjusted for age, onset age, MMSE, education, and CDR. Higher aberrant motor (odds ratio [OR] 1.6, p = 0.009) and appetite (OR 1.6, p = 0.011) scores were associated with increased antipsychotic

563

use, while higher depression (OR 0.482, p = 0.016) and disinhibition (OR 0.635, p = 0.025) were associated with lower use. Antidepressant use was increased with higher agitation (OR 1.3, p = 0.048) and depression (OR 1.6, p = 0.003), but decreased with higher irritability (OR 0.76, p = 0.040).

Dementia with Lewy bodies Currently, only rivastigmine is FDA-approved medications exist for treatment of Parkinson-related dementias (e.g., Lewy body dementia). Clinical trials did not show significant efficacy of medications currently used in the management of AD (Ferman et al., 2004) (Table 23.4). Some improvement of motor function, global clinical status, and behavioral symptoms on NPI scores was noted on these medications. Treatment of dementia with Lewy Bodies (DLB) focuses on managing hallucinations and agitations. Acetylcholinesterase inhibitors are thought to be beneficial to most. Rivastigmine may alleviate apathy, anxiety, hallucinations, and

Table 23.3 Summary of published open-label and randomized clinical trials and case reports in patients with frontotemporal dementia (FTD) through 2009 Study

Medications

Number of Study duration subjects Main findings

Kertesz et al. (2008) Lebert et al. (2004)

Galantamine Trazadone

18 weeks 12 weeks

36 26

No improvement in FTD. Improvement in neuropsychiatric symptoms. No effect on cognitive status.

Mendez et al. (2007)

Donepezil

6 months

24

No difference in cognitive function between treated and untreated. Neuropsychiatric impairments worse, reversible after drug removal in 33% treated subjects.

Moretti et al. (2004)

Rivastigmine

12 months

20

Improvement in neuropsychiatric symptoms and caregiver burden, while cognitive function declined.

Mendez (2009)

Sertraline

6 months

18

Decreased stereotypical movements.

Moretti et al. (2003b)

Olanzapine

24 months

17

Improved agitation, misconduct, delusions. Decreased caregiver distress.

Ikeda et al. (2004)

Fluvoxamine

12 weeks

16

Improved stereotyped and other behaviors.

Moretti et al. (2003a)

Paroxetine

14 months

16

Improvement in neuropsychiatric impairments and caregiver stress. Few adverse events.

Diehl-Schmid et al. (2008) Memantine

6 months

16

No improvement in behavior. Worsening of cognitive dysfunction.

Swartz et al. (1997)

SSRIs

3 months

11

Improvement in neuropsychiatric impairments in more than half of patients.

Deakin et al. (2004)

Paroxetine

6 weeks

10

No improvement in neuropsychiatric impairments. Mild worsening in cognitive function in treated group.

Rahman et al. (2006)

Methylphenidate One dose

8

Decreased risk-taking behavior on gambling task.

Swanberg (2007)

Memantine

3 months

3

All three patients had improved NPI scores, especially for apathy, agitation, and anxiety.

Ishikawa et al. (2006)

Fluvoxamine

NA

2

Improved stereotyped behaviors, fewer pain complaints.

Goforth et al. (2004)

Methylphenidate NA

1

Partial normalization of quantitative electroencephalogram (EEG) pattern.

Anneser et al. (2007)

Sertraline

1

Decrease in inappropriate sexual behavior and physical aggression in FTD–amyotrophic lateral sclerosis (ALS) patients.

Cruz et al. (2008)

Topiramate

6 months

1

Reduction in alcohol abuse, but no change in other compulsive behavior.

Curtis and Resch (2000)

Risperidone

NA

1

Improved behavior.

Fellgiebel et al. (2007)

Aripiprazole

1 month

1

Stabilization of clinical symptoms. Improved frontal glucose metabolism on PET.

NA

Source: Adapted from Boxer and Boeve (2007) and Vossel and Miller (2008) with permission from Lippincott Williams & Wilkins.

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Therapeutics for the Geriatric Neurology Patient

Table 23.4 Summary of published open-label and randomized clinical trials and case reports in patients with Lewy body dementia Study

Medications

Number of Study duration subjects Main findings

McKeith et al. (2000a)

Rivastigmine 20 weeks

120

Clinically significant behavioral effects in patients with Lewy body dementia.

Wesnes et al. (2002)

Rivastigmine 20 weeks

92

Benefits of the cognitive functioning, as well as improvement in MPI scores.

Grace et al. (follow-up of McKeith et al., 2000a)

Rivastigmine Up to 96 weeks

29

Improved MMSE at 12 and 24 weeks, with no change at 36 weeks reported. Decreased NPI scores at weeks 12 and 24, baseline at weeks 36 and 96.

Levin et al. (2009)

Memantine

23

Reductions in the severity of fluctuations in mental state, aggressivity, lack of spontaneity, and disinhibition.

16 weeks

Lebert et al. (1998)

Tacrine

14 weeks

19

Increased cognition in Mattis Dementia Rating Scale (MDRS) in 11 cases.

Mori et al. (2006)

Donepezil

12 weeks

12

Significant improvements in NPI-11 scores. Significant improvement in ADAS-J-cog until week 4. Deterioration in Unified Parkinson’s Disability Rating Scale (UPDRS) scores.

McKeith et al. 2000b (follow- Rivastigmine 12 weeks up of McKeith et al., 2000a)

11

No change in cognition—MMSE. NPI scores decreased 47%.

Shea et al. (1998)

Donepezil

8–24 weeks

9

Improved cognition—MMSE and ADL. Decreased fluctuations.

Maclean et al. (2001)

Rivastigmine 3–24 weeks

8

Decreased NPI. Improved ADL. Improved sleep reported.

Lanctôt and Herrmann (2000)

Donepezil

7

Improved MMSE (two out of three cases). Decreased NPI scores at 4 weeks. Three out of seven cases discontinued.

Grace et al. (2001)

Rivastigmine 12 weeks

6

Cognition improved. MMSE increased from 18.5/30 to 23/30 at week 12. Decreased sleep.

Querfurth et al. (2000)

Tacrine

24 weeks

6

Increased cognition in DLB responders: MDRS memory subscale and Functional Assessment Scale (FAS) Fluency task.

Samuel et al. (2000)

Donepezil

6 months

4

Improved cognition noted.

Coulson et al. (2002)

Donepezil

6 months

1

Increased cognition. MMSE 23/30 at baseline and 27/30 6 months post-baseline.

Rojas-Fernandez et al. (2001) Donepezil

3 months

1

Increased cognition. Increased ADL. Decreased fluctuations.

Aarsland et al. (1999)

Donepezil

7 weeks

1

Increased cognition. MMSE 23/30 at baseline and 30/30 at three and seven weeks post-baseline.

Skjerve and Nygaard (2001)

Donepezil

14 weeks

1

Improved cognition. MMSE 11/30 at baseline and 20/30 at 6 weeks, as well as 21/30 at 14 weeks.

Geizer and Ancill (1998)

Donepezil

10 weeks

1

Improved cognition. 25/30 at baseline and 27/30 at 2 and 10 weeks post-baseline.

8 weeks

delusions (McKeith et al., 2000a; Fernandez et al., 2003). Memantine may also help improve cognition and behavioral symptoms (Emre et al., 2010). Atypical neuroleptics are also prescribed, but clinical trial results have been nonsignificant. Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice in managing depression. Levodopa/carbidopa (Sinemet) may improve motor function, but the results are limited by sample size (Lucetti et al., 2010). Low doses of Zonisamide may be effective in managing behavioral symptoms such as apathy and aggression (Odawara et al., 2010; Sato et al., 2010). See Chapter 9.3 for additional details.

Overall approach to pharmacotherapy of dementia Although it is hard to generalize treatment to diseases other than AD, the volume of evidence suggests at least that an empirical trial of medications approved for AD

be used as off label in Lewy body dementia and even more selectively in FTD. The role of approved medications is even more limited in rapidly progressive dementias. It is advisable to start with one of the acetylcholinesterase inhibitors (ACHEIs) and titrate up to a tolerable dose, based on an individualized approach to each patient. A geriatric neurology consultation for careful titration of medication is required to safely manage the medications. Frequent neurologic evaluations (biweekly or monthly) until the dose is titrated up to a tolerable dose are required. Once the patient is on a stable dosing, serial follow up every 3–6 months with a geriatric neurologist is highly recommended for continued patient safety. In addition, a short-form neuropsychological test measure (such as the MOCA test, available at http://mocatest.org) is also recommended, to document decline, two to three times a year. Table 23.5 summarizes current medications with their dosages, precautions, and interactions.

Seizures, asthma, sick sinus syndrome, or other supraventricular conduction abnormalities. Peptic ulcer disease.

Precautions

Documented hypersensitivity. May cause serious agranulocytosis. May worsen WBC count <3500 cells/μL confusion and EPS. Possibly may increase lethargy and before or during therapy. cause tachycardia, dizziness, and increased sweating. Never stop abruptly. Must perform WBC testing q2wk for duration of therapy.

12.5 mg once daily.

25 mg PO twice daily.

10–15 mg PO, once daily.

75 mg per day, PO.

Clozapine (Clozaril)

Quetiapine (Seroquel)

Aripiprazole (Abilify)

Venlafaxine (Effexor)

Documented hypersensitivity with monoamine oxidase inhibitors (MAOIs) within 14 days.

Patients may experience hypertension. Fatal reaction may occur if taken concurrently with an MAOI. Use caution in patients with cardiovascular disorders.

Documented hypersensitivity. Common AE include headache, anxiety, somnolence, or insomnia. Rare reports of tardive dyskinesia and neuroleptic malignant syndrome have been noted. May cause orthostatic hypotension, seizure, dysphagia, or suicidal ideation.

Documented hypersensitivity. May induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. Neuroleptic malignant syndrome and tardive dyskinesia have been associated with treatment. Hyperglycemia may occur.

Documented hypersensitivity. Not to be prescribed in patients with severe renal dysfunction (i.e., <10 mL/min creatinine clearance).

Galantamine 8 mg PO once daily. Increase by (Razadyne) 5 mg every 30 days till diarrhea limits further dosing increase.

Decrease dose in moderate renal insufficiency or moderate-to-severe hepatic impairment. Use caution in asthmatic patients; may cause bradycardia or AV block, or syncope may occur with doses >24 mg/day. Also use caution in patients with sick sinus syndrome or other supraventricular conduction. Some cases of worsening of motor features of PD or exacerbation of bradycardia have been reported but have not yet been clinically proven.

Rivastigmine 1.5 mg PO twice daily. Increase by Documented hypersensitivity. Significant nausea, vomiting, anorexia, and weight (Exelon) 1.5 mg every 30 days till diarrhea loss, history of peptic ulcer disease, sick sinus limits further dosing increase. syndrome, urinary obstruction, COPD, bradycardia or supraventricular conduction conditions. Some cases of worsening of motor features of PD or exacerbation of bradycardia have been reported but have not yet been clinically proven.

5 mg PO once daily (start at night; Hypersensitivity, Chronic if excessive dreaming, may switch Obstructive Pulmonary to morning dosing). Increase by Disease (COPD). 5 mg every 30 days till diarrhea limits further dosing increase.

Donepezil (Aricept)

Contraindications

Starting dose

Drug

Table 23.5 Pharmacotherapy of dementia

(continued)

Cimetidine, MAOIs, sertraline, fluoxetine, class IC antiarrhythmics, TCAs, and phenothiazine may increase effects. (Also discussed in Chapter 24)

CYP450 3A4 and 2D6 isoenzyme substrate inhibitors (for example, ketoconazole, quinidine, fluoxetine, and paroxetine) or inducers (such as carbamazepine) may increase or decrease serum levels. (Also discussed in Chapter 24)

May antagonize levodopa and dopamine agonists. Phenytoin, thioridazine, and other liver enzyme inducers may reduce levels. CYP450 3A inhibitors (such as ketoconazole and fluconazole) may increase serum concentrations. (Also discussed in Chapter 24)

Epinephrine and phenytoin may decrease effects. Tricyclic antidepressants (TCAs), neuroleptics, CNS depressants, guanabenz, and anticholinergics may increase effects.

When given with other cholinesterase inhibitors, may increase toxicity. CYP2D6 or CYP3A4 inhibitors may decrease elimination and increase serum levels.

Reduces effects of anticholinergics. Increases effects of cholinergic agonists and neuromuscular blockers. May lead to bradycardia when used with beta-blockers without ISA.

Increases effects of succinylcholine, cholinesterase inhibitors, or cholinergic agonists. Counteracts effects of anticholinergics used for bladder control.

Interactions

Evidence-Based Pharmacologic Treatment of Dementia 565

Starting dose

10 mg per day, PO.

Start 12.5 mg PO once daily. Increase by 12.5– 25 mg every 3–7 days.

20 mg/day PO, once daily in the morning.

0.25 mg PO, once at night. Increase by 0.25 mg nightly, not to exceed 1 mg.

25/100 mg tablet. Start with half tablet PO; twice daily, titrate by half to one tablet per dose every week until tolerated or effect.

Quinidine 10/dextromethorphan 20 mg combination tablet. Start one tablet PO once daily. Increase to twice daily after 1 week.

Start XR 7 mg PO once daily. Increase by 7 mg every week till 28 mg once daily. (IR formulation is not approved at doses above 20 mg)

Drug

Paroxetine (Paxil)

Sertraline (Zoloft)

Fluoxetine (Fluzac)

Clonazepam (Clonopin)

Levodopa/ Carbidopa (Sinemet)

Nuedexta

Memantine (Namenda)

Table 23.5 (continued)

Known or suspected history of mania or hypomania. Use caution in hepatic impairment and history of seizures. MAOIs should be discontinued at least 14 days before initiating fluoxetine therapy.

Congenital long QT syndrome, prolonged QT interval, torsades de pointes, heart failure, complete atrioventricular (AV) block without implanted pacemaker.

Concomitant use with quinidine, quinine, or mefloquine is contraindicated. Thrombocytopenia, hepatitis, hypersensitivity to dextromethorphan, within 14 days of stopping an MAOI.

Drugs that both prolong QT interval and are metabolized by CYP 2D6 (e.g., thioridazine). MAOIs.

Hydantoins, pyridoxine, phenothiazine, and hypotensive agents may decrease effects. Toxicity increases when administered concurrently with antacids or MAOIs. (Also discussed in Chapter 12)

Phenytoin and barbiturates may reduce effects. Coadministration of CNS depressants increases toxicity. (Also discussed in Chapter 24)

Inhibits CYP450 isoenzymes 2C9, 2C19, 2D6, and 3A4. Increases toxicity of diazepam and trazodone by decreasing clearance. Increases toxicity of MAOIs and highly protein-bound drugs. May cause serotonin syndrome, which pertains to myoclonus, rigidity, confusion, nausea, hyperthermia, autonomic instability, coma, and eventually death, occurs with simultaneous use of other serotonergic agents (such as tramadol or buspirone). (Also discussed in Chapter 24)

Decrease dose in moderate renal insufficiency, No drug interactions systematically studied. Combination dizziness or moderate-to-severe hepatic impairment. with cholinesterase inhibitors recommended. Use caution in seizures and alkaline urine (high pH) due to any condition.

May increase agitation, lethargy, dyskinesias, postural hypotension, hallucination, and confusion. Psychiatric symptoms (such as hallucinations) may be exacerbated.

Documented hypersensitivity, narrow-angle glaucoma, malignant melanoma, or undiagnosed skin lesions.

Documented hypersensitivity. Not to be prescribed in patients with severe renal dysfunction (i.e. <10 mL/min creatinine clearance).

Phenobarbital and phenytoin decrease effects. Alcohol, cimetidine, sertraline, phenothiazines, and warfarin increase toxicity. (Also discussed in Chapter 24)

Interactions

May increase confusion and agitation. May increase Increases toxicity of MAOIs, diazepam, tolbutamide, and sleepiness or cause insomnia. May be associated with warfarin. (Also discussed in Chapter 24) weight gain or weight loss. Must discontinue MAOIs at least 14 days before initiating therapy.

Use caution with a history of seizures, mania, renal disease, cardiac disease, or hepatic impairment. Must discontinue MAOIs at least 14 days before initiating therapy.

Precautions

Documented hypersensitivity, Use caution in chronic respiratory disease or impaired renal function. Withdrawal symptoms can result from severe liver disease, and acute narrow-angle glaucoma. abrupt discontinuation.

Documented hypersensitivity when used concurrently with MAOIs or in the last 2 weeks, coadministration with thioridazine.

Documented hypersensitivity when used concurrently with MAOIs.

Documented hypersensitivity with MAOIs within 14 days.

Contraindications

566 Therapeutics for the Geriatric Neurology Patient

Evidence-Based Pharmacologic Treatment of Dementia

Vascular dementia Currently, no treatment is approved to treat vascular dementia (VaD). Preventing vascular risk factors associated with an increased risk of dementia, including hypertension, hypercholesterolemia, diabetes mellitus, smoking, obesity, and lack of physical exercise (in midlife and, to a lesser extent, in later life), is important. Preventing further strokes by antiplatelet agents is the mainstay of treatment. (Table 23.6 shows some commonly used treatments for VaD.) Silent cerebral infarcts and white matter lesions increase the risk of future dementia. Aspirin has been found to slow progression of VaD, along with the use of various antiplatelet drugs and modification of vascular risk factors (Devine and Rands, 2003). See Chapter 9.4 for additional details. Most available evidence from randomized, controlled clinical trials comes from cardiovascular studies using stroke, coronary heart disease, or mortality as primary outcome measures, and assessing cognitive function or incident dementia as a secondary endpoint. Hypertension is the strongest risk factor for VaD (Sharp et al., 2011). Only the Syst-Euro trial reported 55% absolute risk reduction in incident VaD with anti-hypertensive use over 3.9 years (Staessen et al., 2004). A meta-analysis including four randomized clinical trials (RCTs) conducted with BPlowering therapy revealed a hazard ratio of 0.87 (95% CI 0.76–1.00) for incident dementia.

567

Two RCTs did not show cognitive effects of cholesterollowering therapy with statins. Another RCT on a diabetic subset to evaluate the effect of intensive glycemic control versus standard control did not show cognitive improvement and incident dementia. A third RCT conducted to compare multicomponent interventions and regular care against vascular risk factors in an AD patient population with cerebrovascular lesions on MRI did not find any significant effect on cognitive decline, but the treatment arm decreased progression of the white matter lesions as compared to control group (Staessen et al., 2004). Cognitive decline after stroke is more common that stroke recurrence (Alvarez-Sabín and Román, 2011). Cognitive decline risk doubles after stroke. Post-stroke VaD affects 30% of stroke survivors, and the incidence of new-onset dementia increases from 7% one year after stroke to 48% after 25 years. Use of citicoline (CDP-choline) and choline alfoscerate has been observed through various RCTs to be associated with improved memory and attention for choline alfoscerate, whereas improved memory, behavior, and clinical global impression were associated with the use of CDP-choline. CDP-choline enhances cognitive, neurologic, and functional recovery. Compared with placebo, CDP-choline-treated patients with acute ischemic stroke with an NIHSS score of >8 were more likely to have a full recovery (García-Cobos et al., 2010; Alvarez-Sabín and Román, 2011).

Table 23.6 Commonly used treatments, side effects, interactions, and contraindications for managing vascular dementia (VaD) Drug

Dose

Aspirin (Anacin, Ascriptin)

325 mg PO qd

Ticlopidine (Ticlid)

Clopidogrel (Plavix)

Contraindications

Documented hypersensitivity, liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, asthma, use in children (<16 years) with flu (associated with Reye syndrome). 250 mg PO bid Documented hypersensitivity, neutropenia or thrombocytopenia, liver damage, active bleeding disorders. 75 mg PO qd Documented hypersensitivity, active pathologic bleeding (e.g., peptic ulcer), intracranial hemorrhage.

Pentoxyfylline 400 mg bid (Trental)

Documented hypersensitivity, cerebral or retinal hemorrhage.

Precautions

Interactions

May cause transient decrease in renal function and aggravate chronic kidney disease. Avoid use in patients with severe anemia, patients with history of blood coagulation defects, or patients on anticoagulants.

Action may decrease with antacids and urinary alkalinizers. Corticosteroids decrease salicylate serum levels. May lead to increased bleeding time when used with anticoagulants. May antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid. Doses >2 g/day may potentiate glucoselowering effect of sulfonylurea drugs. Discontinue if absolute neutrophil Effects may decrease with coadministration of count decreases to <1200/μL or if corticosteroids and antacids. Toxicity increases platelet count falls to <80,000/μL. when taken concurrently with theophylline, cimetidine, aspirin, and NSAIDs. Use caution in patients at increased risk of bleeding from trauma, surgery, or other pathologic conditions. Also use caution in patients with lesions with propensity to bleed (such as ulcers). Renal impairment.

Coadministration with naproxen is associated with increased occult GI blood loss. Prolongs bleeding time. Safety of coadministration with warfarin not established yet.

Coadministration with cimetidine or theophylline increases effects and toxic potential. Increases effect of antihypertensives.

568

Therapeutics for the Geriatric Neurology Patient

In a double-blinded, placebo-controlled, multicenter study, treatment with pentoxifylline (European Pentoxifylline Multi-Infarct Dementia Study, 1996) was found to be beneficial for patients with multi-infarct dementia. Significant improvement was observed in areas of intellectual and cognitive function (Black et al., 1992). Also, the extent to which neuroprotective drugs such as nimodipine, propentofylline, and posatirelin can be useful is currently underway and may be useful for VaD when ongoing studies are complete. Preliminary studies have showed a decrease in cognitive deterioration in patients with cerebrovascular disease with the use of Nicardipine (dihydropyridine calcium channel blocker). Cerebrolysin, a neuropeptide earlier used in the treatment of AD-related dementia, has been shown to be an effective therapy in managing VaD. Cerebrolysin (daily dose of 20mL) used in combination with Aspirin in a multicenter, randomized, double-blind clinical trial for 24 weeks reported positive primary outcomes for ADAS-cog and CIBIC scores, as well as improved scores on MMSE and ADAS-ADL (secondary efficacy measures). In the treatment group, 75.3% of the patients had improved CIBIC scores, whereas only 37.4% had improved scores in the placebo arm (Guekht et al., 2010).

Parkinson’s disease dementia Cognitive impairment and dementia are common features of Parkinson’s disease (PD). Estimated point prevalence for dementia in PD population (usually elderly with more severe extrapyramidal signs) is about 30% (Aarsland and Kurz, 2010). Parkinson’s disease dementia (PDD) manifests with impairment of executive function and attention at first, whereas memory and visuoconstruction impairment develop at a later stage. See Chapter 12.1 for additional details on how to treat motor aspects of PD. Significant neuropsychiatric burden accompanies cognitive decline, as well as fluctuation in attention. Mean duration for the development of dementia through inception is around 10 years. Various RCTs have determined that 48% of patients with PDD develop visual hallucinations in the first year of the disease. The main neurochemical impairment in PD is dopamine, but significant deficits in cholinergic transmission are also in these patients. These deficits are largely localized to the cholinergic system of the basal forebrain and brainstem, in contrast to patients with AD, where cholinergic deficits are primarily seen in the hippocampus. In patients with PDD, cholinergic deficits may be greater than in AD patients with similar levels of cognitive impairment (Poewe et al., 2008). Because no approved medication can stop or reverse disease progression, efforts have been focused on delivering symptom-oriented treatments (Emre, 2007). Significant cholinergic deficits are evident in these patients; hence, appropriate treatment strategies can be initiated using anti-cholinesterase inhibitors.

Cholinesterase inhibitor drugs (ChEIs) improve cholinergically mediated cognitive and neuropsychiatric symptoms in PDD. Various randomized studies have shown the association between functional imaging and use of ChEIs to treat PDD (Kramberger et al., 2010). Increased regional cerebral glucose metabolism and blood flow has determined the positive as well as significant effects of ChEIs in PDD. Use of rivastigmine, donepezil, and galantamine has been most widely seen in studies conducted in this disease state, but use of tacrine has also been discussed in a few small studies. Rivastigmine and donepezil are now the most widely accepted and used medications for PDD, although the use of memantine has been discussed in the literature to some extent. Various studies (mostly RCTs) have shown an improvement in behavioral and psychotic symptoms (hallucinations) with the use of anti-cholinesterase inhibitors. (See Table 23.7 for a summary of published open-label and RCTs and case reports in patients with PDD.)

Rivastigmine The most widely used and approved medication for treatment of cognitive impairments associated with PDD is rivastigmine. Various randomized studies have shown the safety and efficacy of this medication in its ability to treat the disease state. Significant treatment differences have been noted in ADAS-cog and MMSE scales when the patient population with PDD was treated with rivastigmine. One of the largest RCTs conducted by Emre and Colleagues noted improvement in cognition by 2.1 points on the ADAS-cog scale as compared to the control group, which saw deterioration by 0.7 points. Similar improvements were noted on other cognitive assessment measures (ADCS-ADL, CDR, MMSE, and NPI) when this subset was treated with rivastigmine. Nausea, vomiting, worsening tremors, and death were noted in some instances. Various studies are underway evaluating the benefits of capsule formulation versus a transdermal patch.

Donepezil Donepezil is another widely used medication in clinical trials for the treatment of cognitive deficits associated with PDD, but regulatory authorities have not yet approved it. Treatment benefits have been assessed on the basis of various cognitive measures (ADAS-cog, CIBIC, NPI), and significant improvements have been reported. Several clinical trials are underway to confirm the safety and efficacy of donepezil in the management of PDD. Of particular interest is one of the largest clinical trials, by Dubois et al.; results are eagerly awaited.

Memantine Memantine is postulated to modulate the glutamatergic neuronal transmission and, hence, could potentially

Evidence-Based Pharmacologic Treatment of Dementia

569

Table 23.7 Summary of published open-label and randomized clinical trials and case reports in patients with PDD Study

Medications

Study duration Number of (weeks) subjects

Dubois et al. (2007)

Donepezil

24

550

Improvement in MMSE and CIBIC-plus. No significant changes in ADAS-cog, NPI, or motor symptoms.

Emre et al. (2004)

Rivastigmine

24

541

Improvement noted in ADAS-cog, MMSE, ADCS-ADL, NPI, and CDR.

Poewe et al. (2006)

Rivastigmine

24

334

Improvement in ADAS-cog, MMSE, and NPI. No change in motor symptoms.

Thomas et al. (2005)

Donepezil

20

40

Improvement on MMSE and NPI. No change in motor symptoms.

Dujardin et al. (2006)

Rivastigmine

24

28

Improvement noted in total MDRS score.

Giladi et al. (2003)

Rivastigmine

26

28

Improved ASAS-cog and attention component of MMSE.

Müller et al. (2006)

Donepezil

12

24

Improvement in MMSE. No change in Clinician Global Impression (CGI) or motor symptoms.

Rowan et al. (2007)

Donepezil

20

23

Improvements on power of attention and reaction time. No significant improvement in continuity of attention or cognitive reaction time.

Ravina et al. (2005)

Donepezil

10

22

Improvements on MMSE and CGI. No change in ADAS-cog or MDRS.

Leroi et al. (2004)

Donepezil

18

16

Improvement in memory component of MDRS. No change in MMSE.

Reading et al. (2001)

Rivastigmine

14

15

Improvement noted on MMSE and NPI.

Minett et al. (2003)

Donepezil

20

15

Improvement on MMSE after 20 weeks noted. Improvement in behavioral symptoms.

Aarsland et al. (2002)

Donepezil

20

14

Improvement on MMSE and CIBIC-plus.

Werber and Rabey (2001)

Donepezil and 26 tacrine

Main findings

11 (7 on tacrine, Improvement on ADAS-cog. No significant change in MMSE or 4 on donepezil) motor symptoms.

Fabbrini et al. (2002)

Donepezil

6

8

Improvement on PPRS. No change in MMSE.

Bergman and Lerner (2002)

Donepezil

6

6

Improvement on CGI and NPI. No change in MMSE.

Bullock and Cameron (2002) Rivastigmine

20–52

5

Improved cognition and visual hallucinations.

Kurita et al. (2003)

2–56

3

Improvement in hallucinations. Some improvement in cognition.

Donepezil

prevent the toxic effects of raised concentrations of glutamate. Memantine has been shown to be clinically efficacious in AD and VaD. Various small and large RCTs have been and are being conducted, but results from small RCTs have shown that, in PDD, memantine was well tolerated; results are limited due to a sample size, however (Aarsland et al., 2009). Results of larger RCTs are still awaited, and its potential use in combination with ChEIs is highly debated. One of the studies on the use of memantine and ChEIs reported enhanced neurotoxicity in the rat brain, so the use of this regimen needs further studies and clarification. Additional agents are in phase 2 and phase 3 trials, including pimavanserin, a 5-HT2A inverse agonist/ antagonist being studied for its effects in patients with PDD.

Pseudobulbar affect There is increasing recognition of pseudobulbar affect (PBA) among geriatric neurologic diseases and the diagnosis is being made more often, now that the first FDAapproved treatment Nuedexta (quindine sulfate 10 mg

and dextromethorphane HBr) is available for PBA. The typical PBA episode is about 45 seconds with an abrupt onset and end. It can be characterized as “laughter without mirth” or “crying without sadness.” Historically, several terms were been used to describe PBA: pathologic laughing and crying, emotional lability, emotional dyscontrol, emotional incontinence, excessive emotionality, poststroke emotionality, and so on. While families and professional caregivers are negatively affected by this behavior, the patient typically does not have a change in affect or active tearing when crying occurs. This lack of affective disturbance differentiates it from depression. Utilizing psychoactive agents in this subset of patients, who are often misdiagnosed as having depression can potentially have significant side effects and is best avoided. Center for Neurologic Study-Lability Scale (CNS-LS) is a sevenquestion validated scale (Moore et al., 1997; Smith et al., 2004; Phuong et al., 2009) that can provide a score for total PBA frequency and severity and possibly help in differentiating from depression symptoms.

Nuedexta In 2010, the FDA approved Nuedexta, a combination product containing dextromethorphan hydrobromide 20

570

Therapeutics for the Geriatric Neurology Patient

mg (an uncompetitive NMDA receptor antagonist and sigma-1 agonist) and quinidine sulfate 10 mg (a cytochrome P450 (CYP) 2D6 inhibitor) that is indicated for the treatment of PBA. Pivotal studies to support the effectiveness were performed in patients with underlying amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The typical starting dose is one capsule daily by mouth for 7 days after which 1 capsule is used every 12 hours if tolerated. As the quinidine content in Nuedexta is only one-tenth of the lowest dose of quinidine tablets, concomitant use with quinidine, quinine, or mefloquine is contraindicated. Avoid using this drug in patients with a history of quinidine, quinine or mefloquine-induced thrombocytopenia, hepatitis, hypersensitivity reactions to dextromethorphan, within 14 days of stopping an MAOI, prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, or heart failure, complete atrioventricular (AV) block without implanted pacemaker, patients at high risk of complete AV block and patients using concomitant drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine). The agent is used with caution in left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD). In patients with dizziness take precautions to reduce falls. SSRIs or tricyclic antidepressants increases the risk of serotonin syndrome, discontinue the SSRI if this occurs. Anticholinergic effects of quinidine can worsen myasthenia gravis and other sensitive conditions. The most common adverse reactions (incidence of ≥3% and twofold greater than placebo) in patients taking Nuedexta are diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased gamma-glutamyltransferase, and flatulence.

Conclusion Increasing geriatric neurologic diseases such as AD can make the US health-care system unviable. An aging population is a major risk factor for dementia, with more than 100 million individuals projected to have AD by 2050 (Alzheimer’s Disease International, 2010). Only five approved drugs for AD exist, and no FDA-approved medications are available for other dementias, except for the treatment of PBA. There is an urgent need for more clinical trials and effective medications.

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Evidence-Based Pharmacologic Treatment of Dementia

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Chapter 23.2 Immunotherapy for Alzheimer’s Disease Michael Grundman, Gene G. Kinney, Eric Yuen, and Ronald Black Introduction Alzheimer’s disease (AD) and other dementias affect approximately 36 million individuals worldwide. Unless successful treatments or preventives are found, it is expected that the number of individuals with dementia will increase to 66 million by the year 2030 and to 130 million by 2050 (Wimo and Prince, 2010). For an individual, the risk of developing AD doubles with every 5–6 years of advancing age (Ziegler-Graham et al., 2008), with some estimates of disease prevalence surpassing 40% after age 85 (Hebert et al., 2003). Once affected, patients with AD suffer an unrelenting decline of cognition associated with behavioral abnormalities, ultimately leading to loss of functional independence and death. There is an urgent need to discover and develop effective treatments and preventive strategies, both to reduce current AD morbidity and to preempt the predicted increase in disease prevalence as the world’s population ages. The pathologic hallmarks of AD include synaptic and neuronal loss, extracellular amyloid deposition, and intraneuronal neurofibrillary tangles. Extracellular amyloid deposition may be found (1) in neuritic plaques— amyloid plaques surrounded by dystrophic neurites, activated microglia, and gliosis; (2) in diffuse plaques— extracellular amyloid deposits without dystrophic neurites and gliosis; and (3) within cerebral blood vessels (cerebral amyloid angiopathy (CAA)). The major protein component of deposited amyloid is Aβ, a 40–42 amino acid peptide that is generated by the proteolytic processing of the amyloid precursor protein (APP). Soluble amyloid and amyloid deposits may play a pivotal initiating role in the development of AD. This hypothesis is based partly on the observation that certain autosomal dominant genetic mutations lead to overproduction of Aβ, amyloid deposition, and early onset of dementia. Additional genetic evidence for the importance of Aβ comes from studies of apolipoprotein E, a cholesterol carrier that is commonly expressed in three different allelic forms (ε2, ε3, and ε4) that differ from each other by a small number of critical amino acid substitutions. Individuals who carry the apolipoprotein E ε4 allele tend to develop amyloid plaques and CAA with associated clinical symptoms of dementia earlier than those without this allele, although at a later age than those with the autosomal-dominant forms of AD.

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The amyloid hypothesis posits that, in AD, the balance between the production and clearance of Aβ is disrupted, leading to a build-up of excess Aβ in the brain. The excess Aβ is toxic to neurons, contributes to tau hyperphosphorylation and tau pathology, and leads to progressive neurodegeneration, cognitive dysfunction, and functional impairment (Hardy and Selkoe, 2002; De Felice et al., 2008). If the hypothesis is correct, potential therapeutic approaches that lessen the imbalance between production and clearance and restore Aβ concentrations to normal levels may be successful. Toward this end, a number of therapeutic approaches are currently being evaluated both preclinically and in clinical trials. These include beta and gamma secretase inhibitors to reduce Aβ production and anti-Aβ immunotherapy to facilitate Aβ clearance.

Preclinical studies with anti-Aβ immunotherapy Understanding the progression of AD and the potential role of immunotherapy has been enhanced by transgenic mouse models of AD that express AD pathology similar to that of humans (Wilcock and Colton, 2009). Aβ is derived through cleavage of APP by beta and gamma secretase. In humans, familial autosomal-dominant AD is caused by mutations in the APP or presenilin genes, the latter of which express proteins that form gamma secretase. These mutations cause overexpression of Aβ. Transgenic mouse models of AD have been genetically engineered to overexpress human mutations in APP, presenilin 1, and/or presenilin 2, in order to generate amyloid-related pathologies, including amyloid deposition, synaptic loss, and dystrophic neurites. The PDAPP mouse, a transgenic mouse model that overexpresses mutant APP, was the first transgenic mouse reported to exhibit AD pathology (Games et al., 1995). This same mouse model was later utilized by Schenk et al. (1999), who discovered that immunizing PDAPP mice with full-length Aβ could reduce Aβ plaque burden, gliosis, and dystrophic neurites. Bard et al. (2000) later showed that monoclonal antibodies could similarly reduce Aβ pathology in transgenic mice through passive administration. Antibodies produced against the N-terminal regions of Aβ were found to be particularly efficacious for plaque clearance. It was further demonstrated that

Immunotherapy for Alzheimer’s Disease

antibody Fc-mediated activation of microglia facilitated this process. Transgenic mice often develop age- and Aβ-related behavioral deficits that resemble the dementia seen in humans. The behavioral deficits may precede Aβ deposition and formation of plaque (Comery et al., 2005). The latter suggests that soluble Aβ species may be important in causing or contributing to these behavioral deficits. The importance of nonplaque Aβ species is also highlighted by the rapid reversal of behavioral impairments with administration of some antibodies that bind only soluble A β and not fibrillar Aβ (Dodart et al., 2002; Kotilinek et al., 2002). Nevertheless, the potential importance of removing Aβ plaque cannot be discounted. Some investigators have found amelioration of dystrophic neurites in regions where plaque has been removed (Brendza et al., 2005; Serrano-Pozo et al., 2010). It also seems likely that various species of Aβ are in equilibrium, so the targeted removal of only soluble Aβ could lead to replenishment of this pool by Aβ present in plaques. Transgenic mice that have been immunized with Aβ or administered anti-Aβ antibodies show cognitive performance that is superior to that of control transgenic mice (Janus et al., 2000; Morgan et al., 2000). The effectiveness of anti-Aβ antibodies to reduce behavioral deficits in non-plaque-bearing transgenic mice may vary, depending on the species of Aβ to which the antibody binds, the Aβ epitope to which the antibody is directed, and the sequence and structure of the antibody (Basi et al., 2010). Partly because it is unclear whether plaque clearance, binding to soluble Aβ, or other factors may be most relevant for clinical efficacy, a sizeable number of antibodies that are purported to interact differentially with different Aβ species have been generated and are being studied in the clinic. Some transgenic mice treated with anti-Aβ antibodies developed brain microhemorrhages, particularly at high doses (Wilcock and Colton, 2009). It is possible that these microhemorrhages are related to Aβ clearance from amyloid-laden blood vessels. Some evidence indicates, however, that the temporal clearance of vascular amyloid and appearance of microhemorrhages may be a self-limited process, ultimately leading to restoration of vessel integrity (Schroeter et al., 2008).

Clinical experience with Aβ immunotherapy Several therapeutic approaches are currently being evaluated in clinical trials. Aβ immunotherapy can be divided into active and passive forms. Active immunotherapy refers to immunization with the Aβ peptide or fragments derived from it; passive immunotherapy

575

refers to the parenteral administration of anti-Aβ antibodies. The first agent to be used in active immunization was AN1792.

AN1792 Based on the striking results of Aβ immunotherapy in transgenic mice, clinical trials of active vaccination with full-length Aβ (AN1792) were initiated in 2000. In a phase 1, multiple ascending dose study lasting 84 weeks, 80 subjects were randomized to AN1792. Approximately 60% of subjects developed positive antibody responses. Clinical benefits were observed on the Disability Assessment for Dementia (DAD), evidenced by a slowing of decline in the treated group at week 84. One patient developed meningoencephalitis (ME) (diagnosed at autopsy after the patient expired 12 months later). This patient showed findings similar to Aβ immunization in transgenic mice (Nicoll et al., 2003), including extensive areas of cortex that had a lower-than-expected density of amyloid plaques that were devoid of dystrophic neurites and astrocytosis. In a subsequent phase 2 trial (Gilman et al., 2005), 300 patients were randomized to AN1792 and 72 patients to placebo. Dosing in the trial was halted due to the occurrence of ME in 6% of subjects in the active treatment group. However, patients continued to be followed for up to 12 months after dosing was stopped. Most patients in the trial received one or two doses. Approximately 20% of patients developed sufficient antibody responses to be considered antibody responders. No significant treatment differences were observed on most clinical endpoints at the end of 12 months. However, an apparent treatment benefit on the neuropsychological test battery (NTB) was observed in antibody responders (Figure 23.3a). In addition, in a subset of study subjects in whom CSF was obtained before and after treatment, CSF tau was reduced in antibody responder patients, compared to placebo patients. Unexpectedly, antibody responders showed greater reduction in brain volume compared to placebo, despite demonstrating better performance on the NTB. It is unclear whether this volume loss was due to amyloid plaque removal or other mechanisms, leading to fluid shifts from the brain parenchyma to the CSF spaces (Fox et al., 2005). Among those patients in the AN1792 studies who developed anti-Aβ antibodies, most generated antibodies to the N-terminal, or amino terminus of Aβ (Lee et al., 2005). By contrast, studies into the etiology of ME suggested that this side effect was likely caused by a proinflammatory T-cell response against the carboxy terminus of Aβ. Also, because ME was not observed in patients until after the addition of polysorbate 80 to the study drug formulation (added to enhance the solubility of the Aβ in solution), it seems possible that this addition may have altered the conformation of the full-length Aβ antigen, to

Therapeutics for the Geriatric Neurology Patient

(a)

Mean change from baseline on NTB after 1 year

0.10

Placebo

0.05

AN1792 Antibody Responders

(N = 36)

0.00 –0.05 –0.10 –0.15 –0.2 –0.25

(N = 48) p = 0.020

(b) 0

Mean change from baseline on DAD after ~ 4.5 years

576

Placebo

AN1792 Antibody Responders

–10

Figure 23.3 (a) AN1792 phase 2 study

–20 –30 –40 (N = 24) –50 –60

(N = 27)

–70

permit induction of this proinflammatory T-cell response (Schenk et al., 2005; Pride et al., 2008).

AN1792 follow-up studies A long-term follow-up study on the patients included in the AN1792 phase 1 study was reported by Holmes et al. (2008). They found that a number of subjects who had developed elevated titers during the initial study period had a high degree of plaque removal at autopsy, but nevertheless continued to show progressive dementia prior to death. This finding suggests that reducing Aβ may not be sufficient to halt the progressive neurodegeneration at the late stage of AD at which treatment was initiated. The authors suggested that although it is possible for Aβ to be an initiating factor in the neurodegenerative process, it may be less critical in fostering neurodegeneration later after other downstream pathologies (such as neurofibrillary pathology) are underway. Interestingly, among the autopsied subjects, the patients with the longest survival had the least amount of brain Aβ deposits. This raises the possibility that reduction in brain amyloid in patients may be a relatively slow process in immunized patients and that initiating treatment earlier and for a longer period of time when patients are either asymptomatic or have fewer cognitive deficits might be more effective. A follow-up study of the phase 2 AN1792 study was reported by Vellas et al. (2009). Subjects initially identified as antibody responders were compared with placebo-treated subjects approximately 4.5 years after the patients were immunized with AN1792. Most of the antibody responders who were tested (17/19) continued to have detectable antibody responses 4.5 years later, although at much lower levels than during the first year after their initial immunization. Consistent

p = 0.015

neuropsychological test battery (NTB) results showed an improvement on the nine-component NTB composite after 1 year in antibody responders, compared to the placebo group. Data from Gilman et al. (2005). (b) AN1792 follow-up study after approximately 4.5 years found that patients initially classified as antibody responders in the AN1792 phase 2 trial had less decline in activities of daily living as determined by the Disability Assessment for Dementia (DAD), compared with placebo-treated patients. Data from Vellas et al. (2009).

with the original AN1792 results, which showed a potential treatment effect on the NTB in antibody responders, less decline was seen on the DAD (Figure 23.3b), the Dependence Scale and Rey Auditory Verbal learning test, in the antibody responders, compared to the placebo group. The data support the possibility that even sustained, low levels of anti-Aβ antibodies could have long-term cognitive and functional benefits, and support the contention that earlier treatment for longer periods may be the most effective way to avert or lessen decline in patients with AD pathology.

Second-generation immunotherapies Because most patients developed N-terminal antibodies in response to AN1792 and ME is hypothesized to be related to a T-cell response against the carboxy terminus, novel, alternative approaches to immunotherapy are being tested. One approach is to actively immunize patients with Aβ immunogens that are comprised of small Aβ peptide fragments conjugated to carrier proteins. This approach utilizes Aβ peptide fragments that are of insufficient size to elicit a T-cell-specific immune response to Aβ while still allowing B-cells to generate antibodies against the small peptide fragment. The purpose of the carrier protein is to induce a T-helper response that promotes the generation of antibodies. A second approach is passive immunotherapy, wherein anti-Aβ antibodies are produced in modern bioreactors outside the human body and are parenterally administered. Both of these approaches are designed to capitalize on the possible benefits conferred by anti-Aβ antibodies while avoiding the potentially harmful Aβ directed T-cell responses that appear more likely to occur if the full-length Aβ peptide were administered (Schenk et al., 2005; Pride et al., 2008).

Immunotherapy for Alzheimer’s Disease

Passive versus active immunotherapy Active and passive immunization each has relative advantages and disadvantages (Table 23.8). Both methods should circumvent the activation of T cells and reduce the likelihood of ME, as observed with AN1792. With passive immunization, the administered antibodies can be tested and selected for their ability to bind specific Aβ epitopes to soluble or plaque forms of Aβ or to specific conformations of peptide. The dose can be specified or individualized based on patient characteristics. If adverse reactions occur, subsequent infusions can be stopped and the antibody can be cleared from the patient in accordance with its biologic half-life. With active immunization, not everyone will necessarily produce an optimal antibody response or even an adequate antibody response, and the response is polyclonal. Hence, the quantity and quality of the antibody response differ from patient to patient. This usually requires an adjuvant to induce an adequate antibody response, and the adjuvant itself may be associated with or contribute to adverse events. If an adverse event occurs, it may be difficult or impossible to turn off the immune response, and it may take a long time for antibody titers to drop, even if subsequent immunizations are not administered. The principal advantage of active immunization is that it does not require intravenous infusions (they are typically injected intramuscularly), it should be possible to administer the immunizations less frequently at a lower cost, and, if very safe, it would be more acceptable for prevention in preclinical AD or in a prodromal AD population, where the presence of raised antibody concentrations for 5–15 years or longer might be most beneficial. Passive immunization through subcutaneous dosing is yet another option if dosing regimens require long periods of administration to be effective. Subcutaneous dosing has been used in other chronic diseases that require long-term administration, such as interferon

577

beta-1b (Betaseron); glatiramer acetate (Copaxone), used for multiple sclerosis; and omalizumab (Xolair), used for asthma. A number of companies are now studying subcutaneous formulations of anti-Aβ monoclonal antibodies in AD and prodromal AD.

Mechanisms of anti-Aβ immunotherapy A number of hypotheses have been proposed to explain how anti-Aβ immunotherapy clears Aβ deposits from the brain. One possibility is that a small proportion of the peripherally administered anti-Aβ antibodies crosses the blood–brain barrier and induces the opsonization of Aβ aggregates. According to this proposal, activated microglia bind the anti-Aβ antibodies at their Fc region and phagocytize the Aβ and anti-Aβ antibody complexes via Fc receptor-mediated phagocytosis. While microglial activation may play an important role for some antibodies, microglial-independent mechanisms are also possible. Anti-Aβ antibody fragments (Fab) that lack the Fc domain necessary for microglial activation seem effective at removing plaques (Bacskai et al., 2002), as do anti-Aβ antibodies that have had their Fc function decreased through enzymatic deglycosylation (Wilcock et al., 2006). Active immunization in transgenic mice that lack functional Fc receptors is similarly capable of reducing plaque burden (Das et al., 2003). These findings suggest that “catalytic disaggregation” of Aβ plaques is a potential mechanism of anti-Aβ immunotherapy. This mechanism proposes that anti-Aβ antibodies bind amyloid fibrils and disrupt their tertiary structure. This then leads to solubilization of Aβ deposits and efflux of the soluble Aβ from the brain via perivascular pathways (Weller et al., 2009). According to a recent study, Aβ42 the form of Aβ that is typically found in plaques in AD patients, was increased in the cerebral blood vessels of some patients after immunization with AN1792 (Boche et al., 2008). This increase may be a transient phenomenon because it was not apparent in the patients with the longest follow-up

Table 23.8 Comparison of passive and active immunotherapy Passive

Active

Drug product

Peripherally administered anti-Aβ antibodies that are uniform Aβ antigen induces anti-Aβ titers by the patient’s native over time, with well-characterized Aβ epitope specificity immune system; often includes carrier proteins and added adjuvants; polyclonal antibody response changes over time within patients and variable between patients

Treatment frequency

Dependent in part on the half-life of the antibody; may range from every few days to every few months

Route

Typically intravenous or subcutaneous

Relatively few administrations generally required to induce and maintain anti-Aβ titers Typically intramuscular or subcutaneous

Control over antibody Antibody concentrations more readily controllable due to titers strong dose dependence

Antibody concentrations vary, depending on patient’s immune response

Ability to reduce Antibody levels decline in relation to antibody half-life when antibody exposure if antibody administration is stopped; plasma exchange is an adverse events occur option

Anti-Aβ antibody immune response more long lasting; titers may remain elevated for years

Therapeutics for the Geriatric Neurology Patient

578

after treatment with AN1792, suggesting that, over time, Aβ was cleared from both the parenchyma and cerebral vasculature. The data are consistent with the hypothesis that anti-Aβ immunization solubilizes plaque Aβ42, which then at least partially exits the brain via the perivascular pathway. The “peripheral sink” hypothesis is yet another proposed mechanism to explain how anti-Aβ immunotherapy may clear Aβ deposits from the brain. In this model, peripheral anti-Aβ antibodies bind circulating Aβ; this then leads to a shift in the Aβ concentration gradient between brain and blood, with a net increase in Aβ efflux from the brain (DeMattos et al., 2001).

A phase 1 study determined a half-life for bapineuzumab of 24 days (Black et al., 2010), permitting an IV infusion schedule every 13 weeks. A bapineuzumab phase 2, multiple ascending dose trial that enrolled 234 subjects (124 on bapineuzumab and 110 on placebo) did not show statistically significant benefits over 78 weeks when analyzed by individual dose cohorts, but a number of exploratory analyses were promising: When all the dose cohorts were combined, favorable treatment trends were observed on the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAScog) (Figure 23.4) and NTB (Salloway et al., 2009). Favorable treatment differences were also observed on the ADAS-cog and DAD in study completers (subjects who received all doses of bapineuzumab during the study). Exploratory analyses in ApoE ε4 noncarriers also suggested potential treatment benefits on a number of cognitive and functional endpoints. In contrast to the results in the AN1792 study, however, bapineuzumab-treated ApoE ε4 noncarriers demonstrated less brain volume loss on MRI compared to placebo-treated patients, paralleling the clinical findings. In a CSF substudy among patients in whom CSF was obtained before and after treatment, there was a trend (p = 0.056) for reduced CSF phosphorylated tau protein (phosphotau) in bapineuzumab-treated subjects compared to placebo (Figure 23.5). A smaller, phase 2 bapineuzumab clinical trial (n = 28) was conducted in patients who also received a series of carbon-11-labelled Pittsburgh compound B, positron emission tomography (PIB PET) scans during their course of treatment (Rinne et al., 2010). PIB PET was used as a measure of cortical fibrillar amyloid-β load. Compared to placebo, bapineuzumab-treated patients showed an approximate 25% reduction in amyloid load as measured by PIB PET over the course of the 78-week study

Clinical experience with passive immunization Aβ immunotherapy can be divided into active and passive forms. Passive immunotherapy refers to the parenteral administration of anti-Aβ antibodies in contrast to active immunotherapy, which refers to immunization with the Aβ peptide or fragments derived from it. The largest published data is on bapineuzumab, while a large number of other immunotherapies are in clinical trials. Tables 23.9 and 23.10 summarize these.

Bapineuzumab Bapineuzumab is a humanized monoclonal antibody directed against the N-terminus of Aβ. N-terminal antibodies have been shown to bind both deposited and soluble Aβ to reduce amyloid burden and plaques and to produce beneficial effects on dystrophic neurites, synapses, and behavior in transgenic mice (Bard et al., 2000; Bussiere et al., 2004; Buttini et al., 2005; Games et al., 2006; Shankar et al., 2008; Basi et al., 2010). It is therefore hypothesized that bapineuzumab should similarly bind to Aβ in the brain, facilitate its removal, and result in beneficial clinical effects.

mITT Population

Completers

(a)

Change from baseline

–2 –4 –6 –8 –10 –12

2

Placebo Bapineuzumab

0 Change from baseline

Figure 23.4 Bapineuzumab

(b) 2

Rx difference at week 78 = 2.3 p = 0.078 0

11

24 37 50 Weeks

63

78

Placebo Bapineuzumab

0 –2 –4 –6 –8

–10 –12

Rx difference at week 78 = 4.3 p = 0.003 0

11

24 37 50 Weeks

63

78

phase 2 exploratory analyses for four combined dose cohorts in (a) the modified intent-to-treat (mITT) and (b) the completer populations. Figure shows estimated mean change from baseline over time on Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog). Error bars represent one standard error. A positive change from baseline represents improvement. The p values are not adjusted for multiple comparisons. Source: Salloway et al. (2009). Reproduced with permission of Lippincott Williams & Wilkins.

Change in CSF phospho-tau from baseline

Immunotherapy for Alzheimer’s Disease

2 0 –2 –4 –6 Placebo (n = 15)

–8 –10 –12 –14 –16

Bapineuzumab (n = 20)

p = 0.056

Figure 23.5 One-year change from baseline in CSF phospho-tau

(pg/mL) in bapineuzumab- and placebo-treated groups from bapineuzumab phase 2 clinical trial 201. Graph shows mean change (+/− SE) and p value from analysis of covariance model. Source: Salloway et al. (2009). Reproduced with permission of Lippincott Williams & Wilkins.

(Figure  23.6). The amyloid reduction (Figure 23.7) was apparent in all six brain regions prespecified for analysis, and the treatment difference between the bapineuzumabtreated group and placebo group increased over the course of the study. Some of the patients in the study also had CSF collected before and after treatment. Post hoc analyses combining the CSF phospho-tau and total tau data from both bapineuzumab phase 2 studies demonstrated a lowering of CSF phospho-tau (p < 0.05) in the treated group versus placebo group (Blennow et al., 2010). The lowered phospho-tau would appear to support potential downstream physiologic effects for bapineuzumab beyond the reduction of amyloid and would be consistent with downstream effects on tau as posited by the amyloid cascade hypothesis (Hardy and Selkoe, 2002) and seen in preclinical models (Oddo et al., 2004, 2006; De Felice et al., 2008) and at autopsy in AN1792

immunotherapy-treated patients (Boche et al., 2010b; Serrano-Pozo et al., 2010). Collectively, these phase 2 results, including the possible treatment benefits observed, the slower brain atrophy on MRI in ApoE ε4 noncarriers, the reduced phospho-tau in CSF, and reduced brain amyloid load as measured by PIB PET, argue for further testing of bapineuzumab in phase 3 pivotal trials. The current phase 3 bapineuzumab program is designed to evaluate clinical efficacy, safety, and evidence of disease modification based on a combination of clinical and biomarker (Liu et al., 2010). Bapineuzumab is currently being tested in four phase 3 trials of 18 months’ duration. More than 4000 subjects worldwide are participating. ApoE ε4 carriers and noncarriers are being evaluated in separate trials. The presumption is that if clinical benefits with bapineuzumab are sustained over 18 months with evidence of slowed disease progression on cognitive and functional measures, and if alterations in AD-related biomarkers (such as CSF phospho-tau and PIB PET) are confirmed, these findings would provide compelling evidence for disease modification. [Note: The bapineuzumab phase 3 program has concluded since the original submission of this chapter. In the North American phase 3 studies both in ApoE 4 carriers and non-E4 carriers, no significant differences were found on the primary clinical endpoints. In carriers, the 0.5 mg/kg dose was associated with reductions in amyloid plaque accumulation and CSF p-tau. In non-carriers, the 1.0 mg/kg dose was associated with a reduction in CSF p-tau. No significant differences in brain volume were observed in either study. Amyloid-related imaging abnormalities (ARIA) increased with bapineuzumab dose and number of ApoE ε4 alleles. The investigation team concluded that in mild-to-moderate AD, clinical efficacy was not demonstrated despite evidence of target engagement and changes in a downstream biomarker. Intervention earlier in the course of AD may be necessary to demonstrate clinical benefits with antiamyloid immunotherapeutic agents such as bapineuzumab (Salloway et al., in press).]

time in mean ¹¹C-PIB PET for bapineuzumaband placebo-treated groups. Data shown are least squares means and 95% CIs. Difference between patients in the placebo group and those in the bapineuzumab group at week 78 = −0.24 (p = 0.003). PiB = Pittsburgh compound B. Source: Rinne et al. (2010). Reproduced with permission from Elsevier.

Estimated mean change from baseline in mean 11C-PiB

0.4

Figure 23.6 Estimated change from baseline over

579

Placebo Bapineuzumab

0.3 0.2 0.1 0 –0.1 –0.2 Baseline

20

45 Week

78

580

Therapeutics for the Geriatric Neurology Patient

Bapineuzumab treated patients

Screen (a)

Week 78 –0.09

Screen (b)

Week 78 –0.33 4.0

0.06

0.25

(d)

Placebo treated patients

(c)

0.0 11C-PIB PET images in two bapineuzumab-treated (a, b) and two placebo-treated (c, d) patients. Average 11C-PIB PET changes from baseline to week 78 are shown at the top center of each panel for each patient (a–d). The scale bar shows the PiB uptake ratios relative to the cerebellum. Source: Rinne et al. (2010). Reproduced with permission from Elsevier. (For a color version, see the color plate section.)

Figure 23.7

In addition to bapineuzumab IV, a subcutaneous formulation of bapineuzumab, administered monthly, is being studied in mild-to-moderate AD (NCT01254773).

Vasogenic edema with anti-Aβ immunotherapy An intriguing side effect was also observed on brain MRI in some of the study participants of the phase 2 study (Salloway et al., 2009). In about 10% of patients, cerebral hyperintensities on the FLAIR MRI sequence appeared after dosing that resolved when dosing was stopped (Figure 23.8). Some of the patients were eventually able to be redosed at lower doses after the MRI abnormalities resolved without recurrence. Radiographically, the findings appeared to resemble vasogenic edema (VE), or excess brain tissue water. In some patients, the Predose

7 weeks

VE was asymptomatic and detectable only by MRI; in others, transient symptoms such as headache and confusion were noted. VE occurred with greater incidence in ApoE ε4 carriers and patients exposed to higher doses of bapineuzumab. The cause of VE in immunotherapy-treated patients is unknown, but it is interesting to speculate about the potential mechanisms. One possibility is that VE is related to rapid clearance or mobilization of Aβ. The association of VE with higher doses in the bapineuzumab studies supports this possibility. Another possibility is that rapid mobilization of amyloid from the parenchyma into perivascular drainage pathways may overload the capacity of the drainage system, with resulting extravasation of fluid (Boche et al., 2010a). Yet another possibility is that direct removal of Aβ from cerebral 13 weeks

19 weeks

58 weeks

Figure 23.8 MRI scans from a 69-year-old woman with vasogenic edema (VE) after

treatment with bapineuzumab 1.0 mg/kg IV. She remained asymptomatic despite the appearance of multiple areas of VE evident on the MRI. The VE was apparent on MRI by 7 weeks after her first infusion and resolved by 19 weeks. The patient was redosed at 0.5 mg/kg of bapineuzumab IV and followed for more than 2 years without recurrence of VE. Source: Salloway et al. (2009). Reproduced with permission of Lippincott Williams & Wilkins.

Immunotherapy for Alzheimer’s Disease

vessel walls results in increased vascular permeability. Such a mechanism could explain the occurrence of microhemorrhages observed on T2* MRI sequences in some VE patients (Sperling et al., 2009). Presumably, if vascular Aβ removal was sufficiently robust, the increased permeability of the vessel wall might permit some red cells to leak out along with the fluid. ApoE ε4 carriers are known to have more CAA than noncarriers (Greenberg et al.. 1995). The greater risk of VE in ApoE ε4 carriers in the bapineuzumab phase 2 trials (Salloway et al., 2009) supports the possibility that more severe vascular amyloid burden (CAA) at baseline may be a contributing risk factor to VE. The greater amyloid burden in the vasculature of ApoE ε4 carriers at baseline could promote increased vascular permeability in treated patients when the vascular amyloid is removed. It is also possible that a focal inflammatory component may contribute to VE. Reports of spontaneous VE in patients with CAA, some of whom showed inflammatory changes, support this possibility (Oh et al., 2004; Kinnecom et al., 2007; Lim et al., 2008). Lastly, if it is true that vascular Aβ, amyloid plaque, and soluble Aβ are in equilibrium with each other, VE in the setting of immunotherapy might be mediated by accelerated Aβ clearance relative to Aβ production. In this case, other amyloid-lowering treatments in addition to immunotherapy, such as lowering Aβ production and deposition, might also induce VE by tipping the balance between Aβ deposition and clearance in favor of Aβ clearance.

Other passive immunotherapies in clinical development Little long-term data from immunotherapy trials other than bapineuzumab have been published to date, but a large number of other immunotherapies are in clinical trials. Tables 23.9 and 23.10 summarize these. Solanezumab is the human analog of the murine antibody 266 (Siemers et al., 2010). It is a monoclonal antibody that binds to the mid-domain of Aβ and is thought to be

581

selective for soluble Aβ rather than deposited Aβ In contrast to N-terminal antibodies, which, at least in part, are thought to clear Aβ through microglial phagocytosis, it is proposed that solanezumab may promote Aβ clearance from the brain by altering the equilibrium of soluble Aβ between the central nervous system and the periphery (see the peripheral sink hypothesis discussed earlier). Results for a single-dose phase 2 study in mild-to-moderate AD patients showed a significant dose-dependent increase in plasma Aβ and a trend toward increased CSF Aβ with a solanezumab dose. As expected in a single-dose study, no significant changes in cognition were observed (Siemers et al., 2010). Two phase 3 clinical trials are underway to study the efficacy of solanezumab in patients with mild-to-moderate AD (NCT00905372, NCT00904683). The primary cognitive and functional outcomes in these trials are the ADAS-cog and ADCS-ADL. Solanezumab is being infused intravenously every 4 weeks for 80 weeks. Each trial has approximately 1000 patients enrolled. [Note: The solanezumb phase 3 program has concluded since the original submission of this chapter. Solanezumab did not show a statistically significant difference between treatment and placebo after 18 months of treatment in either study on ADAS or ADCS-ADL. In a prespecified pooled analysis of the studies, solanezumab showed a significant reduction in the rate of decline compared to placebo in mild subjects (Vellas et al., 2013). Additional studies are planned.] Ponezumab (PF-04360365) is a humanized, monoclonal antibody that binds to amino acids 33–40 at the C terminus of Aβ (Bednar, 2009). It is an IgG2 antibody that has two site mutations in the Fc region designed to minimize monocyte activation, complement activation, and Aβ— dependent cell-mediated cytotoxicity. Preliminary results from single-dose IV infusion studies found a dose-dependent increase in plasma Aβ and an increase in CSF Aβ at the 10 mg/kg dose. Ponezumab CSF concentrations were measurable in only two of eight patients at the highest

Table 23.9 Passive anti-Aβ immunotherapies in clinical trials Company

Product

Phase

Aβ epitope

NCT # on clinicaltrials.gov

Janssen Alzheimer Immunotherapy/Pfizer

Bapineuzumab IV (AAB-001)

3

N-terminus

NCT00575055; NCT00574132; NCT00667810; NCT00676143

Janssen Alzheimer Immunotherapy/Pfizer

Bapineuzumab SC

2

N-terminus

NCT00663026; NCT01254773

Janssen Alzheimer Immunotherapy/Pfizer

AAB-003

1

N-terminus

NCT01193608

Lilly

Solanezumab (LY2062430) IV

3

Central domain

NCT00905372; NCT00904683

Pfizer

PF-04360365 IV Ponezumab

2

C-terminus

NCT00722046

Roche/Morphosys

RG1450 IV gantenerumab

2

N-terminus and central domain

NCT00531804 NCT00736775; NCT00997919

Genentech/AC Immune

Anti-Aβ (MABT5102A) IV

1

Conformational

Glaxo-SmithKline

GSK933776 IV

1

Not disclosed

NCT00459550

Baxter

Intravenous immunoglobulin (IVIG); gammaguard)

3

Mixed

NCT00299988; NCT00818662

Octapharma

IVIG (Octagam)

2

Mixed

NCT00812565

582

Therapeutics for the Geriatric Neurology Patient

Table 23.10 Active anti-Aβ immunotherapies in clinical trials Company

Product

Phase

Aβ epitope

NCT # on clinicaltrials.gov

Janssen Alzheimer Immunotherapy/Pfizer

ACC-001

2

N-terminus

NCT00498602; NCT00479557; NCT00752232; NCT01284387; NCT01227564

Novartis/Cytos AG

CAD106

2

N-terminus Ab 1–6

NCT00795418; NCT00956410; NCT01023685

Glaxo-SmithKline/Affiris

Affitope AD1/AD2

1

N-terminus mimetic Ab 1–6

NCT00495417; NCT00633841; NCT01117818 (early AD); NCT01093664; NCT00711321; NCT00711139

Merck

V950

1

Multiepitope

NCT00464334

United Biomedical

UB 311

1

N-terminus 1–14

NCT00965588; NCT01189084

AC Immune

ACI-24

1

N-terminus 1–15

dose tested (10 mg/kg), suggesting limited CNS penetration (Zhao et al., 2010). Multiple ascending dose studies of ponezumab with different dosing regimens are ongoing, with the frequency of administration ranging from monthly to every 90 days (NCT00722046, NCT00945672). Gantenerumab (R-1450) is a monoclonal antibody that has completed a multiple ascending dose study in patients with AD (NCT00531804). Two subcutaneous doses of gantenerumab are also now being studied in a 2-year study in patients with prodromal AD (NCT01224106). Inclusion criteria include a history of memory loss and MMSE > 24. A substudy is evaluating change in brain amyloid imaging with PET. Doses are administered every 4 weeks for 104 weeks. The primary outcome of the study is the change on the CDR sum of boxes. Secondary clinical outcomes include the ADAS-cog and the Functional Activities Questionnaire. MABT-5102A, a monoclonal antibody also targeting Aβ, recently completed a phase 1 study in AD with an IV formulation (NCT00736775), as well as a phase 1 study with a subcutaneous formulation in younger healthy volunteers (NCT00997919). GSK-933776 is an anti-Aβ antibody that recently completed single- and multiple-dose phase 1 studies (NCT00459550). Beyond monoclonal antibodies, passive immunotherapy utilizing intravenous immunoglobulin (IVIG) is being tested (Dodel et al., 2010). The primary hypothesis behind this polyclonal approach is that IVIG contains naturally occurring autoantibodies that are specific for Aβ. IVIG could also have effects in AD by modulating the immune system independently of Aβ-specific antibodymediated activity. Promising results from a small study with IVIG have been published (Relkin, 2008). A phase 3, 18-month trial with IVIG involving more than 360 AD

patients has recently concluded. In this trial, subjects were randomly assigned to receive intravenous infusions with either two doses of IGIV or placebo every 2 weeks for 70 weeks (36 infusions). The primary outcomes of the study were cognitive and global function. Like bapineuzamab and solanezumab, IVIG failed to reach statistically significant difference from placebo on cognitive measures after 18 months of treatment.

Active immunotherapies in clinical development ACC-001 is a second-generation active immunotherapy in which an N-terminal fragment of Aβ is conjugated to a carrier protein (Pride et al., 2008). The concept behind this vaccine construct is that it should be capable of generating anti-Aβ antibodies, while not inducing specific anti-Aβ T-cell responses, thought to be responsible for the ME observed with AN1792. The short N-terminal Aβ fragment is of insufficient length to be bound by MHC class 1 or class 2 molecules required for an anti-Aβ T-cell response. Phase 2 studies of ACC-001 in mild-to-moderate AD and in early AD are in progress (NCT00479557, NCT01284387, NCT01227564). ACC-001 is administered through IM injections. Inclusion criteria for the early AD trial, a 2-year study, include a change in cognition, a global CDR rating of 0.5, a MMSE > 25, and the presence of amyloid detected on a PET scan. Reducing the amyloid burden as determined by PET is the primary outcome (NCT01227564). Another active immunization approach is based on affitopes, in which short peptides that mimic fragments of native Aβ1-42, but are not identical to it, are used as the antigenic component. Affitopes AD-01 and AD-02 target the N-terminal Aβ fragment (Schneeberger et al., 2009).

Immunotherapy for Alzheimer’s Disease

Affitope AD-02 is currently in phase 2, being studied in a 1-year clinical trial in early AD (MMSE > 20). Entrance criteria include a memory deficit and hippocampal atrophy. The primary clinical outcomes are change in the modified ADAS-cog and ADCS-ADL (NCT01117818). CAD-106 is a vaccine in which the Aβ1–6 peptide is conjugated to the Qβ virus-like particle. It is currently in phase 2 in mild-to-moderate AD (NCT01097096). It is being administered with repeated IM injections over 90 weeks. The study calls for testing two different doses, with two different adjuvants to evaluate anti-Aβ-specific antibody responses. V-950 is a multiepitope anti-Aβ peptide fragment vaccine (Savage et al., 2010). It is being studied in a dose-escalating study in which multiple Aβ fragments are conjugated to the outer membrane complex of Neisseria meningitidis (OMPC) as a protein carrier. They are administered with an aluminum-containing adjuvant with or without ISCOMATRIX, an adjuvant containing saponin, cholesterol, and phospholipids (NCT00464334). ACI-24 is a vaccine that contains Aβ1–15 embedded within a liposomal surface. ACI-24 is designed to stimulate the patient’s immune system to produce beta-sheet conformation-specific antibodies that prevent plaque deposition or enhance clearance of plaques (Muhs et al., 2007). ACI-24 entered a phase 1 clinical trial in 2009 (AC Immune website). UB-311 is a vaccine in which the immunogen Aβ1–14 is associated with the UBITh peptide (Wang et al., 2007). A small phase 1 study to evaluate the safety and immunogenicity of UB-311 is ongoing (NCT01189084; NCT00965588).

Future directions Based on the delay between amyloid deposition in AD in relation to clinical symptoms, it seems possible that treating earlier in the course of AD for a longer period of time may provide greater benefits than those seen to date. Some scientists and clinicians have argued that amyloid is only an initiating factor in AD, and intervening in mildto-moderate patients with advanced neurofibrillary and synaptic pathology may be too late. There is circumstantial neuropathologic and amyloid imaging evidence that amyloid may be deposited up to 15 years prior to diagnosis (Rowe et al. 2010). Assuming this is correct, starting immunotherapy treatment earlier in the disease course may be advantageous. Prior MCI trials were unsuccessful, in part, due to the clinical heterogeneity of the enrolled population (Grundman et al., 2006); for example, a significant percentage of patients have demonstrated the absence of amyloid deposition in recent MCI cohorts that have undergone amyloid imaging (Jack et al., 2009; Rowe

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et al., 2010). The finding that donepezil showed a positive treatment difference in MCI subjects who were ApoE ε4 carriers suggests that some treatments may be successful at the stage of MCI if a more definitive subgroup with AD could be identified (Petersen et al., 2005). The current availability of PET ligands that can detect brain amyloid deposits (Klunk et al. 2004; Clark et al. 2011) and Aβ assays that can measure reduced CSF Aβ in patients in the prodromal or preclinical stage of the disease (Shaw et al., 2009) provide important opportunities for future research. Immunotherapy may be most efficacious if started earlier and Aβ is removed during the preclinical and prodromal phases of the illness when downstream pathology, synaptic loss, and clinical symptoms are less advanced. Despite the apparent theoretical advantages that should accrue by treating patients earlier, patients at the very early clinical stage of AD are more difficult to diagnose and progress more slowly on clinical scales. Trials for prodromal AD will undoubtedly require different inclusion criteria, more follow-up time, and possibly different outcome measures than those classically used in mild-to-moderate AD trials (Aisen et al., 2011). Nevertheless, a number of immunotherapy clinical trials are just now beginning to evaluate patients with prodromal AD. The convergence of improved diagnostics and earlier diagnosis with secondgeneration immunotherapies suggests cautious optimism that timely and effective disease-modifying AD treatments may soon be achievable.

References Aisen, P.S., Andrieu, S., et al. (2011) Report of the task force on designing clinical trials in early (predementia) AD. Neurology, 76 (3): 280–286. Bacskai, B.J., Kajdasz, S.T., et al. (2002) Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci, 22 (18): 7873–7878. Bard, F., Cannon, C., et al. (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med, 6 (8): 916–919. Basi, G.S., Feinberg, H., et al. (2010) Structural correlates of antibodies associated with acute reversal of amyloid beta-related behavioral deficits in a mouse model of Alzheimer disease. J Biol Chem, 285 (5): 3417–3427. Bednar, M.M. (2009) Anti-amyloid antibody drugs in clinical testing for Alzheimer’s disease. IDrugs, 12 (9): 566–575. Black, R.S., Sperling, R.A., et al. (2010) A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Alzheimer Dis Assoc Disord, 24 (2): 198–203. Blennow, K., Zetterberg, H., et al. (2010) Immunotherapy with bapineuzumab lowers CSF tau protein levels in patients with Alzheimer’s disease. Alzheimers Dement, 6 (4): S134–S135. Boche, D., Zotova, E., et al. (2008) Consequence of Aβ immunization on the vasculature of human Alzheimer’s disease brain. Brain, 131 (Part 12): 3299–3310.

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Boche, D., Denham, N., et al. (2010a) Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer’s disease pathogenesis. Acta Neuropathol, 120 (3): 369–384. Boche, D., Donald, J., et al. (2010b) Reduction of aggregated tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer’s disease. Acta Neuropathol, 120 (1): 13–20. Brendza, R.P., Bacskai, B.J., et al. (2005) Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest, 115 (2): 428–433. Bussiere, T., Bard, F., et al. (2004) Morphological characterization of Thioflavin-S-positive amyloid plaques in transgenic Alzheimer mice and effect of passive Abeta immunotherapy on their clearance. Am J Pathol, 165 (3): 987–995. Buttini, M., Masliah, E., et al. (2005) Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer’s disease. J Neurosci, 25 (40): 9096–9101. Clark, C.M., Schneider, J.A., et al. (2011) Use of florbetapir-PET for imaging beta-amyloid pathology. J Am Med Assoc, 305 (3): 275–283. Comery, T.A., Martone, R.L., et al. (2005) Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci, 25 (39): 8898–8902. Das, P., Howard, V., et al. (2003) Amyloid-beta immunization effectively reduces amyloid deposition in FcRγ −/− knock-out mice. J Neurosci, 23 (24): 8532–8538. De Felice, F.G., Wu, D., et al. (2008) Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging, 29 (9): 1334–1347. DeMattos, R.B., Bales, K.R., et al. (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA, 98 (15): 8850–8855. Dodart, J.C., Bales, K.R., et al. (2002) Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci, 5 (5): 452–457. Dodel, R., Neff, F., et al. (2010) Intravenous immunoglobulins as a treatment for Alzheimer’s disease: rationale and current evidence. Drugs, 70 (5): 513–528. Fox, N.C., Black, R.S., et al. (2005) Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology, 64 (9): 1563–1572. Games, D., Adams, D., et al. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature, 373 (6514): 523–527. Games, D., Buttini, M., et al. (2006) Mice as models: transgenic approaches and Alzheimer’s disease. J Alzheimers Dis, 9 (3 Suppl.): 133–149. Gilman, S., Koller, M., et al. (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64 (9): 1553–1562. Greenberg, S.M., Rebeck, G.W., et al. (1995) Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol, 38 (2): 254–259. Grundman, M., Petersen, R.C., et al. (2006) Alzheimer’s association research roundtable meeting on mild cognitive impairment: what have we learned? Alzheimers Dement, 2 (3): 220–233. Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 297 (5580): 353–356.

Hebert, L.E., Scherr, P.A., et al. (2003) Alzheimer disease in the U.S. population: prevalence estimates using the 2000 census. Arch Neurol, 60 (8): 1119–1122. Holmes, C., Boche, D., et al. (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet, 372 (9634): 216–223. Jack, C.R., Jr, Lowe, V.J., et al. (2009) Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain, 132 (Part 5): 1355–1365. Janus, C., Pearson, J., et al. (2000) A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature, 408 (6815): 979–982. Kinnecom, C., Lev, M.H., et al. (2007) Course of cerebral amyloid angiopathy-related inflammation. Neurology, 68 (17): 1411–1416. Klunk, W.E., Engler, H., et al. (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol, 55 (3): 306–319. Kotilinek, L.A., Bacskai, B., et al. (2002) Reversible memory loss in a mouse transgenic model of Alzheimer’s disease. J Neurosci, 22 (15): 6331–6335. Lee, M., Bard, F., et al. (2005) Abeta42 immunization in Alzheimer’s disease generates Abeta N-terminal antibodies. Ann Neurol, 58 (3): 430–435. Lim, S.Y., Wesley Thevathasan, A., et al. (2008) Vasogenic oedema with no mass lesion. J Clin Neurosci, 15 (9): 1048, 1075–1076. Liu, E., Black, R., et al. (2010) Bapineuzumab phase 3 trials in mildto-moderate Alzheimer’s disease: trial design for a potential disease modifying therapy. J Nutr Health Aging, 14 (2): S18. Morgan, D., Diamond, D.M., et al. (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature, 408 (6815): 982–985. Muhs, A., Hickman, D.T., et al. (2007) Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci USA, 104 (23): 9810–9815. Nicoll, J.A., Wilkinson, D., et al. (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med, 9 (4): 448–452. Oddo, S., Billings, L., et al. (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron, 43 (3): 321–332. Oddo, S., Vasilevko, V., et al. (2006) Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem, 281 (51): 39413–39423. Oh, U., Gupta, R., et al. (2004) Reversible leukoencephalopathy associated with cerebral amyloid angiopathy. Neurology, 62 (3): 494–497. Petersen, R.C., Thomas, R.G., et al. (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med, 352 (23): 2379–2388. Pride, M., Seubert, P., et al. (2008) Progress in the active immunotherapeutic approach to Alzheimer’s disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis, 5 (3–4): 194–196. Relkin, N.R. (2008) Current state of immunotherapy for Alzheimer’s disease. CNS Spectr, 13 (10 Suppl. 16): 39–41.

Immunotherapy for Alzheimer’s Disease

Rinne, J.O., Brooks, D.J., et al. (2010) 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol, 9 (4): 363–372. Rowe, C.C., Ellis, K.A., et al. (2010) Amyloid imaging results from the Australian imaging, biomarkers and lifestyle (AIBL) study of aging. Neurobiol Aging, 31 (8): 1275–1283. Salloway, S., Sperling, R., et al. (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology, 73 (24): 2061–2070. Salloway, S., Sperling, R., et al. Bapineuzumab phase 3 trial results in mild to moderate Alzheimer’s disease. NEJM, (In press.) Savage, M.J., Wu, G., et al. (2010) A novel multivalent Abeta peptide vaccine with preclinical evidence of a central immune response that generates antisera recognizing a wide range of Abeta peptide species. Alzheimers Dement, 6 (4): S142. Schenk, D., Barbour, R., et al. (1999) Immunization with amyloidbeta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400 (6740): 173–177. Schenk, D.B., Seubert, P., et al. (2005) A beta immunotherapy: lessons learned for potential treatment of Alzheimer’s disease. Neurodegener Dis, 2 (5): 255–260. Schneeberger, A., Mandler, M., et al. (2009) Development of AFFITOPE vaccines for Alzheimer’s disease (AD)—from concept to clinical testing. J Nutr Health Aging, 13 (3): 264–267. Schroeter, S., Khan, K., et al. (2008) Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci, 28 (27): 6787–6793. Serrano-Pozo, A., William, C.M., et al. (2010) Beneficial effect of human anti-amyloid-beta active immunization on neurite morphology and tau pathology. Brain, 133 (Part 5): 1312–1327. Shankar, G.M., Li, S., et al. (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med, 14 (8): 837–842. Shaw, L.M., Vanderstichele, H., et al. (2009) Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol, 65 (4): 403–413. Siemers, E.R., Friedrich, S., et al. (2010) Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single

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Chapter 24 Geriatric Psychopharmacology Sandra A. Jacobson University of Arizona College of Medicine-Phoenix, Banner Sun Health Research Institute and Cleo Roberts Center for Clinical Research, Sun City, AZ, USA

Summary • Treatment effectiveness depends on correct diagnosis, use of an effective drug, and persistence with the therapeutic trial until achievement of the desired effect. • Differences among age peers involves both pharmacokinetic and pharmacodynamic differences. • Pharmacokinetics: the way drugs move through the body. It depends on absorption, distribution, metabolism, and excretion as well as drug half-life. • Pharmacodynamics: the effect of the drug at the receptor. Variables include receptor number and affinity, signal transduction, cellular response, and homeostatic regulation. • The pharmacodynamics, drug interactions, adverse effects, indications, and clinical uses of antipsychotics, antidepressants, anxiolytics, sedatives, and mood stabilizers are reviewed. • Definitions and treatments for anxiety disorders and substance use disorders are reviewed. For both, initial treatments should be nonpharmacologic.

Introduction: psychopharmacology and aging The practice of geriatric psychopharmacology is significantly complicated by the interplay of aging, disease, and polypharmacy. Partial treatment of syndromes is common and often results in formes frustes presentations. Although periodic review of medications is actually the purview of the patient’s primary care provider, it is not uncommon to find that the patient suffers from neurologic symptoms (such as cognitive impairment or ambulation difficulty) that are actually caused by psychotropic medications. In these cases, communication between the neurologist and the primary care provider or psychiatrist is essential.

Optimizing treatment effectiveness The three primary determinants of treatment effectiveness are correct diagnosis, use of an effective drug, and persistence with the therapeutic trial until the desired effect is achieved. A common reason for psychotropic treatment failure is incorrect diagnosis. Misconceptions about psychiatric disease are still prevalent among practicing physicians. Most psychiatrists and behavioral health clinicians in practice today in North America use the Diagnostic and Statistical Manual of Mental Disorders as the basis

of diagnostic formulation. The Diagnostic and Statistical Manual of Mental Disorders (DSM) has helped considerably in standardizing psychiatric diagnosis over the past several decades. The current version, DSM-V was released in 2013. One problem with the DSM for the geriatrician is that the manual was not written for the geriatric population and incompletely captures the characteristics of psychiatric disease in elderly patients. Even more important is that human psychopathology is highly complex, rooted as it is in genetics and early development, and tempered by factors of personality, experience, and comorbid disease. Although some proportion of psychiatric presentations can be reduced to medication-responsive syndromes (such as depression, anxiety, or psychosis), this is not true for all presentations. For individual patients, a more complete diagnostic formulation may be required, and for this, a psychiatric referral is indicated. Of the three determinants of treatment effectiveness, effective drug is arguably the most easily addressed. The range of treatment options currently available in geriatric psychopharmacology is, in the opinion of this author, adequate to treat most psychiatric conditions that arise in the course of primary care and specialty neurologic care of the geriatric patient. Much depends on the knowledge and skill of the prescribing physician. The “References” section at the end of the chapter lists resources available to assist the clinician (Jacobson et al., 2007; AHFS, 2011).

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Failure to follow through with a therapeutic trial until the desired effect is seen—ensuring that an adequate trial has been given—is possibly the most common reason for psychotropic treatment ineffectiveness. It is a frequent occurrence in psychiatric consultation practice to see patients who are said to be “failing” treatment with a drug such as an serotonin-selective reuptake inhibitor (SSRI) antidepressant, when, in fact, they are undertreated—that is, on a low initial dose of the drug over months or years. Knowledge of target doses, taking into account the individual patient’s renal and hepatic functions, is essential. In addition, medication side effects often develop in the geriatric patient, so advance discussion about what to expect can help both the patient and the physician stay the course of treatment, at least in the face of “nuisance” side effects.

Screening for psychotropic use Whether to use a psychotropic drug at all depends first on whether the symptoms are primary, or are secondary to a medical condition (for example, as with panic attacks in a patient with underlying pheochromocytoma) or a medication (for example, as with apparent depression in a patient on a statin drug). When the condition is secondary, the cause is treated first; only if the symptoms are persistent is the condition then treated with an appropriate psychotropic or other modality, such as electroconvulsive therapy or repetitive transcranial stimulation. The choice of a particular psychotropic drug is driven by the patient’s diagnosis, comorbid medical problems, current list of medications, past history with that drug or class, family history with that drug or class, physical examination findings, and laboratory test results. Major depression or panic disorder may be particularly drug responsive, whereas personality disorders or somatoform disorders may not be. Comorbid medical problems may direct treatment away from particular drug choices; for example, tricyclic antidepressants should be avoided in patients with coronary artery disease or cardiac conduction problems. In addition, current medications may direct treatment; for example, for many patients treated with olanzapine, mirtazapine should probably be avoided because of the high risk of significant weight gain with this combination. If a patient has had a good response to a particular drug in the past, this predicts future response. To a lesser extent, the same is true for a good response in the case of a first-degree relative. Table 24.1 summarizes specific elements in the screening evaluation. Reducing adverse effects and drug interactions To reduce the adverse effects of medications used in geriatrics in general, it is recommended that certain drugs be avoided in treating this population (Beers, 1997; Fick

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Table 24.1 Screening for psychotropic use in the geriatric patient History Are the symptoms caused by a medical illness? Are the symptoms caused by a medication? Is the patient’s condition one that is responsive to psychotropic treatment? What medication has been used for the patient in the past for this condition? What medication has been used for first-degree relatives? Examination Vital signs (including orthostatic blood pressure and pulse) Evidence of cardiopulmonary disease Evidence of hepatic disease Evidence of primary neurologic disease Laboratory tests Albumin Liver function tests Blood urea nitrogen (BUN), creatinine Complete blood count (CBC) with platelets Chemistries (glucose, electrolytes including Ca++) TSH Lipid panel EKG Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.

et al., 2003). Particular drugs of interest to neurologists include those with anticholinergic effects (amitriptyline, dicyclomine, diphenhydramine, doxepin, hydroxyzine, oxybutynin, and thioridazine), benzodiazepines (particularly flurazepam), barbiturates, muscle relaxants and antispasmodics (methocarbamol, carisoprodol, chlorzoxazone, metaxolone, and cyclobenzaprine), certain opioids (propoxyphene, meperidine), and amphetamines Table 24.2 Selected list of potentially inappropriate medications for older adults Amitriptyline and other tricyclic antidepressants Amphetamines Barbiturates Benzodiazepines Dicyclomine Diphenhydramine Doxepin Fluoxetine (if used daily) Flurazepam Hydroxyzine and other anticholinergic agents Meperidine Muscle relaxants and antispasmodics (methocarbamol, carisoprodol, chlorzoxazone, metaxolone, cyclobenzaprine) Oxybutynin (especially XL form) Promethazine Propoxyphene Thioridazine Source: Adapted from Fick et al. (2003) with permission of American Medical Association.

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(see Table 24.2). The patient and family members should also be educated about potential adverse effects, particularly those representing more serious conditions such as cardiac dysrhythmias. Drug interactions can be predicted based on published resources or web-based programs such as that offered by American Association of Retired Persons (AARP) (http://healthtools.aarp.org/ drug-interactions).

Initiating treatment At the time treatment is initiated, the actual treatment plan should be decided in collaboration with the patient and involved family. The frequency of follow-up visits should be determined in advance. At these visits, interval checks should be made to determine partial response versus no response. In case of a partial response, the original plan is continued. In case of no response, the drug should be tapered off so that an alternative can be introduced. Improving treatment adherence Medication nonadherence among community-dwelling adults 60 years and older ranges from 26% to 59% (van Eijken et al., 2003). Nonadherence can be expected to reach 100% when the patient is not able to afford medication. This has been a frequent problem in recent years, with many elders in the United States falling into the “donut hole” of Medicare coverage. The summary guidelines on the practice of geriatric psychopharmacology shown in Table 24.3 offer several suggestions that are known to be helpful in improving medication adherence.

Table 24.3 Summary guidelines: the practice of geriatric psychopharmacology Obtain consultation, if necessary, to clarify diagnosis. If possible, perform a psychotropic-free baseline evaluation. Identify a set of target symptoms. Use objective ratings of effect. Avoid drugs not recommended for elderly patients. Discuss the cost of medication with the patient before selecting the drug. Use geriatric doses and titration schedules. Make only one medication change at a time. Use monotherapy to the extent possible. Use the simplest regimen possible (e.g., daily dosing rather than bid). Give medication instructions in writing. Encourage the patient to use pillboxes and other adherence aids. At each visit, ask the patient explicitly about relevant side effects. Regularly assess the patient’s continuing need for the drug. Obtain drug levels when indicated. For each drug trial, clearly document adequacy (dose and duration). Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.

Pharmacology and aging It is a well-known fact that individuals age differently and at different rates. In reference to pharmacology, a “typical” 80-year-old is much less like her age peers than is a “typical” 30-year-old. The differences among age peers involve both pharmacokinetics, the movement of drugs through the body, and pharmacodynamics, the effect of drugs at the receptor. Further heterogeneity among elders is introduced by genetic differences involving genes that encode drug-metabolizing enzymes, drug transporters, and target receptors. These genetic differences continue into old age and assume even greater importance as the individual’s list of daily medications grows.

Pharmacokinetics and aging The four steps of drug pharmacokinetics include absorption, distribution, metabolism, and excretion. Absorption is the least affected by aging. It is affected by genetics, which influence not only CYP3A4 metabolism, but also P-glycoprotein pump (ABCB1 transporter) activity at the level of the intestinal wall. The P-glycoprotein pump serves as the gatekeeper in the gut, determining how much drug gets into the system. It acts as an efflux pump, transporting molecules that have entered the cells lining the gut lumen by diffusion or active transport and depositing them back into the lumen. Inhibitors of the pump increase drug bioavailability by reducing efflux, while inducers of the pump decrease bioavailability by increasing efflux. Drugs that induce both the P-glycoprotein pump and CYP3A4 activity, such as St John’s wort, are known as double inducers. These drugs greatly decrease bioavailability of substrates because the CYP3A4 enzyme is found in proximity to the effluxed drug in the lumen and rapidly metabolizes the drugs for excretion. Table 24.4 lists selected drugs of interest to neurologists that are substrates, inducers, and inhibitors of the P-glycoprotein pump. In the absence of disease, the extent of absorption is unaffected by aging, although the rate of absorption can be slowed with reduced gastric motility. In addition, the use of fiber supplements or antacids containing aluminum, magnesium, or calcium can slow absorption. For many drugs, slow absorption does not detract from the main effect and may even reduce the incidence of adverse effects. A number of psychotropics are available in alternative formulations, such as orally disintegrating tablets or long-acting intramuscular (IM) injections. The speed with which administered drugs enter the circulation is as follows: intravenous (fastest); short-acting IM; oral liquid, oral capsule, or oral tablet; and then long-acting IM or depot (slowest). The time to onset of action for oral liquids

Geriatric Psychopharmacology

Table 24.4 Selected substrates, inhibitors, and inducers of the p-glycoprotein pump Substrates

Inhibitors

Inducers

Amitriptyline Carbamazepine

Amitriptyline Atorvastatin

Dexamethasone Phenobarbital

Ciprofloxacin

Bromocriptine

St John’s wort

Corticosteroids

Chlorpromazine

Trazodone

Erythromycin

Cyproheptadine

Estradiol

Desipramine

Fexofenadine

Diltiazem

Levodopa

Erythromycin

Loperamide

Fentanyl

Lovastatin

Fluphenazine

Morphine

Garlic, grapefruit juice, green tea

Ondansetron

Haloperidol

Phenytoin

Hydroxyzine

Protease inhibitors

Imipramine

Quetiapine

Ketoconazole Lovastatin Methadone Midazolam Nefadozone Orange juice Phenothiazines Pimozide Propranolol Protease inhibitors Simvastatin Testosterone Trifluoperazine Vitamin E

Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.

is about the same as for short-acting IM formulations. Adverse effects such as hypotension occur as a function of speed of onset—the faster, the more likely to occur—so this should be taken into account in selecting a particular formulation.

Distribution Once absorbed, a drug passes from the small bowel through the hepatic portal system to the liver, where it undergoes first-pass metabolism. ABCB1 transporter (p-glycoprotein pump) activity in cells lining the bile canaliculi influences the extent of first-pass metabolism. Inducers and inhibitors of transporter activity exert effects here, as they do at the gut lining and the blood–brain barrier. Metabolites that exit the liver enter the general circulation. Those that have been rendered water-soluble (for example, by conjugation) can be excreted directly by the kidneys. Drugs entering the circulation are distributed to target organs such as the brain and heart, but also to the liver, kidneys, and peripheral storage sites in fat and muscle.

589

The extent to which a drug is taken up in peripheral storage depends on body composition, which is significantly affected by aging. Lean body mass decreases with aging, such that fat stores are relatively increased, even in thin individuals. Highly lipophilic drugs such as diazepam are rapidly taken up by adipose tissue (so that the time of initial efficacy is reduced) but then remain in adipose storage sites for prolonged periods, with irregular release and unpredictable effects. This is one reason drugs such as diazepam should be used with caution—if at all— in elders.

Metabolism Drug metabolism is considered in two phases: Phase I (oxidation reactions) and Phase II (most importantly, glucuronidation reactions). In general, Phase I processes are less efficient with aging, whereas UGT processes are little affected. Although enzymes for both phases are found throughout the body, the most important general metabolic processes occur in the liver. The major drug-metabolizing enzymes include the Phase I cytochrome P450 (CYP450) enzymes and the Phase II UGT enzymes. Both CYP450 and UGT exist as isoenzymes, each with its own specific substrate drugs, inhibitors, and inducers. In the presence of inhibitor drugs or foods, metabolism of substrate drugs is reduced. In the presence of inducer drugs, metabolism of substrate drugs is facilitated. Because most drugs are metabolized to inactive metabolites, enzyme inhibition results in increased drug activity, while induction results in reduced drug activity. Most significant drug interactions involve the CYP450 system. Three CYP450 families are of interest in psychopharmacology: CYP1, CYP2, and CYP3. Polymorphisms exist for CYP isoenzymes, resulting in differences in activity of these enzymes among individuals, and accounting in part for differences in blood levels of drugs among patients administered the same dose. Table 24.5 shows a partial listing of drugs metabolized by CYP isoenzymes that may be of interest to neurologists. A complete and up-to-date listing is available on the website of Dr. David Flockhart at the Indiana University School of Medicine Division of Clinical Pharmacology at the website (http://medicine.iupui.edu/clinpharm/ ddis/) Note that drugs such as carbamazepine appear on several different lists, as both substrates and inducers or inhibitors of a single isoenzyme, or involving different isoenzymes. UGT enzymes are involved in the metabolism of numerous chemicals and carcinogens, as well as pharmacologic agents. Two UGT subfamilies are of interest in psychopharmacology: UGT1A and UGT2B. Drugs that are metabolized by UGT enzymes include (via UGT1A) acetaminophen, buprenorphine, chlorpromazine, clozapine, cyproheptadine, diphenhydramine, doxepin, entacapone, ibuprofen, lamotrigine, lorazepam, loxapine, meperidine,

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Therapeutics for the Geriatric Neurology Patient

Table 24.5 Selected CYP450 substrates, inhibitors, and inducers Substrates 1A2

2B6

2C9

2C19

2D6

3A4,5,7

Amitriptyline Caffeine Clomipramine Clozapine Cyclobenzaprine Estradiol Fluvoxamine Haloperidol Imipramine Naproxen Olanzapine Ondansetron Propranolol Riluzole Ramelteon Tacrine Theophylline Verapamil Warfarin (R) Zolmitriptan

Bupropion Efavirenz Methadone

Amitriptyline Celecoxib Diclofenac Fluoxetine Fluvastatin Glipizide Glyburide Ibuprofen Meloxicam (S) Naproxen Phenytoin

Amitriptyline Carisoprodol Citalopram Clomipramine Diazepam Hexobarbital Imipramine Indomethacin Mephenytoin (S) Mephobarbital (R) Moclobemide Nelfinavir Omeprazole Pantoprazole Phenobarbitone Phenytoin Primidone Progesterone Propranolol Warfarin (R)

Amitriptyline Amphetamine Aripiprazole Atomoxetine Carvedilol Chlorpheniramine Chlorpromazine Clomipramine Codeine Desipramine Dextromethorphan Donepezil Duloxetine Fluoxetine Fluvoxamine Halperidol Imipramine Metoclopramide Metoprolol (S) Nortriptyline Ondansetron Oxycodone Paroxetine Perphenazine Promethazine Propranolol Propafenone Risperidone Tamoxifen Thioridazine Timolol Tramadol Venlafaxine

Alfentanil Alprazolam Aripiprazole Atorvastatin Buspirone Cafergot Caffeine Calcium channel blockers Chlorpheniramine Clarithromycin Cocaine Codeine Dexamethasone Diazepam Erythromycin Fentanyl Gonadal steroids Haloperidol Indinavir Methadone Midazolam Nelfinavir Ondansetron Pimozide Propranolol Quetiapine Quinine Risperidone Ritonavir Saquinavir Sildenafil Statin drugs Trazodone Triazolam Zaleplon Ziprasidone Zolpidem

Inhibitorsa 1A2

2B6

2C9

2C19

2D6

3A4,5,7

Amiodarone Cimetidine Ciprofloxacin Fluoroquinolones Fluvoxamine Interferon Ticlopidine

Ticlopidine

Amiodarone Fluconazole Fluvastatin Fluvoxamine Isoniazid Lovastatin Ritonavir Sertraline

Chloramphenicol Cimetidine Felbamate Fluoxetine Fluvoxamine Indomethacin Ketoconazole Lansoprazole and other PPIs Modafinil Omeprazole Oxcarbazepine Ticlopidine

Amiodarone Bupropion Celecoxib Chlorpheniramine Chlorpromazine Cimetidine Citalopram Clemastine

Amiodarone Aprepitant Chloramphenicol Cimetidine Ciprofloxacin Clarithromycin Delavirdine Diltiazem

Clomipramine Cocaine Diphenhydramine Doxepin

Efavirenz Erythromycin Fluconazole Fluvoxamine

Sulfamethoxazole Zafirlukast

(continued)

Geriatric Psychopharmacology

591

Table 24.5 (Continued) Inhibitorsa 1A2

2B6

2C9

2C19

2D6

3A4,5,7

Topiramate

Duloxetine Escitalopram Fluoxetine Haloperidol H1 receptor antagonists Hydroxyzine Methadone Metoclopramide Midodrine Moclobemide Paroxetine Perphenazine Quinidine Ranitidine Ritonavir Sertraline Terbinafine Ticlopidine

Grapefruit juice Indinavir Itraconazole Ketoconazole Mifepristone Nefazodone Nelfinavir Norfluoxetine Saquinavir Ritonavir Star fruit Telithromycin Verapamil

Inducers 1A2

2B6

2C9

2C19

2D6

3A4,5,7

Broccoli Brussels sprouts Char-grilled meat Insulin Modafinil Nafcillin Omeprazole Tobacco

Phenobarbital Phenytoin Rifampin

Rifampin Secobarbital

Carbamazepine Prednisone Rifampin

Dexamethasone Rifampin

Barbiturates Carbamazapine Efavirenz Glucocorticoids Modafinil Oxcarbazepine Phenobarbital Phenytoin Rifampin St John’s wort

Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing. aStrong

and moderately strong inhibitors appear in bold type.

morphine, nalorphine, naloxone, olanzapine, oxazepam, promethazine, propofol, propranolol, tolcapone, and trifluoperazine; and (via UGT2B) codeine, diclofenac, hydromorphone, lorazepam, morphine, nalorphine, naloxone, naltrexone, naproxen, oxazepam, oxycodone, temazepam, valproate, and nicotine. Most benzodiazepines are metabolized first by the CYP450 system and then by UGT enzymes. The three exceptions to this rule—lorazepam, oxazepam, and temazepam—are directly glucuronidated. Because glucuronidation is less affected by hepatic dysfunction, these drugs are the agents of choice in treating a patient with hepatic disease. It is a persistent myth that changes in serum protein levels with aging and/or displacement of proteinbound drugs by other drugs with higher affinity for

proteins result in increased drug action or increased risk of drug interactions. Even in elderly patients, neither reduced protein levels nor drug displacement from proteins has significant pharmacologic effects. Although drug displacement from proteins does result in a transient increase in an unbound drug, that drug is as available for metabolism and excretion as for target receptor binding. Changes in protein binding can affect interpretation of drug levels, however, because the laboratory reports total drug concentrations rather than free drug concentrations. If serum albumin levels are low, such that the unbound percentage of the drug is high, then the drug level may underestimate the amount of drug available to act on the target organ (or be excreted).

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Excretion Clearance is the rate at which a drug is removed from the circulation through hepatic metabolism and renal excretion. Clearance is inversely related to concentration at steady state. More precisely, drug concentration = dosing rate/clearance. P-glycoprotein pump activity in the cells lining the bile canaliculi and luminal edge of the proximal tubule promotes clearance through drug efflux. Aging is associated with reduced clearance of many drugs because of reduced glomerular filtration rate (GFR) and hepatic blood flow. When clearance decreases, steady-state concentrations increase unless the dosing rate is reduced, by either smaller unit doses or longer dosing intervals. This is why prescribers are urged to “start low and go slow” when determining doses for elderly patients. Drugs cleared entirely by renal excretion (such as lithium) show clearance decrements with aging proportional to the decline in GFR. The average GFR for a male of 70 years is 70 mL/min. A GFR <60 mL/min defines Stage III kidney disease. An estimated GFR is often reported along with serum creatinine. If the laboratory does not provide this service, an estimated GFR using the Modification of Diet in Renal Disease (MDRD) study equation can be calculated automatically by entering patient data (age, ethnicity, gender, and serum creatinine value) into a calculator such as that found on the NIH website (www.nkdep .nih.gov/professionals/gfr_calculators/idms_con.htm). Reduced hepatic metabolism is mostly a function of decreased blood flow to the liver with aging, a reduction that may be on the order of up to 45% in the absence of disease (Greenblatt et al., 1982). There is currently no way to calculate the degree of reduction in hepatic metabolism, and liver function tests used clinically do not correlate well with the liver’s drug-metabolizing ability. Drug half-life The elimination half-life of a drug is inversely related to clearance and directly related to the volume of drug distribution, both of which are affected by aging. Drug half-life helps predict the time to steady state (when the amount of drug in the body remains constant) and the time to drug washout. A general rule of thumb is that steady state or washout is reached in 4–5 times the half-life of a drug. The half-life of many psychotropic medications is increased in elders because of reductions in clearance. When a drug is titrated and the target dose is not known, it is prudent to wait until steady state is achieved at a given dose, to avoid overshooting and causing toxicity. This is particularly true for drugs with a narrow therapeutic index, such as lithium. Drugs with very short half-lives can be associated with between-dose rebound of symptoms or withdrawal symptoms if doses are missed. More problematic

in the elderly population is that drugs with very long half-lives (even longer in elders) can accumulate with repeated dosing and cause toxicity.

Pharmacodynamics and aging Pharmacodynamic changes with aging have been much less studied and, in general, are poorly characterized. Factors that affect pharmacodynamics include receptor number and affinity, signal transduction, cellular response, and homeostatic regulation. Aging is associated with reduced density of muscarinic, μ opioid, and dopaminergic D2 receptors. The facility with which postsynaptic receptors are upregulated or downregulated may be reduced with aging. Enzyme activities are generally also reduced except for monoamine oxidase-B activity, which is increased.

Psychotropic drugs

Antipsychotics Until the FDA issued a warning in 2005 about the use of atypical antipsychotic medications in elderly patients (particularly those with dementia), these drugs were widely prescribed, even for relatively minor conditions, such as anxiety and insomnia. In the same year as the FDA warning, the CATIE-AD trial results emerged, showing an increased mortality risk in elders with Alzheimer’s disease. Other concerns about these medications were raised, including stroke risk and risk of metabolic syndrome (Schneider et al., 2005). Use of these drugs now requires careful informed consent, and use as first-line agents to treat nonpsychotic conditions in elders is generally discouraged. This presents a dilemma for many prescribers, because these drugs are highly effective in treating a variety of behavioral conditions, particularly in patients with dementia.

Pharmacokinetics of antipsychotics Antipsychotic medications, both conventional and atypical, are generally well absorbed when taken orally, although antacids and anticholinergic drugs may slow the rate of absorption. Among low-potency drugs (such as chlorpromazine and quetiapine), bioavailability is highly variable and dose ranges are wide-ranging. For higher-potency drugs (such as haloperidol and risperidone), dose ranges are narrower so that more specific dosing recommendations can be made. With the possible exception of clozapine, therapeutic blood level ranges are not established for antipsychotics in elderly patients. Antipsychotic medications are highly lipid soluble. For reasons noted in an earlier section, this results in a relatively large volume of distribution and slow

Geriatric Psychopharmacology

elimination. These drugs reach high levels in the brain relative to plasma. The drugs are released slowly from lipid storage sites such as adipose tissue, resulting, in some cases, in protracted toxicity and in persistence of urine metabolites. Antipsychotics are generally metabolized in the liver, first by oxidation via CYP450 isoenzymes and then by glucuronidation. Reduced activity of CYP1A2 with aging is associated with reduced metabolism of clozapine and olanzapine. Clozapine is also metabolized by demethylation, a process also affected by aging. Clearance of both conventional and atypical antipsychotic drugs declines with aging. Atypical drugs appear to be cleared faster in men. Smoking increases clearance by CYP1A2 and is a factor for drugs cleared primarily by this isoenzyme, such as clozapine and olanzapine.

Pharmacodynamics and mechanism of antipsychotics For all antipsychotic drugs, dopamine D2 receptor binding is a major determinant of both efficacy against positive symptoms (such as delusions and hallucinations) and severity of extrapyramidal effects. Effective doses of atypical agents are associated with more serotonin receptor occupancy than D2 occupancy. Clozapine and, to a lesser extent, other second-generation drugs are also effective against negative symptoms (such as avolition). Pharmacodynamic changes with aging are associated with increasing sensitivity of the dopaminergic system to pharmacologic challenge. In elders, both therapeutic and toxic effects are seen at lower serum drug levels than for younger patients. This is particularly true for elderly patients with dementia. Taking haloperidol as an example, effective serum levels for elderly patients with dementia (0.32–1.44 ng/mL; (Lacro et al., 1996) are much lower than for younger patients with schizophrenia (2–15 ng/mL; Van Putten et al., 1992). The PET study has confirmed that, for many elders, sufficient D2 occupancy can occur at very small doses, such as haloperidol 2 mg daily (Kapur et al., 1996). Antipsychotics: drug interactions The most important drug interactions involving antipsychotic medications relate to clozapine. The combination of clozapine and benzodiazepines is associated with respiratory depression and sudden death (Grohmann et al., 1989). Benzodiazepines should generally be stopped before clozapine is initiated. If absolutely required for effective treatment, benzodiazepines can be added carefully to a stable clozapine regimen. Clozapine used in combination with carbamazepine further heightens the risk of bone marrow suppression associated with the latter drug. Several first-generation antipsychotics potently inhibit CYP2D6 enzyme function, including the following: chlorpromazine, fluphenazine, haloperidol, perphenazine, pimozide,

593

and thioridazine. Atypical antipsychotics generally have little potential to interfere with the metabolism of other drugs. All antipsychotics are substrates for CYP enzymes (mostly CYP2D6 and/or CYP3A4), and some are substrates for UGT enzymes, so other coadministered drugs can affect their metabolism.

Adverse effects of antipsychotics Motor side effects of antipsychotic medications relate to D2 receptor antagonism in the basal ganglia. Sedation and weight gain are associated with H1 receptor antagonism, hypotension to peripheral α1 receptor blockade, and anticholinergic effects to muscarinic M1 receptor antagonism. Adverse effects of individual drugs depend on relative drug affinities for each of these receptors. Table  24.6 shows receptor binding profiles for various antipsychotic drugs. Among elderly patients, the most important adverse effects of antipsychotics generally include QTc prolongation, orthostasis and hypotension, sedation, anticholinergic effects, and metabolic effects. The latter are particularly problematic with chronic treatment and include weight gain, glucose dysregulation, and dyslipidemia. Indications for antipsychotics In the elderly population, antipsychotic medications are prescribed for schizophrenia, mania with psychotic symptoms, dementia with delusions and agitation or aggression, major depression with psychotic features, delusional disorder, delirium, and psychotic disorders secondary to medical conditions. Expert consensus guidelines have also enumerated conditions for which antipsychotic medications are not indicated in elderly patients, including the following: generalized anxiety disorder (GAD), panic disorder, hypochondriasis, nonpsychotic major depression, insomnia or other sleep disturbances, primary irritability or hostility, motion sickness, neuropathic pain, or nausea and vomiting due to chemotherapy (Alexopoulos et al., 2004). Clinical use of antipsychotics Pretreatment evaluation for antipsychotic use should include the following: examination for abnormal involuntary movements (preferably using a standardized scale such as the AIMS), orthostatic blood pressure and pulse, fasting blood sugar, lipid panel, WBC count with differential, liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin), and ECG with QTc calculated. In addition, laboratory tests listed earlier in Table 24.1 may be needed, if they were not already performed. When antipsychotic medications are used to control agitation or aggression, either scheduled or as-needed (prn) dosing may be used. When antipsychotic medications are

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Table 24.6 Receptor binding of various antipsychotic drugs Adrenergic

α2

Dopaminergic

Drug

α1

Conventional antipsychotics

✗

Haloperidol

✗

✗

Aripiprazole

✗

✗

D1

D3

Serotonergic 5-HT D4

✗

✗

Asenapine

D2

✗

✗

✗

✗

✗

✗

✗

✗

Iloperidone

✗

✗

Olanzapine

✗

Quetiapine

✗

✗

✗

Risperidone

✗

✗

✗

Ziprasidone

✗

✗

✗

✗

✗ ✗

✗

✗

✗

✗

✗

M1

✗

✗

Clozapine

✗

✗

H1

✗

NRI

SRI

1A

✗

✗

✗

1D

2A

2C

✗

✗

✗

✗

✗

✗

✗

✗

✗

✗

✗

✗

✗

✗

✗ ✗

✗

✗

✗

✗

6

✗

✗

✗

✗

✗

✗

✗ ✗

✗ ✗

3

7

✗ ✗

✗

✗

Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing. NRI, norepinephrine reuptake inhibitor; SRI, serotonin reuptake inhibitor.

used to treat psychosis (including agitation/aggression driven by psychotic thinking or hallucinations), scheduled dosing should be used. A constant level of drug at the receptor is needed to control symptoms. Titration of antipsychotic medications in elderly patients should proceed slowly, at a rate of 1–2 dose increases per week (and more slowly for frail elders). Even in treating schizophrenia in elderly patients, the “start low and go slow” rule applies; there is no evidence that rapid neuroleptization confers any benefit, and rapid titration does cause harm to elders. Selected patient populations should avoid specific antipsychotic drugs. Patients with diabetes, dyslipidemia, or obesity, should avoid clozapine. Patients with hypotension or orthostasis should avoid low-potency agents (such as thioridazine, quetiapine, and clozapine) and risperidone. Patients with Parkinson’s disease (PD) should avoid haloperidol and risperidone. Patients with seizures should avoid clozapine. Those with tardive dyskinesia should avoid first-generation antipsychotics. Those with significant xerophthalmia or xerostomia should avoid thioridazine and clozapine. For the treatment of delirium, haloperidol remains the drug of choice in elders, as in younger patients. The dose of haloperidol used currently is several orders of magnitude lower than that used traditionally, which was associated with serious adverse effects, including significant QTc prolongation. The currently recommended dosing for the treatment of elders with delirium is haloperidol 0.25–0.5 mg IV q8h (and q6h prn) or 0.5–1 mg PO q12h (and q8h prn) (Liptzin and Jacobson, 2009). The total daily dose should be kept below 2 mg (Meyer-Massetti et al., 2010). For indications other than delirium, many psychiatrists consider atypical antipsychotics to be the treatment of choice in elders, in spite of significant risk of stroke and an increased rate of associated mortality in elders

with dementia. With regard to metabolic syndrome and dyslipidemia, clozapine and olanzapine appear to have the greatest risk. Clozapine is generally reserved for treatment-refractory conditions, when alternatives have been exhausted. For the treatment of psychosis in PD, first-line therapy is quetiapine, starting at 12.5–25 mg daily. The mean effective dosage is 75 mg daily, and the dosage range is 25–300  mg daily (Weintraub and Hurtig, 2007). Clozapine is actually the only drug that has demonstrated efficacy for PD with psychosis, but its use is reserved for those who do not benefit from quetiapine because of its serious adverse effect profile and the requirement for blood monitoring during therapy. Ideally, when clozapine is used, the dose is kept low—50 mg daily or less— with the modal effective dose being 25 mg daily. Dosing should be initiated at 6.25 mg daily and titrated slowly. The dosage range for PD with psychosis is 6.25–150 mg daily. In treating psychotic symptoms in the patient with dementia with Lewy bodies (DLB), antipsychotics are best avoided. Some evidence, and a great deal of anecdotal experience, suggests that cholinesterase inhibitors treat psychotic as well as cognitive and motor symptoms in DLB (Weintraub and Hurtig, 2007). For the treatment of psychotic symptoms in dementias other than DLB or PDD, either first- or second-generation antipsychotics could be used. These drugs should be prescribed at low doses on a scheduled basis. For sundowning in dementia, the medication should be given 1–2 hours before the time of usual behavioral escalation. Optimal dosages for this indication are as follows: risperidone 1 mg daily (Katz et al., 1999), haloperidol 2 mg daily (Devanand et al., 1998), quetiapine 50–200 mg daily (Alexopoulos et al., 2004), and olanzapine 5–20 mg daily (Alexopoulos et al., 2004).

Geriatric Psychopharmacology

595

Table 24.7 Antipsychotic dosage and titration in elders Drug

Initial dosage

Titration rate

Dosage range

Aripiprazole Asenapine

5 mg daily (qhs) 5 mg daily

2.5–15 mg daily (typical dose is 10 mg qhs) 5 mg daily to bid

Clozapine Fluphenazine Haloperidol Molindone Olanzapine Quetiapine Risperidone

6.25–12.5 mg daily (qhs) 0.25–0.5 mg daily to bid 0.25–0.5 mg daily to tid 5 mg bid 2.5 mg daily (qhs) 25 mg daily (qhs) 0.25–0.5 mg daily (qhs)

Ziprasidone

20 mg bid

Increase by 5 mg after 2 weeks. Increase to 5 mg bid as tolerated (watch for orthostasis). Increase by 6.25–12.5 mg every 7 days. Increase by 0.25–0.5 mg every 4–7 days. Increase by 0.25–0.5 mg as tolerated. Increase by 5–10 mg daily every 4–7 days. Increase by 2.5 mg after 3–4 days. Increase by 25 mg daily every 2–4 days. Double dose (to bid) after 2–3 days; thereafter, increase by 0.25–0.5 every 7 days. Increase by 20 mg bid every 4–7 days.

Used at effective doses and for sufficient time, all antipsychotic medications will treat positive symptoms such as delusions and hallucinations. Second-generation drugs (atypicals) also treat negative symptoms such as avolition and social withdrawal. The choice among antipsychotic drugs is made on the basis of cost and adverse effect profiles. First-generation drugs are cheaper but are associated with a higher rate of extrapyramidal effects. Second-generation drugs are associated with other significant adverse effects, including glucose dysregulation, hyperlipidemia, metabolic syndrome, and orthostatic hypotension. Table 24.7 shows suggested geriatric dosages and titration schedules for selected antipsychotic medications. Geriatric patients who are prescribed antipsychotic medications require more frequent follow-up than is usual in a neurology clinic. The following guidelines have been suggested (Alexopoulos et al., 2004). • After the antipsychotic is initiated, the patient should be seen within 1–2 weeks. • After a dose change, the patient should be seen in 10 days to 1 month. • When the patient is stable on a particular dose for 1 month, the patient should be seen every 2–3 months. • During maintenance treatment, after 6 months on a stable dose (for example, with an elder with schizophrenia), the patient should be seen every 3–6 months.

Antidepressants The conditions for which antidepressants are used in the treatment of geriatric patients include primary depression (major depression and dysthymia), depression in dementia, failure to thrive, bipolar depression, secondary mood disorders, panic disorder, social phobia, obsessive– compulsive disorder (OCD), posttraumatic stress disorder (PTSD), GAD, pain disorders including fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, insomnia, and stress urinary incontinence.

6.25–150 mg daily (≤50 mg daily ideal) 0.25–4 mg daily (higher doses divided) 0.25–4 mg daily (higher doses divided) 10–100 mg daily (typical dose is 20 mg qhs) 2.5–15 mg daily (typical dose is 5 mg qhs) 50–400 mg (divided bid to tid) 0.25–3 mg daily (typical dose is 0.5 mg bid) 20–80 mg bid

Pharmacokinetics of antidepressants Antidepressants are rapidly and completely absorbed in the small intestine, and although food can delay absorption significantly, this has little clinical effect. Over the usual dosage range, linear kinetics is seen, so any dosage increase results in a proportional serum level increase. Antidepressants are highly lipophilic, so the volume of distribution and half-life are significantly increased in elders. In general, antidepressants are extensively metabolized, primarily via CYP2D6, CYP3A4, and CYP2C9/19 pathways. Fluvoxamine and TCAs are also metabolized via CYP1A2. Reduced renal function in elders does affect clearance of water-soluble antidepressant metabolites such as10-hydroxy-nortriptyline. Pharmacodynamics and mechanism of antidepressants In general, antidepressants increase the concentration of specific neurotransmitters in the synaptic cleft and enhance pre- and postsynaptic receptor sensitivity to those neurotransmitters. Antidepressants also affect REM sleep and neuroendocrine and neuroimmune functions. Specifically, SSRI antidepressants inhibit the serotonin transporter responsible for moving serotonin from the synaptic cleft into the presynaptic neuron. Relative potencies of transporter inhibition are as follows: paroxetine > citalopram > sertraline > fluvoxamine > fluoxetine. At higher doses (for example, fluoxetine ≥60 mg daily), some SSRIs also inhibit reuptake of norepinephrine and dopamine, with sertraline having the greatest dopamine reuptake effect (Tulloch and Johnson, 1992). Paroxetine has a small capacity to block muscarinic receptors; the significance of this is minimal, except possibly in patients with a cholinergic deficit, such as patients with Alzheimer’s disease. Bupropion is a noradrenergic and dopaminergic drug with no serotonergic effects. Mirtazapine has a unique mechanism as a noradrenergic and specific serotonergic antidepressant (NaSSA), with effects due to enhanced release of serotonin and norepinephrine,

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mainly via α2 antagonism. Venlafaxine and duloxetine are serotonin and norepinephrine reuptake inhibitors. With venlafaxine, serotonergic effects predominate at lower doses, and norepinephrine effects at higher doses (>150 mg daily). Table 24.8 shows receptor binding profiles for antidepressants.

inducer. One case in point is the use of St John’s wort, an inducer of CYP3A4. This drug can be associated with reduced efficacy of cyclosporine, with consequent heart transplant rejection or with reduced levels of antiretroviral drugs. Pharmacodynamic interactions are probably more significant than is generally appreciated. Examples of known dynamic interactions include upper gastrointestinal (GI) bleeding with SSRI drugs used in combination with NSAIDs, and serotonin syndrome with SSRIs used in combination with linezolid. As a rule, greater the number of receptors bound by a drug, greater is the potential for dynamic interactions. Accordingly, older tricyclic antidepressants and MAO inhibitors have significant potential for these types of interactions.

Antidepressant drug interactions With antidepressants, both pharmacokinetic and pharmacodynamic drug interactions are seen. Pharmacokinetic interactions are straightforward and reasonably predictable, whereas pharmacodynamic interactions are complex and dependent upon concomitant medications, as well as comorbid conditions. Clinically significant CYP450 inhibition is seen with fluoxetine, fluvoxamine, paroxetine, bupropion, and nefazodone. With the exception of fluvoxamine, inhibition primarily involves CYP2D6, as shown in Table 24.5. Fluvoxamine is the “great inducer” among SSRIs, in that it strongly inhibits CYP1A2 and CYP2C19 and moderately inhibits CYP3A4 and CYP2C9. Nefazodone is a potent inhibitor of CYP3A4, and several antidepressants are substrates of this isoenzyme. Paroxetine is the only SSRI metabolized by a single CYP pathway (CYP2D6). When CYP2D6 is inhibited, significant effects on paroxetine metabolism can be seen. Citalopram and escitalopram generally have low potential for pharmacokinetic interactions. As a practical issue, CYP inhibition is usually less problematic than CYP induction. Caution is advised when a CYP450 substrate drug is administered along with an inhibitor of that isoenzyme, particularly when the therapeutic index of the substrate is narrow. Potentially more troublesome is the administration of a substrate with an

Adverse effects of antidepressants Antidepressant adverse effects that are problematic for elderly patients include orthostasis, cardiac conduction disturbance, bleeding, constipation, urinary retention, blurred vision, sedation, dizziness, delirium, cognitive impairment, hyponatremia, syndrome of inappropriate ADH secretion (SIADH), sexual dysfunction, and weight gain. Most adverse effects occur early in treatment, and for many, tolerance does not develop over time, no matter how low the starting dose and how slow the titration. Specifically, tolerance does not develop to orthostasis, cardiac rhythm disturbances, or delirium (Glassman et al., 1993). On the other hand, tolerance to sedation, dizziness, and GI distress often develops. In general, SSRI antidepressants have fewer and less serious adverse effects than other classes of antidepressants, and this is why these drugs are usually considered first-line agents in

Table 24.8 Receptor binding of various antidepressant drugs Transporters

Receptors

Drug

Norepinephrine

Serotonin

Dopamine

H1

M1

α1 Adrenergic

Amitriptyline Clomipramine Desipramine Desvenlafaxine Doxepin Nortriptyline Citalopram and escitalopram Fluoxetine Paroxetine Sertraline Bupropion Duloxetine Mirtazapine Nefazodone Venlafaxine

+++ +++ +++++ ++ +++ ++++

++++ ++++++ +++ +++ +++ +++

– – – – – –

+++++ +++ ++ – ++++++ ++

+++ +++ ++ – ++ ++

+++ +++ ++ – +++ ++

–

+++++

–

+

–

+

++ +++ + + ++++ – ++ +

+++++ ++++++ ++++++ – ++++++ – ++ ++++

– + +++ + + – ++ –

– – – – – ++++++ +++ –

– ++ + – – + – –

– – ++ – – + +++ –

Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.

Geriatric Psychopharmacology

geriatrics. SSRIs are associated with sexual dysfunction, weight gain, and sleep disturbance with daytime somnolence. Tricyclic antidepressants (TCAs) are well known to have cardiac, anticholinergic, and neuropsychiatric side effects. All TCAs affect cardiac conduction and are relatively contraindicated in patients with ischemic heart disease, preexisting bundle branch block, or intraventricular conduction delay (Roose and Glassman, 1994). Newer, dual-acting antidepressants may cause hypertension. Mirtazapine is associated with sedation and weight gain. Use of monoamine oxidase inhibitors (MAOIs) is limited in elders because of associated orthostasis and the need for dietary restriction.

Indications for antidepressants Antidepressant medications are used for a range of indications beyond major depression, the following of particular interest to neurologists: dementia with behavioral disturbance, panic disorder, OCD, PTSD, GAD, pain syndromes, chronic fatigue syndrome, failure to thrive, and primary insomnia. For mood and anxiety disorders secondary to general medical conditions, antidepressants may be used when the condition is prolonged or only partially treatable. When these disorders are secondary to substance use, antidepressants can be helpful in facilitating abstinence; the only caveat is that these drugs are metabolized by the liver, so careful dosing and titration is needed. Clinical use of antidepressants Pretreatment evaluation for antidepressant use includes the following: • History: Alcohol and drug use, caffeine and nicotine consumption (for those with anxiety symptoms), hypertension, ischemic heart disease, cardiac conduction disease, prostate enlargement, glaucoma, seizures, orthostatic hypotension, sexual dysfunction, current medications (including herbals), and drug allergies. • Physical examination: Orthostatic vital signs, cardiac and pulmonary examinations, neurologic and mental status examinations. The latter must elicit current suicidal thinking or plan, psychotic symptoms (delusions or hallucinations), presence of hypomanic or manic symptoms, and cognitive screening. Depression and anxiety rating scales are useful in documenting symptoms that can be followed over time to determine treatment effectiveness. • Laboratory studies: Complete blood count (CBC), electrolytes (including calcium and magnesium), creatinine, liver function tests (AST, ALT, alkaline phosphatase, bilirubin), B12 level, RBC folate level, TSH (with or without FT4), and ECG. Safety monitoring during continuation and maintenance therapy with antidepressant medications should minimally include the following: for SSRI antidepressants, pulse checks, electrolytes, and liver function tests

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every 6 months, along with periodic weight checks; for tricyclic antidepressants, orthostatic vital signs, electrolytes, creatinine, and liver function tests every 6 months, along with periodic weight checks. TCA level should be checked with every dosage change or change in concomitant medication that could affect TCA metabolism. For any patient with significant weight gain, workup for metabolic syndrome is indicated. Elderly patients without significant physical illness, comorbid personality dysfunction, or unremitting life stress will eventually respond to treatment with antidepressant medications, although often they respond more slowly than younger counterparts. This population is at high risk of undertreatment, mostly because of the low expectations of clinicians regarding their potential for recovery. In general, although the evidence regarding relative efficacy of antidepressant classes is mixed, experienced psychopharmacologists consider TCAs, MAOIs, and newer dual-acting drugs to be more efficacious than SSRIs. On the other hand, because of a superior adverse effect profile, SSRI antidepressants are widely viewed as first-line drugs in the treatment of geriatric patients. The use of newer dual-acting agents such as venlafaxine and duloxetine may be limited by hypertensive effects. Bupropion is useful for elders with anergia. Low-dose bupropion given in the morning in combination with an SSRI given at night is often an effective and well-tolerated treatment for elders with dementia and depression. Mirtazapine has a particular niche in the treatment of elders with poor appetite and insomnia. Cardiovascular risk associated with older TCAs has relegated this class to third-line use; these drugs are used either when cost is a prohibitive issue or because of patient preference. Nonselective MAOIs are also third-line agents used in treatment-refractory cases. All factors considered, antidepressants preferred for use in elderly patients include citalopram, escitalopram, and sertraline. For a selected subset of patients (discussed previously), mirtazapine is the drug of choice. Secondline drugs include fluoxetine, paroxetine, and venlafaxine. As noted previously, low-dose bupropion can be used in combination with an SSRI, to good effect. When an SSRI antidepressant is used to treat panic disorder, it is imperative that the initial dose of the drug be very low and that the titration proceed very slowly, to avoid acute exacerbation of panic. Table 24.9 shows suggested dosages and titration schedules for selected antidepressant medications. Among elders treated for depression, some symptom improvement may be seen in as little as 2 weeks, but remission of symptoms requires 6–12 weeks of treatment (Flint, 1997). When remission is achieved, the patient enters the continuation phase, in which improvement is preserved and treatment must be maintained. The duration of antidepressant treatment (acute remission plus

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Table 24.9 Antidepressant dosages and titration schedules in elders Drug

Initial dosage

Titration rate

Typical dosage and dosage range

Bupropion SR

100 mg daily

Increase by 50–100 mg every 3–4 days.

100 mg bid Range: 100 mg daily to 150 mg bid

Bupropion XL

150 mg qam

If needed and tolerated, increase to 300 mg qam.

150 mg qam Range: 150–300 mg qam

Citalopram

10–20 mg daily

Increase by 10 mg after 7 days. Maintain at 20 mg for 3–4 weeks, with further titration as needed and tolerated.

20 mg daily Range: 10–40 mg daily

Desvenlafaxine

50 mg daily

Usually not indicated.

50 mg daily Range: 50–100 mg daily

Duloxetine

20 mg daily

Increase by 20 mg after 7 days.

20 mg bid Range: 20 mg daily to 30 mg bid

Fluoxetine

10 mg daily (depression or OCD) 5 mg daily (panic disorder)

Depression/OCD: Increase to 20 mg after 1–2 weeks. Maintain at 20 mg for 3–4 weeks before further dose increases, and increase only if response is partial. Panic disorder: Increase to 10 mg after 1–2 weeks, then to 20 mg after 1–2 weeks if tolerated.

20 mg daily for depression Ranges: 5–40 mg daily for depression 5–30 mg daily for panic 20–60 mg daily for OCD

Mirtazapine

Sleep aid and appetite stimulant: 3.75–7.5 mg qhs Antidepressant: 7.5 mg q evening

Depression: Increase by 7.5–15 mg every 1–2 weeks.

30 mg daily (evening) Range: 7.5–45 mg daily for depression

Nortriptyline

10–25 mg daily

Increase by 10 mg or 25 mg every 7 days.

50 mg daily Range: 10–100 mg daily

Paroxetine

10 mg daily

Increase to 20 mg after 1–2 weeks. Maintain at 20 mg for 3–4 weeks before further dose increases, and increase only if response is partial.

20 mg Range: 5–40 mg daily (up to 60 mg for OCD)

Paroxetine CR

12.5 mg daily

Increase to 25 mg after 1–2 weeks.

25 mg daily Range: 12.5–50 mg daily

Sertraline

12.5–25 mg daily

Increase by 12.5–25 mg every 2–3 days, as tolerated.

100 mg daily Range: 25–200 mg daily (higher for OCD)

Trazodone

Hypnotic: 12.5–25 mg qhs

Increase by 12.5–25 mg every 3–5 days, as needed for sleep and as tolerated.

25–50 mg qhs Range: 12.5–300 mg qhs

Venlafaxine XR

37.5 mg daily

Increase to 75 mg after 4–7 days; may need to increase to 150 or 225 mg if response is inadequate.

75–150 mg daily Range: 37.5–225 mg daily

continuation phase) for elders depends on the number of previous episodes of depression. For the first episode, the recommended duration of treatment is 1 year; for the second episode, 2 years or more; and for the third episode, more than 3 years (Alexopoulos et al., 2001). Maintenance (indefinite) treatment should be considered for those with greater numbers of episodes or more severe episodes. For continuation and for maintenance treatment, the same dose of antidepressant is used as in acute treatment. Little data are available to guide the duration of treatment for anxiety disorders in elderly patients. For the treatment of OCD in elders, SSRIs are the drugs of choice. The equivalent of 60 mg daily of fluoxetine may be required for control of symptoms. For the treatment of depression in elders, titration of SSRI doses above those recommended for this indication (refer to Table 24.9)

usually leads to worsening of adverse effects without improving the antidepressant effect. For depressed patients who do not improve at standard antidepressant doses, options include switching drugs or augmentation with bupropion, lithium, thyroid hormone, and/or cognitive-behavioral therapy. For bipolar depression, lamotrigine can be used as monotherapy or as an adjunct to a mood stabilizer. Alternatively, an atypical antipsychotic can be used. Psychotic depression should be treated with both an antidepressant and an antipsychotic medication; use of an antidepressant alone can have dangerous consequences when a patient who remains psychotic is activated with the use of an antidepressant. Alternatively, electroconvulsive therapy (ECT) can be used for psychotic depression and is the foremost indication for this mode of treatment. Elderly patients with dementia

Geriatric Psychopharmacology

and depression should be started on smaller initial doses of antidepressants and titrated more slowly than other elders. Some respond at lower-than-usual doses; others require titration to full doses for symptom improvement. For the treatment of vascular depression and poststroke depression, SSRIs, nortriptyline, venlafaxine, and duloxetine may be useful. Among SSRIs, those with relatively lower risk of bleeding—citalopram and escitalopram— are preferred in poststroke depression.

Anxiolytic and sedative–hypnotic drugs Benzodiazepines, nonbenzodiazepine hypnotics, and related drugs such as buspirone all have some role in the treatment of geriatric patients, but these drugs are so often misused in this population that even legitimate use is questioned. In general, primary or chronic anxiety disorders in elderly patients are often best treated with antidepressant drugs, and insomnia is often best treated with aggressive sleep hygiene measures.

Pharmacokinetics of anxiolytics and sedatives The pharmacokinetics of benzodiazepines are influenced by aging, concomitantly administered medications, comorbid diseases, and smoking. In general, benzodiazepines are well absorbed, although food and coingested antacids can delay absorption. Drugs such as nonbenzodiazepine hypnotics designed for the treatment of initial insomnia may have such a rapid onset of action that they are safely taken only when the patient is already in bed for the night. For IM administration, lorazepam should be used in preference to diazepam or chlordiazepoxide, as only lorazepam is rapidly and completely absorbed by this route.

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The volume of distribution for all benzodiazepines except alprazolam increases with age. The most lipophilic of these drugs (including diazepam) have a short duration of action with single dosing because of rapid distribution to adipose tissue (Greenblatt, 1991). With repeated dosing, redistribution is reduced and duration of effect is prolonged. More hydrophilic drugs such as lorazepam have a longer duration of action with single dosing and a smaller change in duration of effect with multiple dosing because tissue distribution is limited (Greenblatt et al., 1977; Greenblatt and Shader, 1978). An important distinction is made between benzodiazepines that are oxidatively metabolized, including alprazolam, chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, quazepam, and prazepam; and those that are metabolized by conjugation (glucuronidation), including lorazepam, oxazepam, and temazepam. Drugs metabolized by oxidation generally have active metabolites, many with very long half-lives. These drugs are not recommended for use in elderly patients. Drugs metabolized by conjugation generally have no active metabolizes. Lorazepam and oxazepam have half-lives of less than 24 hours, whereas temazepam has a half-life of up to 40 hours. When a benzodiazepine is indicated for the treatment of an elderly patient, lorazepam and oxazepam are good choices. Clearance of conjugated benzodiazepines is little affected by aging, whereas clearance of oxidatively metabolized benzodiazepines is reduced with aging. Reduced clearance results in increased half-life, necessitating dosage and/or schedule adjustments to avoid daytime sedation and psychomotor impairment. Table 24.10 shows pharmacokinetic data and metabolic pathways for benzodiazepines and related drugs.

Table 24.10 Benzodiazepines and non-benzodiazepine hypnotics: pharmacokinetics and metabolic pathways Drug

Onset of effect

Peak level (hours)

Parent half-life (hours)

Metabolite half-life (hours)

Benzodiazepines Alprazolam Chlordiazepoxide Clonazepam Diazepam

Intermediate Intermediate Intermediate Rapid

1–2 2–4 1–2 0.5–2

12–15 5–30 18–50 20–80

– 24–96 – 50–100

Lorazepam Midazolam Oxazepam Temazepam

Intermediate Rapid Slow Slow

1–6 0.4–0.7 (IV only) 2–4 2–3

10–20 2–5 5–20 10–40

– – – –

CYP3A4, glucuronidation CYP2C19, 3A4 CYP3A4, acetylation CYP2C19, 3A4, 2B6, 2C9, glucuronidation UGT2B7 CYP3A4, glucuronidation various UGTs UGT2B7, CYP2C19, 3A4

Nonbenzodiazepine hypnotics Eszopiclone Ramelteon Zaleplon Zolpidem

Intermediate Intermediate Intermediate Intermediate

1 0.5–1.5 1 2.2

9 1–2.6 1–2 2–2.6 (longer in elderly)

– – – –

CYP2C8, 3A4 CYP1A2, 3A4, 2C family Aldehyde oxidase, CYP3A4 CYP3A4, 1A2, 2C9

Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing. type indicates major pathway.

aBold

Metabolic pathwaysa

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Pharmacodynamics and mechanism of anxiolytics and sedatives Benzodiazepines bind to the GABAA-benzodiazepine receptor complex located on postsynaptic neurons in the cerebral cortex, cerebellar cortex, and limbic regions. This receptor complex also contains binding sites for barbiturates, neurosteroids, and several nonbenzodiazepine hypnotics, including zolpidem, zaleplon, zopiclone, and eszopiclone. These drugs all act at least partly as GABA agonists, causing an influx of negatively charged chloride ions into the neuron, leading to hyperpolarization of the neuron and a reduced rate of firing. The GABAA receptor consists of five subunits in a rosette formation, usually comprising two α subunits, two β subunits, and one γ subunit. The subunits have variant forms, such as α-1, α-2, and so forth. GABA itself binds to the β subunit of the GABAA receptor. Benzodiazepines bind to receptors containing α subunits (either 1, 2, or 3). Zolpidem and zaleplon also bind to the benzodiazepine site on the GABAA receptor, but these drugs bind with high affinity only to receptors containing the α-1 subunit. Eszopiclone also interacts with the benzodiazepine site on the GABAA receptor, probably binding to specific “microdomains” within the γ subunit. Because different α subunits are variably expressed in specific brain regions (cortex, brainstem, and so on), these binding differences among agents may have clinical implications in terms of differential amnestic, sedative, and true hypnotic effects (Davies et al., 2000). Buspirone acts not by interaction with the benzodiazepine receptor complex, but as a serotonin (5HT) agonist at the presynaptic 5HT1A receptor and as a partial agonist at the postsynaptic 5HT1A receptor. Buspirone binding causes downregulation of 5HT2 receptors, similar to the action of antidepressants. This medication is anxiolytic at usual doses and possibly antidepressant at higher doses. Buspirone also has complex dopaminergic effects that are not fully understood. The nonbenzodiazepine hypnotic ramelteon acts by an entirely different mechanism, binding selectively to melatonin type 1 (MT1) and type 2 (MT2) receptors, which act on the suprachiasmatic nucleus to regulate circadian rhythms. Elderly individuals exhibit greater pharmacodynamic sensitivity to benzodiazepines than younger counterparts. Conditions such as traumatic brain injury (TBI), stroke, and dementia further increase this sensitivity.

Anxiolytics and sedatives: adverse effects In general, benzodiazepines are effective in the treatment of anxiety, are well tolerated, and are safe in overdose unless ingested with alcohol or other sedatives. In the geriatric population, however, these drugs have dose-dependent sedative, cognitive, and motor effects that can be limiting. In elders, sedative effects include weakness, inattention, slowed thought processing, ataxia, and balance

problems (Shader and Greenblatt, 1993). Tolerance to sedative effects may develop within the first few weeks of treatment but is persistent in some cases. Benzodiazepineassociated cognitive impairment sufficient to meet criteria for dementia may be reversible with drug discontinuation. Motor effects include slowed reaction time, reduced tracking ability and hand–eye coordination, and impaired judgment. Drugs with a half-life of more than 24 hours are associated with a 45% increased risk of motor vehicle accident with injury in the first 7 days of use (Hemmelgarn et al., 1997). The increased risk of falls and accidents persists as long as these drugs are taken. On the other hand, inadequate doses of benzodiazepines are associated with persistent anxiety symptoms or between-dose withdrawal. This is particularly problematic with alprazolam, as there is a large inter-individual variation in the half-life of this drug. While some individuals are well maintained on alprazolam, many experience between-dose rebound of anxiety because the halflife is too short for the dosing interval prescribed. On the other hand, benzodiazepines with long elimination halflives such as diazepam accumulate in fatty tissues with repeated dosing and can lead to toxic effects, as discussed in an earlier section. It has been observed clinically that elderly patients with coarse brain disease or mental retardation may exhibit “paradoxical reactions” with benzodiazepines that is not dose dependent, with symptoms of agitation, aggressiveness, and hyperactivity. The mechanism underlying this phenomenon remains unexplained (Shader and Greenblatt, 1993). Hemodynamic and respiratory depressant effects of benzodiazepines are seen in ICU settings, where large doses of drugs are administered intravenously. These effects are not covered in this chapter. The only caveat with outpatient use is that benzodiazepines should be avoided in patients with sleep apnea, whether obstructive or central in origin. The most common adverse effects of nonbenzodiazepine hypnotics include headache, somnolence, dizziness, lightheadedness, amnesia, and GI disturbances (including nausea, diarrhea, and constipation). Hallucinations and confusional states may be seen with zaleplon and zolpidem, possibly related to high levels resulting from coadministered drugs that inhibit metabolism via CYP3A4 (Terzano et al., 2003). These symptoms are more commonly seen in elderly patients than in the younger patients prescribed these drugs. No evidence indicates that tolerance develops to anxiolytic effects of benzodiazepines or to hypnotic effects of the benzodiazepine-like drugs, even with chronic use (Dubovsky, 1990; Farnsworth, 1990; Hollister et al., 1993; van Steveninck et al., 1997). On the other hand, tolerance does develop to most adverse effects of these drugs, including daytime sedation, but not to amnesic effects (Hollister et al., 1993). How long it takes for tolerance to

Geriatric Psychopharmacology

develop depends on the half-life of the individual benzodiazepine, as well as the specific effect in question (Byrnes et al., 1993). The potential for benzodiazepine abuse is low among elders, except for those with a previous history of alcohol or sedative abuse (Shader and Greenblatt, 1993; Ciraulo et al., 1997). For patients with this history, benzodiazepine use is complicated by rekindling of craving, coingestion of alcohol with the prescribed medication, and increased risk of motor vehicle accidents; similar problems could conceivably occur with the nonbenzodiazepine hypnotics (Gericke and Ludolph, 1994). Benzodiazepines with a faster onset of action—alprazolam, diazepam, and lorazepam—have higher abuse potential (greater “street value”) because of the rapid “kick” associated with ingestion (Griffiths and Wolf, 1990). Unlike abuse and addiction, physical dependence is a universal phenomenon defined by the appearance of an objective withdrawal syndrome after a drug is discontinued. Physical dependence occurs when a sufficient dose of drug is taken for a sufficient length of time (Kruse, 1990; Shader and Greenblatt, 1993). For elderly patients, physical dependence occurs at usual therapeutic doses (Shader and Greenblatt, 1993) and after as few as 2 weeks of treatment (Ayd, 1994). All benzodiazepines are equally likely to produce physical dependence. Discontinuation of a benzodiazepine can result in symptom recurrence, symptom rebound (in which symptoms are more intense than they were to begin with), or withdrawal symptoms (in which physical effects of reduced GABA neurotransmission are seen). It is difficult at times to distinguish these phenomena. In general, interruption of a therapeutic dose of a benzodiazepine is associated with rebound symptoms, while interruption of a high dose is associated with withdrawal symptoms (Pourmotabbed et al., 1996). Rebound symptoms include anxiety, restlessness, dysphoria, anorexia, and insomnia; in elderly patients, disorientation and confusion can be prominent. Withdrawal symptoms can include fever, tachycardia, postural hypotension, headache, sweating, photosensitivity, sensory distortion, delirium, tremor, myoclonus, and seizures; catatonia has also been reported in elderly patients (Rosebush and Mazurek, 1996). Severe benzodiazepine withdrawal can be as serious as severe alcohol withdrawal; in medically compromised elders, severe withdrawal can be life-threatening. The timing of the appearance of withdrawal symptoms depends on the half-life of the drug. In patients of unselected age, withdrawal reactions peak at 2 days for short half-life (<6 hours) agents and at 4–7 days for longer half-life agents (Rickels et al., 1990). Gradual taper of benzodiazepines, particularly shorteracting drugs, mitigates withdrawal symptoms. Most patients tolerate a taper of 10–25% of the total dose each week, although the last few dose reductions often require

601

longer intervals for the patient to be comfortable (Schweizer et al., 1990; Shader and Greenblatt, 1993). Patients unable to tolerate dose reductions may benefit from one of the following: carbamazepine 200–800 mg daily, with a plasma level of approximately 6 μg/ml; gabapentin 300–900 mg daily; propranolol for autonomic symptoms; or a switch to a longer-acting agent and subsequent taper of that agent.

Anxiolytics and sedatives: drug interactions Benzodiazepines that are metabolized primarily via CYP3A4 include alprazolam, clonazepam, midazolam, and triazolam. Concomitant use of CYP3A4 inhibitors such as antifungals, antibiotics, nefazodone, fluvoxamine, or grapefruit juice can cause elevated levels of these drugs. Use of CYP3A4 inducers such as St John’s wort, carbamazepine, chronic alcohol consumption, or smoking can be associated with reduced levels. Benzodiazepines that are recommended for elders (lorazepam and oxazepam) are not CYP3A4 substrates. In addition to CYP450 effects, benzodiazepines have important additive sedative effects with other sedative/ hypnotics and alcohol. Benzodiazepines can be associated with hypotension and slowing of the heart rate, particularly when combined with other medications such as opioids. The potentially serious interaction of benzodiazepines with clozapine is discussed earlier in the section “Anxiolytics and sedatives: adverse effects.”

Indications for anxiolytics and sedatives Few primary psychiatric disorders exist for which benzodiazepines are drugs of choice in elderly patients. These drugs are most often used in geriatrics for sedation (as in during procedures or mechanical ventilation), symptomatic anxiety that is expected to be short-lived (as in during ICU admission), or for specific conditions such as restless legs syndrome. These agents can be used as adjuncts in the treatment of psychiatric conditions such as mania and psychosis, but in general, their use is time limited. Nonbenzodiazepine hypnotics and other drugs discussed shortly may be used to treat insomnia when nonpharmacologic measures have proved inadequate.

Clinical use of anxiolytics and sedatives When benzodiazepines are used in elders, small doses of short- or intermediate-acting drugs are preferred. Alprazolam, a drug reputed to have a short half-life, is an exception to this rule because of wide inter-individual variability in its kinetics, as mentioned earlier in the section “Pharmacodynamics and mechanism of anxiolytics and sedatives.” Benzodiazepines that are not recommended for use in elders because of prolonged sedative and motor effects include flurazepam, diazepam, chlordiazepoxide, quazepam, halazepam, and clorazepate (Fick et al., 2003). In geriatrics, IM administration of drugs should be avoided because of the discomfort of injection associated

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with low muscle mass and (for some drugs) erratic absorption. For oral use, first-line drugs include lorazepam and oxazepam. If longer half-life drugs such as clonazepam are prescribed (t1/2 = 18–50 hours), frequency should be once daily or every other day. For parenteral use, lorazepam is recommended. With IV use, much smaller doses and more careful patient monitoring are needed for adverse effects such as respiratory depression. For patients unable to swallow, other routes/means of benzodiazepine administration include rectal, sublingual, and orally disintegrating forms. For elders with insomnia, sleep hygiene measures are tried before pharmacologic treatment is considered. When medication is needed, several options exist: trazodone and gabapentin (both off-label use), melatonin, ramelteon, and the nonbenzodiazepine hypnotics. The latter drugs— which include eszopiclone, zaleplon, and zolpidem— reduce sleep latency but do not reduce slow-wave sleep, so they reportedly have a profile superior to that of the benzodiazepines (Hemmeter et al., 2000; Uchimura et al., 2006). Doxepin has recently been marketed in a 3 mg dose for insomnia, which may be effective for a subset of young-old patients in the absence of Alzheimer’s disease, but is likely to have limiting anticholinergic effects for others. Drugs that are not recommended for the treatment of insomnia in elders include diphenhydramine, chloral hydrate, antipsychotics such as quetiapine, barbiturates, meprobamate, ethchlorvynol, glutethimide, and methyprylon (The Medical Letter, 2000). Before starting a benzodiazepine, a corroborated history of substance use/abuse should be obtained, for reasons previously described. Current use of alcohol should prompt a discussion of alternatives to benzodiazepine use because of the dangers of concomitant benzodiazepine use. The list of current medications should be reviewed to identify other drugs with sedative properties, which could result in additive effects causing falls or accidents. Informed consent should be obtained, detailing the plan for dosage and duration of use, as well as risks. In particular, elders who drive need to be informed that driving while taking these drugs can be hazardous, just as driving while intoxicated with alcohol can be hazardous; in some cases, the hazard is prolonged to the day after taking a benzodiazepine or benzodiazepine-like drug for sleep. If a benzodiazepine or related drug is to be prescribed for an elderly patient presenting for the first time with GAD, panic disorder, insomnia, or severe anxiety as an isolated symptom, a possible medical cause should be sought. Laboratory studies recommended for routine workup for GAD include CBC, fasting glucose, calcium, vitamin B12, RBC folate, TSH, and ECG (Flint, 2005). Laboratory studies recommended for routine work-up of panic disorder include CBC, fasting glucose, calcium, thyroid panel, and ECG (Flint and Gagnon, 2003). Depending on the description of panic attacks, an EEG may be indicated to evaluate complex

partial seizures. Patients treated with stimulants such as theophylline should have levels drawn to exclude toxicity.

Monitoring treatment with anxiolytics and sedatives Treatment response is gauged clinically, by changes in target signs and symptoms and/or the appearance of adverse effects. The only drug for which a meaningful serum level can be drawn is alprazolam, and only for the treatment of panic disorder. For this condition, alprazolam levels between 20 and 40 ng/mL are associated with therapeutic response in patients of unselected age with spontaneous panic attacks (Greenblatt et al., 1993). Therapeutic levels for geriatric patients have not been established. Elderly patients requiring chronic treatment with benzodiazepines or nonbenzodiazepine hypnotics should be evaluated at least every 3–6 months, to assess cognitive and psychomotor function and to adjust dose downward as indicated. Older patients treated chronically with benzodiazepines may begin to develop signs of toxicity with aging, probably a function of gradual alteration in drug clearance. Escalation of benzodiazepine dosage over time or concurrent excessive alcohol consumption should be understood as serious evidence of misuse. The length of time that the drug is continued in the elderly patient depends on the specific disorder being treated, whether it is comorbid with depression or secondary to a treatable medical condition, and which class of medication is used for treatment. Early-onset GAD may require lifelong treatment, while late-onset GAD with comorbid depression may be treated according to guidelines governing depression (Flint, 2005). For lateonset GAD without depression, some experts recommend treatment for 1 year after remission of symptoms (Flint, 2005). For symptomatic anxiety in the context of a medical disorder such as hyperthyroidism, treatment with a benzodiazepine can be continued until the underlying condition is treated and then gradually withdrawn. For panic disorder, initial treatment may consist of both an SSRI or dual-acting antidepressant and a benzodiazepine, with the latter continued only for 1–2 weeks as the antidepressant dose is titrated. The SSRI should then be continued for a period of 6 months to 1 year, with shorter times possible in cases where cognitive-behavioral therapy or other nondrug treatment has been used in tandem with medication. For insomnia, the benzodiazepine or related drug should be used for 1–2 weeks, and then the need should be reassessed. If insomnia persists at 2 weeks, a comorbid psychiatric or medical condition should be considered. Some patients do benefit from an extension of treatment, but it is best if the medication is taken only intermittently (such as fewer than 4 times per week). The efficacy of intermittent longer-term use of nonbenzodiazepine hypnotics has been demonstrated (Perlis et al., 2004).

Geriatric Psychopharmacology

Treatment of specific anxiety disorders in elderly patients Anxiety in the context of dementia may manifest as agitation, anxious mood, or generalized anxiety. In many cases, it is associated with depression. For acute anxiety in the patient with dementia, behavioral and environmental approaches are tried first. If the anxiety persists or worsens, pharmacologic options include SSRIs, lorazepam, oxazepam, trazodone, buspirone, and gabapentin. Nonbenzodiazepines are preferred, as benzodiazepines generally worsen cognitive function. SSRI doses are kept low for this indication (for example, sertraline 12.5–25 mg or fluoxetine 5–10 mg suspension or capsule). Buspirone can be used at doses ranging from 5 mg bid to 20 mg tid. Gabapentin can be used at doses ranging from 300 mg to 2400 mg daily divided tid. For any of these drugs, a trial of at least 12 weeks is needed to determine efficacy. When no response is seen, a switch to another agent is indicated. Table 24.11 shows dosage and titration of sedative drugs. In the elderly population, anxiety is often seen in association with depression, particularly major depression. Antidepressant medication effectively treats anxiety along with other symptoms. SSRIs and dual-acting agents are effective anxiolytics. Use of an anxiolytic alone for treatment of depression with anxiety is associated with a very poor outcome (Flint, 2005). A subset of patients

603

with significant anxiety in the context of depression will require a benzodiazepine for the first 1–2 weeks of treatment. When an antidepressant is initiated for patients with depression and panic attacks, very slow titration of the antidepressant is needed, as discussed shortly. Anxiety can be secondary to medical illness, particularly conditions that compromise breathing, such as asthma, COPD, sleep apnea, and head/neck cancer. For anxiety in patients with COPD or sleep apnea, SSRIs or buspirone may be useful because these medications do not depress the respiratory drive or cause sedation or cognitive impairment. For panic anxiety in this population, SSRI antidepressants may be used. For patients with terminal lung disease, dyspnea is the focus of a treatment algorithm involving the correction of physical causes of dyspnea (hypoxia, anemia, bronchospasm), and then symptomatic management with opioids along with pharmacotherapy for anxiety using antidepressants (sertraline, venlafaxine) and/or benzodiazepines (Periyakoil et al., 2005). Among patients with PD, anxiety may be especially prominent during “off” periods and appears to be more prevalent among those with left-sided symptoms (Walsh and Bennett, 2001). Optimal pharmacologic treatment has not been established. Management involves lowering PD medications to the lowest effective dose and adding antidepressant medication such

Table 24.11 Dosage and titration of drugs for anxiety in elders Titrationa

Typical daily dosage

Dosage range

Isolated symptom of anxiety Buspirone 5 mg bid Lorazepam 0.5 mg daily to 0.5 mg bid

Increase by 5 mg every 2–3 days. Increase by 0.5 mg every 4–5 days.

10 mg tid 0.5–1 mg bid to tid

5 mg bid–20 mg tid 0.5–3 mg daily

Oxazepam

10 mg bid to tid

Increase by 5–15 mg every 4–5 days.

10 mg tid

10 mg daily–15 mg tid

Trazodone

12.5 mg bid to tid

Increase by 12.5 mg every 3–5 days.

25 mg tid

25–50 mg tid

Sertraline

12.5 mg daily

Increase by 12.5 mg every 3–7 days.

12.5–25 mg daily

12.5–100 mg daily

Fluoxetine

5–10 mg daily

Increase by 5 mg every 7 days.

5–10 mg daily

5–20 mg daily

Buspirone

5 mg bid

Increase by 5 mg every 2–3 days.

5–10 mg tid

5 mg bid–20 mg tid

Gabapentin

100 mg bid to tid

Increase by 100 mg every 3–5 days.

100 mg tid

100 mg tid–800 mg tid

Indication/drug

Initial dose

Anxiety in dementia

Generalized anxiety disorder Citalopram

10 mg daily

Increase by 10 mg after 7 days.

20 mg daily

10–40 mg daily

Escitalopram

5–10 mg daily

Increase by 5 mg after 7 days.

10 mg daily

5–20 mg daily

Venlafaxine XR

37.5–75 mg daily

Increase to 75 mg after 1–2 weeks; further increases at same interval.

37.5–75 mg daily

≤ 150 mg daily

Buspirone

5 mg bid

Increase by 5 mg every 2–3 days.

10 mg tid

5–20 mg tid

Pregabalin

50 mg daily

Increase to 100 mg after 3 days, and to 150 mg 2 days later (doses divided bid to tid).

150–200 mg daily (doses divided bid to tid)

150–600 mg daily (doses divided bid to tid)

Citalopram

5–10 mg daily

Increase after 7 days.

20 mg daily

5–40 mg daily

Sertraline

12.5–25 mg daily

Increase after 7 days.

50–100 mg daily

12.5–200 mg daily

Venlafaxine SR

37.5 mg daily

Increase by 37.5 mg after 1–2 weeks.

37.5–75 mg daily

≤150 mg daily

Panic disorder

aDose

increases should be made as needed and tolerated.

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Therapeutics for the Geriatric Neurology Patient

as an SSRI. Benzodiazepines can be used but may exacerbate PD symptoms. The GABA-agonist effect of benzodiazepines reduces dopaminergic outflow in the basal ganglia and, theoretically, could interfere with the effects of levodopa (Yosselson-Superstine and Lipman, 1982). Catatonia is a syndrome involving motor abnormalities and mental status changes that occurs in the context of medical or neurologic disease, or severe psychiatric disease such as major depression or schizophrenia. In current practice, this syndrome is greatly underdiagnosed and often is mislabeled in the hospital setting as delirium or depression. The distinction is important because initial treatment of catatonia differs significantly from treatment of these other syndromes. Like delirium, the diagnosis of catatonia requires timely medical workup and accurate diagnosis. While this is ongoing, however, the patient requires symptomatic treatment. Cardinal signs of catatonia include mutism, immobility or excessive motor activity, negativism, posturing, stereotypy, and echophenomena (echopraxia, echolalia). Optimally, diagnosis should be made using a standardized instrument such as the Catatonia Rating Scale (Bush et al., 1996). Catatonia is classified into retarded, excited, and malignant types, the latter including neuroleptic malignant syndrome and serotonin syndrome. In addition to definitive treatment of the underlying medical condition, symptomatic treatment of catatonia is needed to maintain basic bodily functions (hydration and nourishment) and to decrease morbidity from immobility. Catatonia can be treated with benzodiazepines and/or ECT. Catatonia is a primary indication for ECT in the elderly population; although controlled studies for this indication are lacking, substantial clinical experience supports its use. Clinical experience also suggests that the response of elderly patients to benzodiazepines may not be as robust as that of younger catatonic patients. The benzodiazepine of choice for diagnostic challenge and for treatment of catatonia is lorazepam, based on its availability in IV and IM formulations, rapid onset of action, and other favorable pharmacokinetic properties. The following algorithm for lorazepam use in catatonia is recommended (Fink and Taylor, 2003). • Score the Catatonia Rating Scale. • Administer lorazepam 1–2 mg IV test dose. • Score the Catatonia Rating Scale. • At intervals of 20–30 minutes, repeat dose of IV lorazepam and score the Catatonia Rating Scale, up to lorazepam 10 mg total dose, administered over several hours. • If significant improvement is seen, calculate how much lorazepam was given. • Give that amount of lorazepam daily IV in divided doses until definitive treatment corrects the underlying problem and/or the syndrome resolves. • Anticipate the need for ECT.

When GAD occurs as a primary disorder, several treatment options exist. Antidepressants are the first line of treatment for GAD for most elderly patients, regardless of whether depression is present. For the treatment of elderly patients, preferred drugs include escitalopram, citalopram, and venlafaxine. Benzodiazepines generally have a limited role in the treatment of GAD in elderly patients, but if they are used, lorazepam and oxazepam are recommended. Other options include buspirone in the benzodiazepine-naive patient and pregabalin (Montgomery et al., 2006). Primary OCD in elderly patients usually represents the persistence of illness that developed earlier in life. Hoarding behaviors are less likely a manifestation of OCD than of psychotic illness or dementia. Treatment involves both exposure and response prevention therapy and high-dose SSRI therapy. Primary OCD in elders is an indication for psychiatric referral. Panic attacks and panic disorder in elderly patients may be idiopathic, or secondary to a medical condition or medication. For primary panic disorder, the recommended treatment is an SSRI such as citalopram or sertraline. Venlafaxine is another option. If an SSRI is initiated too aggressively, panic is exacerbated. (Dosage and titration recommendations are shown earlier in Table  24.11.) When venlafaxine is used, the optimal dose is usually ≤150 mg daily because noradrenergic effects become more prominent at higher doses. A benzodiazepine such as lorazepam may be needed as adjunctive therapy during the initial weeks of treatment. Buspirone is not effective for the treatment of panic. When symptoms have been controlled for 6–12 months, an attempt should be made to slowly taper and discontinue medication. Patients who have been treated with cognitive behavioral therapy generally do very well with discontinuation. Others may require several discontinuation attempts because of recrudescence of panic. A minority will require lifelong treatment. In a small subset of elderly patients, benzodiazepines may be required for control of panic anxiety, in spite of dependence issues and adverse effects. The frequent association of panic with alcohol dependence complicates this use. Either lorazepam or oxazepam could be used for this indication. In adults, agoraphobia is seen as a complication of panic, but this phenomenon is not as common in elders. In this population, agoraphobia more often results from onset of dementia, depression, or apathy, or occurs as a consequence of serious medical illness or trauma. There is no evidence that drug therapy is helpful for agoraphobia. PTSD with onset in earlier life may again manifest in later years. The diagnosis of PTSD is complicated in elders by cognitive deficits and medical comorbidities. The recommended treatment for PTSD is

Geriatric Psychopharmacology

cognitive-behavioral therapy, so psychiatric or psychological referral is indicated for this condition. The pharmacologic treatment of choice is an SSRI antidepressant, with a target dosage equivalent to fluoxetine 60  mg daily. Dual-acting antidepressants, trazodone, and lamotrigine may also be useful. The required duration of treatment has not been established. Benzodiazepines have little or no role in the treatment of PTSD and are particularly problematic for affected patients with substance abuse issues. For PTSD-associated nightmares, the adrenergic antagonist prazosin titrated to a daily dose of 5 mg was found to be helpful in one case series (Raskind et al., 2000); clonidine, guanfacine, and cyproheptadine have also been reported to be useful (Horrigan, 1996). For social phobia (social anxiety disorder), referral for cognitive-behavioral therapy is indicated. Recommended medications include SSRI antidepressants, venlafaxine, pregabalin, and gabapentin. Buspirone is not effective for this condition. The treatment of insomnia first involves the use of sleep hygiene measures. If these interventions are ineffective, pharmacotherapy may be tried. The first step is to discontinue current treatments that have not worked, including sedating antihistamines (diphenhydramine, in particular) and prescription hypnotics. If insomnia persists longer than 2 weeks after this step and there is no evidence that a treatable medical condition underlies the insomnia, another hypnotic should be considered. For insomnia of less than 3 weeks’ duration in elderly patients, any of the following drugs could be used: zolpidem, zaleplon, eszopiclone, gabapentin, mirtazapine, trazodone, nortriptyline, or temazepam. Drugs not recommended for insomnia in this population include diphenhydramine, chloral hydrate, and barbiturates and related sedatives (The Medical Letter, 2000). For chronic insomnia, the same drugs can be used, although nortriptyline and temazepam should be used chronically with caution. Table 24.12 shows dose information.

Table 24.12 Hypnotic dosing in elders Drug

Dose (mg h.s.)

Doxepin Eszopiclone Gabapentin Mirtazapine Nortriptyline Ramelteon Temazepam Trazodone Zaleplon Zolpidem

3 1–2 100–300 3.75–7.5 10 8 15 25–50 10 5

605

Mood stabilizers The population of elders with primary bipolar disorder is highly heterogeneous, with individuals differing in genetic loading for other psychopathologies, age of disease onset, number and polarity of episodes, access to treatment, substance abuse history, and comorbid disease. With a few notable exceptions, the presenting signs and symptoms of mania, depression, and mixed states is similar in elders as in younger patients. Response to treatment is variable, however, and formes frustes presentations are common (Young, 2005). Hypertension, diabetes, and cerebrovascular disease are frequent comorbidities. More than half of bipolar elderly patients have cognitive deficits on basic screening such as the MMSE (mini-mental state examination; Gildengers et al., 2004). Secondary mania should be considered in any patient presenting as manic for the first time in old age. Secondary mania can be due to medication, metabolic disturbance, endocrine disease, or cancer, among many other conditions. Treatment of secondary mania requires treatment of the underlying condition driving the syndrome. For pharmacologic treatment of bipolar mania, first-line drugs include lithium and valproate. Carbamazepine is relegated to second-line treatment because of adverse effects and drug interaction. For treatment of bipolar depression, lithium and lamotrigine are drugs of choice. Lamotrigine is also useful in the treatment of rapid cyclic illness. Atypical antipsychotics also labeled for use in bipolar illness include aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. Although these drugs are effective, caution is warranted in their use in elderly patients because of the risk of increased mortality.

Mood stabilizers: pharmacokinetics Aging significantly alters lithium pharmacokinetics. The volume of lithium distribution decreases with aging because of a relative decrease in total body water that occurs in tandem with a relative increase in total body fat. Lithium is not metabolized. Clearance of lithium is reduced in proportion to reduction in GFR. The half-life of lithium in elders is 28–36 hours, compared with 24 hours in nongeriatric patients. Diseases such as congestive heart failure and renal insufficiency further reduce lithium clearance. Valproate is rapidly absorbed when taken orally, and the enteric-coated formulation is designed to slow absorption and minimize GI effects. The enteric-coated form is distinct from the sustained-release form, which is designed for once-daily dosing. Valproate is highly protein bound, so the free fraction of drug is increased in elders with low albumin levels. This could result in overdosing if total drug levels are used to guide dose changes,

606

Therapeutics for the Geriatric Neurology Patient

as discussed in an earlier section. Once absorbed, distribution of all forms of valproate is rapid; the drug reaches the central nervous system within minutes. Valproate is extensively metabolized, primarily through glucuronidation and mitochondrial β-oxidation, but also through CYP450 enzymes as minor routes. Active metabolites are produced. Clearance of valproate is reduced by more than one-third in elders, necessitating lower initial doses and slower titration. Lamotrigine is rapidly and completely absorbed when taken orally, a process unaffected by food. This drug is metabolized by glucuronidation to an inactive metabolite and is mostly renally excreted. As renal clearance is reduced with aging, drug exposure is increased in elderly patients by more than 50%. Carbamazepine is very slowly absorbed, with peak levels reached after four to eight hours. This drug is a substrate for the P-glycoprotein pump. It is hepatically metabolized via CYP3A4 to an active epoxide metabolite that can be toxic in high concentrations. Autoinduction of carbamazepine results in a reduction in half-life with repeated dosing, which may necessitate upward dosage adjustment after two to four weeks. In elderly patients, clearance of carbamazepine is reduced by about one quarter. Carbamazepine significantly induces CYP3A4 and CYP2C19, and thus is associated with reduced concentrations of psychotropic and cardiac drugs, among other medications.

Mood stabilizers: pharmacodynamics and mechanism The mechanism of action of lithium is not known, although a number of hypotheses have been advanced. Among other effects, lithium downregulates AMPA GluR1 synaptic expression, an effect shared by valproate. Valproate also increases availability of GABA. Lamotrigine is believed to act through voltage-gated sodium channels to inhibit the release of excitatory amino acids such as glutamate and aspartate. Pharmacodynamic effects of carbamazepine resemble those of phenytoin, primarily related to inhibition of synaptic transmission. Mood stabilizers: drug interactions Lithium has the potential for important drug interactions with ACE inhibitors, calcium channel blockers, thiazide diuretics, NSAIDs, COX-2 inhibitors, and virtually all psychotropic drugs. Use of these drugs in combination with lithium requires closer monitoring of lithium levels. In addition, any dietary modifications involving a change in salt intake (especially sodium chloride) can have significant effects on lithium levels. Carbamazepine affects levels of other drugs metabolized by CYP3A4 and CYP2C19 (as noted earlier) but also is prone to metabolic inhibition

by other drugs because it is metabolized by a single isoenzyme: CYP3A4. This isoenzyme can be inhibited by grapefruit juice or antifungal medications, among other agents. The combination of carbamazepine with valproate can be hepatotoxic and requires careful monitoring of liver function. Lamotrigine can be problematic when used in combination with any other anticonvulsant. Carbamazepine interacts with most coadministered drugs and, for this reason, is, at best, a second-line choice for elderly patients.

Adverse effects of mood stabilizers Lithium is associated with numerous adverse effects in elderly patients, including cognitive impairment, drowsiness, fatigue, ataxia, tremor, cerebellar dysfunction, dysarthria, fasciculations, polyuria, urinary frequency, urinary incontinence, constipation, fasting hyperglycemia, weight gain, exacerbation of skin conditions such as psoriasis, exacerbation of arthritis, peripheral edema, and hypothyroidism. Episodes of lithium toxicity, as well as multiple daily doses, may be risks for structural injury to the kidneys and should be avoided. Cardiac effects of lithium include ECG changes, conduction abnormalities, and dysrhythmias. T-wave depression occurs commonly, in about onequarter to one-third of treated patients. Neuropsychiatric effects listed earlier may occur even when lithium levels are in the therapeutic range. Tolerance does not develop to these neuropsychiatric effects, but the symptoms may improve with dose reduction or discontinuation. Half of lithium-treated patients gain substantial weight with chronic treatment. Laboratory abnormalities associated with lithium treatment include elevated TSH (with clinical hypothyroidism in about 6% with chronic treatment) and leukocytosis involving mature WBCs (no left shift). Indications for mood stabilizers Mood stabilizers are used to treat primary bipolar disorders (bipolar I and bipolar II), cyclothymia, certain secondary mood disorders (such as substance-induced disorders), schizoaffective disorder, behavioral and psychological symptoms of dementia, pain syndromes, movement disorders, anxiety disorders, and alcohol/ sedative withdrawal. Mood stabilizers: clinical use Primary bipolar disorder is an indication for psychiatric referral. One issue in the care of elderly patients presenting with depression is that it is important to elicit any history of mania or hypomania before initiating antidepressant therapy; for this reason, many nonpsychiatric physicians also consider depression an indication for psychiatric referral. In elderly patients presenting for

Geriatric Psychopharmacology

the first time with mania, the index of suspicion should be high for secondary mania, and a cause should be investigated. The diagnostic evaluation for mania or bipolar illness is usually performed and ordered by the psychiatrist. It should include vital signs (orthostatic), physical and neurologic screening examination, cognitive screening, CBC with platelets, comprehensive metabolic panel, thyroid screening, and ECG. Brain MRI may be indicated. The treatment of patients with secondary mania involves discontinuing any offending drug (such as a steroid) or treating the underlying medical condition. For primary mania or hypomania, antidepressant treatment should be stopped, and initial monotherapy with lithium, valproate, or an atypical antipsychotic should be initiated. For mixed states (mania with depressive features), secondary mania, or rapid cycling, valproate is preferred. The patient should be observed for several weeks with initial therapy before any decision is made on whether a switch in drug or augmentation is needed. For bipolar depression, initial monotherapy with lamotrigine or lithium should be initiated. If initial treatment with one of these drugs is ineffective, a switch to the other should be tried. If neither is effective, an atypical antipsychotic should be tried as monotherapy or add-on therapy. If this is ineffective, either an antidepressant in combination with a mood stabilizer or ECT should be considered, in consultation with a psychiatrist. Rapid remission of symptoms can occur after four to six ECT treatments, and the course is followed by treatment with a mood stabilizer to maintain remission. Elderly patients treated with mood stabilizers should be monitored for efficacy and adverse effects by physical and mental status examination and laboratory testing, including drug levels (Jacobson, 2012). Psychiatric follow-up is recommended for these patients. Table  24.13 shows suggested dosages and titration of mood stabilizers.

607

Treatments for substance-related disorders Substance abuse is not common in the current cohort of elders, but when present, it is associated with significant morbidity. In this cohort, the substances most likely to be abused are alcohol and tobacco. Of prescribed drugs, benzodiazepines are the most commonly abused; opioid abuse does occur but is much less common. In general, substance-related disorders are classified as either substance use disorders (abuse and dependence) or substanceinduced disorders (intoxication, withdrawal, cognitive disorders, mood disorders, and so on). Substance abuse is a maladaptive pattern of repeated use of alcohol, a drug, or a medication that results in harmful consequences. An elderly alcohol abuser could meet this criterion by failing to maintain adequate hygiene, having repeated falls, failing to seek needed medical care, or alienating children through constant argument about the consequences of intoxication. Substance dependence is a maladaptive pattern involving the development of tolerance, withdrawal symptoms on discontinuation, compulsive use, restriction of activities, and/or continued use despite adverse physical or psychological effects. In regard to alcohol, substance dependence is more commonly known as alcoholism. In general, alcohol abuse is more prevalent than alcohol dependence, and “problem drinking” (which is not a DSM term) is more prevalent than abuse. Different definitions of problem drinking exist; for older drinkers, this could be defined by daily intake of more than 2 drinks per day in men or more than 1 drink per day in women, or recurrent binge drinking. When benzodiazepines are prescribed, physiologic dependence develops with normal clinical use, and a withdrawal syndrome would occur upon abrupt discontinuation, so physical dependence is expected. Moreover, some patients with anxiety disorders increase or reduce the dose of benzodiazepine on their own, depending on the severity of symptoms. Patients who do so responsibly do not warrant a diagnosis of addiction.

Table 24.13 Dosage and titration of selected mood stabilizers in eldersa Indication/drug

Initial dose

Titration

Typical daily dosage

Dosage range

Lithium Valproate

75–150 mg daily 125–250 mg daily to bid

Increase by 75–150 mg every 4–7 days Increase by 125–250 mg every 3–5 days

300–900 mg 500–1000 mg (divided bid)

Carbamazepine

100 mg bid

Increase by 100–200 mg every 3–5 days

300 mg bid

Lamotrigine

12.5 mg daily

Increase by 12.5–25 mg every 2 weeks

50 mg bid

150–1800 mg daily 250–1500 mg (divided bid) 200–800 mg daily (divided bid) 100–300 mg daily (divided bid)

aAtypical

antipsychotics are also labeled for the treatment of bipolar illness. Dosing of these drugs is shown in Table 24.7.

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Therapeutics for the Geriatric Neurology Patient

Diagnosis of substance-related disorders Substance abuse/dependence is usually covert, so detection requires a high index of suspicion. Diagnosis requires a careful and corroborated history, physical and mental status examinations, and laboratory testing. In the emergency room, drug screens need to be done quickly and, if possible, sent within 1 hour of presentation. Alcohol can be detected in the urine for only a brief period, up to 7–12 hours (Moeller et al., 2008). Both serum and urine specimens should be obtained. Serum drug screening is usually performed for ethanol, acetaminophen, and salicylates, the latter to exclude overdose. Urine drug screening is usually performed for opioids, heroin, methadone, benzodiazepines, cocaine, amphetamines, methamphetamines, and barbiturates. Specific included drugs vary by laboratory. Often laboratories do not distinguish individual opioids or metabolites, but can perform more specific analyses upon request. Falsepositive test results occur with many coadministered drugs (Moeller et al., 2008). Alcohol-related disorders

Alcohol dependence Although a variety of drinking patterns are seen, most elders who drink do so in small amounts on a daily basis. The effects of aging, medications, and comorbid medical conditions on alcohol kinetics and dynamics are such that these small amounts can have large effects. Drinking patterns can be longstanding with persistence into old age or can be of late onset (after age 60). Those with earlyonset disease are often easily identified because of serious medical comorbidities (such as COPD, cirrhosis, or history of TBI) and legal and family problems. Cases of more recent onset may be more difficult to detect. Elderly drinkers often present with a constellation of individual signs, symptoms, and conditions, which are listed in Table 24.14. This list can be used as a “review of systems” for alcoholism. Eliciting the patient’s report of quantity and frequency of drinking is also helpful after completing a screening such as the Michigan Alcoholism Screening Test-Geriatrics version (MAST-G) because this can mitigate the tendency to minimize drinking. Laboratory abnormalities supporting the diagnosis of alcoholism include the following (Jacobson, 2012). • Elevated gamma glutamyl transerase (GGT) (>47 U/L in men or >25 U/L in women) is consistent with four or more drinks daily for 4 weeks or more. Takes 2–3 weeks of abstinence to normalize. • Elevated carbohydrate-deficient transferring (CDT) (≥ 2.6%). • Elevated AST > ALT (ratio >2:1). • Elevated mean corpuscular volume (MCV). • Elevated uric acid level. • Elevated total homocysteine level (>15 μmol/L).

Table 24.14 Alcoholism: signs, symptoms, and associated conditions Abdominal obesity

Hostility

Aggression

Hygiene problems

Amnesia

Hypercortisolemia

Anemia

Hyperhomocysteinemia

Anxiety

Hypertension

Apathy

Infection

Ataxia

Insomnia

Bruising

Irritability

Cardiomyopathy

Legal problems

Cerebellar degeneration

Malignancy

Cirrhosis

Malnutrition

Dehydration

Medical noncompliance

Delirium

Nausea/vomiting

Delusions

Neuropathy

Dementia

Osteoporosis

Dental caries

Pancreatitis

Depression

Panic attacks

Electrolyte derangements

Pneumonia

Esophageal varices

Seizures

Falls

Sexual dysfunction

Fractures

Social isolation

Gastritis

Suicidal ideation

Gastrointestinal bleeding

Trauma

Hallucinations

Ulcers

Hepatitis

Wernicke’s encephalopathy

Homicidal ideation Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.

In males, GGT and CDT together provide a reliable indicator; in females, GGT alone has better predictive value. GGT and CDT begin to normalize within days of cessation of drinking and return to normal levels within 2 weeks. Although physician counseling about alcohol overuse has definite short-term effects in decreasing consumption, continued abstinence depends on participation in a multifaceted program involving regular attendance at groups such as Alcoholics Anonymous or Rational Recovery, an ongoing 1:1 relationship with a supportive family/ friend surrogate (usually a sponsor or counselor), regularly scheduled medical and psychiatric follow-up visits, and repeated reinforcement for abstinence. Some elders do well in group therapy directed toward resocialization, as long as they are placed with age-peers with the same history of alcohol dependence. Family therapy is useful to reduce enabling, deal with family conflicts, and address poor family dynamics. For homebound elders, identification and education of the “supplier” of alcohol is a critical step. Helping the patient and family to identify appropriate medical, dental, and home health services can be useful, as can the arrangement of Meals on Wheels or participation in senior center activities.

Geriatric Psychopharmacology

Medications currently approved by the FDA for treatment of alcohol dependence include naltrexone (oral and long-acting injectable forms), acamprosate, and disulfiram. Although these drugs can be used to treat elders, none have been extensively studied in this population. Naltrexone is a nonspecific opioid antagonist that reduces the reinforcing effects of alcohol, making it less likely that the patient will continue drinking after a slip. Limited available data suggest that naltrexone is safe and effective in older patients (Oslin et al., 1997). The drug should always be administered in conjunction with the nonpharmacologic interventions listed earlier. Treatment should not be initiated until the patient is completely detoxified from opioids, with abstinence verified by urine opioid screening and/or a naloxone challenge test. Oral naltrexone (Revia) should be initiated in elderly patients at 25 mg daily and either maintained there or increased to 50 mg daily for the duration of treatment (Oslin et al., 1997). Pharmacokinetics of the long-acting injectable form (Vivitrol) have been understudied in the geriatric population. The initial dose of Vivitrol for patients of unselected age is 380 mg IM every 4 weeks. Acamprosate is a GABA agonist and glutamate antagonist that may have a role not only in treatment for alcohol dependence, but also in neuroprotection during withdrawal. This drug is understudied in geriatrics; its efficacy and safety have not been demonstrated in this population. When the drug is used, it should be started as soon as possible after abstinence has been achieved and continued for 12 or more months, even through relapses. The geriatric starting dose is 333 mg 3 times daily, increased to 666 mg 3 times daily after 1 week. The drug promotes continued abstinence and reduces the severity of relapses. In nongeriatric populations, the drug has been used successfully in combination with other drugs such as naltrexone or disulfiram. Disulfiram is little used in geriatrics because of the seriousness of adverse effects in patients who drink during treatment. Disulfiram inhibits the enzyme aldehyde dehydrogenase, resulting in the buildup of toxic metabolites when ethanol is ingested. The effects vary among individuals and are dose dependent. Symptoms range from flushing and nausea to marked tachycardia or bradycardia, hypotension, myocardial infarction, cardiovascular collapse, heart failure, and seizures. The more severe reactions are seen with high doses of disulfiram, with significant alcohol ingestion, or in patients with preexisting cardiovascular disease. There is no specific antidote. The “antabuse reaction” can occur with any alcohol-containing substance, including some over-the-counter cough syrups and mouthwashes, and prescribed medications such as metronidazole, tolbutamide, and trimethoprim/ sulfamethoxazole (Bactrim). There are numerous medical contraindications to disulfiram use. When disulfiram is prescribed to an elderly

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patient, the dose should be maintained at 125–250 mg daily. Some question centers on whether this dose generates a blood level sufficient to produce an alcohol–disulfiram reaction if the patient drinks; the deterrent might be merely the threat of a reaction. In regular users, disulfiram compliance can be determined by testing urine for diethylamine, a metabolite. When disulfiram is prescribed, liver function tests should be checked at baseline, then every 2–3 weeks for 2 months, and then every 3 months. Other drugs used to treat alcohol dependence include SSRI antidepressants and anticonvulsants. Among nongeriatric patients, SSRI use is associated with reduced craving and drinking during the first weeks of treatment, but these effects may not be sustained in all patients. As with all other pharmacologic interventions for alcohol dependence, treatment using SSRIs is best carried out in a structured abstinence program with close follow-up, as discussed earlier. Although topiramate up to 300 mg daily has been found effective in treating alcohol dependence in a nongeriatric cohort, this drug can be associated with significant adverse effects in elderly patients. Other anticonvulsants reported to have some effect in treating alcohol dependence include valproate, carbamazepine, and lamotrigine, but none of these medications have been studied systematically in the geriatric population for this indication.

Alcohol withdrawal The signs and symptoms of alcohol withdrawal in elderly patients are like those seen in younger counterparts, but they may be more severe and longer lasting (Brower et al., 1994). These include fever, tachycardia, tachypnea, hypertension, unstable blood pressure, diaphoresis, tremor, hyperreflexia, marked startle response, mydriasis, seizures, headache, disorientation, anxiety, agitation, insomnia, delusions (usually persecutory), perceptual disturbances/ hallucinations, and nausea/vomiting. Minor withdrawal symptoms such as tremor and anxiety are seen early, usually 6–12 hours after the last drink. Hallucinations occur after 8–24 hours, seizures after 24  hours, and delirium tremens (DTs) after 72  hours (Rubino, 1992). An episode of DTs may begin earlier in patients with a prior history of delirium tremens. DSM-IV-TR refers to any delirium that is secondary to alcohol withdrawal as delirium tremens, but this latter term also connotes a severe delirious state, often with seizures. Elderly patients with delirium tremens have a high mortality rate due to cardiac arrhythmias, hypovolemic shock, aspiration pneumonia, hepatic failure, and falls or other accidents (Feuerlein and Reiser, 1986). Severity of the withdrawal syndrome can be assessed using a scale such as the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) (Sullivan et al., 1989). Initial supportive measures for the patient in alcohol withdrawal include hydration, nutrition, and rest in a

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quiet environment. Parenteral thiamine 100 mg IM or IV should be given before any glucose-containing IV solution is started because glucose metabolism utilizes thiamine and could precipitate Wernicke’s encephalopathy in marginally deficient patients. Folate and a multivitamin should also be given, and electrolyte derangements should be corrected. Magnesium repletion is particularly important. Parenteral thiamine 100 mg daily should be given for at least 3 days (Mayo-Smith et al., 2004)—longer if the patient has any neurologic or cardiovascular signs to suggest the presence of Wernicke’s encephalopathy. Prescription of one IV Rally Pack (“banana bag”) daily would meet this requirement and also supply folate 1mg, multivitamins 10 mL, and magnesium sulfate 2 g in 1 L of 5% dextrose/water or normal saline. Benzodiazepines are used to control the rate of withdrawal, utilizing either a fixed-dose regimen or symptom-triggered therapy. In general, when medication is administered only for a CIWA-Ar score above a threshold of 8–10 (symptom-triggered therapy), less medication is used and the duration of detoxification is shortened (Daeppen et al., 2002). Compared with the fixed-dose strategy, however, symptom-triggered therapy is associated with higher average CIWA-Ar scores for more days (Daeppen et al., 2002), and this could place the frail elder at risk for an adverse medical outcome. Thus, although some clinicians prefer symptom-triggered therapy for use in nonelderly patients, low fixed doses of medication may be preferable to prevent symptom progression in elders. Any benzodiazepine can be used to control withdrawal, but pharmacokinetic differences make some agents better choices for elderly patients. Lorazepam is the first-line drug for elders in alcohol withdrawal because it can be given PO or IV (as well as IM, although IM administration is problematic in elderly patients with reduced muscle mass), has a relatively rapid onset of action and a moderate duration of effect, is not oxidatively metabolized and thus can be used for patients with hepatic impairment, and is not highly lipophilic and thus does not accumulate in the body. Except for IV availability, oxazepam has the same advantages. Chlordiazepoxide (Librium) can be used in young–old patients in withdrawal whose hepatic function is intact; in old–old patients and in those with even moderate degrees of hepatic dysfunction, this drug should be avoided. Librium has the advantage of a longer half-life, which facilitates a smoother withdrawal and possibly greater effectiveness in preventing withdrawal seizures. The disadvantage of the longer half-life in elders is the increased risk of oversedation. Diazepam is not a good choice because of its tendency to move rapidly into lipid compartments and out of the general circulation. For fixed-dose treatment, lorazepam is dosed 2 mg every 6 hours for 4 doses, then 1 mg every 6 hours for 8 doses, along with 2–4 mg every 1–2 hours prn

(Mayo-Smith, 1997). For symptom-triggered treatment, lorazepam is dosed 2–4 mg every 1–2 hours when the CIWA-Ar score is ≥8. Lorazepam should be dosed IV if the patient has severe withdrawal symptoms, is vomiting, or has GI bleeding or pancreatitis. When the IV route is used, initial doses should be half of those recommended, with rapid upward titration as needed and tolerated. Hallucinations may respond to benzodiazepine treatment alone, but an antipsychotic should be added for severe or persistent psychotic symptoms. Haloperidol is usually selected for this indication, although any antipsychotic may be used. It should be noted that all antipsychotics lower the seizure threshold. Anticonvulsants such as valproate, carbamazepine, and gabapentin have been used as adjunctive treatments for alcohol withdrawal, with some benefit in terms of reducing the burden of withdrawal symptoms and lowering the total dose of benzodiazepine administered. β Blockers such as atenolol have been used to treat patients in withdrawal with persistent hypertension and/ or tachycardia. Alcohol withdrawal seizures are usually of the generalized tonic–clonic type, with a brief postictal period. Adequate treatment of alcohol withdrawal with a benzodiazepine prevents the development of seizures. When an alcohol-withdrawal seizure does occur, IV lorazepam 2 mg can decrease the likelihood of recurrence (D’Onofrio et al., 1999).

Nicotine-related disorders

Nicotine use disorder (tobacco dependence) Smoking is the most common substance-related disorder among the current cohort of elders in the United States. It is associated with significantly increased morbidity and mortality, particularly among smokers grown old. Regardless of age, quitting smoking confers health benefits (LaCroix et al., 1991). Elders who stop smoking for 5  years reduce cardiovascular mortality to that of nonsmokers and also reduce their risk of lung cancer. Medically based smoking cessation programs are a particularly important intervention in the geriatric population. Pharmacologic treatments include nicotine-replacement therapies and bupropion. With a few caveats, these treatments are considered safe in elders when used in accordance with prescribing recommendations. Nicotine-replacement therapies (gum, lozenges, patches, sprays, and inhalers) double the rate of quitting smoking compared with placebo. Effects are maintained over time in many patients. Patient selection may be necessary, as caution is advised in using nicotine replacement for those with coronary artery disease, severe or worsening angina, recent myocardial infarction (MI), uncontrolled hypertension, or serious cardiac dysrhythmia. In addition, the two forms of nicotine replacement available by prescription only—intranasal spray and oral inhaler— should be used with caution. When nicotine-replacement

Geriatric Psychopharmacology

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Table 24.15 Selected nicotine replacement therapies Form of nicotine Trade name

Strength

Amount of nicotine delivered

Time to peak level

Chewing gum

Nicorette, various generics

2 mg

Up to 0.8 mg

20–30 min

4 mg

Up to 1.5 mg

Commit, various generics

2 mg (geriatric dose)

25% more than gum

Nicoderm CQ, Habitrol, others

16-h patch: 5, 10, 15 mg

Lozenge

20–30 min

Instructions for use

Initial taper

Alternate chewing and parking gum for 20 min. 1 piece q 1–2 h and prn; NTE 24 pieces/day.

6 weeks

Weeks 1–6: 1 lozenge q 1–2 h

6 weeks

Weeks 7–9: 1 lozenge q 2–4 h

4 mg

Weeks 10–12: 1 lozenge q 4–8 h Lozenge should not be chewed or swallowed.

Transdermal patch

Variable

24-h patch: 7, 14, 21 mg

8–9 h

Apply new patch every 24 h to hairless, clean, dry skin on upper body or arm. Rotate sites.

4–6 weeks

For Nicoderm CQ or Habitrol, dose for “young–old” depends on smoking history: ≥10 cigarettes daily—21 mg for 4–6 weeks, then 14 mg for 2 weeks, then 7 mg for 2 weeks. For frail or low body weight elders or those with cardiovascular disease—14 mg for 4–6 weeks, then 7 mg for 2–4 weeks.

Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.

therapy is initiated, the patient must quit smoking to avoid toxic levels of nicotine. Table 24.15 shows nicotine doses delivered by gum, lozenges, and patches. Although the nicotine content of one cigarette ranges from 6 to 11 mg, the actual amount of nicotine delivered by smoking may be only 1–3 mg per cigarette. The amount of nicotine delivered by a replacement product varies according to the dose used. The particular product selected depends primarily on patient preference, although the patch appears to be particularly well suited to elderly patients because it provides a constant rate of nicotine exposure. Both 16- and 24-hour patches are available; the 16-hour patches should be removed at bedtime, and the 24-hour patches should be removed in the morning before the next patch is applied. Removal of the 24-hour patch at bedtime may be indicated if the patient develops insomnia. Patches with smaller doses of nicotine (7, 14, or 15 mg) should be used for elderly patients. Higher doses may be tolerated by young–old patients and are required for those who smoke more than ten cigarettes daily. It is important that tobacco use not continue while the patch is in use, or nicotine levels can become toxic. The recommended treatment period for the patch is 8 weeks. There is no evidence of significant withdrawal when the patch is discontinued. Use of the antidepressant bupropion SR doubles the quit-smoking rate. When used with behavioral interventions, the drug also reduces withdrawal-related dysphoria and weight gain. In acute withdrawal, bupropion is about as effective as nicotine-replacement therapies, and the combination of bupropion with

nicotine replacement may be superior to monotherapy, although the safety of this combination has not been specifically studied in elders. For smoking cessation, bupropion is started while the patient is still smoking, and a “quit date” is selected, usually 1–2 weeks in the future. Bupropion SR should be initiated in most elderly patients at a dose of 100 mg daily; this should be increased to 100 mg bid after 4–7 days, as tolerated. SR doses should be separated by 8 hours. Young-old patients may tolerate an initial dose of bupropion SR 150 mg (Zyban), with a dose increase to 150  mg bid after 4–7 days. Bupropion SR should be continued for 7–12 weeks; at 7 weeks, if the patient has made no progress toward quitting, the medication should be discontinued. The goal of therapy is complete cessation of smoking. Ideally, when this is achieved by 12 weeks, the medication is stopped; tapering is not necessary, although the patient should be monitored for the emergence of depressive symptoms.

Benzodiazepine dependence Psychological dependence on benzodiazepines (“addiction”) may manifest as escalation of dose over time, disagreements with health-care professionals about use, and sometimes antisocial behaviors (such as using multiple providers and/or pharmacies). Addiction to benzodiazepines is more likely to develop in patients with a current or previous history of substance abuse, usually involving tobacco or alcohol. Benzodiazepines most likely to induce psychological dependence are those with fast onset (high lipophilicity) and short duration of action (such as alprazolam) (Ciraulo et al., 2005).

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In contrast, physical dependence is an expected consequence of use of a sufficient amount of a benzodiazepine for a sufficient length of time. Physical dependence does not define addiction. Many individuals who take benzodiazepines chronically to treat an anxiety disorder do not require increasing doses over time, as tolerance to their anxiolytic effects does not develop. On the other hand, even in the absence of psychological dependence, chronic use of benzodiazepines in some elderly patients is associated with depression, residual anxiety, cognitive impairment, daytime sedation, ataxia, falls, and poor physical health. Cognitive impairment with benzodiazepines may present as an amnestic syndrome or as a dementia characterized by inattention, memory problems, psychomotor slowing, and incoordination. Cognitive symptoms generally resolve when these medications are tapered and discontinued. For older patients treated chronically with therapeutic doses of benzodiazepines, a trial off-drug may be indicated. For these patients, a slow taper (by 10–25% per week) is usually tolerated. When very short-acting agents such as alprazolam are used, a switch to a longer-acting drug may be necessary; if so, the equivalent dose of the second drug should be cut by 10–25% to avoid overdosing (Ciraulo et al., 2005). A subset of patients will do poorly, even with slow withdrawal. These patients are likely to have underlying conditions such as GAD, with benefit from chronic treatment that may or may not outweigh the risk. The use of flumazenil is not recommended to expedite withdrawal in elderly patients. Withdrawal for patients treated over the long term with high doses of a benzodiazepine should be accomplished in an inpatient medical setting. The patient should be on a cardiac monitor with frequent checks, and vital signs should be taken on a schedule (for example, every 4 hours). The drug should then be tapered at a rate of 10–25% per day. If the patient develops fever, tremulousness, or diaphoresis, the dose of drug should be increased again, and the patient should be hydrated and watched more closely until stable. The emergence of new symptoms or a new perceptual disturbance (such as tinnitus) can help to identify too-rapid withdrawal and to distinguish it from anxiety (Ciraulo et al., 2005). Propranolol (30–60 mg daily divided tid) may be used to attenuate adrenergic signs and symptoms, and an anticonvulsant may prevent or treat seizures. After the period of detoxification, medications that can help promote abstinence include buspirone, SSRI antidepressants, and venlafaxine (Ciraulo et al., 2005).

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Van Putten, T., Marder, S.R., Mintz, J., and Poland, R.E. (1992) Haloperidol plasma levels and clinical response: a therapeutic window relationship. Am J Psychiatry, 149: 500–505. van Steveninck, A.L., Wallnofer, A.E., Schoemaker, R.C., et al. (1997) A study of the effects of long-term use on individual sensitivity to temazepam and lorazepam in a clinical population. Br J Clin Pharmacol, 44: 267–275. Walsh, K., and Bennett, G. (2001) Parkinson’s disease and anxiety. Postgrad Med J, 77: 89–93. Weintraub, D., and Hurtig, H.I. (2007) Presentation and management of psychosis in Parkinson’s disease and dementia with Lewy bodies. Am J Psychiatry, 164: 1491–1498. Yosselson-Superstine, S., and Lipman, A.G. (1982) Chlordiazepoxide interaction with levodopa. Ann Int Med, 96: 259–260. Young, R.C. (2005) Bipolar disorder in older persons: perspectives and new findings. Am J Geriatr Psychiatry, 13 (4): 265–267.

Chapter 25 Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia Gary A. Martin1 and John Ranseen2 1 2

Integrated Geriatric Behavioral Health Associates, Scottsdale, AZ, USA Department of Psychiatry, University of Kentucky College of Medicine, Lexington, KY, USA

Summary • Dementia patients commonly exhibit neuropsychiatric and behavioral symptoms such as physical and nonphysical aggression, anxiety, irritability, dysphoria, aberrant motor behavior, disinhibition, delusions, and hallucinations. • Behavioral problems are associated with a worse prognosis that can diminish the quality of life for both the patient and the caregiver and is one of the main reasons for institutionalization. • Most dementia-related behavioral problems are linked to confusion, delirium, medication-induced delirium, pain, environmental factors, and the intrusive aspects of caregiving. • Models of nonpharmacologic treatments include good care/comfort care, unmet needs, environmental intervention, learning theory, antecedent control, family and caregiving education and training, and psychosocial and individualized therapies. • Treatments for specific dementias • AD: Antecedent control strategies are more effective than consequence-oriented learning, especially in advanced stages. • VD: Variability in clinical presentation and severity makes it difficult to prescribe a certain treatment. Those with higher cognitive ability may benefit from social learning approaches. • LBD: Environmental and antecedent control techniques may be most effective. Caregiver education and training also help to manage LBD behaviors. Physical restlessness may be addressed with “on the run” care. • FTDs: Environmental and behavioral treatments are most recommended, including “on the run” care. • PD: Environmental, psychoeducational, and counseling-oriented interventions are most recommended. Research suggests that caregivers speak and act slowly with frequent repetition, avoid multi-tasking, and make use of compensatory strategies.

Introduction

Prevalence

Health-care professionals in the field of geriatrics are well aware that behavioral and psychiatric symptoms are extremely common in persons with dementia. When it comes to treating these problems, a majority of the energy, funding, and literature has focused on pharmacologic options to treatment. However, over the past decade, there has been a growing interest in the development and use of nonpharmacologic treatment approaches to addressing dementia-related behavioral problems. This chapter provides an overview of the use of nonpharmacologic interventions in treating behavioral problems associated with common types of dementia.

More than 60% of community-dwelling persons with dementia exhibit some sort of neuropsychiatric or behavioral symptoms. The rate of aggressive behavior for this population is from 34% to 64% (Lyketsos et al., 2000; McNeese et al., 2009). In institutional settings, such as nursing homes and assisted living centers, the percentages are even higher, at more than 80% exhibiting neuropsychiatric or behavioral symptoms. The lifetime risk of developing such problems approaches 100% (Lyketsos et al., 2000; Jeste et al., 2008). The prevalence of nonphysical aggression or agitation in nursing homes is reported to be between 48% and 82%, with physically aggressive

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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behavior ranging from 11% to 44% (Zuidema et al., 2007). Other overall symptom prevalence rates for persons with dementia include anxiety (48%), irritability (43%), dysphoria (38%), aberrant motor behavior (38%), disinhibition (36%), delusions (22%), and hallucinations (10%). Prevalence of psychosis is 25% in cross-sectional studies and 50–70% in longitudinal studies (Mega et al., 1996).

Common behavioral problems The list of behavioral problems commonly exhibited by persons with dementia is lengthy and includes such behaviors as combative with care, assaultive to peers and caregivers, sexual acting out, verbal abuse, physical restlessness, wandering, rummaging, hoarding, elopement, inappropriate urination, sleep disturbances, eating disorders, repetitive/disruptive vocalizations (crying, moaning, yelling), disrobing in public, and “sundowning.” Related psychiatric conditions such as depression, anxiety, and psychotic thinking are also reported, including related symptoms of apathy, social withdrawal, obsessive–compulsive behaviors, delusions, and hallucinations (Zuidema et al., 2007). The literature discusses behavioral problems in broad, vaguely defined terms like agitated, aggressive, and disruptive. Phrases like behavioral disturbances and neuropsychiatric symptoms are often used interchangeably, without being more specific or descriptive in their definitions. As such, problematic behaviors in dementia patients lack accepted uniform definitions, making it difficult to compare studies in this area. Agitation, for example, is a widely used term in the literature, yet it includes a variety of related but discretely different behaviors such as irritability, restlessness, physical and verbal aggression, resisting caregivers, pacing, and wandering (Teri et al., 1998). “Aggressive behavior” is often associated with acts of violence against others, but it can also include verbally threatening/abusive behaviors or even various forms of property destruction and disruptive behaviors (Turner, 2005; Pulsford and Duxbury, 2006). While this inconsistency in nomenclature poses obvious problems for researchers and academicians, it does not negate the fact that behavioral problems are not only common, but nearly universal when it comes to persons with dementia, especially as their dementia progresses.

Clinical repercussions The clinical repercussions of these behavioral problems can be quite serious. Dementia patients who exhibit neuropsychiatric and behavioral symptoms have a worse prognosis than their peers. They tend to follow a more rapid course of decline in cognition, exhibit diminished

functional skills, have a higher mortality rate, and experience a diminished quality of life (Jeste et al., 2008). In addition, their caregivers experience greater problems with distress, negative feelings, emotional exhaustion, and general burnout (Pulsford and Duxbury, 2006). This, in turn, increases the possibility of caregivers acting physically or emotionally abusive toward the persons for whom they provide care (Gates et al., 2003). Moreover, for noninstitutionalized patients who live in the community, neuropsychiatric and behavioral symptoms are often the reason for families placing their loved ones in nursing homes and other institutional settings (Buhr et al., 2006).

Rationale for nonpharmacologic approaches The most common treatment modality for dementia patients with behavioral problems is pharmacologic. A 2005 comprehensive review of 2.5 million Medicare beneficiaries residing in nursing homes found antipsychotic medications being prescribed at the highest levels in more than a decade (Briesacher et al., 2005) with the greatest number going to persons with dementia who exhibit behavioral disturbances (Jeste et al., 2008). A recent study of nursing home admissions found that, in the first 3 months, 71% of all new admissions received at least one psychoactive medication, with 15% receiving four or more such medications. This occurred even though, 6 months prior to admission, nearly two-thirds of those patients were receiving no psychoactive medications. Conversely, only 12% of those same newly admitted patients received some sort of nonpharmacologic treatment (Molinari et al., 2010). But psychoactive medications have their challenges and pitfalls. First, many behavioral problems are the direct result of environmental stressors and poor caregiving practices rather than being a function of any neuropsychiatric condition (Kitwood, 1997; CohenMansfield and Mintzer, 2005; Pulsford and Duxbury, 2006). For example, patients will become agitated when physical and emotional needs are not met (Algase et al., 1996; Cohen-Mansfield, 2000). While medications may diminish neuropsychiatric and behavioral symptoms, they do not address the cause of the behavior, which may go undetected and unresolved. (Cohen-Mansfield and Mintzer, 2005). Second, many of the drugs used to treat neuropsychiatric and behavioral symptoms can cause lethargy, cognitive slowing, and increased confusion and greatly increased risk for morbidity and complications from falls, failing mobility, and the development of parkinsonism. These medications can further incapacitate dementia patients who already suffer cognitive and functional decline

Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia

from their dementia, potentially depriving them of what limited resources are still available to them (Cohen-Mansfield and Mintzer, 2005). Third, studies suggest that the pharmacologic treatment of problems such as psychosis and agitation may not be as effective as was once believed (Sink et al., 2005). While some clinical trials have shown modest efficacy in symptom reduction, others have yielded limited or no positive results (Schneider et al., 2006). Moreover, the placebo response rate in clinical trials on the use of antipsychotic medications with dementia patients is between 30% and 50%, raising questions about the use and efficacy of those medications, especially when balanced with their side effect burden (Jeste et al., 2008). Fourth, elderly persons with dementia are particularly susceptible to the adverse side effects of psychoactive medications. Anticholinergic, extrapyramidal, and parkinsonian side effects are common. To date, the FDA has not approved any medications for the treatment of behavioral symptoms in patients with dementia, so all such treatment is “off label.” There is also a growing concern over the potential for cerebrovascular adverse events and higher mortality rates with the use of certain antipsychotic medications, prompting the FDA to issue “black box” warnings in 2003 and 2005 (US FDA, 2005). As a result, the American Geriatrics Society and the American Association for Geriatric Psychiatry in a consensus statement ( American Geriatrics Society and the American Association for Geriatric Psychiatry, 2003) recommended, “After associated medical conditions are assessed and treated, the initial treatment of behavioral symptoms should be nonpharmacologic when there are no psychotic features and when there is no immediate danger to the resident or others” (p. 1295). This recommendation was reinforced in a white paper article by the American College of Neuropsychopharmacology (Jeste et al., 2008) recommending that “good clinical care, independently from pharmacotherapy, may be helpful for patients with dementia-related psychosis and/or agitation, and their caregivers, through nonspecific and specific interventions. Nonspecific interventions such as empathy and attention to interpersonal and social issues may be particularly helpful [while] specific interventions include environmental, psychosocial, behavioral, and medical interventions” (p. 965). It was further noted that “not all psychotic symptoms or agitations need pharmacotherapy. Only severe symptoms that are persistent or recurrent and cause clinical significant functional disruption would generally be considered appropriate for ongoing pharmacologic management” (p. 966). Overall, these conclusions seem unequivocal. The pharmacologic treatment of behavioral problems exhibited by persons with dementia should be considered as a last resort rather than first resort.

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Types of dementia: the brain, cognition, and behavior Although numerous types of dementias arise, the nonpharmacologic treatment of dementia has focused on those with the highest prevalence rates, including Alzheimer’s disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD), Parkinson’s disease with dementia (PDD), and vascular dementia (VD). Although AD, LBD, FTD, and PD are considered distinctly different entities, there is a great deal of overlap in etiology, underlying neuropathology, symptom presentation, and course of illness (Holmes et al., 1999; Barker et al., 2002). All involve degenerative neuronal changes leading to brain atrophy. Additionally, it is not unusual for VD to coexist with other dementias, particularly AD (Roman, 2001; Karlaria, 2002). Thus, all the dementias can display typical cognitive impairment with decline over time, affecting attention and memory, language, visuospatial skill, and executive functions. All dementias can directly impact areas of the brain implicated in modulating emotional control such as the amygdala, cingulate gyrus, insula, and inferior frontal cortex. Thus, patients with dementia often exhibit increased behavioral volatility, emotional lability, and impulsivity. Similarly, other problematic behavioral presentations, including apathy or inactivity, psychosis, loss of self-awareness, inappropriate social behavior, and resistance to caregiving, can be evident in any of the dementia types. However, differences in underlying neuropathology lead to different general patterns of cognitive and behavioral functioning between the dementias particularly early in the disease course. Understanding these distinct behavioral problems and cognitive profiles is critical in differential diagnosis and behavioral treatment strategy.

Alzheimer’s disease AD, by far the most commonly encountered dementia, is characterized by loss of neurons in the cerebral cortex, usually starting in the medial temporal lobes and including the hippocampus, parahippocampal gyri, and subiculum. A loss of cholinergic neurons in the nucleus basalis of Meynert and locus ceruleus is found, with the loss of cortical neurons predominantly affecting large pyramidal neurons. Cell loss extends fairly rapidly to the parietal and frontal lobes. Microscopic neuronal changes include distinct contortions of neurofibrils termed neurofibrillary “tangles,” with structures outside of the neuron known as neuritic plaques, composed of an amyloid core surrounded by degenerating dendrites and axons. Early changes to the cholinergic projection system result in the typical early clinical presentation involving impairment in memory and new learning. Due to the involvement of limbic structures, some change in emotionality is common, yet relative preservation of

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social tact and personality is often noted until later in the disease course. This is attributed to relative preservation of frontal lobe neurons, which is in notable contrast to FTD. Progressive cortical atrophy, however, leads to impairment across multiple cognitive domains leading to a full range of behavioral problems and necessitating increasingly higher levels of care as the disease progresses. Along with diminishing self-help skills and safety-related problems (driving, cooking, getting lost), behaviors typical of early-stage AD are often associated with depression and anxiety, including social withdrawal, personal neglect, temper outbursts, and repetitive verbalizations and actions. Behavioral problems found in the middle/ moderate stages of AD are quite varied and tend to be associated with confusion and the subjective distress found in individuals who do not fully understand their surroundings and the actions of others, especially caregivers. Thus, their behavioral problems are often classified as “agitated,” “aggressive,” or “disruptive.” Patients with advanced AD are most susceptible to issues of comfort and tend to exhibit behavioral problems in response to physical, environmental, and psychosocial discomforts.

Vascular dementia VD is a term used for a heterogeneous group of disorders in which dementia is due to cerebrovascular insufficiency. Considered the second most common general dementia, VD can result from multiple causes, including large or small vessel disease, thromboembolism, a stroke affecting a critical brain area, small cortical and/or subcortical strokes, cortical hypoperfusion, hemorrhagic events, or mixed VD–AD pathology. In fact, half of all dementias are thought to involve a mixed VD–AD process (Mendez and Cummings, 2003). VD is determined by a history of vascular risk factors, focal neurologic signs, and neuroimaging. Multiple small vessel lacunar infarcts and white matter lesions account for a majority of VD cases. Given its heterogeneous nature, multiple clinical presentations can be seen. Some generalizations regarding VD with multiple infarcts include a less continuous decline in function with stepwise deterioration of cognitive and behavioral functions, reflecting abrupt changes due to new infarcts. Focal neurologic signs might include weakness, hemiparesis, sensory deficit, dysarthria, incontinence, and gait disturbance. Abrupt neuropsychological signs might include transient confusion, language impairment, memory impairment, or changes in emotions and personality. However, VD patients typically exhibit less severe memory impairment and retain good awareness for these changes relative to their AD counterparts. They often have a greater degree of motor and cognitive slowness. In contrast to the other dementias, patients with VD can have highly variable clinical course with progressive decline, lengthy static periods, or even some degree of remission.

Because of this highly variable clinical course, patients with VD tend to exhibit an idiosyncratic pattern of behaviors that varies greatly from one person to the next. As with AD and FTD, apathy, irritability, and agitation are common. Patients with VD tend to exhibit more overt symptoms of depression and emotional lability than patients with the other dementias. As with patients with AD and LBD, VD patients tend to exhibit problems associated with disinhibition. Nevertheless, some studies have found no significant difference between VD and AD on neuropsychiatric symptom profiles (Srikanth et al., 2005).

Lewy body dementia LBD is a disease characterized by overlapping clinical characteristics with both AD and PD. Although there is diffuse cortical involvement, neuropathology finds Lewy body inclusions but a lesser or absent number of neurofibrillary tangles and senile plaques characteristic of AD. There is a loss of dopamine-producing neurons in the substantia nigra similar to PD neuropathology, as well as a loss of acetylcholine-producing neurons in the basal nucleus of the Meynert and elsewhere similar to AD. Specific symptoms and behavioral patterns of patients with LBD vary; however, the core features include progressive dementia, but with fluctuating cognition with variations in attention and alertness, recurrent visual hallucinations, and motor symptoms similar to PD (McKeith et al., 2005). These patients may tend to be quite reactive to medications, particularly antipsychotic medications, but also including L-dopa. Up to 50% of patients with LBD who receive antipsychotic medication experience severe neuroleptic sensitivity, including worsening cognition, heavy sedation, increased parkinsonism, or neuroleptic malignant syndrome (Lewy Body Dementia Association, 2010). Neuropsychiatric symptoms generally include apathy that is characterized by decreased spontaneity, motivation, and effortful behavior. Changes in personality and mood are common and can include symptoms of depression and anxiety. Visual hallucinations occur in approximately 80% of LBD patients (Keister, 2006). Symptoms also often include paranoid delusions and excessive daytime sleepiness. Delusional thinking may include reduplicative paramnesia. REM sleep behavioral disorder may present years before the onset of dementia, as may symptoms of parkinsonism. Frontotemporal dementias FTDs include a group of degenerative brain disorders that share many neuropathologic features with each other and with AD. However, neural degeneration is seen predominantly within the frontal and temporal lobes rather than the temporal and parietal lobes, which is more characteristic of AD. One defined FTD is that of Pick’s disease (also known as behavioral variant FTD (bvFTD) or frontal variant FTD (fvFTD)) that is diagnosed on neuropathologic

Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia

criteria rather than on clinical presentation. Atrophy tends to be more circumscribed and asymmetric than seen in AD. Histology finds that neurons are swollen, with a characteristic argentophilic or “Pick body” within the cytoplasm. It is unclear whether other FTDs that do not show Pick’s bodies are distinct disorders, but the clinical presentation tends to be quite similar. In contrast to AD, FTD is more likely to strike at a younger age and to first present with personality and emotional changes attributable to executive functioning deficits associated with frontal lobe changes (Mendez et al., 1993). Primary progressive aphasia and semantic dementia are FTD variants that result from atrophy of the temporal lobes. Patients suffer from prominent language impairment with decreased fluency, word-finding difficulty, paucity of speech, and eventual loss of language comprehension and mutism. Patients with these FTD variants are not prone to exhibiting significant behavioral problems. Loss of social tact, social disinhibition, poor selfawareness, and lack of judgment are symptomatic of the bvFTD/fvFTD and often cause serious social and family problems. Early on, patients may lose their sense of safety and demonstrate poor financial judgment, compulsive buying, and other compulsive behaviors (such as hand washing). As the FTD progresses, patients often exhibit increasing problems with apathy and social withdrawal. They are also prone to exhibiting more overt signs of disinhibition, including hypersexuality (sexually touching others, public masturbation, exhibitionism) and/or an insatiable appetite and food-seeking (Srikanth et al., 2005; Weiss, 2010). Patients may have relatively preserved memory, so psychiatric diagnosis and treatment prior to recognition of dementia are quite common (McKhann et al., 2001). Active behavioral and family intervention often is necessary in such cases early in the course of the illness. Over time, patients with FTD typically become gradually less involved in routine daily activities and withdraw emotionally from others. Additional behavioral problems include impulsivity, repetitive and stereotyped behaviors, and poor personal hygiene.

Parkinson’s disease Parkinson’s disease (PD) is a disorder that affects motor systems due to basal ganglia disease, leading to the core features of bradykinesia, resting tremor, postural instability, and rigidity. PD is associated with a loss of pigmented cells in the substantia nigra, impacting dopaminergic projection systems. Remaining cells contain eosinophilic cytoplasmic inclusions surrounded by a halo, known as Lewy bodies. Patients may display very subtle motor problems, typically asymmetric at first, predating formal diagnosis, such as mildly reduced movement, stiffness, and reduced eye blinking. With disease progression, patients may develop slowed voluntary

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movement, an expressionless face (sometimes referred to as “mask-like”), tremor of fluctuating severity, a gait that may become shuffling with small steps to avoid falling (“festinating”), and significant muscular rigidity. Although a majority of patients exhibit difficulties largely confined to motor changes, a significant number (approximately 30%) also exhibit a progressive dementia with changes similar to AD (Aarsland et al., 2005). Such cases sometimes involve multisystem atrophy and are referred to as one of the “Parkinson’s plus” disorders (as is LBD). Subtle cognitive changes in patients with PDD include significantly slowed mentation, impairment in memory recall (less than typical of AD), difficulty with effortful memory tasks, visuospatial impairment, and diminished executive functioning. With disease progression, deterioration in problem solving, cognitive flexibility, and decreased initiative may reflect relative atrophy of frontal executive control systems. Depression, apathy, anxiety, and other neuropsychiatric problems are common in PDD, although slowed movement and facial rigidity can also be misdiagnosed as indicative of mood disturbance. Dopaminergic medications used to treat PD can result in additional neuropsychiatric symptoms, including visual hallucinations, delusions, and sleep disturbances; as well as problems with impulse control and repetitive behavioral disorders, such as compulsive buying, gambling, engaging in sexual behavior, and punding (Lee et al., 2010; Sohtao lu et al., 2010).

Aggravating factors Researchers and clinicians have posited a number of models to explain the underlying causes of neuropsychiatric and behavioral symptoms in persons with dementia. The medical model focuses on biologic and genetic causes, with behaviors characterized as psychiatric or neurologic syndromes. This model emphasizes a pharmacologic approach to treatment and strives to develop psychoactive agents that are more effective in modifying and alleviating neuropsychiatric symptoms and behaviors. In contrast, various psychosocial models emphasize the impact of social and environmental factors on dementia patients. These models are not mutually exclusive, and most experts acknowledge that biomedical, genetic, environmental, and social factors all come into play when considering the reasons people with dementia exhibit behavioral problems. Regardless of the origins of a person’s dementia and associated symptoms and behaviors, it is clear that exigent factors, including confusion, delirium, pain, medication interactions, and environmental stressors, aggravate these symptoms and must be considered when assessing and treating patients with dementia who exhibit behavioral problems.

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Confusion While the issue of confusion seems all too obvious when discussing problems associated with dementia, it is nonetheless a subject worth addressing. A clear relationship exists among a patient’s severity of dementia, level of confusion, and severity of neuropsychiatric and behavioral symptoms. Thus, the more confused a person becomes, the greater the likelihood of behavioral problems (Teri et al., 1988). Confusion is at the heart of most dementia-related behavioral problems. People with early-stage dementia become confused with handling money, driving their cars, and managing their lives, resulting in misunderstandings, missteps, accidents, and increased frustration and depression. People with moderate-stage dementia have difficulty understanding their surroundings and the actions of others, including and especially caregivers, to the point of acting on their confusion in highly problematic ways (wandering, intrusions, defensive/reactive aggression, elopement, paranoid actions). With advanced dementia, the confusion is so profound that virtually any type of stimulation, including well-intentioned handson caregiving, can be emotionally distressing, and simple sensory stimuli can be startling and overwhelming (Martin and McCarthy, 2011). When confused dementia patients do not understand what is going on around them or do not understand the actions of others, they are more likely to become upset, scared, and reactive. They are prone to seek familiar surroundings when none exist, and they are more likely to retaliate against caregivers who are perceived as strangers violating them. In addition, they are more likely to have problems identifying, understanding, and controlling such basic feelings as pain, discomfort, loneliness, and boredom, so the expression of subjective discomfort and distress is often reduced to basic and reflexive emotional and behavioral responses (fight-or-flight reactions, physical restlessness, distressed vocalization). Although psychoactive medications might be helpful in alleviating a sense of distress, those same medications may result in an overlay of additional confusion that could actually exacerbate behavioral symptoms. Conversely, efforts to make the environment and social interactions clearer and less confusing can diminish situational confusion and help alleviate behavioral symptoms, with no such side effects. Delirium Older adults, including those with dementia, are at increased risk of experiencing delirium. Persons with dementia are especially prone to delirium, even from such seemingly minor stressors as urinary tract infections, mild injuries, or low levels of pain. It is significant to note that the superimposition of delirium on dementia has been estimated to be high, ranging from 22% in patients living in the community, to 89% in hospital patients (Fick et al., 2002). Statistically, delirium in persons with dementia

is associated with significant morbidity, mortality, and resource utilization (Fick et al., 2002). Because of their impaired cognition and diminished functional abilities, it can be difficult to distinguish delirium from dementia, or to recognize delirium superimposed on dementia. As a result, delirium can go unrecognized, and underlying acute medical disorders such as infection, electrolyte imbalance, dehydration, metabolic disturbances, and adverse drug reactions then may go undiagnosed and untreated (Fick and Foreman, 2002). In persons with dementia, sudden changes in behavior are often symptomatic of delirium. These behaviors are usually accompanied by changes in levels of consciousness and attention. In nearly all persons with moderate or greater dementia, delirium causes a significant decline in cognitive, behavioral, and functional abilities. Associated behaviors may include agitation, restlessness, extreme lethargy, crying/moaning, repetitive vocalizations (including yelling), changes in appetite, and/or changes in sleep pattern. In addition, patients with delirium may also exhibit neuropsychiatric symptoms, including hallucinations, paranoia, and delusions. Because delirium is such a grave prognostic sign, health-care professionals, caregivers, and family members must be suspicious of its occurrence whenever they observe abrupt behavioral changes in persons with dementia.

Medications Virtually any medication or medication interaction can have adverse effects on the behaviors of persons with dementia, much in the same way that many acute medical conditions trigger delirium. Because the aging process changes the pharmacokinetics and pharmacodynamics of medications in elderly patients, they are more prone to adverse reactions than other age groups. Moreover, most drugs in the market do not have clear dosing recommendations for the elderly, and polypharmacy prescribing is high. As a result, iatrogenic drug-related delirium is common in the elderly, and even more so in persons with dementia, due to their relatively high rate of psychotropic drug use and the potential for adverse affects from those medications (Whitehouse and George, 2008). As with delirium, adverse effects from medications often cause neuropsychiatric and behavioral symptoms in dementia patients, including agitation, restlessness, extreme lethargy, changes in appetite, changes in sleep pattern, and psychosis. A sudden onset of behavioral symptoms or rapid changes and unusual presentations of current behaviors are the behavioral hallmark of medication-induced delirium, especially when symptoms coincide with a change in medication regimen. In cases of medication-induced delirium, sometimes the only symptoms present are changes in behavior, so it is important for hands-on caregivers to observe and report to their health-care providers any such changes noted.

Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia

Pain Pain of any sort potentially alters and aggravates the behaviors of persons with dementia. Dementia patients who are in pain tend to express their pain through their behaviors. Common behavioral problems associated with dementia can be very basic and reflexive responses to pain and, as such, are diagnostic indicators of pain. Examples include moaning, crying, yelling, repetitive vocalizations, verbal abuse, fidgeting, pacing, rocking, motor restlessness, resisting care, physical aggression, and irritability (Buffman, Hutt, Chang, Craine and Snow, 2007). Unfortunately, these patients often cannot identify, describe, locate, or otherwise verbalize their pain; as a result, they are less likely to be assessed or treated for pain (Fries et al., 2001). Instead, caregivers and medical providers are likely to interpret the behavioral symptoms as “agitation” and prescribe psychoactive agents rather than pain medications. Consequently, pain may go unrecognized and untreated while psychotropics are given that can mask the pain, making it even more difficult to recognize and treat (Dougherty, Sgrillo, and Swan, 2011). Of the more than two million elders living in nursing homes today, as many as 65% suffer from some form of persistent pain (Brown, 2001). Yet less than half of the nursing home patients who experience pain are prescribed routine pain medications (Hutt et al., 2006). Moreover, while persons with cognitive impairment experience pain at a higher rate than those who are cognitively clear, they are less likely to be assessed and treated for their pain (Fries et al., 2001). In effect, as their dementia progresses, patients are more likely to experience pain but are less likely to be treated for it. This is one of the several reasons, there is a significant correlation between severity of dementia and the severity of neuropsychiatric symptoms (Cohen-Mansfield and Libin, 2005). Environmental stressors The behaviors of persons with dementia often reflect their environment. If the environment is either over-stimulating or under-stimulating, or has noxious, disturbing, or sterile (in other words, institutional) qualities, the person with dementia will often behave in a distressed or agitated fashion. The list of environmental stressors in longterm care settings is lengthy and includes such things as high volumes on televisions or stereos, darkness or bright lights, heavy foot traffic and intrusions by peers and caregivers, loud and busy meals, high-energy activity programs, and loud talking and laughing between caregivers. Additionally, each person is unique and has his or her own idiosyncratic environmental stressors. Yet the patient is often unable to articulate what is bothersome. Consequently, unsuspecting caregivers may never realize the cause-and-effect of the situation and are likely to ignore the behavior or seek further pharmacologic treatment, rather than remedy the problem in the environment.

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As a general rule, the environment must be made as warm, personable, comfortable, and homelike as possible. A large body of literature addresses environmental design for persons with dementia (Fazio, 1999; Brawley, 2001; Calkins, 2001; Werezak and Morgan, 2003; Chalfont, 2007; Cutler, 2007; Rabig et al., 2007; Dewing, 2009; Geboy, 2009; Martin et al., 2011). Recommendations tend to cover issues including the use of space, furniture placement, seating arrangements, personalizing space, accessibility of activity props, and dining arrangements. They also make recommendations about decorations, colors, flooring materials, window treatments, and other aspects of the physical environment that can impact subjective comfort and behavior. Nursing homes and other care facilities can be unpleasant places for any person to live. The nursing home resident must contend with bright lights, hard surfaces, cold hallways, loud noises, and unpleasant odors. There is often a constant commotion as caregivers perform their jobs, residents engage in activities, visitors come and go, housekeepers clean, and maintenance workers make repairs. The sounds of televisions, call bells, overhead intercoms, telephones, alarms, and cleaning equipment combine with loud activity programs, staff conversations, and disruptive residents. The onerous smells of disinfectants, detergents, and urine are common, while mealtimes and shift-change times can be chaotic. In this type of environment, it is easy to understand why confused persons with dementia exhibit agitated and aggressive behaviors.

Caregiving As patients with dementia decline, they require an everincreasing hands-on care. They become increasingly dependent on others for assistance in all aspects of their lives, including basic issues of grooming and hygiene. Eventually, they come to need total care, relying on others to handle all activities of daily living, including ambulation, continence care, and feeding. Caregiving for persons with dementia involves highly personal, intimate, and intrusive actions on the part of caregivers. These actions can be, and often are, physically and emotionally uncomfortable and distressing to persons with dementia, especially because their increasing confusion renders them unable to comprehend their own need for care or the actions of their caregivers. The intrusiveness and physicality of caregiving can trigger reflexive emotional and behavioral responses in confused patients, including resisting, fighting, yelling, crying, and other symptoms of emotional distress. Aggressive behavior exhibited by persons with dementia occurs most frequently when they are receiving the most intimate types of care, such as incontinence care and bathing (Keene et al., 1999). Moreover, aggressive behavior increases when a caregiver’s approach is characterized by negative communication or disrespect, or by rushing and not giving

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verbal prompts (Skovdahl et al., 2003; Somboontanont et al., 2004). The common practice of focusing on getting the task done quickly instead of on the process of interacting with the person receiving the care significantly increases the likelihood of aggression.

Nonpharmacologic treatment The fairly large body of nonpharmacologic treatment research shows results that, overall, are positive and impressive. Experts agree that nonpharmacologic treatment approaches are often effective in diminishing dementia-related behavioral problems (Cohen-Mansfield, 2001; Livingston et al., 2005; Spira and Edelstein, 2006; O’Connor et al., 2009). The accepted protocol for treating behavioral problems in patients with dementia is to first assess for possible delirium, including issues relating to medication reactions and possible undiagnosed pain. Nonpharmacologic interventions should be attempted before proceeding to psychopharmacologic treatment, especially if there are no psychotic features and there is no immediate danger to patients or their caregivers (American Geriatrics Society and the American Association for Geriatric Psychiatry, 2003; Cohen-Mansfield and Mintzer, 2005; Pulsford and Duxbury, 2006; Salzman et al., 2008; Kalapatapu and Neugroschl, 2009). However, the current nonpharmacologic treatment research has drawbacks. Most of the studies are based on single-case designs or include relatively few participants. Additionally, most of the research is conducted in residential care settings, where standardization and strict adherence to research protocols are challenging. As a result, caution is advised when drawing conclusions from a number of these studies (Ayalon et al., 2006; Pulsford and Duxbury, 2006; Jeste et al., 2008). Moreover, most of the research does not meet the strict requirements necessary to be considered evidencebased treatments. The reasons for this include the following: • Poor funding (Cohen-Mansfield, 2001; CohenMansfield, 2003; O’Connor et al., 2009) • General frailty, cognitive deterioration, and high attrition (illness, death) in research subjects (CohenMansfield, 2001; Logsdon et al., 2007) • Poorly controlled research settings (Cohen-Mansfield 2001) • Variability and inconsistencies in caregivers (Logsdon et al., 2007) • A culture of care that resists change (O’Connor et al., 2009) • Simultaneous and confounding use of psychoactive medications (Cohen-Mansfield, 2001) • A lack of methodological rigor in research designs (Spira and Edelstein, 2006; Logsdon et al., 2007)

Nonpharmacologic treatment models

Good care/comfort care Treating behavioral problems begins with the concept and practice of good patient care. People with dementia who do not receive good care are much more likely to experience the pains and discomforts that lead to exacerbated behavioral problems. Cohen-Mansfield and Mintzer (2005) reported that a substantial portion of dementia-related behavioral problems occur when the needs of persons with dementia either go unrecognized or are not adequately addressed by their caregivers. Such needs include hunger and thirst, cleanliness and hygiene, and the appropriate treatment of pain. But this also includes more complex social and emotional needs, such as treatment for boredom and loneliness. The practice of good care assumes that quality time will be spent with patients so that caregivers will more likely be able to identify and resolve the causes of problematic behavior without the need for psychopharmacology. Health-care professionals should never assume that this type of good patient care is the norm or that it is being provided to their individual patients. In a similar vein, Martin and McCarthy (2011) discuss the importance of subjective comfort, labeling dementia care as “comfort care.” In this regard, making the person with dementia comfortable, both physically and emotionally, is one of the primary considerations in the care of all persons with dementia, including those with behavioral problems. Persons with dementia, who are truly comfortable, are likely to be less confused, are more functional, and exhibit fewer behavioral problems than those who are physically or emotionally uncomfortable. Patients who are comfortable rarely hit, scream, moan, or cry, and are much less likely to be agitated or restless (Pelletier and Landreville, 2007).

Unmet needs The unmet needs model for the care of persons with dementia considers behaviors as indicators of unmet needs. In this model, problematic behaviors stem from normal human needs—physical, emotional, and social— that caregivers fail to recognize, understand, or address. Effective interventions require that caregivers gain a deep understanding of the persons for whom they care so that they can anticipate, prevent, and/or resolve needs, thus diminishing or eliminating the behaviors associated with those needs. This includes basic care issues associated with hunger and thirst, hygiene and grooming, and toileting procedures, as well as sufficient lighting, better communication, and proper treatment of pain. Just as important, less tangible needs must be addressed, including quality social interactions, adequate and appropriate sensory stimulation, and engagement in meaningful activities. The unmet needs model covers a wide range of approaches and greatly overlaps general health-care practices and virtually all other nonpharmacologic treatment

Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia

models. The literature from this model includes studies involving environmental approaches, antecedent control, sensory stimulation, and psychosocial interventions. Additionally, all caregiver training should include ways to identify, anticipate, and address the many needs of dementia patients. The evidence-based treatment (EBT) research strongly supports the efficacy of these treatment efforts (Cohen-Mansfield and Mintzer, 2005; Kovach et al., 2005; Turner, 2005).

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reductions in behavioral problems (Ayalon et al., 2006; Logsdon et al., 2007) and others reporting inconsistent results or no effects (Cohen-Mansfield, 2001; Spira and Edelstein, 2006). Some authors note that consequenceoriented approaches should be viewed with caution because persons with dementia exhibit deficits in learning new skills (Weiner and Teri, 2003). Others argue that dementia patients can potentially learn new behaviors and that interventions based on learning theory should be further explored (Spira and Edelstein, 2006).

Environmental interventions The literature includes a plethora of information concerning the importance of environmental interventions on minimizing dementia-related behavioral problems. Environmental interventions are often inexpensive, are easy to administer, and appear to intuitively make sense to caregivers. For example, simply removing objects or other stimuli that cause patients to become agitated or to act inappropriately can reduce many problematic behaviors. This can be as simple as locking or unlocking doors, improving lighting, eliminating noxious sounds, or changing flooring patterns at exit doors. This can also include interventions such as changing paint colors and other furnishings, using environmental prompts to aid with orientation, and strategically using light, music, or even television to help comfort or stimulate a person. Virtually all reviews of the research have found wellconstructed environmental interventions effective in reducing problematic behavior, including wandering, physical aggression, and verbal aggression, as well as various forms of agitation (Spira and Edelstein, 2006). In addition, aroma therapy and individualized music have been effective in calming agitated dementia patients (O’Connor et al., 2009) as has bright light therapy (Lovell et al., 1995).

Learning theory model Learning theory involves identifying the antecedent conditions and the consequences that trigger, reinforce, and control problematic behavior so that learning situations can be modified to improve the behavior. Consequences can either encourage or discourage new behaviors and are given strategically to increase positive behaviors and decrease problematic behaviors. The most commonly cited use of the learning theory with dementia patients is the A-B-C approach to behavioral analysis. In this approach, A stands for antecedents, B is behavior, and C is consequences, with an emphasis on the relationship between B and C and how the consequences of behaviors impact those behaviors. Interventions typically involve the immediate delivery of reinforcing positive consequences to patients after they exhibit positive behaviors, as a means of promoting repetition and encouraging them to learn those positive behaviors. Results in studies using the learning theory model are inconsistent, with some studies reporting significant

Antecedent control Antecedent control focuses on the relationship between antecedents and behaviors (the A-B connection in the “A-BC” triad) and how the antecedents to behaviors can alter and control those behaviors. Unlike learning theory, antecedent control does not require the individual to remember or learn anything new for behaviors to change. This form of behavioral treatment first identifies the aspects of the situation that trigger a behavioral problem (characteristics of the environment, caregivers’ approaches, and so on) and then changes the antecedents to something more likely to trigger more appropriate behaviors. Researchers note that interventions using antecedent control are particularly useful with dementia patients because they capitalize on already-established aspects of an individual’s behavioral repertoire and do not require new learning to take place. Many of the reviews of the research report positive results from interventions based on this model, especially for problems with wandering, physical aggression, verbal aggression, and a broad spectrum of “agitated” behaviors (Spira and Edelstein, 2006).

Family/caregiver education and training Another approach to managing dementia-related behaviors is to educate and train families and professionals on how to effectively deal with such behaviors. To date, a large body of literature addresses the importance and efficacy of educating and training families and care staffs in recognizing, assessing, treating, and monitoring behavioral problems. Models and approaches used in training vary greatly, from simple and practical (for example, the “3 Rs” of repeat, reassure, and redirect) to more involved behavioral approaches, such as the A-B-C approach. A number of more structured and standardized training programs also are available, including Savvy Caregiver, Staff Training in Assisted-Living Residences-Caregivers, Resources for Enhancing Alzheimer’s Caregiver Health, Activity-Based Alzheimer’s Care, and CarePro (Salzman et al., 2008; Alzheimer’s Association, n.d. Coon et al., 2010). Research results strongly support the use of caregiver education and training as an effective treatment approach to dementia-related behavioral problems. Trials have shown that caregivers can acquire behavioral techniques that decrease problematic behaviors, reduce the use of

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antipsychotic medications, and delay institutionalization for those who live at home (Ray et al., 1993; Doody et al., 2001; Burgio et al., 2002; Teri et al., 2005; Livingston et al., 2005; Logsdon et al., 2007).

Psychosocial Psychosocial interventions include those that emphasize social contact as the intended treatment effect. Such disparate treatment strategies as music therapy, pet therapy, sensory stimulation, enhanced therapeutic activities, social interaction, one-to-one interaction, and simulated interaction fit into this general model. Research in this area finds that whenever family members and caregivers spend extra time with patients, especially when they offer attention and affection, it has a positive impact on behaviors. This occurs during many different types of treatment interventions, even when attention is incidental to the actual research design (Doody et al., 2001; Pulsford and Duxbury, 2006; O’Connor et al., 2009).

Individualized approaches to treatment Many researchers contend that perhaps the most critical factor in the use of nonpharmacologic treatment approaches is how the intervention is individualized and customized to best fit the person, the person’s unique behaviors and living situation, and the resources available for treatment (Maslow, 1996; Cohen-Mansfield et al., 2007). Moreover, it is important to match the treatment intervention with the function of the behavior being treated, which requires the inclusion of functional assessments in intervention protocols (Spira and Edelstein, 2006; Zec and Burkett, 2008). When treatment interventions and behaviors are well matched, most treatment strategies have been found to be highly effective.

Evidence-based treatment research A small but significant number of studies on nonpharmacologic treatment interventions meet the stringent criteria set forth by the American Psychological Association (APA Presidential Task Force on Evidence-Based Practice, 2006; Yon and Scogin, 2007) so that they achieve EBT status. These studies provide greater insight into the effectiveness and potential of nonpharmacologic treatment approaches in dementia and lend considerable support to the legions of professionals and caregivers who currently practice such approaches and believe in their efficacy. A number of review articles critique the nonpharmacologic treatment research relative to these stringent EBT standards. In one of the more recent review articles, O’Connor et al. (2009) found that only 25 of 118 studies of psychosocial treatment approaches met methodological criteria for inclusion. In reviewing those 25 studies, they concluded that aromatherapy (Ballard et al., 2002; Holmes et al., 2002), use of preferred music (Burgio et al.,

1996; Ragneskog et al., 1996), person-centered bathing techniques (Sloane et al., 2004), simulated family presence (Garland et al., 2007), and muscle relaxation therapy (Suhr et al., 1999) all reduced behavioral symptoms, compared with controlled conditions. In a similar review, Logsdon et al. (2007) examined 57 randomized clinical trials and found that only 14 of those studies met EBT methodological criteria. Of those 14 studies, they were able to identify two general psychological interventions that were effective in treating dementia-based behavioral problems: (1) structured behavioral approaches based on behavioral and social learning theory (Teri et al., 1997, 2003, 2005) and (2) individualized counseling or consultation interventions that focus on decreasing behavioral problems by modifying the caregiving environment (Gerdner et al., 2002). Other reviews of the research found similar results. In a more ambitious review process, Livingston et al. (2005) examined 1632 studies and found that 162 (or 10%) of those studies met methodological inclusion criteria. Positive treatment effects were found for interventions involving caregiver education, individualized behaviormanagement techniques, cognitive stimulation (Teri et al., 1997), and, to a lesser extent, music therapy (Remington, 2002), Snoezelen therapy (Baker et al., 1997), and sensory stimulation (Burgio et al., 1996). In their examination of the research on behavioral interventions with agitation behaviors, Spira and Edelstein (2006) identified 23 articles that met strict methodological criteria. They found that wandering behavior and physical aggression improved with antecedent control interventions and that physical aggression also improved with the differential reinforcement of other behaviors and with cognitive behavioral interventions. Caregiver training was also effective in reducing agitation in nursing home residents. In each of these review articles, the authors concluded that the research shows great promise for the efficacy of environmental, behavioral, and psychosocial treatment of neuropsychiatric and behavioral symptoms in persons with dementia. However, they also noted that, other than the EBT-qualified studies, much of the research in this area is too limited, loosely designed, and inadequately reported to warrant definitive conclusions about what aspects of the treatment have been found to be effective.

Treatment of specific types of dementia

Alzheimer’s disease More has been written on AD than any other type of dementia, and the literature is rich with material that deals with behavioral problems associated with AD. Moreover, research conducted on persons with unspecified “dementia” draws primarily from an AD population. As a result, much of the treatment issues discussed in this chapter are relevant and applicable to persons with AD.

Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia

When considering nonpharmacologic treatment approaches with AD patients, it is important to consider the patient’s degree of cognitive impairment. The social learning model emphasizes the effects of consequences on behaviors, yet AD causes deterioration in memory and learning to the point that consequences to behaviors may no longer achieve desired learned behavioral change. It is not uncommon for this treatment approach to cause patients to become frustrated and exhibit an exacerbation of their behaviors. Therefore, consequence-oriented behavioral approaches are often not recommended when treating persons with moderate or advanced dementia. On the other hand, behavioral approaches that focus on antecedent control strategies can continue to be effective in managing behaviors well into the advanced stages of AD (Martin and McCarthy, 2011).

Vascular dementia In contrast to AD, VD is not well represented in the dementia literature. A search of the literature found no studies on the use of nonpharmacologic treatment approaches specifically with VD patients. This may be because VD patients exhibit higher variability in their clinical course, with behavioral problems differing greatly in type and severity from one person to the next. Consequently, behavioral trends and consistencies are difficult to identify across patients, making treatment highly variable and quite individualized. It is fair to say that many of the nonpharmacologic treatments found to be effective with AD patients may also be effective with VD patients, as long as their levels of confusion and behavioral presentations are comparable to those of AD patients. However, such assumptions should be made with caution because persons with VD often exhibit different cognitive and emotional patterns, as compared with AD patients. In residential settings, VD patients are generally found to be more cognitively capable than their AD counterparts, exhibiting greater learning and memory skills and with a more fluctuating cognitive presentation. As such, social learning-based treatment approaches may be much more applicable and effective than with AD patients. Conversely, distraction techniques may be less effective with VD patients. VD patients tend to present with more obvious signs and symptoms of depression and anxiety, and to be more emotionally labile than AD patients. Persons with VD are more likely to exhibit persistent problems with crying, moaning, and disruptive vocalizations that can be quite challenging to treat. These problems may dissipate when caregivers distract and engage VD patients in some personally meaningful fashion (such as 1:1 attention, personal grooming, preferred snacks, and multisensory effects) while not directly attending to the behavior. Persons with VD are also more likely to exhibit perseveration of thoughts and behaviors and to act repetitious and

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disruptive in demanding food/drink or cigarettes or asking to be taken to the toilet or bed. Putting the individual on a reasonable, responsive, and highly personalized care/attention schedule (for example, assisted to the toilet every hour) can help alleviate these problems.

Lewy body dementia Although there is a rapidly expanding body of literature on LBD, it is lacking in studies that specifically examine nonpharmacologic treatment approaches with LBD patients. One reason may be that LBD-based behaviors are not seen as severe or as problematic as the behaviors associated with AD and FTDs. However, because up to 50% of patients with LBD experience neuroleptic sensitivity, especially to antipsychotic medications, the development of nonpharmacologic alternatives in treating the neuropsychiatric and behavioral symptoms of LBD is clearly needed. Caregivers often describe LBD patients as being “in their own world,” responding more to internal stimuli than the physical and social environment around them. Thus, effective nonpharmacologic treatment strategies might include environmental considerations (such as making the living environment safe, comfortable, and clear), antecedent control involving the environment and caregiving, and the education and training of caregivers on best-care practices for dealing with LBD-based behaviors. Psychotic symptoms, including visual/auditory hallucinations and delusional thinking, are best managed by providing comforting support, distracting and engaging patients’ attention with more reality-based activities, and avoiding discussing with patients or confronting patients about their thinking and behavior. Physical restlessness and akathisia can be challenging and may include caregiving strategies associated with providing care “on the run” (allowing patients to move and walk freely while providing care) and allowing them to eat “on the run,” often with finger foods.

Frontotemporal dementia FTD has a more substantial literature base than VD and LBD, including a small number of studies that specifically address the nonpharmacologic treatment of behavioral problem (Merrilees, 2007; Wittenberg et al., 2008; Arvanitakis, 2010; Lough and Hodges, 2002). The focus of this research is mostly on the bvFTD. The two most commonly recommended nonpharmacologic treatment approaches are environmental and behavioral. Environmental approaches focus on modifying the environment to ensure safety and comfort, and also to more directly diminish behavioral problems. Environmental changes include locking exit doors, securing food storage areas, and ritualizing set daily schedules and routines. As with LBD, physical restlessness and akathisia may require caregivers to provide care and meals “on the run.”

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Behavioral strategies tend to focus on antecedent control and, to a lesser degree, interventions based on the social learning model. Consequence-oriented interventions are worth considering because memory functions remain more intact with FTD patients, as compared to AD patients (McKhann et al., 2001). This can be done by consistently rewarding positive behaviors such as self-help skills, cooperation with caregiving, and desirable therapeutic activities. Preferred snack items are often effective rewards, especially for patients who exhibit aggressive food-seeking behavior.

Parkinson’s dementia Although there is a large body of literature on PD, most of the research on treatment of PDD problems focuses on medication management, with only an occasional mention of nonpharmacologic treatment strategies (Rongve and Aarsland, 2006). The actual study of such strategies is rare (Rongve and Aarsland, 2006; Rosner and Henchcliffe, 2010). Effective nonpharmacologic treatment approaches tend to focus on environmental, psychoeducational, and counseling-oriented interventions. The Parkinson’s Disease Foundation (Marsh, 2010) recommends many such interventions on its website. For example, caregivers are instructed to avoid multitasking, keep activities and tasks simple, and focus on one goal or concept at a time. They also recommend that caregivers act and talk slowly, use frequent repetition, and assist with developing compensatory strategies (for example, using clocks, timers, planners, notes, and voice recorders). Special mention is made of ways to help PD patients with impulse-control problems (such as pathologic gambling, hypersexuality, medication abuse, and excessive shopping), with environmental strategies being most recommended for dealing with such problems.

Conclusion Patients with dementia constitute a rapidly expanding population of adults who suffer from diminished cognitive capacity, functional skills, and ability to live independently. Behavioral disorders are the inevitable result of these conditions as persons with dementia struggle to understand their condition, accept a need for care, and communicate underlying problems such as pain, discomfort, or emotional distress. Humane caretaking, including medical care, requires a range of treatments to lessen behavioral disorders. Such approaches extend to environmental design to promote safety and comfort, psychosocial planning to better meet emotional needs, and individualized behavior-management techniques to directly target such problems as agitation and aggression. Admittedly, a gap exists between the relative lack of well-designed, evidence-based, nonpharmacologic treat-

ment studies and the general acceptance that nonpharmacologic approaches should be the primary treatment approach. Nevertheless, research to date supports the use of these techniques. Future research will need to further address their efficacy in specific populations of persons with different types of dementia at different stages of the illness.

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Chapter 26 Expressive Art Therapies in Geriatric Neurology Daniel C. Potts1, Bruce L. Miller2, Carol A. Prickett3, Andrea M. Cevasco3, and Angel C. Duncan1 1

Cognitive Dynamics Foundation, Veterans Affairs Medical Center, The University of Alabama, Tuscaloosa, Alabama Memory and Aging Center, University of California, San Francisco, CA, USA 3 School of Music, College of Arts and Sciences, University of Alabama, Tuscaloosa, AL, USA 2

Summary • Expressive art therapies work to improve quality of life, enhance self-worth, and promote human dignity; all of which contributes to better health. • Music and art therapies have been shown to significantly improve social participation, communication, and mood while reducing symptoms of depression, anxiety, and agitation. • Dance and movement therapies combine movement with counseling and rehabilitation to reduce stress and improve ambulation. • Drama, poetry, and bibliotherapy have been shown to improve both physical and psychological symptoms through self-expression and reflection. • Reminiscence and story-telling therapies promote communication and interaction using memorabilia, photographs, and narration of the patients’ life history.

Introduction The present is an age of unrivaled scientific advancement in health care. Molecular geneticists, biotechnologists, physician scientists, and others are elucidating the pathophysiology of disease at its most fundamental level. Such burgeoning information will make possible targeted therapies to both prevent and effectively treat (and perhaps cure) many of the chronic illnesses of our time. This scientific progress parallels an increasing life expectancy in most developed countries, bringing neurologic diseases of aging to the forefront of interest—diseases such as Alzheimer’s and other dementias, Parkinson’s disease (PD), and stroke. Though advances may lead to more effective treatments and potential cures, the burden of geriatric neurologic disease will remain high. There will be nonresponders to treatment, not all will have access to therapies, and there will always be struggling caregivers. The need to nurture and preserve the psychological, emotional, and spiritual well-being of patients will still exist, helping them maintain their dignity and sense of self-worth. Furthermore, caregiver respite will always be a crucial need.

Depersonalization of care threatens our modern healthcare system as much as rising costs and lack of access. Most current models fail to incentivize actually caring for the “core” of a human being, for tuning all senses toward expressions of need, for validating each person in the condition of loss or ill health, for providing therapies to promote restoration of wholeness, and for supporting caregivers. Instead, providers are rewarded for spending as little time as possible with patients so that schedules may be filled and for meeting as many “quality indicators” as possible. Geriatric patients who are more likely to have experienced loss (loss of productivity, independence, cognitive and physical capabilities, and so on), are the ones who stand to suffer the most from such a system. And this population is the fastest growing segment of society. An emerging body of evidence supports expressive art therapies as a means of improving quality of life, enhancing a sense of self-worth, and promoting human dignity. Such therapies include music, art, drama and dance, poetry, and bibliotherapy, and often incorporate reminiscence therapy, storytelling, and cognitive/behavioral therapy in the treatment plan. Creativity is an essential human characteristic. Philosopher Erich Fromm once

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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wrote, “Being creative means considering the whole process of life as a process of birth and not interpreting each phase of life as a final phase” (Hannemann, 2006). According to Gene Cohen, founder of the National Center for Creative Aging, creativity reinforces neuronal connections, improves emotional resiliency, enhances a sense of well-being, and improves memory. Aesthetic forms of expression, including music, painting, and literature, help to confront a negative view of aging by offering individuals a new way of looking at themselves and the world. Such forms of expression provide a channel for communication and lessen feelings of isolation, thereby generating a sense of community. “Art in all its forms is the purest medium of human connection, the one which most truly promotes holistic communion between individuals. The innate power of art lies in its ability to meld the heart and mind of the artist with that of the observer, to call to consciousness in another the depth of emotion, experience, spirituality, and intellect behind the creation of the artistic work” (Potts, personal communication, 2010). Creativity is a necessity for healthy and fruitful living and is a casualty of cognitive impairment. Expression through artistic creation helps bypass roadblocks to creativity, again promoting self-worth and dignity (Hannemann, 2006). Assimilation of life elements into a story of which one is cognizant is also an innately human trait. Many neurologic diseases of the elderly inhibit one’s ability to formulate and share this life story and to have it heard and appreciated. Conditions such as Alzheimer’s disease (AD), for example, rob one’s ability to express oneself through language, producing isolation and the inability to be understood. This contributes in no small way to the morbidity of the dementing illnesses. Expressive art therapies can improve an individual’s ability to communicate his or her story and can stimulate memories, foster community, promote positive relationships with caregivers, diminish adverse behaviors, enhance cognitive abilities, and elevate and stabilize mood. The end result is an enlivened sense of self-worth and fostering of dignity, which should be important outcomes of any health-care intervention. The World Health Organization defines health as “a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity” (Cohen, 2009). In the Creativity and Aging Study, principal investigator Cohen concluded from statistically significant findings that elderly participants in health interventions utilizing the expressive arts had better health, fewer doctor visits, less medication usage, and increased activities and social engagement (Cohen, 2007). Obvious secondary benefits include substantial cost savings to the health-care system. The use of art and music in the inpatient setting reduces the length of hospitalization and is associated with a decreased need for pain medication in critical care patients (Stuckey and Nobel, 2010). Scientific evidence also indicates that exposure to a rich,

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stimulating environment in older age (including participation in artistic creativity) increases the length and number of neuronal dendrites and their connections (Hanna and Perlstein, 2008). Research has shown brain activity to be less lateralized in older adults than in younger adults, enabling better integration of left- and right-hemispheric function (Cohen, 2009). It has been hypothesized that activities that facilitate integrated right/left function are appealing to the brain. Virtually every form of art provides optimal utilization of the benefits of synchronized hemispheric involvement. Furthermore, gerontologic research has shown positive health benefits in elderly individuals who can experience a sense of control (mastery) over their environment. The act of creating fosters such a sense of control (Cohen, 2009). The field of creative aging—comprising the arts, aging, education, health, and humanities—has developed a variety of categories of arts programs that address the needs of older people. Educational programs include lifelong learning through arts in conjunction with higher education extension services and community schools of the arts. Community-building programs offer social and civic engagement through participation in arts initiatives. Health-care programs provide professional arts and artstherapy opportunities for frail older people who are in the care of others at home, in long-term care facilities, or in health-care institutions. The Global Alliance for Arts and Health is a leading national organization that supports developing and sustaining arts programs within medical settings, including long-term care facilities (Hanna and Perlstein, 2008). Furthermore, as medical professionals are beginning to recognize the role the expressive arts play in the healing process, arts in medicine programs, such as the Arts in Medicine Program at the University of Florida, are beginning to emerge worldwide (Stuckey and Nobel, 2010). Research at Florida has shown that participation in such a program is related to improved qualityof-life measures, as well as trends toward improvement in depression and certain laboratory and hemodialysis measures (Stuckey and Nobel, 2010). The following discussion outlines the benefits of expressive art therapies, reviews pertinent literature, and makes a call to embrace such therapies as a focus for research, reimbursement, and implementation in practice.

Music therapy The intuition that music may facilitate physical and emotional well-being appears to be as old as humankind. As anthropology and ethnomusicology developed during the twentieth century, major figures in these fields noted that, in every civilization studied, even preliterate societies, music and rhythm not only were a part of the cultural climate, but were assumed to have a unique role in healing

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rituals, spiritual rites, and expressions of the essence of human nature (Nettl, 1956; Merriam, 1964; Sachs, 1965). Whether reading the biblical story of David playing his harp to dispel King Saul’s tormenting spirit, reading William Congreve’s seventeenth-century poetry stating that “Musick has Charms to sooth a savage Breast,” or investigating the strict music censorship by totalitarian governments in current times, a strong connection between music and states of mind to promote maximum functioning has been a continuing theme in human development. Only within the past 60–75 years has an accountable professional discipline been developed that uses music in therapeutic ways. The field of music therapy has been made possible by the development of two aspects of modern behavioral sciences: (1) standardized formats for social/behavioral research, which generate reliable and comparable quantitative and qualitative findings, and (2) development of technologies that monitor subtle behavioral and physiologic changes associated with emotional phenomena. The information that neuroimaging will reveal in coming years will assist in determining why brains and bodies react to music in certain ways. However, almost five decades of behavioral research in musical responses already have yielded sufficient information for effective clinical use of music by Board Certified Music Therapists (MT-BC) (Solomon, 1993; Heller, 2000). “Best practice” in music therapy, across all populations, rests on three foundational principles. Music therapy combines standard therapeutic strategies with a musical (or rhythmic) format to address clients’ specific nonmusical therapeutic needs. Music therapy is interactive, involving participation at whatever musical level a client may be. Music therapy incorporates recipients’ favorite music, with no genre being innately therapeutic. MT-BC engage in assessment, treatment planning, and delivery in line with clients’ individualized needs and documentation of the efficacy of treatment. Music therapy’s unique contributions to the aged were brought to public attention in 1991 when the United States Senate Committee on Aging held a hearing supporting the inclusion of music therapy in the list of services to be provided for elderly people (Special Committee on Aging, United States Senate 1991). Subsequently, the reauthorization of the Older Americans Act cited music therapy as an appropriate service for the geriatric population. Although testimonials concerning music therapy’s effectiveness in the special issues associated with dementias began to accumulate since the beginning of the profession, as recently as 1988, there were no data-based research articles to support treatment decisions. By the turn of the century, however, a review of the research literature yielded 60 studies with enough data and experimental control to be useful in designing effective treatment sessions for people with Alzheimer’s and related

dementias (Prickett, 2000). As national interest in dealing with dementias has increased, the number of investigations has continued to keep pace. The rigor of the studies, the number of people included in each project, and the replicability of the results has improved dramatically in the past decade. Brotons et al. (1997, 1999) reviewed the empirical literature available at the end of the 1990s; overall, the following seminal conclusions were well established and provide context for more recent investigations (example studies are cited): 1 People diagnosed with Alzheimer’s and related dementias can continue participating in structured music activities late into the disease (Clair, 1996). 2 Playing instruments and dancing/moving can be very effective even into later stages and are well liked by participants (Brotons and Pickett-Cooper, 1996). 3 The therapist’s or caregiver’s skill in modeling a desired response increases participation (Clair and Ebberts, 1997). 4 Individual and small group settings are far more useful than larger groups in facilitating participation (Clair et al., 1995). 5 Social/emotional skills, including interaction and communication, can be improved during music sessions and for a period of time after the sessions conclude (Sambandham and Schirm, 1995). 6 Cognitive recall may be enhanced, particularly for personal memories, when music associated with those memories is sung or played (Prickett and Moore, 1991). 7 Music interventions may be an alternative to pharmaceutical or physical restraints in controlling agitation or wandering (Brotons and Pickett-Cooper, 1996; Thomas et al., 1997; Clark et al., 1998). 8 Additional studies during the 1990s laid the groundwork for later clinical work by establishing protocols for singing, rhythmic, and musical activities (Clair and Bernstein, 1990). Building on this groundwork, twenty-first-century music therapy researchers have worked to define situations and refine techniques in two basic areas: increase in desired behaviors such as communication or participation with others, and decrease in undesirable behaviors such as agitation, anxiety, and depression. Additionally, although live music presented by a professional therapist has been shown to be most effective, the potential to gain some degree of improvement through ambient or background music has been explored. Increasing participation in sociable group activities and with caregivers has been a focus of research in this century. Cevasco and Grant (2003) assessed clients’ involvement in exercise to music sessions when vocal or instrumental music was used and found that more people joined in during the instrumental music; in a second portion of this study, more people were able to be

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successful when simply exercising to music rather than when moving while playing instruments. In both cases, the investigators deduced that eliminating competing stimuli (vocal music conflicted with verbal cues; actions required to hold or play an instrument conflicted with simply moving the limbs) increased the likelihood of successfully completing the task. In a later study, the same authors (Cevasco and Grant, 2006) explored the efficacy of various commonly used musical instruments, as well as a cappella singing, during a variety of singing, instrument playing, and movement activities. The details of their findings offer guidance to clinical music therapists for structuring sessions that will elicit a high participation rate. Initial findings exploring verbal communication, especially with caregivers, revealed significantly improved scores for speech content and fluency in spontaneous speech during and following music therapy sessions (Brotons and Koger, 2000; Brotons and Marti, 2003). Nonverbally, clinicians working with patients with dementia employ touch to increase alertness. Belgrave (2009) explored differential effects of expressive touch (such as nurturing and caring) versus instrumental touch (assisting in completing a task such as stroking wind chimes) during musical activities, as well as a no touch condition. Both touch conditions increased ratings of client/ therapist rapport, with expressive touch being significantly more effective in initial sessions for increasing alert behavior in individuals who have late-stage dementia. The use of small group music therapy interventions, particularly those structured to engage reminiscence, has proved effective in reducing symptoms of depression and anxiety (Ashida, 2000; Guétin et al., 2009; Sung et al., 2010) and behavior problems associated with irritability, anxiety, and depression at mealtime (Liao et al., 2004). It is particularly important that, in each of these studies, the reduction of symptoms continued to be evident for a notable period of time after the last session. It is extremely difficult to verify whether any person is actually listening to music in the environment. If the musical task is singing and the person sings along with a music source, measures such as counting the number of words sung (judged by lip movements) may indicate that, to some degree, the singer is also listening; with people who have dementia, differential response rates for musical versus spoken stimuli have been demonstrated (Prickett and Moore, 1991). A later study (Groene, 2001) demonstrated that when a leader is singing, whether accompanied by live or recorded music with simple or complex structure, seniors with a dementia diagnosis participated equally well in all conditions. However, behaviors such as leaving after the song decreased when accompaniments were complex (more harmonies and more rhythmic enhancement). Patients’ differential response to the accompaniments indicates that they were listening to the music.

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Gregory (2002) attempted to measure listening attention by asking older adults in an Alzheimer’s care group to respond in real time to music versus silence conditions, indicating their perception using a Continuous Response Digital Interface dial. Compared with college students or older peers with no diagnosis, people with mild cognitive impairments performed somewhat less accurately, but with the same basic pattern of distinguishing different music excerpts or silence as the older adults and college students. Establishing that people with dementia diagnoses can respond in ways that indicate the ability to make aural discriminations, even when the ability for meaningful verbal communication has been compromised, is an important distinction for differences in processing music versus speech communication. Two studies have explored the effect of ambient music in the environment (background music), especially music that can be documented as being preferred by the clients (Park and Specht, 2009; Ziv et al., 2007). Both articles report significant reductions in agitated behaviors and an increase in positive social behaviors, even though the patients were not engaged in any structured activity while the music was playing. Music therapy researchers never claim to “cure” or reverse symptoms of dementia. The aim of music therapy with this population is to maximize quality of life and facilitate interactions with caregivers. The usefulness of music-based assessments of cognition, especially compared with the MMSE, has been demonstrated with a “uniqueness to the melodic, singing, and rhythmic aspects of music cognition” (Lipe et al., 2007). Improved MMSE scores immediately after a music therapy session and, even more, the next day have been demonstrated, although after a week had passed, the improvement had faded, indicating that frequent sessions may maintain cognitive function across time (Bruer et al., 2007). A two-year follow-up of patients receiving weekly music therapy sessions found a significantly lower increase in systolic blood pressure, compared to control subjects, as well as better maintenance of other indicators of physical and mental states (Takahashi and Matsushita, 2006). In short, clinical and research evidence continues to support hypotheses that music elicits different—and beneficial— responses from people with Alzheimer’s disease and related dementias, even though the neurologic mechanisms responsible for this have yet to be established. The uses of music therapy in poststroke rehabilitation draw on both the physical attributes of musical stimuli (such as the emphasis of a beat or pulse, and regular predictability of a steady beat in time), the physical requirements inherent in singing (control of all aspects associated with producing an oral sound), and the reinforcing effects of musical participation. The research examples that follow explore various useful clinical techniques of music therapy.

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Establishing a steady gait is one of the primary focuses of therapy for many stroke patients. An early study (Staum, 1983) employed music and percussive rhythm as a template for persons in therapy for gait disorders; footfalls increasingly matched the rhythmic stimulus and, over time, the stimulus was effectively faded so that rhythmic walking and consistency of speed could be maintained outside the clinic. Later work (Thaut et al., 2007) has replicated and expanded this idea, putting to use more advanced technology for documenting results and extremely fine variations in responses. Based on research, Thaut has developed a systematic training program (Rhythmic Auditory Stimulation [RAS]) for this and other aspects of neurorehabilitation (Schauer and Mauritz, 2003; Jeong and Kim, 2007); training is offered to MT-BC, and graduates of this training may be identified by the letters MT-BC, NMT after their names. After publishing in numerous peer-reviewed journals, Thaut compiled the major points of RAS into one book, Rhythm, Music, and the Brain: Scientific Foundations and Clinical Applications (2007). The following are examples of peer-reviewed research projects that have demonstrated the efficacy of music therapy in commonly encountered poststroke rehabilitation challenges: 1 Nonfluent aphasia: Speech therapists have employed versions of Melodic intonation therapy for decades, but recent advances in imaging and consistencies in clinical observations have allowed the development of a protocol that uses music therapy to increase speech fluency (Kim and Tomaino, 2008). 2 Grasp strength: Using common orchestral percussion instruments (such as tambourine, cymbal, drum, or claves), patients can measurably increase grasp strength while playing the instruments in a musical setting (Cofrancesco, 1985). 3 Swallowing: Preliminary results for a protocol that alternates singing, breathing training, and laryngeal elevation exercises across a 30-minute period of time were statistically significant after only six sessions, with increasing effectiveness demonstrated after 12 sessions (Kim, 2010). 4 Mood and social interaction: When music therapy sessions were paired with standard rehabilitation techniques, participants’ families and treatment staff rated them significantly higher with regard to posttreatment social interaction, active involvement in therapy, and cooperation with therapeutic regimens (Nayak et al., 2000). Besides the formal training in RAS mentioned already, research-based clinical applications of music therapy for all categories of stroke populations have been made available to the entire music therapy profession by Elizabeth Wong, MT-BC. Her book Clinical Guide to Music Therapy in Physical Rehabilitation Settings (Wong, 2004) has become a standard textbook in university music therapy degree programs.

Art therapy The Merriam-Webster dictionary defines art as a “skill acquired by experience, study, or observation; the conscious use of skill and creative imagination, implying a personal creative power which cannot be analyzed: the creation of beautiful or significant things.” Perhaps art may be thought of as a form of self-expression, a means of communicating with the self, a process by which shape and meaning may be given to something that otherwise may have remained unformulated. Aesthetically, creating art may give one the satisfaction of bringing something into being that enriches life. Artistic expression may thus allow the person to function with a greater degree of personal contentment (Allan and Killick, 2000). Historically, art has been used as a means to communicate ideas with religious and cultural significance to the masses when the ability to read was not widespread (Allan and Killick, 2000). The ability to communicate is one of the most defining of human traits. Unfortunately, many people suffering from degenerative brain diseases progressively lose their ability to communicate through verbal, linguistic methods. Conditions such as AD take away the full mosaic of a person’s past (Sandrick, 1995). However, where words are lost, images can remain. Visual art provides a means of communication that bypasses roadblocks to traditional expression. Furthermore, for those who are nearing life’s end, artistic expression gives the opportunity to shape inner experience before that capability is lost. Neurologist Oliver Sacks describes the “undiminished possibility of reintegration by art, communion, and touching the human spirit.” Grounded in human developmental theory and psychological theory formulated initially by Carl Jung and Sigmund Freud, the field of art therapy arose in the 1930s (Pratt, 2004). The American Art Therapy Association defines art therapy as “a mental health profession that uses the creative process of art making to improve and enhance the physical, mental, and emotional well-being of individuals of all ages. It is based on the belief that the creative process involved in artistic self-expression helps people to resolve conflicts and problems, develop interpersonal skills, manage behavior, reduce stress, increase self-esteem and self-awareness, and achieve insight” (American Art Therapy Association, 2010). Medical art therapy may help the patient synthesize and integrate issues such as pain, loss, and death (Pratt, 2004). It also offers a unique opportunity to help elderly clients engage in the creative process to facilitate communication, manage emotions, exert control over their environment, and engage in the process of life review. Furthermore, art therapy provides a means of nonverbally assessing cognitive and developmental deficits, and analysis of a client’s artwork may be useful in determining diagnosis or response to treatment. The American Art Therapy Association was formed in 1969 and provides certification to qualified therapists.

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Art therapists typically work in either group settings or individual sessions engaging participants to create expressive images. Trained professionals use high-quality materials to foster a mature, dignified activity for this selfexpression. Where necessary or helpful, guided directives are provided to advance the process. Evaluation of the work can provide diagnostic insight to the therapist as well as positive, validating effect to the individual participant. Evaluation of the artwork and stories told by images often reveals persistent communication abilities in patients thought to lack self-awareness. The artwork becomes a compelling way for an individual to say to the world, “I’m still here,” and lends support for personcentered, validating care even in patients with end-stage impairment. It also serves as a means of organization to a ravaged mind and raises questions about preserved capabilities even in those with advanced cognitive disorders. For example, Potts describes abstract representations of family members in the late-stage Alzheimer’s watercolors of his father after verbal expression was essentially lost (Potts, personal communication, 2011). Art therapy is an essential component of person–environment systems of care that are supportive and safe, heightening an individual’s sense of normalcy, competency and wellbeing despite cognitive impairment, whether that be for a moment or an hour (Rentz, 2002). Such systems will be increasingly common with the aging of the population and rising prevalence of AD and other dementias. For the artist, participation can also be a valuable tool for improving quality of life and enhancing self-worth, bringing a sense of pride and satisfaction from completing a work (Duncan and Potts, personal communication, 2010). Art therapy brings respect and dignity to people who are often isolated and infantilized, yet whose lives were previously full of accomplishment and adventure. Figures 26.1 and 26.2 show some examples of Lester Potts’s artwork created after the diagnosis of Alzheimer’s disease. For those with cognitive disorders, creating visual art becomes a means of enlivenment and communication in a world otherwise laden with confusion, isolation, and stigma from society. As Gibson observes, “Dementia strips people down to the essence of their being and frees them to be in more direct touch with their emotions. They communicate with greater authenticity than our customary conventional reliance on controlled emotional expression” (Gibson, 1998). In the medical arena, art therapy interventions are commonly used as a tool to distinguish between symptomatically similar clinical presentations and have been shown to offer benefits in many different conditions. For example, major depressive disorders with psychotic features may present similarly to dementia of the Alzheimer’s type, and an apparent bipolar disorder presentation could, in fact, represent frontotemporal dementia (FTD). By

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Figure 26.1 Blue jay.

evaluating a patient’s use of space, line, and shape, art therapists are able to help in this differentiation as well as aid in staging the disease process. Numerous small anecdotal and observational studies have shown beneficial effects of art therapy in patients with traumatic brain injury, stroke, depression, bereavement, cancer, pain management, sexual abuse, and HIV disease (Pratt, 2004). Case studies in cancer patients have shown that art therapy helps individuals explore the meanings of past,

Figure 26.2 Three birds.

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present, and future, thereby integrating cancer into their life story and giving it meaning. Artistic self-expression is thought to contribute to maintaining or reconstructing a positive identity (Stuckey and Nobel, 2010). Art can be a refuge from the intense emotions associated with illness (Stuckey and Nobel, 2010). It has been suggested that, when incorporated into treatment programs for the elderly, art therapy can help clients cope with the challenges aging brings (Johnson and Sullivan-Marx, 2006). Though research involving art therapy interventions in the geriatric population is relatively sparse, a few key studies have demonstrated benefits, primarily in those with cognitive disorders. Some of its documented positive effects include promotion of well-being, enhanced communication and socialization, facilitated decision making, improved mood, maintenance of function, and improved expression of emotions. In 2003, a collaborative study was conducted by the Alzheimer’s Association of Northern California, Northern NV, the VA Palo Alto Health Care System, and the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine. Researchers evaluated patients with AD to compare benefits derived from participating in an art therapy group versus a current events group, the latter being a more commonly employed group activity in dementia care facilities. Thirty-five male and female dementia patients between the ages of 65 and 100 years participated in the study. Due to cognitive and communication deficits and inability to respond to traditional psychometric assessments, researchers used the Apparent Affect Rating Scale (AARS; Lawton et al., 1996) as a measuring assessment for direct observation. Trained raters used the scale to indicate how long a subject displayed each of five emotions (anger, anxiety/fear, sadness, pleasure, and alertness) over 5–10 minutes. Participants in the art therapy group were shown to be more alert, more aware of their environment, and more socially interactive, and had levels of positive affect seldom seen outside this group. Family members reported that these effects persisted past group activities, with some participants remembering their experience and talking about how much they enjoyed it. Memories in the Making, originating from California’s Orange County Alzheimer’s Association program model, is an art program for those in the early and middle stages of dementia (Rentz, 2002). Despite diminished verbal and organizational skills, participants in this program (guided by trained facilitators) use watercolors and acrylics to express themselves by creating visual images on paper or canvas. In an outcome-based evaluation of this program’s effect on well-being conducted by researchers affiliated with the Greater Cincinnati Chapter of the Alzheimer’s Association, results indicated that participants more often worked with sustained attention, had a pleasurable sensory experience, derived pleasure from the activity as evidenced

by laughter and relaxed body language, and verbalized feeling good about themselves and their accomplishments. More than two-thirds of the clients always smiled, and more than 80% of the artists never displayed agitation or discomfort during the sessions. Comments such as “This gives my hand such pleasure” and “In here I feel like a person again” lend support for the intervention’s beneficial effects (Rentz, 2002). Those with mild cognitive impairment and early stage AD need an outlet to express their thoughts and emotions in a safe and trusting environment, especially following initial diagnosis, when emotions are raw. Art therapy groups provide this “safe place” where emotions can be distributed on paper and processed accordingly (Duncan, personal communication, 2010). Viewing products of the creative effort has been shown to have benefits as well and may often inspire the writing of poetry or the telling of stories, which have added therapeutic effects (Johnson and Sullivan-Marx, 2006). In the “MoMA Alzheimer’s Project: Making Art Accessible to People with Dementia” program (Metropolitan Museum of Modern Art in New York), specially trained museum educators engage participants with mild-to-moderate dementia and their caregivers in lively discussions by focusing on iconic art from MoMA’s collection. Results from an evaluation of the program by researchers at New York University showed that the warm and interactive approach of the educators rekindled feelings of self-worth. The participants felt that having the opportunity to learn, to be intellectually stimulated, and to experience great art together was of significant benefit. Family members expressed gratitude that the participant with dementia could have such an experience and, just as important, that they could share it together with the caregiver. The sense of safety and feelings of regard for the participants created by the educators and staff at least temporarily removed the stigma of AD so that participants could enjoy the experience. Both the persons with dementia and their caregivers felt positive changes to mood both directly after the program and in the days following the museum visit. Caregivers reported fewer emotional problems, and all but one person with dementia reported elevated mood. The program also served as a catalyst for new conversation in the days to follow (Meet Me at MoMA, 2009). Miller has written extensively about creativity in the context of neurologic illness, including the neurology of art production and the phenomenon of the discovery of artistic talent in the dementias (Cummings et al., 2008; Miller et al., 1998; Miller and Hou, 2004;). The emergence and evolution of visual creativity in dementia offers a window into the artistic process while hinting at the extraordinary cognitive flexibility of individuals experiencing progressive loss of cortical neurons (Miller and Hou, 2004), particularly when the injury is localized to the language hemisphere. Two visual streams, a dorsal stream that localizes where an item has been perceived

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and a ventral stream involved in the recognition of what is seen, are essential for visual art production (Miller and Hou, 2004). Internally represented visual scenes absorbed over one’s lifetime are perceived through components of the ventral stream that localize to the occipital and temporal cortices. Such internal imagery provides the creative soil for the production of visual art. Precision is added through the dorsal stream, which frames scenes perceived in the ventral stream and helps to place them on canvas (Miller and Hou, 2004), as shown in the artwork in Figures 26.3 and 26.4. The “nondominant” hemisphere is dominant for visual art, and right parietal injury, with its attendant neglect and loss of visuoconstructive skills, is devastating for artistic creation (Miller and Hou, 2004). Many other brain regions are likely also involved in the production of visual art, including dorsolateral prefrontal cortex (artistic planning and organization), cingulate cortex (drive and emotion), motor and premotor frontal regions, basal ganglia, and cerebellum (precise motor control). Furthermore, the language hemisphere

contributes symbolic and linguistic concepts drawn upon in much visual art (Miller and Hou, 2004). AD is characterized by progressive loss of visuospatial skills caused by the degeneration of posterior parietal and temporal brain regions. One might speculate that this would make creation of visual art difficult, if not impossible. This is not always the case. However, art generated by Alzheimer’s patients does tend to lose realistic precision, albeit retaining appealing color and form (Miller and Hou, 2004). This phenomenon is apparent in the art of Dutch– American abstract expressionist Willem de Kooning, who is believed to have developed AD complicated by other conditions that adversely affected cognition (alcoholism, atherosclerosis, depression, and so on; Espinel, 1996). In the case of de Kooning, not only was his later art intriguing and aesthetically appealing, but also it apparently provided therapeutic benefits to the artist (Espinel, 1996). Potts describes the previously unknown artistic talents of his father, an Alabama saw miller, which emerged in early to midstage AD (Potts, 2006). Characteristic loss of accurate spatial representation was followed by vibrant use of color (especially blues and greens) and production of imagery from childhood (saws, fences, trees, and so on). In late-stage disease, after the loss of linguistic ability, the elder Potts painted abstractions of his father and his childhood home, easily recognizable by family members (Figure 26.5) (Potts, personal communication, 2011). FTD is associated with a different pattern of visual artistic expression. In some cases, especially in the subtype semantic dementia, spontaneous bursts of creativity seem to have been triggered by the illness, most often in the presence of aphasia. In this entity, focal degeneration of the left anterior temporal lobe is seen. Remarkably, some patients develop a new interest in art and produce progressively more successful paintings (Miller and Hou, 2004). These works are generally approached compulsively and are characterized by realistic or surrealistic content

Figure 26.4 Yoshida palm.

Figure 26.5 Blue collage, a late-stage Alzheimer’s watercolor of Lester Potts, depicting his father’s hat, shoes and saw.

Figure 26.3 Sunset in Kauai.

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with lack of symbolic or abstract themes (Miller and Hou, 2004). Explanatory theories regarding this visual creativity include sparing of nondominant posterior parietotemporal function, compulsivity regarding the creative act, and disinhibition of the nondominant hemisphere through hypometabolism and the dominant left anterior temporal region (Miller and Hou, 2004). In both AD and FTD, the study of art in dementia is a model for recognizing strengths, not just weaknesses of patients. As such, the use of art therapy in dementia helps to conquer disability and degeneration (Cummings et al., 2008) and plays an important role in validating, person-centered dementia care. One of the premises held in art therapy is that art can serve as a unifying language, even across cultural and socioeconomic divisions. In art therapy settings, artists from different backgrounds and cultures sit together, paint, and share their life stories. Art becomes the common thread. The goal of art therapy in each participant is not the production of beautiful art; it is the fostering of dignity in a life that is isolated, demeaned, and sometimes noncoherent. Self-expression through art making gives the satisfaction of making oneself known to the world as seen in the Figures 26.6, 26.7, and 26.8. (Potts and Duncan, personal communication, 2010).

Figure 26.6 Cabin by the lake.

Figure 26.7 Dad’s barn.

Figure 26.8 Yoshida beach sunset.

Dance/movement and drama therapies Although dance has been a mode of emotional expression for millennia, dance therapy originated in the realm of inpatient psychiatry in the 1940s (Pratt, 2004). Marian Chace, a dancer and choreographer influenced by psychiatrist Carl Jung, conducted dance classes at St. Elizabeth’s Hospital in Washington, D.C., among patients who had been traumatized by World War II. As an alternative to verbal therapies (Westbrook and McKibben, 1989), this early dance therapy resulted in improvement in many patients. Over the next few decades, dance therapy continued to be developed under the influence of psychodynamic psychotherapy (Pratt, 2004). The American Dance Therapy Association, founded in 1966, defines dance/movement therapy as “the psychotherapeutic use of movement to promote emotional, cognitive, physical, and social integration of individuals” (Pratt, 2004). This organization has more than 1200 professional and nonprofessional members. According to its published materials, it maintains high standards for education, training, and professional practice for dance/movement therapists (American Dance Therapy Association, 2010). A growing interest in dance and movement therapy has accompanied recognition of mind and body benefits of motor activity (Stuckey and Nobel, 2010). Such therapy combines body movement with the skills of psychotherapy, counseling, and rehabilitation (Pratt, 2004) to produce improvements in perceived stress and anxiety, physical symptoms and ambulation, range of motion and body image, quality of life and concept of self, and other cognitive and psychological measures. Movement-based creative expression focuses on nonverbal, primarily physical forms of expression as psychotherapeutic or healing tools (Killick and Allan, 1999).

Expressive Art Therapies in Geriatric Neurology

Though much of the research on the benefits of dance and movement therapy has been conducted in the psychiatric inpatient population, a growing body of literature is showing its benefits in patients with cancer (Killick and Allan, 1999), PD (Westbrook and McKibben, 1989), stroke (Pratt, 2004), and dementia (O’Maille and Kasayka, 2005), as well as in the cognitively normal elderly population (Stuckey and Nobel, 2010). Involvement in leisure activities has been shown to delay the onset of AD for those at risk of the disorder. Dance was at the top of the list of activities that were shown to have this effect (Cohen, 2009). Among breast cancer survivors in Connecticut, statistically significant improvement was seen in quality of life measures, body image and shoulder range of motion after 12 weeks of dance/movement therapy in a small, randomized controlled trial (Stuckey and Nobel, 2010). When standard outpatient therapy with exercise was compared to dance/movement therapy in patients with PD, the latter produced statistically significant relative improvements in walking times, including improvement in movement initiation (Westbrook and McKibben, 1989). Subjective improvements in mood were also observed. Patients who had suffered stroke and participated in 45-minute dance/movement therapy sessions twice weekly for 5 months gained improvements on measures of physical, psychological, and cognitive function. A meta-analysis published in 1996 suggests that dance/movement therapy may help elderly persons with anxiety (Ritter and Low, 1996). Inactivity is one of the leading causes of morbidity and mortality in the elderly. Occupational therapy programs for older people often include dance /movement therapy interventions. Improvements in range of motion have been documented in persons treated in this way (Ritter and Low, 1996). Furthermore, dance/movement therapy has been touted to reestablish connections with others in persons who have withdrawn inwardly due to dementia (Zeisel, 2009). Tai chi, a form of semi-meditative movement therapy derived from the martial arts, has been used to help reduce falls on older adults and to improve health status. In a 48-week randomized controlled trial, tai chi was compared with wellness education in a cohort of elderly women. The tai chi group exhibited significant improvements in physical functioning and ambulation, as well as borderline significant improvements in the Sickness Impact Profile body care and movement category (Stuckey and Nobel, 2010). Mindful Affective Timalation Dance/Movement Therapy is a holistic group psychotherapy process for persons with end-stage dementia, developed by O’Maille and centered in Kitwood’s philosophy of person-centered care (O’Maille and Kasayka, 2005). It combines the techniques of traditional dance/movement therapy with engagement of the senses, incorporating elements of spirituality, bodywork, and dance/movement theory in a process that can be likened to Lamaze (O’Maille and Kasayka,

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2005). Touted to help end-stage dementia patients transitioning into death, this technique has similarities to validation therapy, developed by Naomi Feil, MSW, ACSW (Feil, 1993). Validation is a method of communicating with and helping disoriented very old dementia patients, which has been shown to reduce stress, enhance dignity, and increase happiness. The theory suggests that elderly dementia patients struggle to resolve unfinished life issues before death and are inhibited from doing so due to cognitive and physical impairment. In the socalled “phase of repetitive motion,” movements replace words and are used to work through unresolved conflicts. Therapists trained in the techniques and theory of validation can assist patients during this stage through dance/ movement therapy (Feil, 1993). Psychodrama is closely related to dance/movement therapy. Also known as psychodramatic psychotherapy in the psychiatric disciplines, psychodrama holds that professionally supervised “role playing” can lead patients to perceive new solutions to psychological conflicts (Stuckey and Nobel, 2010). The National Association for Drama Therapy, established in 1979, defines drama therapy as “the intentional use of drama and/or theater processes to achieve therapeutic goals” (North American Drama Therapy, 2012). The benefit of short-term drama therapy and theater to enhance cognitive and affective functioning in adults aged 60–86 years was described by Noice and Noice (2006). In this study, participants were given exercises designed to enable them to experience the essence of acting (to become engrossed in the drama). After 4 weeks of instruction, statistically significant gains were made by the treatment group on both cognitive and psychological well-being measures; specifically, word and listening recall, problem solving, self-esteem, and psychological well-being improved (Noice and Noice, 2006). Similarly, cinema, or movie, therapy employs the judicious use of film-viewing as part of a broader therapeutic process to promote psychological growth and healing (Stuckey and Nobel, 2010). Drama is often employed in combination with dance/movement therapy for greater therapeutic impact (Zeisel, 2009).

Poetry/bibliotherapy, storytelling, and reminiscence Poet Yu Xuanji (A.D. 843–868) alluded to what could later be described as the therapeutic effects of poetry in the following passage: “Reciting poems in the moonlight/ riding a painted boat (el)/Every place the wind carries me is home.” The following was used as a guideline for this text change: http://libguides.pstcc.edu/content. php?pid=24540&sid=1751623 The term therapy encompasses bibliotherapy (the interactive use of literature) and journal therapy (the use of

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life-based reflective writing), as well as therapeutic storytelling, the use of film in therapy, and other languagebased healing modalities. The National Association for Poetry Therapy was formed approximately 30 years ago, as standards were set for the discipline. Certifications in Poetry Therapy may now be obtained (National Association for Poetry Therapy, 2011). Poetry has been used for healing and personal growth since ancient times. Shamans were believed to have chanted poetry for the well-being of the tribe or individual. In ancient Egypt, words were written on papyrus and then dissolved into a solution that the patient could ingest, to take effect quickly. Soranus, the first recorded “poetry therapist,” was a first-century A.D. Roman physician who prescribed tragedy for his manic patients and comedy for the depressed. It is not surprising that Apollo is the god of poetry and of medicine, since medicine and the arts have been historically entwined (National Association for Poetry Therapy, 2011). Remaining obscure for centuries, the link between poetry and the healing arts became somewhat more developed in colonial America. Pennsylvania Hospital, founded by Benjamin Franklin in 1751 and the first hospital in the United States, employed reading, writing, and publishing of results as ancillary treatments for mental patients. Dr. Benjamin Rush, called the Father of American Psychiatry, introduced music and literature as effective treatments, and his patients published poetry in a newspaper. Bibliotherapy was coined as a term in 1916 and refers to the use of literature in medical therapeutics. It was first adopted by librarians who favored having a special designation for the practice of selecting and using books helpful to psychiatric patients. Only with the popularity of group therapy in the 1960s did the term begin to encompass organized discussion of the reader’s personal reactions to the presented materials. Touted by such pioneering physicians as Freud, who said “Not I, but the poet discovered the unconscious,” poetry therapy became an accepted component of group therapy sessions conducted by mental health professionals. Eli Greifer, a poet, pharmacist, and lawyer, began a campaign to show that a poem’s didactic message has healing power. He played a key role in the development of modern poetry therapy in association with psychiatrists Jack J. Leedy and Sam Spector at Cumberland Hospital in New York City in the 1950s and 1960s (Lenkowsky, 1987). Though controlled studies are difficult to find in poetry therapy literature, there is growing interest in its role in palliative care, with regard to treating both patients and their caregivers. (Coulehan and Clary, 2005). However, some literature supports the benefits of writing on health. Studies have shown that expressive writing or journaling about traumatic experiences results in statistically significant improvements in various measures of

physical health, reductions in physician visits, and better immune system functioning (Stuckey and Nobel, 2010). Writing about upsetting experiences produces long-term improvements in mood and health (Stuckey and Nobel, 2010). Dozens of studies have shown that emotional writing can influence frequency of physician visits, immune function, stress hormones, blood pressure, and a number of social, academic, and cognitive variables. These efforts have been shown to hold across cultures, age groups, and diverse samples (Stuckey and Nobel, 2010). Expressive writing can also improve control over pain, depressed mood, and pain severity (Stuckey and Nobel, 2010). Several authors have described the use of poetry to help people find their voice and gain access to the wisdom they already have but cannot experience because they cannot find the words in ordinary language (Stuckey and Nobel, 2010). Finding one’s voice via poetry can be a healing process because it opens up the opportunity for self-expression not otherwise felt through everyday words. Journal writing has also been linked to creativity, spiritual awareness, and expansion of the self (Stuckey and Nobel, 2010). Living Words, a creative writing program for persons with dementia developed by psychologists at Wofford College in South Carolina in collaboration with the Alzheimer’s Association, encourages participants to explore emotions, insights, and memories in a workshop setting (Bopp, personal communication, 2010). Touted benefits include cognitive stimulation, reminiscence and reflection upon one’s life, and release of stress (Bopp, personal communication, 2010). As previously noted, a person’s ability to formulate and relate his or her life story may be adversely affected by disorders of cognition such as AD. This can promote a sense of isolation, as family and friends become less able to interact, grow uncomfortable with the situation, and visit less frequently. As a result, the patient’s life and very existence may be indirectly invalidated, or at least self-perceived this way. Storytelling and reminiscence, alone or in combination with other expressive art therapies, can be an effective means of eliciting the patient’s life story, thereby enhancing communication and promoting validation. In 1975, Robert Butler, MD, published Why Survive?: Being Old in America, which linked psychoanalyst Erik Erikson’s theory of the life cycle to the process of aging. Erikson theorized that in the final stage of aging, which he called “Integrity vs. Despair,” the key developmental task was to examine one’s past, come to terms with one’s losses, and celebrate one’s successes, thereby achieving a sense of integrity. Butler saw reminiscence as central to integrating one’s life—working out unresolved issues from one’s past, present, and future (Hanna and Perlstein, 2008). In this vein, video biographies (Therapeutic/Restorative Biographies) have been developed as a means of making patients’ life histories

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accessible to others and to encourage communication and interaction between patients and caregivers, families, and friends (Cohen, 2002). These biographies are created using videotaped snapshots of old photographs and other memorabilia, with narration provided by family members and friends (Cohen, 2002). Such interventions have been found to enhance memory temporarily in dementia patients and to positively alter the experience for the patient and visitor (Cohen, 2001). Moreover, an important intergenerational dimension is added to the intervention when young family members participate in the creation of the video biography (Cohen, 2002). In addition to benefits as a therapeutic intervention for the patient, video biographies provide families with a biography of their loved one they otherwise may not have had (Cohen, 2002). TimeSlips is a nationwide arts in health-care program developed by Anne Basting, PhD, at the Center on Age and Community at the University of Wisconsin Milwaukee. It is an innovative, effective storytelling method in which groups of people in the middle stages of dementia tell stories (Hanna and Perlstein 2008). The facilitator plays down the importance of memory, using an image to prompt creative responses. She or he asks open-ended questions and weaves together all the answers, from the poetic to the nonsensical, into a story. Other expressive art therapies are often combined as well. The program celebrates the creativity of people struggling with AD and other dementias, and rekindles their hope for human connection (Hanna and Perlstein, 2008). This chapter’s lead author is currently directing a similarly structured collaborative Alzheimer’s life story project in rural Alabama, in which expressive art therapies are utilized to elicit life stories that will be recorded digitally. (Art to Life, sponsored by Cognitive Dynamics Foundation in collaboration with the University of Alabama Honors College; Potts, personal communication, 2011).

Summary The expressive art therapies (music, art, drama and dance, poetry and bibliotherapy, reminiscence therapy, and storytelling) have numerous beneficial effects in geriatric neurology patients and their caregivers. The end result is fostering dignity, preserving a sense of self-worth, and improved quality of life. Though cure is not possible for many neurologic diseases of the elderly, the expressive art therapies are important components of rehabilitative treatment protocols and should be increasingly utilized in the current and future health-care environment. Further research is needed to rigorously document their benefits and to elucidate the scientific basis of the restorative potential of human creativity.

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Lipe, A.W., York, E., and Jensen, E. (2007) Construct validation of two music-based assessments for people with dementia. J Music Ther, 44 (4): 369–387. Merriam, A.P. (1964) The Anthropology of Music. Evanston: Northwestern University. Miller, B. and Hou, C. (2004) Portrait of artists: emergence of visual creativity in dementia. Arch Neurol, 61: 842–844. Miller, B.L., Cummings, J., Mishkin, F., et al. (1998) Emergence of artistic talent in frontotemporal dementia. Neurology, 51: 4978– 4982. doi:10.1212/WNL.51.4.978 National Association for Poetry Therapy (2011). http://www.poetrytherapy.org/ (accessed on August 2012) Nayak, S., Wheeler, B.L., Shiflett, S.C., and Agostinelli, S. (2000) Effect of music therapy on mood and social interaction among individuals with acute traumatic brain injury and stroke. Rehabil Psychol, 45 (3): 274–283. Nettl, B. (1956) Aspects of primitive and folk music relevant to music therapy. In: E. T. Gaston (ed), Music Therapy 1955. Lawrence: Allen Press. Noice, H. and Noice, T. (2006) What studies of actors and acting can tell us about memory and cognitive functioning. Curr Dir Psychol Sci, 15: 14–18. North American Drama Therapy Association (2012) http://www. nadta.org/(accessed on August 2012) O’Maille, T. and Kasayka, R. (2005) Touching the spirit at the end of life. Alzheimer’s Care Q, 6 (1): 62–70. Park, H. and Specht, J.K.P. (2009) Effect of individualized music on agitation in individuals with dementia who live at home. J Gerontol Nurs, 35 (8): 47–55. Potts, D. (2006) The Broken Jar. Tuscaloosa, AL: Wordway Press. Pratt, R. (2004) Art, dance, and music therapy. Phys Med Rehabil Clin N Am, 15: 827–841. Prickett, C.A. (2000) Music therapy for older people: research comes of age across two decades. In: M. S. Adamek and P. A. Codding (eds), Effectiveness of Music Therapy Procedures: Documentation of Research and Clinical Practice, 3rd edn, Silver Spring: American Music Therapy Association. Prickett, C.A. and Moore, R.S. (1991) The use of music to aid memory of Alzheimer’s patients. J Music Ther, 28 (2): 101–110. Rentz, C. (2002) Memories in the making: outcomes-based evaluation of an art program for individuals with dementing illnesses. Am J Alzheimer Dis and Other Dementias, 17 (3): 175–181. Ritter, M. and Low, K. (1996) Effects of dance/movement therapy: a meta-analysis. Arts in Psychother, 23 (3): 249–260. Sachs, C. (1965) The Wellsprings of Music. New York: McGraw-Hill. Sambandham, M. and Schirm, V. (1995) Music as a nursing intervention for residents with Alzheimer’s disease in long-term care. Geriatr Nurs, 16 (2): 79–83. Sandrick, K. (1995) Passage into their pasts. Hosp and Health Netw, 69: 55. Schauer, M., and Mauritz, K.H. (2003) Musical motor feedback (MMF) in walking hemiparetic stroke patients: randomized trials of gait improvement. Clin Rehabil, 17, 713–722. Solomon, A.L. (1993) A history of the journal of music therapy: the first decade (1964–1973). J Music Ther, 30 (1): 3–33. Special Committee on Aging, United States Senate. (August 1, 1991) Forever Young: Music And Aging: Hearing Before the Special Committee on Aging, United States Senate. Serial No. 102-9. Staum, M.J. (1983) Music and rhythmic stimuli in the rehabilitation of gait disorders. J Music Ther, 20 (2): 69–87.

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Part 5 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

Chapter 27 Dietary Factors in Geriatric Neurology Yian Gu and Nikolaos Scarmeas Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA

Summary • Certain dietary factors may influence the risk or progression of Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke. Conclusions from relevant research can be limiting since there are conflicting results. • High intake of vitamin E, vegetables, B vitamins, n-3 PUFA, and fish may reduce risk of AD. • High intake of vitamin E and caffeine, a moderate intake of CoQ, and low intake of dairy may reduce risk of PD. • High intake of vitamin C, folate, tea, whole grains, and a low intake of sodium may reduce risk of stroke. • Moderate consumption of alcohol and adherence to a healthy diet may reduce risk for AD, PD, and stroke.

Introduction Within the next 50 years, approximately 30% of the population will be aged 65 years or older. Neurologic disorders commonly increase in incidence with age. The major geriatric neurologic disorders include Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke. AD is the most common cause of dementia in elderly people (Alzheimer’s Association, 2010). An estimated 5.1 million Americans aged 65 and older currently suffer from AD; nearly 1 in 8 people aged 65 and older (13%) have AD. PD is the second most common neurodegenerative disorder after AD, with a prevalence of 2% among persons of 65 years and older (de Lau and Breteler, 2006). Stroke is the third leading cause of death among US adults age 65 or older (CDC, 2005); nearly three-quarters of all strokes occur in people over the age of 65 (Weir and Dennis, 1997). All together, these conditions lead to disability, cognitive and physical function decline, and loss of independence of the elderly. Although various vascular risk factors have been identified for stroke, including high blood pressure, high cholesterol, cigarette smoking, and diabetes, the etiology for AD and PD remains elusive. Furthermore, no known treatment stops, decelerates, or reverses the progression of AD or PD. Current medications for PD can help patients manage symptoms, but eventually the drugs lose their effectiveness. Therefore, it is important to explore and develop primary preventive strategies that can potentially help prolong healthy life free of aging-related neurologic diseases. Such strategies may target lifestyle factors, with diet being one of the most investigated and promising.

The primary objective of this chapter is to review the evidence for dietary factors as potential modifiable lifestyle factors to prevent cognitive decline, AD, PD, and stroke. Hypotheses and supporting evidence relating dietary factors to these disorders can be obtained from a variety of sources, including in vitro studies; animal experiments; epidemiologic studies, including crosssectional, retrospective, and prospective studies; and randomized clinical trials. Although in vitro and animal studies may provide critical direction for research and aid in the interpretation of epidemiologic studies, species differences may preclude direct extrapolation of findings from animal experiments to humans. Cross-sectional and retrospective case-control studies (in which information about previous diet is obtained from diseased patients and compared to that of subjects without the disease) generally provide information efficiently and rapidly and are useful in generating a hypothesis (Willett, 1998). However, because disease outcome cannot be established as a result of dietary exposure or a cause for dietary changes, cross-sectional and retrospective case-control studies cannot be counted on for a causal inference. Therefore, to identify methodologically sound causation studies (Haynes et al., 2005), this chapter focuses on reviewing data from prospective studies and randomized clinical trials in humans. In prospective studies, information on diet is obtained from disease-free subjects who are followed to determine disease rates according to levels of dietary factors (Willett, 1998). Randomized clinical trials usually randomly assign participants to a treatment group (diet intervention) or placebo group and compare

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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them for outcome, which is either a successful treatment of the disease, control of disease progression, or reduction in disease occurrence. For the purpose of dietary prevention of geriatric neurologic conditions, both of these types of studies may provide valuable information on whether a certain diet can prevent disease or control disease progression and, if so, which diet is best.

Dietary factors in relation to cognitive function and Alzheimer’s disease There is conflicting data about dietary interventions in improving cognitive function in AD. While case series and cohort studies point to a protective effect on cognition with several dietary interventions, confirmatory testing with randomized controlled clinical trials using individual agents have not shown a significant treatment effect on cognition in early AD (See also Chapter 36). Designing clinical trials to accurately test for a combined treatment effect of multiple dietary agents (used concurrently) is prohibitively expensive. This is because the sample size and cost increase exponentially with each agent added into the combination trial design. Designing clinical trials with more than eight treatment arms is significantly limited by the cost factor.

Antioxidants It has been hypothesized that antioxidants from food may reduce the risk of AD because antioxidants may reduce neuronal loss due to oxidative damage. A range of antioxidants from foods—namely, vitamin E (tocopherol), vitamin C (ascorbic acid), other carotenoids (including α-carotene, β-carotene, γ-carotene, lycopene, lutein, β-cryptoxanthin, zeaxanthin, and astaxanthin), and flavonoids (including isoflavone and catechin)—have been investigated regarding their associations with the risk of AD. Important sources of vitamin E are grain, nuts, milk, and egg yolk. Vitamin C is mainly found in citrus fruits, kiwi, sprouts, broccoli, and cabbage. Important sources of β-carotene are kale, carrots, broccoli, and spinach. Flavonoids are found in cranberries, green and black tea, soy foods, and legumes. Several studies have found an inverse association between dietary intake (Engelhart et al., 2002a; Morris et al., 2002; Devore et al., 2010) and total intake (intake from diet plus supplements) (Corrada et al., 2005) of vitamin E and risk of AD. In addition, the French Personnes Agees QUID (PAQUID ) cohort found that subjects with low plasma vitamin E concentrations (Helmer et al., 2003; Larrieu et al., 2004) are at a higher risk of developing a dementia in subsequent years. In contrast, other longitudinal studies (Luchsinger et al., 2003; Laurin et al., 2004; Dai et al., 2006; Vercambre et al., 2009) did not find a significant association between dietary intake of vitamin E and risk of AD.

Among the seven studies that examined the association of vitamin C intake and risk of AD, only an earlier report from the Rotterdam study found that high intake of vitamin C was significantly associated with reduced risk of AD (Engelhart et al., 2002a); other studies (Morris et al., 2002; Luchsinger et al., 2003; Laurin et al., 2004; Corrada et al., 2005; Dai et al., 2006; Vercambre et al., 2009) did not find a significant association. Recently, an updated report from the Rotterdam study again failed to confirm the inverse association between dietary vitamin C intake and risk of AD with a longer (nearly 10 years) follow-up (Devore et al., 2010). Use of vitamin E and vitamin C supplements have also been investigated in a few studies, but the results are inconsistent. Combined use of vitamin E and vitamin C was associated with reduced prevalence and incidence of AD in the Cache County Study (Zandi et al., 2004), with reduced risk of vascular dementia and better cognitive function but not AD in the HonoluluAsia Aging Study (HAAS) (Masaki et al., 2000). Nevertheless, these two studies found no evidence of a protective effect on AD prevention with use of vitamin E or vitamin C supplements alone (Masaki et al., 2000; Zandi et al., 2004). Furthermore, vitamin E and vitamin C supplements were not associated with risk of AD in two other studies (Morris et al., 1998, 2002; Luchsinger et al., 2003). Finally, several clinical trials conducted to date also found conflicting results on the association between antioxidants and cognitive decline or AD progression. In a randomized trial of patients with moderately severe impairment from AD, treatment with vitamin E (alpha-tocopherol, 2000 IU a day) delayed onset of death, institutionalization, loss of the ability to perform basic activities of daily living, and severe dementia but did not slow rates of cognitive deterioration (Sano et al., 1997). However, beneficial effects of vitamin E were lacking in later clinical trials with lower dosage combined with other antioxidants, in either healthy older adults (Yaffe et al., 2004; Kang et al., 2006) or subjects with preexisting cardiovascular disease (CVD) or CVD risk factors (Kang et al., 2009). In the PAQUID cohort, higher intake of antioxidant flavonoids was found to be associated with a reduced risk of incident dementia (Commenges et al., 2000), with better cognitive performance at baseline (Letenneur et al., 2007) and with a better evolution of the performance over time (Letenneur et al., 2007). Another large prospective study, the Rotterdam study, found that flavonoids intake, with or without subjects with supplement flavonoids use, was not associated with a risk of AD (Engelhart et al., 2002a). A short-term (6 month) double-blind, randomized, placebo-controlled clinical trial in postmenopausal women found that isoflavone supplementation had a favorable effect on cognitive function, particularly verbal memory (Kritz-Silverstein et al., 2003).

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β-carotene has been hypothesized to be associated with reduced risk of AD due to its potent antioxidative function. However, none of the six well-established prospective studies found a signification association (Engelhart et al., 2002a; Morris et al., 2002; Luchsinger et al., 2003; Laurin et al., 2004; Dai et al., 2006; Vercambre et al., 2009). The Physicians’ Health Study II (PHS-II), a randomized trial of β-carotene and other vitamin supplements for chronic disease prevention, found that mean global cognitive z-score and verbal memory score were both significantly better in the β-carotene treatment group than in the placebo group after long-term (mean treatment duration 18 years) but not short-term (1 year) treatment (Grodstein et al., 2007). Therefore, it seems there is a threshold, in terms of either amount or duration, for carotene to have beneficial effect for AD.

Fruits, vegetables, and fiber Three observational studies found no association between fruits intake and rates of cognitive decline (Kang et al., 2005; Morris et al., 2006b; Vercambre et al., 2009). Higher consumption of vegetables, on the other hand, has been associated with slower decline of cognitive function (Kang et al., 2005; Morris et al., 2006b) or less functional impairment (Vercambre et al., 2009). With regard to incidence of AD, the Three-City Study in France found that the risk of all-cause dementia or AD was about 30% lower in participants who regularly consumed fruits and vegetables (Barberger-Gateau et al., 2007). Finally, the Kame Project found that fruit and vegetable juice consumption was associated with lower risk of AD; this inverse association tended to be more pronounced among those with an Apolipoprotein E (ApoE) e-4 allele and those who were not physically active (Dai et al., 2006). B vitamins Studies have shown that elevated circulating homocysteine temporally precedes the development of dementia and that there is an inverse linear relationship between plasma homocysteine concentrations and cognitive function in older persons (Seshadri, 2006). Homocysteine is an amino acid that is involved in methionine metabolism and is associated with dietary intake of folate and vitamin B12. The Framingham Study found that deficiencies in folate, vitamin B12, and pyridoxal-5′-phosphate were primary determinants of homocysteinemia in the study cohort (Selhub et al., 1993). Thus, it is conceivable that B vitamins might also be associated with AD risk or cognition. Several longitudinal studies have examined the association between the dietary intake levels of B vitamins (vitamin B2, B6, vitamin B12, folate) and cognitive function or the risk of AD. In the Veterans Affairs Normative Aging (VANA) study, declines in constructional praxis were significantly associated with plasma homocysteine, folate, and vitamins B6

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and B12, as well as with the dietary intake of each vitamin; dietary folate was also protective against a decline in verbal fluency (Tucker et al., 2005). In the prospective Chicago Health and Aging Project (CHAP) study, unexpectedly, high folate intake from food sources and/or supplements was associated with a faster rate of cognitive decline (Morris et al., 2005a), while intake of vitamin B12, with or without vitamin supplementation, was not significantly associated with cognitive change (Morris et al., 2005a). Finally, the E3N study in France found that the odds of functional impairment increased significantly with decreasing intakes of vitamins B2, B6, and B12, but not with intake of folate; none of the B vitamins was associated with cognitive decline (Vercambre et al., 2009). Four well-established cohorts have examined the association between dietary intake of B vitamins and risk of incident AD (Corrada et al., 2005; Morris et al., 2006a; Luchsinger et al., 2007; Nelson et al., 2009). Significant inverse associations between folate intake (total or dietary) and risk of AD were found in two studies (Corrada et al., 2005; Luchsinger et al., 2007), and between vitamin B6 and risk of AD in two studies (Corrada et al., 2005; Morris et al., 2006a); none of the four studies found significant association between vitamin B12 intake and risk of AD. At least six randomized clinical trials have examined the effect of vitamin B6 or B12 or folic acid supplementation, alone or in combination, on cognitive function in subjects with either normal or impaired cognitive function. The Folic Acid and Carotid Intima-media Thickness (FACIT) trial found that folic acid supplementation (800 μg/day) for 3 years significantly improved memory, information processing speed, and sensorimotor speed in healthy elderly people in the Netherlands (Durga et al., 2007). In contrast, none of the other studies found a significant effect of vitamin B6 or B12 or folic acid supplementation, alone or in combination, on cognitive decline (Eussen et al., 2006; McMahon et al., 2006; Sun et al., 2007; Aisen et al., 2008; Kang et al., 2008).

Fish and unsaturated fatty acids Unsaturated fatty acids (UFAs) include polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs). Fish is a major dietary source of long-chain ω-3 (n-3) PUFAs, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are critical for brain structure and function (Salem et al., 2001). Foods that contain the highest level of MUFA are nuts, olive oil, and oil made from seeds and vegetables. Existing epidemiologic data relating fish or UFAs to cognition or dementia risk are somewhat mixed, however. Only a few studies have investigated the relationship between fish consumption and the intake of n-3 PUFA and cognitive decline. Results of an early analysis of the Zutphen Elderly Study found no clear inverse association between fish, linoleic acid (an n-6 PUFA), EPA, or DHA

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consumption and 3 year cognitive decline (Kalmijn et al., 1997a), but with longer follow-up (5 years), a strong inverse association between fish, EPA, or DHA consumption and cognitive decline was observed (van Gelder et al., 2007a). The CHAP showed that fish consumption but not dietary intake of n-3 PUFA was associated with less cognitive decline (Morris et al., 2005b). No significant associations between fatty fish or n-3 PUFA intake and 6 year cognitive change was observed in the VANA study (van de Rest et al., 2009). In the E3N study, higher fish and total n-3 PUFA consumption were both associated with lower odds of recent (over the past year) cognitive decline measured 13 years later (Vercambre et al., 2009). In the European Prospective Investigation into Cancer and Nutrition (EPIC)–Greece cohort, intake of PUFA was inversely associated with cognitive function. This association was largely accounted for by a similar association with seed oils. Intake of olive oil, MUFA, and saturated fatty acid (SFA) showed weak positive but not significant associations with cognitive function (Psaltopoulou et al., 2008). In the Italian Longitudinal Study on Aging (ILSA), high MUFA, PUFA, and total energy intakes were significantly associated with a better cognitive performance after a median follow-up of 8.5 years (Solfrizzi et al., 2006a). Additional findings from ILSA demonstrated that although dietary fatty acids intakes were not associated with incident mild cognitive impairment (MCI), high PUFA intake appeared to have borderline nonsignificant trend for a protective effect against the development of MCI (Solfrizzi et al., 2006b). The Three-City Study found participants with intensive use of olive oil (used for both cooking and dressing), a major source of MUFA, compared to those who never used olive oil, showed lower risk of cognitive decline for visual memory during the 4 year follow-up (Berr et al., 2009). Some (Kalmijn et al., 1997b; Morris et al., 2003; Larrieu et al., 2004; Huang et al., 2005; Barberger-Gateau et al., 2007) but not all (Engelhart et al., 2002b; Schaefer et al., 2006; Devore et al., 2009) large prospective studies found that higher intakes of fish and DHA from dietary sources were associated with a lower risk of dementia or AD. In the Rotterdam study, fish intake was inversely associated with dementia over a 2 year follow-up (Kalmijn et al., 1997b), but n-3 or n-6 PUFA intake (Engelhart et al., 2002b) was not associated with dementia risk over a 6 year follow-up. Furthermore, a longer follow-up (9.6 years, on average) of the same cohort found that neither total fish intake nor n-3 PUFAs (EPA and DHA) was associated with dementia risk or AD risk (Devore et al., 2009). In the Framingham Heart Study, fish intake was nonsignificantly associated with reduced risk of incident dementia, but plasma DHA levels were significantly associated with reduced risk of all-cause dementia (Schaefer et al., 2006). In the CHAP study, although EPA intake was not associated with AD risk, weekly consumption of fish,

consumption of DHA, or consumption of total n-3 PUFA was each associated with reduced risk of AD, and alphalinoleic acid (ALA, an n-6 PUFA) was associated with reduced risk only in ApoE e4 noncarriers (Morris et al., 2003). Participants of the PAQUID cohort who ate fish or seafood at least once a week had a significantly reduced risk of incident dementia (Larrieu et al., 2004). In the Cardiovascular Health Cognition Study (CHCS) in the United States, consumption of fatty fish more than two times per week was significantly associated with reduced risk of AD in comparison to those who ate fish less than once per month—and the effect was selective for noncarriers of the ApoE e4 allele (Huang et al., 2005)—while lean fried fish or total fish intake was not associated with AD risk. In the Three-City cohort study, weekly consumption of fish was associated with a reduced risk of AD and all-cause dementia, but again, only among ApoE e4 noncarriers. Regular use of oils rich in n-3 was marginally associated with a decreased risk of all-cause dementia, while regular consumption of oils rich in n-6 was associated with an increased risk of dementia among ApoE e4 noncarriers (Barberger-Gateau et al., 2007). In the Zutphen Elderly Study, fish, EPA, or DHA consumption was not associated with risk of incident cognitive impairment, but an increased risk was found for linoleic acid (an n-6 PUFA) (Kalmijn et al., 1997a). Current evidence from clinical trials does not support a beneficial effect of n-3 PUFA (especially EPA+DHA) supplementation on cognitive function. In a randomized clinical trial with 302 Dutch cognitively healthy subjects age ≥65  years, there were no significant differential changes in any of the cognitive domains for either low-dose (400 mg/d) or high-dose (1800 mg/d) EPA+DHA supplementation, compared with placebo (van de Rest et al., 2008). In addition, intake of 1500 mg/day EPA+DHA for 3 months was found not to have beneficial effect on cognitive function in another study with 218 mildly-to-moderately depressed individuals (Rogers et al., 2008). Similarly, no beneficial effect of 2 year 200 mg/day EPA + 500 mg/day DHA supplementation on cognition was found in a recent study of 867 cognitively healthy adults (Dangour et al., 2010). In another study, however, compared to subjects in the control arm, subjects receiving 800 mg/day DHA, 12  mg/day lutein, or combined supplementation of both had improved cognitive function, including verbal fluency, memory, and rate of learning (Johnson et al., 2008). However, these findings need to be confirmed because the study was small (49 subjects) and follow-up was short (4 months) (Johnson et al., 2008). In the OmegAD study, another randomized, double-blind clinical trial, 6 months’ administration of 1.7 g/day of DHA and 0.6 g/day of EPA in patients with mild-to-moderate AD did not delay the rate of cognitive decline (Freund-Levi et al., 2006). However, beneficial effects were observed in a small group of patients with very mild AD (Freund-Levi et al., 2006).

Dietary Factors in Geriatric Neurology

Alcohol To date, alcohol drinking is one of the mostly investigated dietary factors with regard to their associations with dementia. While a few studies did not find any association between alcohol intake and AD risk or cognitive change (Broe et al., 1998; Yip et al., 2006; Peters et al., 2009; Vercambre et al., 2009), the vast majority of observational investigations have reported a protective association. In the Hisayama Study in Japan, researchers found alcohol intake was associated with increased risk of overall dementia and vascular dementia, but not with risk of AD (Yoshitake et al., 1995). However, in this study, alcohol consumption was dichotomized into “yes” and “no,” and no detailed information was collected for further analysis of dose–response relationship (Yoshitake et al., 1995). Later, the PAQUID study found that moderate drinkers (three or four glasses of wine daily) had a decreased risk of developing dementia or AD compared to nondrinkers, while subjects with alcohol intake more than moderate did not seem to have reduced risk compared to nondrinkers (Orgogozo et al., 1997). Furthermore, in the Kungsholmen Project, light to moderate alcohol consumption (1–21 drinks per week in men, 1–14 drinks per week in women) was associated with a 50% decrease in incidence of dementia or AD (Huang et al., 2002). In general, moderate alcohol consumption (compared to nondrinking), has been repeatedly confirmed to be associated with reduced risk of dementia or AD in many cohorts, including the Copenhagen City Heart Study (monthly and weekly consumption of wine) (Truelsen et al., 2002), the CHCS (one–six drinks weekly of alcohol) (Mukamal et al., 2003), the Washington/Hamilton Heights–Inwood Columbia Aging Project (WHICAP) (>0 and ≤4 servings per day of wine) (Luchsinger et al., 2004), and a Chinese cohort (1–21 drinks per week in men, 1–14 drinks per week in women of total alcohol or wine) (Deng et al., 2006). In addition, the Cardiovascular Risk Factors Aging and Dementia (CAIDE) study found that participants who drank no alcohol and those who drank alcohol frequently (several times a month) at midlife were both twice as likely to have MCI in old age as participants who drank alcohol infrequently (less than once a month) (Anttila et al., 2004). The Rotterdam study did not find a significant association between alcohol drinking and AD, but the study found mild-to-moderate alcohol drinking (one to three drinks a day) was associated with a decreased risk of any dementia or vascular dementia (Ruitenberg et al., 2002). In these studies, more than moderate alcohol consumption in general was found to be either not associated or positively associated with increased risk of AD, suggesting a U-shape relationship between alcohol intake and AD risk. Interestingly, several studies found that the potential beneficial effect of alcohol consumption may be mostly due to wine consumption. For example, both the PAQUID study (Orgogozo et al., 1997) and the Three-City cohort

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study (Barberger-Gateau et al., 2007) found a reduced risk of AD associated with moderate intake of wine, while beer and liquor were not investigated. The Copenhagen City Heart Study (Truelsen et al., 2002) and the Chinese study (Deng et al., 2006) found moderate intake of wine associated with decreased risk of AD, while monthly intake beer or spirits increased AD risk. The Canadian Study of Health and Aging (CSHA) study (Lindsay et al., 2002) and the WHICAP study (Luchsinger et al., 2004) found moderate intake of wine protective, while beer, spirits, and other types of alcohol were not associated with AD risk. The Rotterdam study was the only study that did not suggest a different effect of specific types of alcoholic beverages beyond the effect of alcohol itself (Ruitenberg et al., 2002). In the Kame project, wine intake (at least once per week) was associated with a nonsignificant reduced risk of AD (Dai et al., 2006).

Coffee, tea, and caffeine Five longitudinal studies have investigated the relationship between coffee, tea, or caffeine consumption and dementia/AD or cognitive decline (Lindsay et al., 2002; Laurin et al., 2004; van Gelder et al., 2007b; Ritchie et al., 2007; Eskelinen et al., 2009). In the CSHA study, daily coffee drinking decreased the risk of AD by 31% during a 5 year follow-up (Lindsay et al., 2002). The Finland, Italy, and Netherlands Elderly (FINE) study also found that drinking more than three cups of coffee per day was associated with the least 10-year cognitive decline among elderly men (van Gelder et al., 2007b). Furthermore, results from the Three-City Study indicated that ≥3 cups/ day of caffeine (from coffee and tea) were associated with less decline in verbal cognitive functioning and, to a lesser extent, in visuospatial memory among women, but not among men (Ritchie et al., 2007). Caffeine consumption did not reduce dementia risk over a 4 year period in the same study (Ritchie et al., 2007). Recently, the CAIDE study reported that coffee drinkers at midlife had the lower risk of dementia and AD later in life, compared with those who drank no coffee or only little coffee; the lowest risk (65% decreased) was observed in people who drank three to five cups per day (Eskelinen et al., 2009). In contrast, tea drinking (Lindsay et al., 2002; Dai et al., 2006; Eskelinen et al., 2009), or flavonoid intake from tea (Laurin et al., 2004), has not been associated with a reduced risk of dementia/AD in longitudinal studies. Dietary patterns In addition to the studies on single nutrients and foods reviewed earlier, there has been growing interest in assessing the relationship of diseases with dietary patterns, because people eat combinations of foods/nutrients that are likely to be synergistic (or antagonistic). One dietary pattern that has attracted increasing interest is the Mediterranean diet (MeDi). The MeDi is characterized

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by high intake of vegetables, fruits, nuts, legumes, cereals, and fish; high intake of UFAs (mostly in the form of olive oil in salad dressing and cooking) and low intake of SFA; low to moderate intake of wine; and low intake of red meat and poultry (Roman et al., 2008). The MeDi seems to encapsulate many of the components reported in literature as potentially beneficial for various diseases (Sofi et al., 2008; Babio et al., 2009). Therefore, it is conceivable that a MeDi may also be associated with reduced risk for neurologic disorders. Based on analyses among more than 2000 participants of WHICAP (Scarmeas et al., 2006), subjects with higher adherence to MeDi at baseline had a lower risk of incident AD over an average follow-up period of 4 years, even after adjustment for potential confounders (Scarmeas et al., 2006). The association between MeDi and risk of incident AD was independent of physical activity (Scarmeas et al., 2009a). In the same cohort, higher adherence to the MeDi was also associated with a trend for reduced risk of developing incident MCI and reduced risk of MCI conversion to AD (Scarmeas et al., 2009b). The role of MeDi was further investigated in the Three-City cohort study, which demonstrated that better adherence to the MeDi was associated with slower rates of cognitive decline (Feart et al., 2009). No associations with incident dementia or AD were noted in this study (Feart et al., 2009), but power to detect such associations was extremely limited. In addition, no association between MeDi adherence and risk of MCI was found in the Mayo Clinic Study of Aging study after a short (median of 2.2 years) follow-up (Roberts et al., 2010), and baseline adherence to a MeDi was not associated with cognitive function 6–13 years later in the EPIC–Greece cohort (Psaltopoulou et al., 2008). A recent report from the WHICAP further supports the beneficial role of a MeDi-like dietary pattern (Gu et al.,2010). In this study, 33 food groups were combined in search for the existence of dietary patterns that can explain variation in seven AD-related (based on previous literature) nutrients using reduced rank regression analysis. The study identified a dietary pattern that was positively correlated with n-3 PUFA, n-6 PUFA, folate, and vitamin E, and negatively correlated with SFA and vitamin B12 intakes. The dietary pattern was characterized by higher intakes of oil and vinegar-based salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, and dark and green leafy vegetables; and a lower intake of highfat dairy products, meat, and butter, thus resembling the MeDi, to some extent. This dietary pattern was strongly associated with lower incident AD risk (Gu et al., 2010). Other dietary patterns have also been explored. The Recommended Food Score (RFS) (Kant et al., 2000) is a measure of dietary diversity by summing the number of foods recommended by current Dietary Guidelines for Americans (Ritchie et al., 2007). In the Cache County Study on Memory and Aging in Utah (Wengreen et al., 2009), compared with participants who had lower RFS

score, participants who had a higher RFS score (indicating consumption of more recommended foods, including fruits, vegetables, whole grains, nuts, fish, and low-fat dairy products) had higher cognitive function at baseline and experienced less cognitive decline over 11 years of follow-up (Wengreen et al., 2009). In another report from the Three-City cohort, participants consuming diets high in fruits, vegetables, fish, and n-3 fatty acids had decreased incidence of all-cause dementia and AD compared with those with diets low in these foods and nutrients (Barberger-Gateau et al., 2007). Only one clinical trial investigated dietary patterns in relation to cognition or AD risk. The Dietary Approaches to Stop Hypertension (DASH) diet is characterized as rich in fruits, vegetables, and low-fat dairy foods and having reduced amounts of saturated fat, total fat, and cholesterol (Appel et al., 1997). In a recent randomized clinical trial of 124 participants with elevated blood pressure who were sedentary and overweight or obese, subjects on either the DASH diet plus weight management arm or the DASH diet alone arm exhibited greater neurocognitive improvements, compared with subjects on the usual diet (Smith et al., 2010).

Summary Overall, some evidence from observational studies shows an inverse association between higher fish or n-3 PUFA consumption and slower cognitive decline or reduced risk of AD. Higher intake of folate, vitamin B6, or vitamin B12 has been associated with a slower cognitive decline or a reduced risk of AD in some but not all observational studies. In addition, consistent observational epidemiologic evidence indicates that moderate alcohol consumption (particularly wine consumption) and coffee or caffeine consumption (but not tea consumption) are inversely associated with the incidence of AD or with cognitive decline. Finally, as for antioxidants (vitamin E or C, carotenes, or flavonoids) either from dietary or supplement sources, there is little or conflicting evidence that they play an important role in preventing or treating AD and cognitive decline. Observational studies also found several beneficial dietary patterns (including the MeDi, RFS score, and others) that might be related to lower risk of cognition decline or AD. Of interest, fruits, vegetables, fish, nuts, and n-3 PUFA have been consistently included in these dietary patterns as beneficial components, while meat and SFA have been considered detrimental components in some of the examined dietary patterns. The current evidence from intervention studies does not suggest a protective role of n-3 PUFA or B vitamins supplementation. Clinical trials conducted to date also found conflicting results on the association between antioxidants and cognitive decline or AD progression. No randomized trials have studied the effects of alcohol or coffee consumption on cognitive function or dementia risk. The only

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intervention trial of dietary pattern suggests some benefits on preventing cognitive decline among subjects assigned to the DASH diet, alone or with weight management.

Dietary factors in relation to Parkinson’s Disease Similar to AD, case series and cohort studies suggest a protective effect of dietary intervention on PD symptoms, but confirmatory testing with randomized controlled clinical trials failed to show a robust treatment effect.

Antioxidants Several antioxidants, including vitamin E (tocopherol), vitamin C (ascorbic acid), vitamin A, provitamins of vitamin A (α-carotene, β-carotene, β-cryptoxanthin), lycopene, lutein, and zeaxanthin, have been studied regarding their association with PD risk. In a case-control study nested within HAAS, midlife consumption of legumes, which had high vitamin E content, was associated with reduced risk of PD (Morens et al., 1996). Other preselected foods high in vitamin E (vegetable oils and animal fats) and total vitamin E consumption were not associated with risk of PD (Morens et al., 1996). In another nested case-control study based on the Leisure World Laguna Hills (LWLH) cohort in California, a borderline increased risk for PD was reported among individuals in the highest tertile of dietary vitamin C intake and total vitamin A intake, but the association was no longer significant after controlling for other factors (Paganini-Hill, 2001). In the Health Professionals FollowUp Study (HPFS) and the Nurses’ Health Study (NHS) cohorts, the association between various antioxidants and risk of incident PD was evaluated (Zhang et al., 2002). Compared to individuals in the lowest intake, those in the highest dietary intake of vitamin E had a significantly reduced risk of PD (particularly for women) (Zhang et al., 2002). Those in the highest quintile of dietary vitamin C intake (compared to the lowest quintile) had marginally decreased risk of PD (Zhang et al., 2002). Intakes of dietary α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein/zeaxanthin; total vitamin E; total vitamin C; or use of vitamin E or vitamin C supplements or multivitamins was not significantly associated with risk of PD (Zhang et al., 2002). In the Singapore Chinese Health Study (SCHS), higher dietary vitamin E intake was found to be associated with reduced risk of PD, while dietary carotenoids, vitamin A, or vitamin C was not associated with PD risk (Tan et al., 2008). This landmark Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, a large, prospective, randomized, double-blind, placebo-controlled trial (The Parkinson Study Group, 1993), examined the effects of deprenyl (a monoamine oxidase inhibitor)

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10  mg/day and α-tocopherol (vitamin E) 2000 IU/day alone and in combination on 800 untreated patients in early stages of PD, for an average standard deviation (SD) of 14 (6) months. The primary endpoint was progression to initiation of levodopa therapy. Tocopherol supplementation was not found to reduce the probability of requiring levodopa therapy, alone or in combination with deprenyl, compared with placebo (The Parkinson Study Group, 1993).

Fruits and vegetables The only prospective study that investigated the association between dietary intake of fruits or vegetables and PD risk, using data from the NHS and HPFS cohorts, suggested that fruits or vegetables were not associated with risk of PD in either men or women (Chen et al., 2002). B vitamins In the Rotterdam Study, higher dietary intake of vitamin B6 was found to be associated with a significantly decreased risk of PD, which might be restricted to smokers as found in stratified analyses (de Lau et al., 2006). No association with PD was observed for dietary folate and vitamin B12 in this study (de Lau et al., 2006). The study including both the HPFS and the NHS populations found that neither folate, vitamin B6, nor vitamin B12 intakes were associated with risk for PD (Chen et al., 2004). Dietary fat At least four prospective studies have investigated the associations between fat intakes (measured as total, animal fat, vegetable oil, dairy fat, SFA, MUFA, PUFA, and trans-fat) and PD risk. In a case-control study nested in Honolulu Heart Program (HHP) cohort, PD occurrence was not associated with the intake of either vegetable oil or animal fat (Morens et al., 1996). In the pooled analysis of the HPFS and the NHS cohorts, total fat intake was not associated with PD risk. No associations were found for any major types of fat, including vegetable oil, MUFA, PUFA, trans-unsaturated fat or cholesterol. Among individual fatty acids of the PUFA, only arachidonic acid, an n-6 PUFA, tended to be inversely associated with PD risk, while none of the other specific fatty acids (linoleic acid, α-linolenic acid, fish n-3 fatty acid, EPA, and DHA) was significantly associated with risk of PD (Chen et al., 2003). In the Rotterdam Study (de Lau et al., 2005), intakes of total fat, MUFA, and PUFA were significantly associated with a lower risk of PD, while no associations were found for dietary SFA, cholesterol, or trans-fat (de Lau et al., 2005). In the SCHS, only MUFA was found to be marginally associated with reduced risk of PD; there was no association between PD risk and total fat, SFA, PUFA, n-3 PUFA, or n-6 PUFA (Tan et al., 2008). Finally, in a randomized, double-blind, placebocontrolled clinical trial among PD patients, participants

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taking fish oil (containing n-3 PUFA), with or without antidepressants, had improvements in their depressive symptoms, suggesting a possible role of n-3 PUFA in treatment of mood symptoms in PD (da Silva et al., 2008).

Dairy The first investigation of the associations between dairy intakes and PD risk was carried out in a combined analysis of the HPFS and the NHS cohorts (Chen et al., 2002). In this study, a positive association was found between dairy intake and PD risk in men, but not in women. Further analyses among men showed significant positive associations with PD risk for intakes of several dairy foods, including cheese and sour cream, as well as dairy nutrients, including dairy source of calcium, vitamin D, protein, and lactose, but not dairy fat (Chen et al., 2002). In a second prospective study of Japanese American participants in the HAAS cohort, men who consumed >16 oz/day of milk at midlife had a 2.3-fold excess of PD than men who did not drink milk, after adjusting for dietary and other factors. The effect of milk consumption on PD was also independent of the intake of calcium. Calcium from dairy and nondairy sources was not associated with PD risk in this study (Park et al., 2005). The most recent study of the American Cancer Society’s Cancer Prevention Study II Nutrition Cohort (CPS-II) found that, among men and women combined, dairy product consumption was positively associated with risk of PD. A higher risk among dairy product consumers was found for both men and women, although the association in women appeared nonlinear (Chen et al., 2007). In nutrient analyses, dairy source of calcium, vitamin D, protein, and fat was not associated with a higher risk of PD, although total intake from all sources of calcium and protein was associated with increased risk of PD (Chen et al., 2007). Alcohol To date, there have been at least two prospective investigations (Paganini-Hill, 2001; Hernan et al., 2003) of the association between alcohol consumption and risk of PD. A nested case-control study based on the LWLH cohort found that consuming two or more drinks per day reduced risk for PD (Paganini-Hill, 2001). However, in a pooled analysis of HPFS and NHS (Hernan et al., 2003), the risk of PD was similar in individuals who usually consume moderate amounts of alcohol and in nondrinkers/abstainers. Among three common types of alcoholic beverage (beer, wine, and liquor), beer seems to be more consistently associated with decreased risk of PD than wine and liquor. In the California study (Paganini-Hill, 2001), the odds ratio (OR) of PD comparing drinkers (≥2 drinks/day) with nondrinkers was much lower for beer drinkers than for wine or hard liquor drinkers, although none of the associations was significant. In the pooled analysis of HPFS and NHS cohorts (Hernan et al., 2003), beer drinkers (≥1 drink/

week) had a 30% lower incidence of PD than those who consumed beer <1 drink/month; consumption of wine or liquor was not associated with the incidence of PD. Therefore, it is possible that some components of beer, other than the common ethanol among all alcoholic beverages, may be associated with reduced risk of PD. For example, serum antioxidative and neuroprotective uric acid, which has been seen to increase more after beer consumption than after wine or liquor consumption, may contribute to the association between beer and PD (Collins, 2002).

Coffee, tea, and caffeine The associations between frequency of coffee intake, frequency of tea intake, or amount of total dietary caffeine intake and risk of PD have been evaluated in several prospective studies. In the HHP, age-adjusted incidence of PD declined consistently with increased amounts of coffee intake, from 10.4 per 10,000 person-years in men who drank no coffee to 1.9 per 10,000 person-years in men who drank at least 28 oz/day. Similar relationships were observed for total caffeine intake and for caffeine from noncoffee sources. Other nutrients in coffee, including niacin, were unrelated to PD incidence (Ross et al., 2000). In a case-control study nested within the LWLH cohort, intake of ≥2 cups/day of regular coffee was associated with reduced risk of PD compared with nondrinkers, while decaffeinated coffee or tea drink was not associated with PD risk (Paganini-Hill, 2001). Similarly, in the HPFS cohort, an inverse association was observed for consumption of coffee, total caffeine, caffeine from noncoffee sources, and tea, but not decaffeinated coffee (Ascherio et al., 2001). Among women participants of NHS, the relationship between caffeine or coffee intake and risk of PD was U-shaped, with the lowest risk observed at moderate intakes (1–3 cups of coffee per day, or the third quintile of caffeine consumption) (Ascherio et al., 2001). The protective effect of coffee and tea is further supported in two large prospective studies in Finland, which found reduced risk of PD for subjects with more coffee drinking (Hu et al., 2007; Saaksjarvi et al., 2008) or more tea drinking (Hu et al., 2007), compared to nondrinkers. In SCHS, total caffeine intake was inversely related to PD risk. After adjusting for total caffeine intake, smoking, and other covariates, black tea, but not coffee or green tea, was found to be associated with reduced PD risk, suggesting that ingredients of black tea other than caffeine might be responsible for this beverage’s protective effect against PD (Tan et al., 2008). Coenzyme Q10 Coenzyme Q10 (CoQ10) is an intrinsic component of the mitochondrial respiratory chain. In a double-blind, placebo-controlled pilot study, 80 patients with early stage PD were randomized to receive placebo or 300, 600, or

Dietary Factors in Geriatric Neurology

1200 mg/day of oral CoQ10 (Shults et al., 2002, 2004). The study found that high doses of oral CoQ10 (1200 mg/ day) were associated with a reduced rate of deterioration in motor function and an improved daily living activity scores from baseline over the 16-month course of the trial. In another smaller, placebo-controlled, randomized, double-blind trial of oral CoQ10 360 mg/day for 4 weeks, 28 treated and stable PD patients showed a statistically significant mild symptomatic benefit in their PD symptoms (Muller et al., 2003), but motor symptoms did not improve. In a recent clinical trial of 131 midstage PD patients, intake of CoQ10 (300 mg/day for 3 months) did not improve PD symptoms (Storch et al., 2007). Nevertheless, the Hoehn and Yahr scale scores, one of the six secondary clinical outcome variables, improved significantly in the CoQ10 group but not in the placebo group, with a significant difference between groups. Analysis according to the stratification revealed significant changes only in the levodopa stratum of the CoQ10 group (Storch et al., 2007). Despite these conflicting data, a recent futility study, a Phase II clinical trial designed to determine whether it is worthwhile to evaluate the possible disease-modifying effects of an agent in future Phase III trials, suggested that CoQ10 could not be rejected as futile and, therefore, met the criteria for possible further clinical testing (NINDS NET-PD Investigators, 2007).

Other foods The only prospective study that investigated the association between meat products and PD risk, the NHS and HPFS cohorts, reported that there was no statistically significant association between meat, fish, or poultry intake and risk of PD (Chen et al., 2002). The combined analysis of HPFS and NHS cohorts reported that consumption of nuts was significantly associated with a reduced risk of PD (Zhang et al., 2002). Dietary patterns Several dietary patterns have been evaluated in relation to the risk of PD in the HPFS and NHS cohorts. A principal components analysis (PCA)-derived “prudent” dietary pattern (characterized by high intakes of fruit, vegetables, and fish) was inversely associated with PD risk, and a PCA-derived “Western” dietary pattern (characterized by high intakes of red meats, processed meats, refined grains, French fries, desserts and sweets, and high-fat dairy products) was not significantly associated with PD risk. Two additional dietary scores were calculated. The Alternate Healthy Eating Index (AHEI) included nine components, including vegetables, fruit, nuts and soy, ratio of white to red meat, cereal fiber, lower trans-fats, ratio of polyunsaturated to saturated fat, longterm multivitamin use, and alcohol (0.5–1.5 servings/ day contributes most to the total score), with a higher score suggesting a higher dietary quality. The second one, the alternate Mediterranean Diet Score (aMed), was

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based on intake of nine items: vegetables (without potato products), legumes, fruit, nuts, whole grains, fish, ratio of MUFA to SFA, alcohol, and red and processed meat. A higher aMed score suggested a higher dietary quality. The study found a significantly reduced risk of PD associated with AHEI and a borderline reduced risk of PD associated with aMed. No interventional studies of dietary patterns have been performed.

Summary Overall, some evidence from observational studies indicates an inverse association between alcohol (particularly beer), caffeine or caffeinated beverages consumption, and PD risk, and a positive association between dairy consumption and risk of PD. However, data from clinical trials are lacking. Observational evidence in general suggests that dietary vitamin E intake might be associated with reduced risk of PD, while findings of the association between dietary vitamin C intake and risk of PD are conflicting. However, vitamin E has been found to be ineffective regarding PD progression in a clinical trial. The current research on B vitamins is largely inadequate to confidently support the hypothesis that higher dietary intake of B vitamins could reduce the risk of developing PD. Observational studies suggest limited evidence to support an association between fats intake and PD risk, with some exceptions that have reported possible beneficial associations with UFA. A pilot intervention study showed some benefits of n-3 PUFA for improvements in depressive symptoms among PD patients. Overall, minor benefits of uncertain clinical significance for patients with PD have been observed with high doses of CoQ10 in clinical trials. Whether CoQ10 is associated with risk for developing PD has not been adequately explored. The NHS and HPFS cohorts are the only studies to investigate meat products, fruits, vegetables, and various dietary patterns in relation to PD risk. PD risk was not associated with meat products, fruits, or vegetables consumption. Dietary patterns, including a PCA-derived “prudent” dietary pattern (high intakes of fruit, vegetables, and fish), AHEI, and aMeD, are associated with reduced PD risk. No clinical trials in relation to PD on these foods or dietary patterns have been conducted to date.

Stroke Dietary interventions in stroke patients reported benefit in case series and cohort studies, but confirmatory testing with randomized controlled clinical trials using individual agents failed to show benefit. Secondary and subgroup analyses suggest combining multiple dietary factors may augment their effect.

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Antioxidants

Vitamin C (ascorbic acid) Most of the earlier studies worldwide reported that vitamin C intake was not related to the risk for stroke or mortality for stroke, including a study in Gothenburg, Sweden (Lapidus et al., 1986); the Zutphen Study in the Netherlands (Keli et al., 1996); the Chicago Western Electric Study (Daviglus et al., 1997); a prospective study of middle-aged men in Shanghai, China (Ross et al., 1997); and the HPFS (Ascherio et al., 1999). The first hint of a potential protective role of dietary vitamin C came from a small (99 cases) Norwegian study, which showed that intake of vitamin C was inversely related to the risk for hemorrhagic stroke but not ischemic stroke (Vollset and Bjelke, 1983). A much larger British study of 730 elderly (aged ≥65 years), community-dwelling subjects reported that both vitamin C dietary intake and plasma concentrations of vitamin C had a strong inverse correlation with the 20 year risk of death from stroke (Gale et al., 1995). The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study in Finland showed that vitamin C intake was inversely associated with risk for intracerebral hemorrhage, but not cerebral infarction or subarachnoid hemorrhage (Hirvonen et al., 2000). In the Iowa Women’s Health Study (IWHS), overall vitamin C intake was associated with reduced risk for death from stroke, although the association appeared somewhat U-shaped (Yochum et al., 2000). More recently, the Rotterdam Study found that higher intake of vitamin C was associated with a lower risk of first-ever ischemic stroke (Voko et al., 2003). This study also found that the beneficiary effect was mainly confined to smokers (Voko et al., 2003). Results are much more consistent for studies examining the association between circulating (plasma or serum) vitamin C and risk of stroke. Strong inverse associations have been observed between serum/plasma vitamin C concentration and risk for stroke or mortality of total stroke (Gey et al., 1993; Hensrud et al., 1994; Gale et al., 1995; Yokoyama et al., 2000; Kurl et al., 2002; Myint et al., 2008), ischemic stroke (Yokoyama et al., 2000; Kurl et al., 2002), and hemorrhagic stroke (Yokoyama et al., 2000; Kurl et al., 2002). These studies have led to some clinical trials of vitamin C supplementation in the prevention of stroke. The data from the PHS-II (Sesso et al., 2008), however, showed no significant effect of vitamin C (500 mg of vitamin C daily) on the prevention of total stroke in middle-aged and older men (Sesso et al., 2008).

Vitamin E The IWHS found an inverse association between dietary vitamin E intake and death from stroke, but not the risk of incident stroke (Yochum et al., 2000). The Rotterdam Study found that higher intake of vitamin E was

associated with a lower risk of first-ever ischemic stroke, but the reduced risk was limited to smokers only (Voko et al., 2003). Four other studies, including the Zutphen Study in the Netherlands (Keli et al., 1996); a prospective study of middle-aged men in Shanghai, China (Ross et al., 1997); the HPFS study (Ascherio et al., 1999); and the ATBC study (Hirvonen et al., 2000), did not find an association between dietary intake of vitamin E and risk of either stroke or stroke mortality. The ATBC study (Leppala et al., 1999b) found that baseline high serum α-tocopherol (the most active form of vitamin E) was associated with decreased risk of intracerebral hemorrhage by half and of cerebral infarction by one third. No significant association was found between plasma α-tocopherol and stroke incidence in a case-control study nested within the Physician Health Study (Hak et al., 2004). Several randomized clinical trials of vitamin E supplementation have been conducted with regard to its effect on stroke. In the ATBC study, vitamin E supplementation increased the risk of subarachnoid hemorrhage and decreased risk of cerebral infarction in hypertensive men, but had no effect among normotensive men (Leppala et al., 2000a, 2000b). The PHS-II randomized controlled trial found that 400 IU of vitamin E every other day was not associated with total stroke, but was associated with an increased risk of hemorrhagic stroke (consistent with the ATBC study) (Sesso et al., 2008). A daily dose of natural-source vitamin E in the Heart Outcomes Prevention Evaluation (HOPE) trial showed no protective effect for stroke prevention (Yusuf et al., 2000; Lonn et al., 2005). The Heart Protection Study Collaborative Group reported that vitamin E supplementation did not produce any significant reductions in the 5 year mortality from, or incidence of, any strokes of any particular type or severity (Heart Protection Study Collaborative Group, 2002). Similarly, the Women’s Health Study did not find 600 IU of naturalsource vitamin E on alternate days effective for preventing stroke (Lee et al., 2005). Results from the Women’s Antioxidant Cardiovascular Study showed there were no overall effects of ascorbic acid, vitamin E, or β-carotene on cardiovascular events among women at high risk for CVD, but those randomized to both active ascorbic acid and vitamin E experienced fewer strokes (Cook et al., 2007).

Other antioxidants: β-carotene (Pro-Vitamin A), flavonoid, and catechins Observational studies on the association between various antioxidants and stroke have produced mixed findings. The Zutphen Study found that dietary flavonoids (mainly quercetin) and β-carotene were inversely associated with stroke incidence (Keli et al., 1996). The ATBC study found that dietary intake of β-carotene was associated with reduced risk for cerebral infarction, lutein plus zeaxanthin with reduced risk for subarachnoid hemorrhage, and

Dietary Factors in Geriatric Neurology

lycopene with reduced risks of cerebral infarction and intracerebral hemorrhage (Hirvonen et al., 2000). Findings from the Kuopio Ischaemic Heart Disease Risk Factor Study (Mursu et al., 2008) suggest that high intakes of flavonoids may be associated with decreased risk of ischemic stroke. In the HPFS, an inverse relationship between lutein intake and risk for ischemic stroke was seen but was not independent of other dietary factors (Ascherio et al., 1999). Other studies did not find significant associations between these antioxidants (carotenes, flavonoid, and catechins) and stroke risk (Yochum et al., 1999, 2000; Hirvonen et al., 2000; Knekt et al., 2000; Arts et al., 2001; Sesso et al., 2003; Voko et al., 2003; Marniemi et al., 2005; Mink et al., 2007).

Fruits and vegetables Many observational studies (Gillman et al., 1995; Joshipura et al., 1999; Liu et al., 2000a; Bazzano et al., 2002b; Johnsen et al., 2003; Sauvaget et al., 2003a; Hak et al., 2004; Larsson et al., 2009; Mizrahi et al., 2009), with the exception of the Atherosclerosis Risk in Communities (ARIC) study (Steffen et al., 2003), showed that subjects with the highest intake of fruit and vegetable had a lower incidence of stroke and a reduced mortality from stroke. All categories of fruit and vegetables may play a protective role on ischemic stroke risk, particularly cruciferous green leafy vegetables and citrus fruit and juice (Gillman et al., 1995; Mizrahi et al., 2009). Fish and unsaturated fatty acids Cumulative data suggest that a high intake of n-3 fatty acids may be cardioprotective. Thus, fish and seafood, as the main sources of n-3 fatty acids, and their relationship with stroke risk have been evaluated in a number of prospective studies. An early meta-analysis of nine independent cohorts (from eight studies) (Keli et al., 1994; Morris et al., 1995; Gillum et al., 1996; Orencia et al., 1996; Iso et al., 2001; Yuan et al., 2001; He et al., 2002; Sauvaget et al., 2003b) concluded that fish consumption might be inversely associated with risk of stroke, particularly ischemic stroke (He et al., 2004b). The Large-scale Census-based Cohort Study in Japan, which was not included in the meta-analysis, also found an inverse association between fish intake and risk of mortality from hemorrhagic stroke (Kinjo et al., 1999). Conflicting results, however, have been shown in later studies. Some studies confirmed that fish or UFAs intake was associated with reduced risk of stroke (Laaksonen et al., 2005; Mozaffarian et al., 2005), while a few other studies did not show a beneficial effect of fish (Keli et al., 1994; Morris et al., 1995; Orencia et al., 1996; Yuan et al., 2001; Folsom and Demissie, 2004; Nakamura et al., 2005; Myint et al., 2006; Yamagishi et al., 2008; Montonen et al., 2009; Bravata et al., 2007) or UFAs (Seino et al., 1997; He, 2003; Wennberg et al., 2007; Yamagishi et al., 2008)

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on stroke. Moreover, a nested case-control study found increased risk of stroke among men with increasing fish intake (Wennberg et al., 2007), and a Finnish study reported that consumption of salted fish was associated with an increased risk of intracerebral hemorrhage (Montonen et al., 2009). A few studies examined the specific type of fish consumed. Consumption of tuna or other (boiled or baked) fish was associated with lower risk of ischemic but not hemorrhagic stroke, while intake of fried fish or fish sandwiches was associated with a higher ischemic stroke, suggesting that how fish is prepared could be an important factor (Mozaffarian et al., 2005). Similarly, in the Cardiovascular Health Study, tuna/other fish consumption was associated with trends toward lower incidence of subclinical infarcts on MRI examinations, while no significant associations were found between fried fish consumption and subclinical infarcts (Virtanen et al., 2008).

Tea A recent pooled meta-analyses (Arab et al., 2009) of eight cohort studies (Sato et al., 1989; Klatsky et al., 1993; Keli et al., 1996; Yochum et al., 1999; Hirvonen et al., 2000; Sesso et al., 2003; Kuriyama et al., 2006; Kuriyama, 2008; Larsson et al., 2008a) showed that tea consumption was associated with reduced risk of stroke and reduced mortality from stroke. Subjects drinking more than or equal to three cups of tea daily appear to reduce risk of a fatal or nonfatal stroke by approximately 21%, compared with nondrinkers of tea (Arab et al., 2009). In addition, both black tea and green tea may have a similar effect, and the effect did not appear to be specific to Asian or non-Asian populations. However, no associations between tea and stroke incidence or stroke mortality were found in a recent study (de Koning Gans et al., 2010). The mechanism of action by which tea may protect against stroke is not entirely clear, but speculations surround the antioxidant functions and anti-inflammatory actions. Coffee For many years, studies have suggested that coffee consumption may increase the risk of coronary heart disease (CHD) (LaCroix et al., 1986). Thus, a similar association between coffee consumption and stroke was also suspected. The HPFS, however, found for the first time that total coffee consumption was not associated with an increased risk of stroke (Grobbee et al., 1990). Studies continued to support that coffee consumption was not associated with increased risk of or mortality from stroke (Bidel et al., 2006; Zhang et al., 2009; Leurs et al., 2010; Sugiyama et al., 2010). Additionally, several studies showed that coffee drinking could be associated with reduced risk of stroke or stroke mortality. For example, there is a significant reduction in mortality from stroke among those drinking —five to six cups daily as compared to those drinking —zero to

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two cups daily (Bidel et al., 2006). The NHS found longterm coffee drinking (either caffeinated or decaffeinated) associated with reduced risk of stroke in women (LopezGarcia et al., 2009). The ATBC study suggested that high consumption of coffee might reduce the risk of cerebral infarction (but not intracerebral or subarachnoid hemorrhage) among male smokers (Larsson et al., 2008a). Finally, the Japan Collaborative Cohort (JACC) showed coffee consumption was associated with a linear risk reduction for mortality from stroke in men but not in women; a U-shaped association was also observed between caffeine intake and stroke in both men and women (Mineharu et al., 2009). Nevertheless, the HHP found that the risk of thromboembolic stroke (but not of hemorrhagic stroke) was more than double for men who consumed three cups of coffee per day, compared to nondrinkers of coffee (Hakim et al., 1998). A recent EPIC–Netherlands cohort also suggested a modestly increased risk of stroke among coffee consumers, although the linear trend of increasing risk with increasing cups of coffee drink was no longer significant after multivariate adjustment (de Koning Gans et al., 2010).

B vitamins Findings from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study (NHEFS) indicated an inverse relationship between dietary intake of folate and subsequent risk of overall stroke (Bazzano et al., 2002a). In the HPFS, intake of folate was associated with a significantly lower risk of ischemic but not hemorrhagic stroke (He et al., 2004a). Similarly, the Finnish ATBC study (Larsson et al., 2008b) found a high folate intake associated with a statistically significant lower risk of cerebral infarction but not intracerebral or subarachnoid hemorrhages. In the CardioVascular Disease risk FACtor Two-township Study (de Koning Gans et al., 2010), low folate intake was significantly and independently associated with an increased ischemic stroke risk, whereas no association was observed for plasma folate concentration. On the contrary, a nested case-control study based on the Northern Sweden Health and Disease Cohort (NSHDC) found a significant inverse linear association of dietary or plasma folate with hemorrhagic stroke, but not with ischemic stroke risk (Van Guelpen et al., 2005). In a population-based cohort study, stroke mortality rates were reduced after the U.S. Food and Drug Administration in the United States and Canada mandated a folic acid fortification of enriched grain products (Yang et al., 2006). The ATBC and NSHDC studies have reported that vitamin B6 and vitamin B12 intakes were not significantly associated with any subtype of stroke (Van Guelpen et al., 2005; Larsson et al., 2008b). The HPFS was an exception: Intake of vitamin B12 (but not B6) was marginally inversely associated with risk of ischemic stroke (He et al., 2004a). A meta-analysis of eight randomized trials of folic acid supplementation suggested that folic acid supple-

mentation with or without a combination with other B vitamins could effectively reduce the risk of stroke by 18% (Wang et al., 2007). Stratification analysis showed a greater benefit with a treatment duration of more than 36 months, achieving a decrease in the concentration of homocysteine of more than 20%, including populations not consuming fortified grain, and enrolling subjects with absent stroke history (Wang et al., 2007). However, a large placebo-controlled trial of US high-risk women did not show any effect of the combination of folic acid, vitamin B6 and B12 on stroke or total cardiovascular events after 7.3 years (Albert et al., 2008). Similarly, recent updates from two large trials did not support combined folic acid and B vitamin supplementation for secondary prevention of stroke. The VITAmins TO Prevent Stroke (VITATOPS) trial showed that daily administration of folic acid, vitamin B6, and vitamin B12 to patients with recent stroke or transient ischemic attack was safe but did not seem to be more effective than placebo in reducing the incidence of major vascular events (composite of stroke, myocardial infarction, or vascular death) (VITATOPS Trial Study Group, 2010). The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), a double-blind, randomized controlled trial of 12,064 survivors of myocardial infarction, found substantial longterm reductions in blood homocysteine levels with folic acid and vitamin B12 supplementation, but no beneficial effects on stroke risk (Armitage et al., 2010).

Grains Intake of cereal fiber was first found to be inversely associated with risk of total stroke in the HPFS (Ascherio et al., 1998). The Finnish ATBC study found cereal consumption to be marginally associated with reduced risk of intracerebral hemorrhage in male smokers (Larsson et al., 2009). In the IWHS, there was a nonsignificant trend of reduced mortality from stroke associated with higher intake of whole grains (Jacobs et al., 1999). The PHS reported that whole-grain breakfast cereal intake was significantly inversely associated with mortality from stroke (Liu et al., 2003). The NHS observed an inverse association between whole grain intake and ischemic stroke risk (Liu et al., 2000b). Whole-grain intake was inversely associated with incident ischemic stroke among participants of the ARIC study, but the association was attenuated and no longer significant after multivariate adjustment (Steffen et al., 2003). Interestingly, all of these four studies found no association between refined grain (Liu et al., 2000b, 2003; Steffen et al., 2003) or total grain (Liu et al., 2000b) and mortality from or risk of stroke, suggesting that the beneficial effect might be specifically associated with whole grain. This might be the result of refined grains containing mostly starch, providing fewer nutrients and phytochemicals (contained in bran and germ in the whole grain) (Steffen et al., 2003). Indeed, one study found bran

Dietary Factors in Geriatric Neurology

(added to food) to be significantly associated with risk of stroke even after multivariate adjustment (Mink et al., 2007). Nevertheless, in the Finnish Mobile Clinic Health Examination Survey, whole grain, refined grain, or total grain was not associated with ischemic stroke or intracerebral hemorrhage (Mizrahi et al., 2009).

Alcohol Over the last several decades, more than 30 prospective studies have examined the association between alcohol drinking and risk of stroke (Donahue et al., 1986; Kono et al., 1986; Gordon and Doyle, 1987; Stampfer et al., 1988; Klatsky et al., 1989; Shaper et al., 1991; Goldberg et al., 1994; Iso et al., 1995, 2004; Kiyohara et al., 1995; Palmer et al., 1995; Yuan et al., 1997; Maskarinec et al., 1998; Truelsen et al., 1998; Berger et al., 1999; Leppala et al., 1999a; Gaziano et al., 2000; Jousilahti et al., 2000; Sankai et al., 2000; Mukamal et al., 2001, 2005a, 2005b; Djousse et al., 2002, 2009; Klatsky, 2002; Jackson et al., 2003; Emberson et al., 2005; Nielsen et al., 2005; Elkind et al., 2006; Bazzano et al., 2007; Peng et al., 2007; Ikehara et al., 2008, 2009; Lu et al., 2008; Sundell et al., 2008; Bos et al., 2010; Beulens et al., 2007). Overall, as suggested by many investigators and supported by a recent meta-analysis (Patra et al., 2010) of 17 cohort studies, the cumulative results indicate the following. There seems to exist a positive association between heavy alcohol consumption (>30 g/day) and hemorrhagic stroke mortality in both men and women and risk of hemorrhagic stroke in men. Moderate consumption of up to three drinks might be associated with reduced risk of hemorrhagic stroke in women. For ischemic stroke, the association between alcohol consumption and ischemic stroke mortality or risk seems to be more consistent across genders, with an overall J-shaped association—that is, moderate drinking (one to two drinks, or 10–30 g alcohol, per day) is protective, whereas heavy drinking is harmful— compared to the nondrinkers or lowest drinkers. Some studies also explored the association of stroke with different types of alcohol. One study found red wine but not other types of alcoholic beverages was associated with reduced risk of stroke (Bos et al., 2010); another study observed the strongest risk reduction for liquor (Beulens et al., 2007). Thus, although red wine has been postulated to contain additional elements (polyphenols) that provide even greater cardiovascular benefit than alcohol alone, it remains unclear whether red wine has any advantage over other forms of alcoholic beverages (Saremi and Arora, 2008). Dairy The health effects of milk and dairy food consumption on stroke has been evaluated in several prospective cohort studies. Several studies reported a reduced risk of stroke (Abbott et al., 1996; Iso et al., 1999; Kinjo et al., 1999; Umesawa et al., 2006, 2008b; Warensjo et al., 2009) associated

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with higher consumption of dairy or dairy components. The HHP study found a decreased risk of stroke associated with increasing milk intake, and this association could not be explained by intake of dietary calcium (Abbott et al., 1996). In the Large-scale Census-based Cohort Study in Japan, dairy milk, by itself or with meat and fish, was associated with the risk of mortality from total, ischemic, and hemorrhagic strokes (Kinjo et al., 1999). Other studies mainly focused on the effect of dairy components intake (calcium and milk fat) rather than dairy intake itself on risk of stroke incidence or mortality. Analysis of NHS data found an inverse association between calcium intake and with mortality from total stroke, and the association was stronger for dairy than for nondairy calcium intake (Iso et al., 1999). In the JACC study, dairy calcium intake was associated with decreased risks of mortality from total and ischemic stroke, but not for hemorrhage stroke (Umesawa et al., 2006). Another Japanese study, the Japan Public Health Center (JPHC) study, found dairy calcium intake associated with a reduced incidence of total and ischemic strokes (Umesawa et al., 2008b). A nested case-control study in Sweden found biomarkers of milk fat intake, the proportions of fatty acids 15:0+17:0 and 17:0 among plasma lipids, were significantly and inversely related to stroke risk (Warensjo et al., 2009). Recently, the Boyd Orr cohort in England and Scotland found childhood calcium intake inversely associated with stroke mortality in adulthood, but a family diet in childhood high in dairy products was not associated with stroke mortality (van der Pols et al., 2009). A few studies found no association between dairy intake (He et al., 2003; Elwood et al., 2004; van der Pols et al., 2009) and stroke risk, though. Furthermore, the ATBC study even observed positive associations between whole milk intake and risk of intracerebral hemorrhage and between yogurt intake and subarachnoid hemorrhage. However, inverse associations were also found between cream intake with both cerebral infarction and intracerebral hemorrhage in men, and no associations were found between intakes of total dairy, low-fat milk, sour milk, cheese, ice cream, or butter and risk of any stroke subtype (Warensjo et al., 2009).

Various nutrients The relationship between certain electrolytes and risk of stroke has been explored in several studies. In general, the current findings from observational studies suggest that higher intake of magnesium (Larsson et al., 2008c), calcium (Iso et al., 1999; Umesawa et al., 2006, 2008b; Weng et al., 2008; van der Pols et al., 2009), potassium (Iso et al., 1999; Weng et al., 2008), iron (Marniemi et al., 2005; Weng et al., 2008), or lower intake of sodium (salt) (Umesawa et al., 2008a; Strazzullo et al., 2009) is associated with reduced risk of stroke. The NHS reported that intake of calcium was significantly inversely associated with risk of ischemic stroke,

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and potassium intake showed marginally significant inverse association with ischemic stroke, while no association with any stroke subtypes was found for magnesium (Iso et al., 1999). In a population-based health survey, low intake of vitamin D, low serum levels of 1,25-dihydroxyvitamin D, and low serum levels of iron predicted were significantly predictive of stroke (Marniemi et al., 2005). In a Finnish cohort of male smokers, a high magnesium intake was associated with a statistically significant lower risk of cerebral infarction, but no association was found with intracerebral or subarachnoid hemorrhages. Calcium, potassium, and sodium intakes were also examined in this Finnish cohort, but they were not significantly associated with risk of any subtype of stroke (Larsson et al., 2008c). The JACC study found dairy calcium intake associated with decreased risks of mortality from total and ischemic stroke (Umesawa et al., 2006), and the JPHC study found dairy calcium intake associated with reduced incidences of total and ischemic strokes (Umesawa et al., 2008b). The JACC study also found that potassium intake was not associated with stroke risk, but was inversely associated with mortality from total CVD (Umesawa et al., 2008a). In addition, this study found sodium intake positively associated with mortality from total stroke, ischemic stroke, and total CVD (Umesawa et al., 2008a). The CardioVascular Disease risk FACtor Two-township Study found that potassium, iron, and calcium were all associated with ischemic stroke (Weng et al., 2008).

Dietary patterns Two large prospective studies, the Healthy Ageing: A Longitudinal study in Europe (HALE) (Knoops et al., 2004) and the American Association of Retired Persons (AARP) Diet and Health Study (Mitrou et al., 2007), both found that better adhering to a MeDi was associated with a lower risk of mortality from CVD (including stroke events). Recently, in the NHS, women with a higher aMed score, indicating a greater adherence to the MeDi, were associated with a lower risk of incident stroke, as well as lower risk of CVD deaths (fatal CHD and strokes combined) (Fung et al., 2009). In the Women’s Health Study, a large prospective cohort of apparently healthy women, a healthy lifestyle, consisting of healthy diet (high in cereal fiber, folate, and n-3 PUFA, with a high ratio of PUFA to SFA, and low in trans-fat and glycemic load), as well as abstinence from smoking, low body mass index, moderate alcohol consumption, and regular exercise, was associated with a significantly reduced risk of total and ischemic stroke but not of hemorrhagic stroke (Kurth et al., 2006). In the NHS, two major dietary patterns were identified using factor analysis: a “Western” pattern, typified by higher intakes of red and processed meats, refined grains, and sweets and desserts; and a “prudent” pattern, higher in fruits and vegetables, fish, and whole grains. The

Western dietary pattern was significantly associated with increased risk of total strokes, whereas the prudent diet pattern was significantly associated with lower stroke risk (Fung et al., 2004). In the same NHS cohort, the DASH-style diet, which is high in fruits and vegetables, moderate in low-fat dairy products and low in animal proteins, was also examined in relation to incidence of stroke (Umesawa et al., 2008a). The DASH score was found to be significantly associated with lower risk of stroke (Fung et al., 2008). In the Women’s Health Initiative Dietary Modification Trial, 48,835 postmenopausal women aged 50–79 were randomly assigned to a dietary intervention (reduced total fat intake and increased intakes of vegetables, fruits, and grains) versus a free-living setting for more than 8  years. The dietary intervention did not significantly reduce the risk of stroke (Howard et al., 2006).

Summary Some, but not all, epidemiologic studies suggest an inverse association between dietary intake of and blood levels of vitamin C and risk for stroke or stroke mortality, but interventional studies have not confirmed this association or a treatment effect. Observational studies on the association between vitamin E and stroke have produced conflicting results. Many clinical trials have failed to demonstrate a beneficial role of vitamin E in the prevention of stroke. Furthermore, some studies have demonstrated a potentially detrimental effect for vitamin E (increased risk for hemorrhagic stroke). Some, but not universal, evidence from observational studies indicates that intake of folic acid might be associated with reduced risk of stroke. The association between vitamins B6 and B12 and stroke is even more controversial. Findings from randomized clinical trials do not support use of folic acid, vitamin B6, or B12 for primary or secondary prevention of stroke. Some evidence suggests that dietary fibers (especially whole grains), fruits and vegetables, tea, fish, and moderate alcohol consumption might be inversely associated with both reduced risk of stroke and mortality from stroke. The association between coffee or dairy consumption and stroke remains controversial in observational studies. Limited data from observational studies suggest that higher intake of magnesium, calcium, potassium, or iron, or lower intake of sodium (salt) might be associated with reduced risk of stroke. Among the dietary patterns, observational studies have consistently reported MeDi to be associated with a lower risk of mortality from CVD (including stroke events). Other beneficial dietary patterns, including DASH (high in fruits and vegetables, moderate in low-fat dairy products and low in animal proteins), a PCA-derived “prudent” dietary pattern (higher in fruits and vegetables, fish, and whole grains), and a predefined healthy diet

Dietary Factors in Geriatric Neurology

(high in cereal fiber, folate, and n-3 PUFA, with a high ratio of PUFA to SFA, and low in trans- fat and glycemic load) were all associated with reduced risk of stroke. On the other hand, a PCA-derived “Western” diet (high in red and processed meats, refined grains, sweets, and desserts) was associated with increased risk of stroke. However, the only dietary intervention study did not find significant reduction in stroke events among participants assigned to a healthy diet (reduced total fat intake and increased intakes of vegetables, fruits, and grains). Overall, consistent with the previously mentioned findings, according to the current Guideline from the American Heart Association/American Stroke Association Stroke Council, a reduced intake of sodium (≤2.3 g/day) and increased intake of potassium (≥4.7 g/day) are recommended to lower blood pressure, which may thereby reduce the risk of stroke. A diet containing five or more servings of fruits and vegetables per day, moderate alcohol drink, and components of the DASH diet is also recommended (Goldstein et al., 2006).

Conclusions Due to the increasing proportion of older adults in the US population and the absence of an effective cure for major geriatric neurologic disorders, including AD, PD, and stroke, there is an urgent need for effective preventive measures to prolong the period of healthy life and ease the disease burden for society. As we reviewed here, cumulative evidence indicates that regular consumption of certain dietary factors may be associated with risk of AD, PD, and stroke. For example, high consumption of vitamin E, vegetables, B vitamins, n-3 PUFA, and fish; moderate consumption of alcohol; and adherence to healthy dietary patterns (such as MeDI, RFS, and DASH) might be associated with lower AD risk. High consumption of vitamin E and caffeine; moderate consumption of alcohol and CoQ10; low consumption of dairy; and adherence to healthy dietary patterns (such as AHEI) might be associated with lower PD risk. High consumption of vitamin C, folate, tea, and whole grains; moderate consumption of alcohol; low consumption of sodium, and adherence to healthy dietary patterns (such as MeDi and DASH) might be associated with lower stroke risk. However, most evidence derives from observational studies. Given the practical and financial limitations of interventional studies, very few foods and nutrients (mostly vitamin supplementations) have been evaluated in large multicenter, randomized clinical trials in older persons. Furthermore, many controlled trials do not confirm findings from observational studies. As a result, scientific confidence on truly effective dietary habits regarding AD, PD, and stroke is currently quite limited, precluding population recommendations.

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Yamagishi, K., Iso, H., Date, C., et al. (2008) Fish, omega-3 polyunsaturated fatty acids, and mortality from cardiovascular diseases in a nationwide community-based cohort of Japanese men and women: the JACC (Japan collaborative cohort study for evaluation of cancer risk) study. J Am Coll Cardiol, 52 (12): 988–996. Yang, Q., Botto, L.D., Erickson, J.D., et al. (2006) Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation, 113 (10): 1335–1343. Yip, A.G., Brayne, C., and Matthews, F.E. (2006) Risk factors for incident dementia in England and Wales: the medical research council cognitive function and ageing study. A population-based nested case-control study. Age Ageing, 35 (2): 154–160. Yochum, L., Kushi, L.H., Meyer, K., and Folsom, A.R. (1999) Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women. Am J Epidemiol, 149 (10): 943–949. Yochum, L.A., Folsom, A.R., and Kushi, L.H. (2000) Intake of antioxidant vitamins and risk of death from stroke in postmenopausal women. Am J Clin Nutr, 72 (2): 476–483. Yokoyama, T., Date, C., Kokubo, Y., et al. (2000) Serum vitamin C concentration was inversely associated with subsequent 20-year incidence of stroke in a Japanese rural community. The Shibata study. Stroke, 31 (10): 2287–2294. Yoshitake, T., Kiyohara, Y., Kato, I., et al. (1995) Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama study. Neurology, 45 (6): 1161–1168. Yuan, J.M., Ross, R.K., Gao, Y.T., et al. (1997) Follow-up study of moderate alcohol intake and mortality among middle aged men in Shanghai, China. BMJ, 314 (7073): 18–23. Yuan, J.M., Ross, R.K., Gao, Y.T., and Yu, M.C. (2001) Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China. Am J Epidemiol, 154 (9): 809–816. Yusuf, S., Dagenais, G., Pogue, J., et al. (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. The heart outcomes prevention evaluation study investigators. N Engl J Med, 342 (3): 154–160. Zandi, P.P., Anthony, J.C., Khachaturian, A.S., et al. (2004) Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the cache county study. Arch Neurol, 61 (1): 82–88. Zhang, S.M., Hernan, M.A., Chen, H., et al. (2002) Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk. Neurology, 59 (8): 1161–1169. Zhang, W.L., Lopez-Garcia, E., Li, T.Y., et al. (2009) Coffee consumption and risk of cardiovascular events and all-cause mortality among women with type 2 diabetes. Diabetologia, 52 (5): 810–817.

Chapter 28 Exercising the Brain: Nonpharmacologic Interventions for Cognitive Decline Associated with Aging and Dementia Brenna A. Cholerton1, Jeannine Skinner2, and Laura D. Baker3 1

Department of Psychiatry and Behavioral Science, University of Washington School of Medicine and Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA 2 Department of Neurology, Vanderbilt School of Medicine, Nashville, TN 3 Department of Medicine - Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC, USA

The idea is to die young, as late as possible. Ashley Montagu

Summary • Physical activity improves cardiovascular health, increases neurogenesis and neurotrophic factors, reduces inflammation, and maintains insulin-signaling pathways. • Exercise is used as a method of prevention and intervention for cognitive decline in preclinical populations. After diagnosis, the efficacy of exercise therapies is unclear. • Potential moderating factors include the age at intervention, genotype, gender, the intensity and type of exercise, stress, and depression. • Mental activity and exercise are associated with a reduced risk of cognitive decline. After diagnosis, cognitive rehabilitation may improve several areas of cognitive function. • Social activity and support has been linked to higher cognitive function and reduced risk of global cognitive decline and dementia.

Alzheimer’s disease (AD) and other dementias are rapidly increasing in prevalence in the United States and are thus a major source of concern for the aging population and its health-care providers. Neurochemical and structural changes associated with AD likely begin years before the development of even mild cognitive symptoms (Smith et al., 2007); as a result, health-care providers must explore possible interventions before the onset of serious cognitive disability. Established risk factors for cognitive impairment and dementia that are amenable to intervention include medical complications such as cardiovascular disease (Waldstein and Wendell, 2010) and diabetes (Akter et al., 2011), as well as sociologic factors such as an inactive cognitive lifestyle (Fratiglioni and Wang, 2007) and a lack of positive social support (Seidler et al., 2003). In this chapter, we present three potential nonpharmacologic approaches for preventing cognitive decline: physical exercise, mental stimulation, and social support. Whether these interventions prevent or merely slow the progression of cognitive decline, widespread implementation could vastly reduce the socioeconomic and

financial burdens associated with dementia. Each treatment approach is examined with respect to multiple levels of intervention: (1) primary prevention, intended to reduce dementia risk in the entire population; (2) secondary prevention, aimed at individuals at risk for dementia due to either age or the onset of mild cognitive symptoms; and (3) tertiary prevention, meant to mitigate the effects of dementia after it has been clinically diagnosed.

Physical exercise Aerobic exercise has potent remedial effects on multiple body systems, and growing evidence indicates that exercise may benefit cognitive function not only for healthy older adults (Kramer et al., 1999, 2006), but also for adults with cognitive impairments (Lautenschlager et al., 2008; Baker et al., 2010a). The results of numerous human and animal studies support a relationship between increased physical activity and improvements in learning and memory

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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(Archer, 2011). Several interrelated mechanisms underlying the protective effects of exercise in the brain have been proposed, including improved cardiovascular and cerebrovascular functions (Ainslie et al., 2008; Black et al., 2009), anti-inflammatory processes (Colbert et al., 2004; Kampus et al., 2008), neurogenesis (Kannangara et al., 2011), and enhanced insulin-dependent energy metabolism (GomezPinilla et al., 2008). When compromised, any of these confer an increased risk of cognitive decline and dementia. Cardiovascular health and cerebral perfusion. Cardiovascular risk factors, including hypertension, hyperlipidemia, obesity, and impaired glucose regulation, are among the most well-established of the potentially modifiable risk factors associated with both AD and vascular dementia (Altman and Rutledge, 2010; de Toledo Ferraz Alves et al., 2010; Waldstein and Wendell, 2010). Even before the onset of dementia, a steeper downward cognitive trajectory is noted for individuals with one or more cardiovascular risk factors (Waldstein and Wendell, 2010). Cardiorespiratory fitness is also closely linked with cerebral perfusion and brain vascularization; age-related reductions in cerebral perfusion are exacerbated in AD and may represent an early marker of disease pathogenesis (Johnson et al., 2005). The numerous documented benefits of physical activity on cardiovascular and cerebrovascular health, which are likely mediated by improved blood flow (Brown et al., 2010), neurotrophic factors (van Praag et al., 2005), inflammatory influences (Kasapis and Thompson, 2005), and insulin signaling (Teixeira-Lemos et al., 2011), provide a rationale for exercise-based interventions aimed at improving cognitive function and/or preventing cognitive decline. Neurogenesis and neurotrophic growth factors. The link between physical activity and neurogenesis in the dentate region of the hippocampus has been well characterized in animal models. In rodents, physical exercise leads to augmentation of long-term potentiation, hippocampal cell proliferation, increased dendritic arborization, and greater density of dendritic spines for both aged animals and animals exposed to stressful environments and interventions (Archer, 2011). A reversal of age-related decline in new neuron generation in the hippocampus and corresponding improvements on tasks of learning and memory are apparent when rodents are permitted to exercise freely (van Praag et al., 2005). Recent evidence, obtained by measuring regional cerebral blood volume on MRI, suggests that exercise-induced angiogenesis (and likely neurogenesis) occurs in the dentate region of the hippocampus in humans as well (Pereira et al., 2007). These effects are most likely mediated by multiple neurotrophic factors, including brain-derived neurotrophic factor (BDNF) (GomezPinilla et al., 2011), insulin-like growth factor (Trejo et al., 2001), and vascular endothelial growth factor (Yasuhara et al., 2007). Indeed, aerobic exercise is associated with increased hippocampal size in older adults (as compared with nonexercising controls), which coincides with

augmentation of BDNF levels in serum and improved spatial memory (Erickson et al., 2011). Inflammation. Pro-inflammatory markers increase with age and are likely involved in the corresponding age-related decrease in hippocampal neurogenesis (Viviani and Boraso, 2011). AD is associated with even greater cerebral inflammation and oxidative stress (Rogers and Shen, 2000; Lue et al., 2001), and anti-inflammatory drugs have been noted to suppress both inflammation and neurotoxicity in laboratory models (Lim et al., 2000). High levels of inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are found in brains of AD patients, as compared with normal controls (Bauer et al., 1992; Dickson et al., 1993). Exercise has long been lauded for its role in creating an “anti-inflammatory environment” and is associated with lower levels of inflammatory biomarkers (Kasapis and Thompson, 2005). Insulin-signaling pathways. An important established risk factor for cognitive decline and dementia relates to disruptions in insulin sensitivity characterizing type 2 diabetes and even subclinical impaired glucose tolerance (Akter et al., 2011). Disturbed insulin signaling in the brain likely contributes to age- and disease-related changes in cerebral blood flow through its effects on hemodynamic functions such as capillary recruitment and vasoreactivity (Cersosimo and DeFronzo, 2006). Altered insulin signaling in the brain also influences regulation of amyloid-β (Aβ) (Craft, 2007) and other AD biomarkers, such as BDNF (Gomez-Pinilla et al., 2008) and cortisol (Mastorakos and Pavlatou, 2005). Cognitive impairments affecting executive control have been linked to reduced vasodilation, with pronounced effects on frontal–subcortical circuits that are particularly susceptible to insulin-dependent microvascular changes in vulnerable areas with watershed arteriole architecture (Campbell and Coffey, 2001). Aerobic exercise is an effective treatment for impaired glucose tolerance and diabetes, and thus may help to attenuate the negative influence of impaired insulin action on cognition (Baker et al., 2010a; Teixeira-Lemos et al., 2011). Given the multitude of known and suspected beneficial effects of physical activity, aerobic exercise may serve as a cost-effective therapeutic approach with the potential to amend numerous physiologic and cognitive processes compromised by age and AD pathology. The following sections discuss the implications of exercise interventions at all levels of prevention.

Primary prevention: lifetime exercise and dementia risk The beneficial effects of exercise on later cognitive function may begin at an early age, during the course of neural development. This theory is supported by animal models, which suggest that physical exercise may have the most pronounced beneficial effects on neural network reserves at younger ages (Black et al., 1991; Maniam and Morris, 2010). In humans, this connection is less clear; however, the level of

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physical activity during the teens and early 20s (by retrospective self-report) is associated with higher scores on global cognitive function in women aged 65 and over (Middleton et al., 2010) and with improved processing speed in older men (Dik et al., 2003). Lifelong moderate physical activity is linked with improved performance on tasks of working memory, processing speed, and global intelligence in postmenopausal women (Tierney et al., 2010). Regular exercise during midlife is also related to subsequent reduced risk for dementia and milder impairments in memory at older ages (Andel et al., 2008; Geda et al., 2010). In one study, older adults who met the American Heart Association recommendations for exercise (30 min per day, 5 days per week) during the 10 years prior to evaluation had lower levels of amyloid burden in several brain regions (measured using Pittsburgh compound B, PiB, on PET scan), including the prefrontal cortex and lateral temporal areas (Liang et al., 2010). These results support an early and consistent lifelong exercise routine as an important primary method in the prevention of later cognitive decline.

Secondary prevention: the impact of exercise in older age Normal aging. Normal aging is associated with declines in processing speed, executive functioning, and memory (Charlton et al., 2010; Silver et al., 2011; Smith, 2011). Physical activity in older age appears to attenuate cognitive decline, particularly in domains most susceptible to age-related losses (Colcombe et al., 2004; van Uffelen et al., 2008; Baker et al., 2010a, 2010b). Multiple large-scale epidemiologic studies, including the Canadian Study of Health and Aging (Middleton et al., 2008), the Honolulu-Asia Aging Study (Abbott et al., 2004), the Adult Changes in Thought Study (Larson et al., 2006), and others (Yaffe et al., 2001), provide supportive evidence linking increased physical activity in older adults to a reduced risk of cognitive decline. There is even some suggestion that older adults may benefit more from exercise than younger adults in terms of specific physiologic functions, such as cerebral vascular tone (Ogoh et al., 2011), and reduced risk for cognitive decline (Colcombe and Kramer, 2003). Large-scale exercise intervention trials in older adults with and without cognitive impairment are underway to corroborate findings from epidemiologic studies; however, results from smaller-scale studies provide compelling support for the use of aerobic exercise as an intervention to improve cognitive function. To date, the most pronounced salutary cognitive effects are for executive control processes such as selective attention and multitasking (Kramer et al., 2006; Baker et al., 2010a), observed in both physically healthy and glucose-intolerant older adults who are at increased risk of cognitive decline. In addition, aerobic exercise has favorable effects on brain regions that support executive function, with reports of reductions in age-related volume loss (Colcombe et al., 2003, 2006) and improved efficiency

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of brain activity in associated networks (Voss et al., 2010). Recently, Erickson et al. (2011) reported that 12 months of aerobic exercise training increased hippocampal volume by 2%, which effectively reversed age-related volume loss by about 2 years (Figure 28.1). Mild cognitive impairment. Although it appears that exercise may be an effective intervention for those who are at risk for AD by virtue of their age, a more targeted population for intervention includes older adults who are already experiencing mild declines in cognitive function. Mild cognitive impairment (MCI) characterizes a cognitive state that falls on the continuum between normal cognitive aging and dementia (Petersen, 2004; Winblad et al., 2004), and it is a recognized risk factor for dementia (Petersen, 2004; de Rotrou et al., 2005; Petersen, 2006; Schmidtke and Hermeneit, 2008). For this reason, intervention at the MCI stage may be of critical importance for prevention. As with cognitively normal adults, physical activity may represent an effective nonpharmacologic strategy to prevent or delay further cognitive decline in older at-risk adults (Teixeira et al., 2012). Although epidemiologic studies have consistently shown that exercise reduces the risk of developing cognitive impairment, only a limited number of experimental studies have been designed to examine the impact of aerobic exercise on cognition in people diagnosed with MCI. Initial findings from randomized trials that employ moderate- to high-intensity exercise interventions provide promising results. In a small but well-publicized, randomized controlled 6-month trial of aerobic exercise versus a stretching control condition for sedentary adults with amnestic MCI and in the earliest stage of AD pathology (Morris and Cummings, 2005), Baker et al. (2010b) reported exerciseinduced improvements in cardiorespiratory fitness, insulin sensitivity, and performance on four tasks of executive function (Figure 28.2). Consistent with other reports in normal older adults (Colcombe et al., 2003), the cognitive effects in this study were more pronounced for women than for men. For all subjects, plasma levels of Aβ tended to decline, with aerobic exercise signifying a possible disease-modifying effect of this intervention. In another, larger 6-month randomized controlled trial (n = 170) (Lautenschlager et al., 2008), subjects in the active group who exercised at a moderate intensity for 150 min per week over and above what they were completing at the outset of the study (that is, not necessarily sedentary at study entry) showed small but significant improvements on the Alzheimer Disease Assessment Scale (ADAS-Cog) scores. In contrast, a recent study examining the effects of a multimodal exercise program on older adults with MCI residing in a structured living environment demonstrated improved cardiovascular fitness in the absence of improvement in cognitive function (Miller et al., 2011). These results may indicate that, as cognitive impairment progresses and a greater level of structure is required to ensure compliance, individuals may benefit less from a prescribed exercise intervention. This

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cognitively healthy older adults (n = 120). (a) Example of hippocampus segmentation and graphs demonstrating an increase in hippocampus volume for the aerobic exercise group and a decrease in volume for the stretching control group. The Time by Group interaction was significant (p < 0.001) for both left and right regions. (b) Example of caudate nucleus segmentation and graphs demonstrating the changes in volume for both groups. Although the exercise group showed an attenuation of decline, this did not reach significance (both p > 0.10). (c) Example of thalamus segmentation and graph demonstrating the change in volume for both groups. None of the changes were significant for the thalamus. Error bars represent SEM. Source: Erickson et al. (2011). Reproduced with permission of National Academy of Sciences. (For a color version, see the color plate section.)

final point raises some concern on the potential of exercise as an effective intervention for AD.

Tertiary prevention: exercise and dementia Once the clinical symptoms of dementia become evident, is it possible to reverse or at least slow the progression of the disease? This question, of course, is the crux of numerous ongoing pharmacologic and nonpharmacologic investigations. To date, the search for a disease-modifying intervention has proven elusive; it seems apparent that once the disease process produces significant clinical symptomatology, substantial and permanent reversal of symptoms is unlikely. However, a number of interventions are aimed at

slowing the progression of symptoms and improving quality of life for patients with dementia. Given the beneficial effects of an active lifestyle on health conditions associated with dementia, the demonstrated neuroprotective effects of exercise on brain functioning and morphology, and the initially positive findings of exercise on cognition in nondemented and mildly impaired older adults, it is surmised that increased physical activity may be a relatively cost-effective and efficacious strategy to decelerate disease progression. Unfortunately, the small number of trials completed to date do not support substantial improvements in cognitive function for adults once AD symptoms become apparent (Eggermont et al., 2009). Of note, however, there appears to

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aerobic exercise versus stretching (n = 29) on tests of executive function, expressed as residual scores, including (a) Symbol–digit modalities test (number correct in 120 s), (b) Verbal fluency by letter and by category, (c) Stroop color word interference test (computer administered), voice onset latencies (ms) to interference stimuli, and (d) Trails B, time to complete the task (s, log transformed). Source: Baker et al. (2010b). Reproduced with permission of American Medical Association.

be a significant positive correlation between cardiorespiratory fitness and parietal and medial temporal lobe volume (specifically, white matter in the bilateral inferior parietal cortex) in patients with AD (Honea et al., 2009). Increased frailty in this population and related safety concerns typically restrict interventions to include only low-intensity exercise, which may not be sufficient to induce changes in cognitive function. In contrast, even low-intensity exercise programs may improve some aspects of activities of daily living, increase social and cognitive stimulation, and boost mood—factors that could remediate some of the deleterious consequences of dementia (Logsdon et al., 2005).

Non-Alzheimer’s disease dementia syndromes Few studies have investigated the potential benefits of physical activity for non-AD dementia syndromes. Vascular dementia shares many of the same risk factors with AD, and the two often co-occur. As with AD, the risk of vascular dementia may be ameliorated by midlife exercise, with up to a 70% reduction in risk associated with moderate exercise (Ravaglia et al., 2008). Again, less is known about what happens when the disease process significantly impacts activities of daily living. Presumably, however, an exercise-related reduction in stroke risk alone (Ainslie, 2009) may prevent additional decline in some patients

with vascular dementia. Potential problems associated with the implementation of moderate-intensity exercise programs, similar to those for AD groups, include safety concerns linked to high medical comorbidity. Less still is known about the effects of exercise on Parkinson’s-related dementia and on dementia with Lewy bodies. Exercise programs may lead to some improvements in executive function, motor control, and mood for people with Parkinson’s disease (PD) (Tanaka et al., 2009; Dereli and Yaliman, 2010; Combs et al., 2011; Cruise et al., 2011). A number of ongoing trials are exploring the potential PD-modifying effects of aerobic exercise, as indicated by intervention-related changes in brain chemistry (via lumbar puncture), structure (via MRI), and function (via functional connectivity MRI, PET). Again, the efficacy of exercise interventions on cognitive functions after a clinical diagnosis of dementia is made remains unclear.

Potential moderating factors Earlier, we illustrated the potential effects of exercise on a number of neurobiologic risk factors related to cognitive decline, described the association between exercise and dementia risk, and provided initial evidence that exercise may help improve cognitive functions in older adults before the onset of dementia. A number of factors,

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however, may moderate those most likely to benefit from exercise-based interventions. 1 Age at intervention: For health of the body, it is never too late to start. For health of the mind, lifelong exercise likely has the greatest risk benefit. A reduction in dementia risk may be related to the cumulative effects of exercise throughout life. With this in mind, however, a number of reports indicate that older adults show an enhanced cognitive response to exercise compared with young adults, although this trend may reflect limitations of the assessment tools rather than age-related differences in cognitive response. 2 Genotype: Preliminary evidence suggests that the beneficial effects of exercise in older adults may be particularly evident for those without an APoE ε4 allele (Lautenschlager et al., 2008); however, even those with an ε4 allele may derive some cognitive benefit potentially via reparative effects of exercise on the vascular system. Additional studies are needed to more definitively characterize the interaction between exercise and genotype as it relates to cognitive response and risk of dementia. 3 Gender: Some reports indicate greater cognitive response for women (Middleton et al., 2008; Baker et al., 2010b); others do not discriminate by gender (Lautenschlager et al., 2008). To date, no study has compared cognitive response with exercise in men and women in a head-to-head, randomized trial. Further research is needed to elucidate what role, if any, gender plays in predicting response to exercise and to identify potential responder variables that might account for gender differences if they do exist (for example, severity of comorbidities, such as coronary artery disease, with potential consequences for cognitive response to exercise). 4 Intensity of exercise: To date, consensus from a number of studies points to moderate- or high-intensity exercise to improve cognitive function and reduce dementia risk (Etgen et al., 2010; Geda et al., 2010; Tierney et al., 2010). The questions “How much is enough?” and “Is there too much?” have not yet been answered, although a number of trials are now underway to address these issues. As mentioned previously, the low-intensity exercises employed in AD trials may not be sufficient to induce changes in cognition. 5 Type of exercise: The intervention most commonly associated with cognitive benefit to date involves aerobic exercise using stationary equipment such as a treadmill or elliptical trainer, or walking programs. Fewer but promising trials with respect to their cognition-enhancing effects have used multimodal exercise interventions with some combination of aerobic, strength resistance, and flexibility (Marmeleira et al., 2009; Williamson et al., 2009). Other studies have examined the effects of resistance training alone and report a positive effect on executive function in cognitively healthy older adults (Liu-Ambrose and Donaldson, 2009; Anderson-Hanley et al., 2010; Davis et al., 2010; Liu-Ambrose et al., 2010). It is possible that resistance training and/or multimodal exercise regimes may lead to increased mental activity, thereby promoting

improved cognitive function beyond the benefits of aerobic exercise. 6 Role of stress/depression: Depression is often a prominent feature in patients with MCI and dementia, and those with depression are at a higher risk for multiple health conditions that can impact cognition. Physical exercise has been shown to be an effective intervention for depression in older adults (Hill et al., 1993). However, depression may also moderate the likelihood that a person will engage in physical activity. Further evaluation of the complex interplay among depression, exercise, and cognitive impairment is warranted; however, the overall improvement in mood and reduction in stress associated with physical activity provides additional compelling support for exercise as an intervention technique in aging.

Conclusions: physical exercise Despite the uncertainty surrounding the ability of exercise-based interventions to significantly modulate cognition in people already diagnosed with clinical dementia, general consensus supports the role of such interventions in preventing cognitive decline and even enhancing certain cognitive abilities in healthy aging and MCI. Particularly when combined with a multimodal intervention approach that includes mental stimulation and social engagement, physical exercise is a compelling nonpharmacologic approach to prevent cognitive impairment.

Mental exercise An enriched cognitive environment may have a place in the prevention of both age-related cognitive decline and the development of dementia. The results of animal and human studies indicate favorable effects of cognitive training on the aging brain for both structure and function, suggesting that brain plasticity persists late into the lifespan (Costa et al., 2007; Harburger et al., 2007; Engvig et al., 2010; Lovden et al., 2010). The following sections review several potential points of intervention, from early life cognitive enrichment to the treatment of cognitive decline associated with dementia.

Primary prevention: education and lifetime cognitive experiences Lower levels of education are consistently associated with a significantly higher risk of later cognitive impairment (Mortimer et al., 2003; Gatz et al., 2007; Tyas et al., 2007); conversely, highly educated individuals show a lower risk (Lindsay et al., 2002). Although education is the most commonly used marker for lifetime cognitive capacity, occupational complexity and choice of leisure activities throughout the adult lifespan have also been linked with a reduced dementia risk in observational studies (Valenzuela and Sachdev, 2006). Valenzuela, et al. (2008) estimated lifetime cognitive experiences using the Lifetime of Experiences

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Questionnaire, a retrospective self-report measure that produces a score based on education, occupation, social engagement, physical activity, and daily activities and hobbies. They found that higher scores correlated negatively with hippocampal atrophy over time in later life. Despite a general consensus that education and other life experiences are in some way related to later dementia risk, several important questions concern the nature of this association. • Is dementia risk associated with education, per se, or do factors underlie the ability to attain higher levels of education? Level of education is often seemingly inextricable from other factors. Socioeconomic status, in particular, can impact access to nutrition, health care, social support, and education, all of which may be associated with later-life health and dementia risk (Borenstein et al., 2006). In addition, individuals with lower levels of education may be more likely to transition into high-risk occupations that increase the likelihood of injury and exposure to toxins, and may provide a less rich cognitive environment. However, the general consensus is that the relationship between education and dementia risk persists even when other factors, including health, socioeconomic status, and other measures of lifelong cognitive activity, are considered (McDowell et al., 2007). Furthermore, although lower socioeconomic status during childhood is associated with lower lifelong cognitive capacity, it does not necessarily appear to be related to cognitive decline in late life (Wilson et al., 2005a). • Chicken or the egg: what is the direction of the association between education and dementia risk? Neuropathologic processes linked to AD begin decades before the clinical expression of the disease. The question thus arises whether individuals predisposed to develop AD may be more likely to choose less stimulating occupations and leisure activities, and even complete fewer years of education. Conversely, a lack of early and ongoing cognitive stimulation may promote a greater degree of neuropathology and earlier clinical expression of the disease. Although the precise nature of the association is yet unknown, improving access to and quality of education and other mentally stimulating activities during the younger ages may be an important point of early intervention. • Does enhanced cognitive stimulation lead to a true reduction in neurodegenerative pathology, or merely in the expression of the clinical symptoms of the disease? Results from the Nun Study (Riley et al., 2005) show that linguistic complexity in early adulthood is associated with later cognitive function and brain neuropathology. Those with more sparsely written autobiographies (at an average age of 22) were more likely to show clinical symptoms of MCI and dementia. Interestingly, lower levels of linguistic complexity were also associated with greater neuropathology on autopsy, including lower brain weight, higher levels of atrophy, and greater plaque and tangle burden. The same study, however, found that although a low level of education was associated with more frequent

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clinical expression of dementia, it was not associated with greater neuropathology (Mortimer et al., 2003). The final point has relevance for the cognitive reserve hypothesis (Whalley et al., 2004; Fratiglioni and Wang, 2007), which posits that older adults present with extremely varied clinical symptomatology as a function of the overall intellectual capacity, or “reserve,” of the individual. The reserve theoretically comprised all the components that impact cognitive function throughout the lifespan, including genetic factors, education, and lifetime experiences. It is not clear whether this reserve results in specific structural and functional differences in the brain or merely affects the threshold at which neuropathologic changes impact behavior and, thus, clinical expression of the disease. A more intellectually stimulating adult life is associated with larger hippocampal size and reduced AD pathology in later life (Valenzuela et al., 2008). In contrast, cognitive reserve may be associated with a latent onset of dementia, but not necessarily with protection against the AD neuropathology. In support of this hypothesis, individuals with higher levels of education often exhibit faster decline once clinical symptoms manifest (Scarmeas et al., 2006; Bruandet et al., 2008). This phenomenon is consistent with the idea that, for adults with increased cognitive reserve, performance deficits occur at a higher threshold of neuropathologic disease. However, there is one important caveat: those with higher premorbid intelligence may be overlooked by clinicians in the earlier stages of a neurodegenerative condition, while those with lower than average premorbid abilities are less likely to go unnoticed and thus contribute disproportionately to the demographic profile. In the clinical setting, it is particularly important to rely on a thorough history to determine whether current cognitive abilities represent a change from previous functioning.

Secondary prevention: later-life cognitive experiences and cognitive training Normal aging. The observation that brain plasticity and hippocampal neurogenesis persists into old age provides a foundation for the use of cognitive stimulation as a healthpromoting intervention for older adults. Indeed, despite the strong association between earlier-life cognitive experiences and later cognitive function, current mental activity may actually be more predictive of cognitive abilities, even after controlling for lifelong mental stimulation (Wilson et al., 2005b; Boron et al., 2007). Neurobiologic correlates show that memory training is associated with increased cortical thickness (Engvig et al., 2010) and that white matter plasticity may be enhanced by training working memory, episodic memory, and perceptual speed (Lovden et al., 2010), with the greatest effects in areas likely to support prefrontal regions (Figure 28.3). These findings provide the foundation for a number of commercial and noncommercial cognitive training programs aimed at reducing cognitive decline associated with aging and dementia, efforts that have demonstrated at least some level of success.

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(a)

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Change in segment 1 (genu) Younger

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*10–9m2/s Figure 28.3 Midsagittal slice showing corpus callosum subsegmented

(a) and 6-month cognitive training-induced improvements over baseline in genu (likely connecting prefrontal regions) in white matter microstructure, as measured by mean free diffusion of water (b) and directional rate (anisotropy) of water diffusion (c) for younger and older adults (n = 32). *units of measurement for Mean Diffusivity. Source: Lovden et al. (2010). Reproduced with permission of Elsevier. (For a color version, see the color plate section.)

Programs that target training of specific cognitive functions have generally produced enhanced ability in the area trained, but often these improvements do not generalize to other cognitive domains. The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study (Willis et al., 2006), a large-scale, randomized trial that examined the effects of cognitive training in three target areas (processing speed, reasoning, and memory), demonstrated

domain-specific improvements, effects that persisted at 2and 5-year follow-up intervals. These benefits are somewhat enhanced with cognitive “booster” training sessions following the initial intervention. Interestingly, initial and 2-year follow-up data did not show any relation to independent functional abilities; however, those randomized to the reasoning group did report less difficulty in independent activities of daily living 5 years following the initial intervention. A number of smaller studies have also shown benefits from cognitive training, despite utilizing widely disparate methods of intervention (Rebok et al., 2007). In general, interventions that focus primarily on the areas of cognition most strongly associated with decline in normal aging (fluid intelligence) seem to produce the greatest improvement in cognition and may be more likely to generalize to other areas of function (Tranter and Koutstaal, 2009). For example, older adults trained on a verbal working memory task showed not only task-specific improvements, but also enhanced performance on visual working memory, processing speed, verbal memory, and general fluid intelligence (Borella et al., 2010). Cognitive training on processing speed alone may be the most strongly associated with simultaneous gains in activities of daily living, with direct consequences for other areas of cognitive function (Edwards et al., 2002; Ball et al., 2010). Importantly, many studies report promising longitudinal effects of cognitive training (Valenzuela and Sachdev, 2009; Borella et al., 2010). Multimodal approaches—those that not only target specific skills, but also incorporate complex goal management, problem solving for everyday skills, creativity, and psychosocial engagement—have also achieved some success (Carlson et al., 2008; Stine-Morrow et al., 2008). Taken together, there is compelling evidence to indicate that mental stimulation can help maintain and potentially enhance cognitive function in healthy older adults. MCI. Although the previous strategies may be an effective intervention for individuals who exhibit changes associated with normal aging, less is known about the effectiveness for individuals with MCI. However, it does appear that teaching specific mnemonic strategies may be of particular benefit to this group (Belleville et al., 2006; Hampstead et al., 2011). Subgroup analyses of the ACTIVE study showed that individuals with MCI displayed improvement similar to a cognitively healthy sample when trained in the areas of reasoning and processing speed, but not in memory, indicating that the beneficial effects of cognitive training may be attenuated for this group (Unverzagt et al., 2009). Alternatively, this finding suggests that cognitive training may help to optimize existing capacities but cannot overcome marked impairment that results from disease-related changes in neuronal structure or function. Another study comparing treatment with cholinesterase inhibitors alone and in combination with computerized cognitive training found that those who received only the medication intervention showed improvements in mood, while both interventions together produced better performance on tasks of memory and abstract reasoning, in addition to improved behavior (Rozzini et al., 2007). In

Exercising the Brain

addition, some reports indicate that adults with MCI may benefit to some degree from any type of cognitive training when conducted in a small group session; however, these results may be more a function of positive social influences (Jean et al., 2010). Despite the discrepant findings related to the amount and type of benefit achieved through cognitive training techniques, these interventions appear to offer some promise for improving cognitive function in patients with MCI (Li et al., 2011).

Tertiary prevention: cognitive rehabilitation The extent to which some form of cognitive intervention is of benefit after dementia is diagnosed remains unclear. Cognitive training trials, although generally small and with variable methodology, indicate that cognitive stimulation may provide some benefit for individuals with AD across several domains, including attention, executive function, verbal fluency, learning, and daily functional abilities, effects that may persist initially for up to 1 year (Requena et al., 2006; Sitzer et al., 2006). A wide range of cognitive interventions have been employed with AD patients; those that may be most effective use strategies that involve general mental stimulation (problem solving, reading, and general engagement) and mental repetition (or memory “drills”) techniques (Sitzer et al., 2006). Patients who received individualized attention may benefit more than those trained in larger groups; indeed, although the use of “memory notebooks” (in which daily activities, goals, general information, and procedural notes are recorded) appears to improve the ability of patients with AD to utilize memory strategies, the extra attention and interaction from caregivers that helped implement intervention may be at least partly responsible for the improvements (Schmitter-Edgecombe et al., 2008). Conclusion: mental activity Mental activity throughout the lifespan and into old age is associated with improved cognitive function and decreased risk of cognitive decline, effects that may continue even with the onset of neurodegenerative disease. The mechanisms that underlie the relationship between cognitive stimulation and dementia are likely multifactorial and may involve increased brain plasticity and neurogenesis. In addition, the benefits of mental activity may relate not only to cognitive stimulation, but also to social interaction and engagement (Moniz-Cook, 2006).

Social activity In recent years, it has been postulated that social engagement and quality social support may be an important aspect in the prevention of cognitive decline and dementia (Seidler et al., 2003). Hypothesized mechanisms by which social engagement may positively impact cognitive function include increased cognitive stimulation associated with social activities, a reduction in stress and depression, and neurobiologic

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changes that may accompany these influences (Pillai and Verghese, 2009). The level of social activity may be closely related to overall cognitive reserve—that is, people who engage in more social behaviors are likely to participate in more physical and mental activities as well, thereby boosting brain reserve (Scarmeas and Stern, 2003). In addition, social engagement often requires a number of complex cognitive processes, including attention, executive skills, and memory. Individuals who lack positive social stimulation are at higher risk for stress, depression, and loneliness (Cacioppo et al., 2010), which correlates with an increased risk for cognitive decline (Conroy et al., 2010; Panza et al., 2010). Although primates are hardwired for social interaction to ensure survival, areas of the brain that play a key role in social behavior, including temporal and frontal cortices and the amygdala, are often affected even in the early stages of a neurodegenerative process (Adolphs, 1999). Research that examines the link between social support and cognition is in the early stages, yet initial observational studies point to social support as a potentially important constituent of a multidisciplinary approach to intervention.

Primary prevention: lifetime social support and dementia risk A retrospective comparison between people with dementia and case controls showed that, even decades before the onset of dementia, people who subsequently developed the disease were historically less likely to be involved in cultural and sports activities, and had less extensive psychosocial networks (Seidler et al., 2003). Middle-aged adults who live alone are twice as likely to develop dementia, a risk that increases when people are divorced or widowed (Hakansson et al., 2009). Conversely, prospective results from the Honolulu-Asia Aging Study (Saczynski et al., 2006) suggest that midlife social engagement is not predictive of later-life dementia risk. Rather, a decline from a previously high level of social support from middle to older age, paired with reduced social support in old age, was associated with a greater risk of incident dementia. Secondary prevention: social activity in older age Social inactivity in older age may be more closely associated with incident dementia than midlife social isolation; however, this relationship is difficult to interpret and may be primarily an effect of the disease process on sociability. Social engagement in later years is associated with better global function and several other cognitive domains, even after controlling for cognitive and physical activity (Krueger et al., 2009). Older adults with larger social networks and a high degree of social activity have a reduced risk of global cognitive decline and dementia (Crooks et al., 2008). Unfortunately, in the absence of experimental trials, the question of whether social interventions in older age may be protective against dementia remains unclear.

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Tertiary prevention: increasing social interaction in patients with dementia Again, to date, no controlled trials have examined the effectiveness of social interventions on cognition in patients with dementia. However, it is possible that increasing pleasant activities and social interaction can lead to improved mood, as well as reduce wandering and other problematic behaviors associated with advancing AD (Cohen-Mansfield and Werner, 1997; Arai et al., 2007). At this level of intervention, a great deal of focus has been on reducing caregiver burden and stress via increased social support. Intervening in this manner leads to stress reduction, improved mood, and better health profiles for the caregivers, benefits that also have consequent indirect but favorable effects for the care of the dementia patient (Sierpina et al., 2005). Conclusion: social interaction Social interaction is the least well studied of the nonpharmacologic interventions discussed in this chapter. However, cognitive reserve theory and initial observational findings support that social activity may have a positive influence on cognitive function. These effects may occur either directly by influencing the neuropathologic processes associated with cognitive decline or indirectly through increased mental stimulation and feeling of well-being.

Conclusion Cognitive decline and dementia represent an increasing source of concern for health-care professionals and society at large. The anticipated rapid growth in the number of dementia cases over the next few decades and corresponding lack of available pharmacologic interventions fuel concerns that the financial and socioeconomic burden associated with dementia could reach crisis proportions. Fortunately, with appropriate intervention, several modifiable risk factors could lead to a substantial reduction in future dementia cases. Among others, increased physical activity, mental stimulation, and social engagement are promising tools that may help attenuate the cognitive decline associated with aging and dementia. These interventions are associated with positive effects across a range of functions, including cognition, mood, and health status. Used alone or in conjunction with pharmacologic interventions, these strategies may be cost-effective approaches for treating and preventing cognitive decline.

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Chapter 29 Driving Impairment in Older Adults Anne D. Halli-Tierney and Brian R. Ott Warren Alpert Medical School of Brown University and The Alzheimer’s Disease and Memory Disorders Center, Rhode Island Hospital, Providence, RI, USA

Summary • Aging is associated with changes in sensory systems, mobility, and cognition, which affect driving ability. • Drivers with dementia are at high risk for hazardous driving. • Other medical conditions are also associated with impaired driving ability and medical assessments of vision, motor function, and cognition should be done to determine driving competence. • Performance-based evaluations, simulators, and road tests are used as methods to assess and monitor older drivers. • Social networks are heavily relied upon for transportation after cessation of driving. Depression, economic burden, and social withdrawal may develop if such networks are unavailable. • Physicians face uncertainty regarding their responsibility to report unsafe drivers. Older individuals may also resist the revocation of their driving privileges.

Introduction The US population is aging at a rate unseen in the history of the country. From 1998 to 2008, the percentage of the population aged 65 or older has grown by 13% to 34 million; by 2030, this number is expected to increase to 72 million (NHTSA, 2008). This cohort has been largely independent and healthy, and an increasing number of people are remaining active in the workforce and in their communities. It is thought that 38 million of these elderly will be driving as of the year 2020 (Freund, 2006), and as of the year 2007, 31 million licensed drivers (or 15% of all licensed drivers) were over the age of 65 (NHTSA, 2008). Driving is seen as a marker of independence and “adulthood,” and the aging baby boomer cohort is known for its fierce independence; thus, it can be inferred that the number of elderly drivers will continue to increase. The expansion of elderly motorists can give rise to complications, especially when, given physical and mental deterioration, some drivers are no longer fit to operate a motor vehicle. With this impending increase of elderly drivers, it is important to consider their safety and the safety of those with whom they share the road. Elderly drivers cause a great deal of concern because, as a population, they are seen to be a danger on the road. Indeed, drivers over the age of 65 are expected to account for 16% of motor vehicle accidents and 25% of fatal accidents (Eberhard, 2008). The usual cliché is that of the petite elderly lady with the big car who cannot see over

the steering wheel, drives very slowly, runs a red light, and crashes into oncoming traffic. This image is pervasive in the media, and the idea of the “senior Sunday driver” is prevalent in American society; this can lead to negative bias about the safety habits of older drivers. However, elderly persons are actually some of the safest drivers, with the lowest number of crashes per 100 licensed drivers per year (Eberhard, 2008; Centers for Disease Control and Prevention, 2010). Older drivers generally tend to be a self-monitoring population and limit risky driving behaviors (such as rush hour and evening driving), driving duration, and driving time as self-perceived deficits increase. They also are more likely to wear seat belts: 77% of victims aged 65+ in fatal motor vehicle crashes in 2007 were wearing seat belts, as opposed to 63% for younger populations (Office of Statistics and Programming, Centers for Disease Control and Prevention, 2010). And, they are less likely to be driving under the influence of alcohol than are younger drivers. Despite these positive attributes of the older driver, many see them as a general threat on the road, and they are at greater risk of sustaining injury from a motor vehicle accident. Given physiologic changes and increases in frailty, traffic accidents and traffic-related injuries are of particular concern to this age group. Accidental injury is the seventh leading cause of death in the elderly, and motor vehicle accidents are the leading cause of such deaths in persons aged 65–74 and the second leading cause in persons aged  75–84 (Staats, 2008). Because older male

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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drivers tend to drive more than women through the age spectrum, they are more likely to suffer a traffic fatality than their female counterparts (Office of Statistics and Programming, Centers for Disease Control and Prevention, 2010). As mentioned later, older drivers have a higher rate of fatality than any other age group except for drivers under the age of 25, with a disproportionately higher number of chest and head injuries (AMA, 2003; Bauza et al., 2008). These injuries are thought to be due to increased fragility and chronic medical conditions present in older patients (AMA, 2003; Li et al., 2003). Assessing the ability to drive in the elderly is made further complex by the fact that each driver is unique: Although physiologic aging changes occur universally and can have an impact on driving ability, it is important to ascertain which limitations are allowable with caution and which deficits require restricted driving privileges. Because of increasing risk of injury to the older population in the event of a crash, assessing for motor vehicle safety is of utmost importance to elderly drivers themselves, as well as the population as a whole. Any chapter on driving in the elderly, much like any geriatric topic, must be multifactorial and must take into account both normal changes associated with aging and pathologic states that could impact driving ability. We discuss means of assessing the older driver for suitability on the road and explore the ramifications of recommending that someone stop driving, both legally and socially. Also in this chapter, we hope to assist the concerned family member and physician by providing resources to aid in assessment of the older driver and in education about safe driving practices.

The aging driver When determining a particular person’s safety and ability to drive, it is important to consider functional status and comorbid conditions. Elderly drivers do have to contend with an increasing number of medical conditions and diagnoses, as well as reduced physiologic reserve and increasing medication burden. However, many elders continue to be functionally intact, so the decision to limit driving should not be made on chronologic age alone. A thorough medical history, including a geriatric assessment that focuses on particular medical conditions, medications, and functional status, should be performed, along with a physical examination that focuses on strength and coordination. As mentioned, the elderly driver sees and interacts with the world differently than does his younger peer, and some of the changes inherent in aging can impact the ability to drive safely. Even when at optimum health, the elderly patient has less physiologic reserve. Although a person continues to age at the same rate, the differences may be more profound

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in an older subject because, in this person, age-related changes have already taken place and are continuing to accumulate. Every organ system is affected by aging and could potentially be such a detriment to the patient that it impacts driving. However, in regard to the elderly driver, one needs to specifically focus on the physiologic changes that impact the driver’s ability to interact with the world. Namely, one should be most interested in the changes that occur in sensory systems, cognition, and mobility, as these contribute most heavily to awareness of the driving environment, integration of sensory input with the motions of driving, and ability to physically steer a vehicle. The subject’s general health functioning can also contribute to problems with all these systems in several different ways (Boss and Seegmiller, 1981).

Sensory changes As a person ages, it is normal to experience changes in the sensory systems. These changes can greatly impact the way the driver perceives the road and the environment around him. One of the most common changes with aging is decreased visual function, which actually begins as early as aged 40. The elderly eye experiences a number of changes leading to impaired vision. First and most common, the eye has a decrease in the ability to accommodate, or to clearly focus on, close objects: This decrease stems from thickening and opacification of the lens, as well as weakening of the ciliary muscles and flattening of the cornea (Larsen et al., 1997). Elderly people also have a smaller pupil diameter, which leads to difficulty with dark–light adaptation. An elderly person needs three times as much light to see as clearly as a 20-year-old (Gallman, 1995). Compared with younger people, elderly people have a greater problem discriminating between shades of “cool” colors due to age-related yellowish discoloration of the lens, and this change can also affect depth perception. They experience increased sensitivity to glare due to the increased opacity of the cornea, and they experience a decreased visual field due to the combined impairments that occur with age (Gallman, 1995; Larsen et al., 1997). These changes in vision are seen as functions of normal aging, but some pathologic conditions are common in the elderly and need to be taken into account when assessing the older driver. Conditions such as macular degeneration, cataracts, glaucoma, and changes due to systemic illness such as hypertensive or diabetic retinpoathy need to be considered. All these illnesses can lead to blurred or decreased vision, decreased visual fields, and eventual blindness (Matteson, 1988). Thus, it is important to assess patients for such problems and to discriminate between normal aging changes and pathologic changes so that treatments can be implemented early. Although vision is arguably the most important sense needed for successful driving, elderly people experience

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changes in several other sensory realms that can have implications for their safety behind the wheel. Hearing loss is a problem that increases in the elderly: 10% of persons aged 65–75 and up to 25% of persons aged 75 and up have some degree of hearing loss (Gallman, 1995). For the most part, older people have difficulty distinguishing higher-frequency sounds, due to the neurosensory condition of presbycusis, caused by atrophy of the cochlea and degeneration of auditory neurons. The vestibulo-cochlear function of the ear declines with aging, as otoconia, or granules of the otoliths accumulate and the vestibular portion of the eighth cranial nerve degenerates, often due to chronic diseases or some medications. As presbycusis progresses, patients have difficulty distinguishing progressively lower-frequency sounds. This neurosensory condition is often coupled in the elderly with an increase of cerumen, which can build up and cause an effective (albeit manageable) conductive hearing loss (Bade, 2010). These changes have implications for drivers in the setting of emergency vehicles and sirens, which tend to use higher-pitched sounds for warning and also drive in a somewhat unconventional manner to provide the most rapid assistance. Not being able to hear the siren of an approaching vehicle is dangerous for an elderly driver, especially when the situation involves a crossing where the emergency vehicle may be intending to cross against a light or against traffic. Elderly people also experience age-related changes in the sensations of smell and taste, but these are not as germane to the driving experience. Changes in the sense of touch, however, can have an impact on driving. In general, patients’ tactile losses are a combination of agerelated changes (due to neuron atrophy and decreased nerve conduction) and longstanding systemic diseases that may have deleterious effects on the sensation of touch. Elderly people have an overall decrease in tactile sensation, which leads to impairments in response time, proprioception, coordination of fine motor tasks, vibratory sensation, and balance (Blair, 1990; Saleh, 1993). Neurologic changes such as a loss of mass in the cerebellum with particular attention to the anterior vermis and large Purkinje neurons cause mild decrements in balance, gait, and tone. Also, proprioception is impaired because of age-related decline in muscle spindle and mechanoreceptor functioning. As the nervous system ages, myelin is lost selectively from sensory nerves, leading to slower conduction times and neuropathy, which affects vibratory sensation in the extremities. Coupled with a decreased ability to receive visual and auditory input and a deficit in balance caused by alterations in the hearing system, the elderly driver needs a longer response time and may have difficulty carrying out tasks that depend on proprioception (such as changing from accelerator to brake quickly using the feet) in a crisis situation (Blair, 1990).

Cognitive changes One of the most important changes that can affect elderly driving—and, indeed, a change that has garnered a fair amount of public attention—is that of cognitive decline. Pathologic cognitive changes and their implications for driving safety are discussed at length in our clinical assessment section; here we focus on changes associated with normal aging that can have an impact on the driving ability and safety of the elderly driver. Routine anatomic changes can illustrate the alterations in cognition seen in the elderly person, and such changes are not considered pathologic up to a point. As one ages, brain weight decreases up to 15% starting after the age of 20. Gray matter exhibits a linear decrease, while white matter increases until the fifth decade and then decreases at a faster rate. Neuronal dropout and loss is not global but is more concentrated in such areas as the hippocampus and the nucleus basalis of Meynert, with the brainstem and other areas largely spared. Lipofuscin accumulates, as do plaques and tangles, which are present to a much lesser degree even in non-Alzheimer’s disease (AD) brains. White matter gradually loses myelin and dendritic mass, and this loss, along with vessel sclerosis, leads to an overall loss in brain mass. A smaller brain size can be seen on imaging in healthy older individuals, with narrower gyri, wider sulci, and enlarged ventricles and subdural space. These anatomic changes predispose the healthy elder individual to definite declines in certain cognitive domains, while leaving other cognitive abilities intact. Although the focus is often on the cognitive tasks that show deterioration in aging, we must also note abilities that remain unchanged in the elder individual. In the healthy older adult, sustained attention continues to be good, but increases in distractibility can be seen, especially if other information is presented simultaneously. As a function of this increased distractibility, multitasking becomes less efficient in the older individual. Thus, the older driver is more easily distracted, which can have dangerous consequences on the road. Also, processing speed slows and reaction times, information retrieval time, and timed tasks all increase with age. Overall accuracy in recall declines mildly starting after the age of 50, but in a healthy individual, this is a slowly progressing decline. Immediate, or sensory input, which is information based purely on the senses and does not often get encoded as a discrete memory, shows no changes in processing with age, although one could argue that the information being processed may be altered by virtue of the changes in the sensory systems described earlier. Short-term memory, or working memory, where information is stored for a few minutes, likewise does not show any deficits. Longer-term memory, which is on the order of hours to years, can show some declines in some domains, but in a healthy individual, it remains fairly constant in others. In procedural memory, where the person

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remembers how to perform tasks strongly rehearsed in the past, and semantic memory, where the person remembers meanings of situations, there is little decline. However, some decline is seen in episodic memory, which involves recall of discrete events, times, and places. This may impact the healthy older individual’s ability to navigate to new or previously unvisited locations, but it does not have an effect on destinations that were visited several times in the past.

Mobility/strength changes Another system that affects the aging driver is the musculoskeletal system. Aging changes can lead to reduced mobility. Such changes are clearly relevant to risk for falls. Moreover, the same musculoskeletal changes can impair the older driver’s ability to maneuver a vehicle and could increase the risk for serious injury following a motor vehicle accident. Changes in the musculature occur with the normal aging process, with the most marked deterioration due to muscle disuse over time. Muscle mass decreases with age, with a predilection for the dominant side. In addition, lean muscle mass is replaced by fat in the older individual; this replacement further decreases muscle stores and helps perpetuate a cycle of muscle decrement, followed by lack of exercise and further muscle atrophy. Tendons and ligaments stiffen, which further limits exercise and also predisposes to injury and increased stiffness of joints, leading to limited mobility (Boss and Seegmiller, 1981). Muscle fibers experience slowed contraction time, which can decrease agility and cause a slowing in response time. These changes in the musculoskeletal system can impair the driver’s reaction to sudden stimuli and ability to physically manipulate the controls of a vehicle. Changes in the skeletal system can also increase the elderly driver’s chances of being seriously injured in an accident. Over the years, older patients are more likely to have suffered an orthopedic or muscle injury, such as a fracture or rotator cuff tear, simply because they have more time to accumulate such injuries. Decrease in bone mass occurring in older age predisposes to osteopenia and osteoporosis, which increases the risk for fracture in a traumatic situation (Bauza et al., 2008). The elderly hip and knee also have increased flexion capabilities, which can cause joint subluxation in the event of a crash (Bauza et al., 2008; Staats, 2008). Finally, increased bony formation can cause degenerative changes or arthritis, which can limit mobility in several different ways. The hip and knee can be affected by arthritic stiffness and pain, which can increase time needed to move the leg. This increased reaction time combined with decreased muscle strength and changes in the sensory system can compromise the ability of an older driver to react appropriately in an emergent situation. Also, arthritis can limit mobility in the neck, which would decrease the driver’s ability to turn

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the head and assess for “blind spot” vehicles and other obstacles that may cause an accident. Decreased mobility in the neck can further lead to neck/back injury and pain if an accident occurred (Bauza et al., 2008; Staats, 2008; Fedarko, 2010). The aging driver’s ability to safely operate a motor vehicle can be further compromised by the combination of chronic illnesses and treatments and decreased physiologic reserve. As a group, older patients carry more medical diagnoses than do their younger counterparts. These predispose the elderly to what are called the “geriatrics syndromes,” some of which can negatively impact driving. These include impairments in vision and hearing, as mentioned, as well as dizziness, syncope, gait impairment, falls, dementia, and delirium. A host of medical problems are associated with these syndromes: these are discussed in the next section. The additive effects of chronic medical problems cause a decrease in the older person’s ability to adapt in a rapid manner. For example, dizziness may be caused by orthostatic hypotension and may pass after equilibration of the blood pressure, but in an older person, that orthostasis may be accompanied by vision problems, proprioception disturbances, and gait impairment, and is much harder to treat (Nanda, 2010). Thus, it is important to keep in mind which changes result from the normal aging process and which changes result from pathologic processes or iatrogenic effects (such as medications) when assessing an older patient for driving suitability. Also remember that although many older persons are able to remain safe behind the wheel, all people experience aging changes that must be monitored over time and treated whenever possible to maximize their safety and the safety of those around them.

Clinical assessment of the older driver Driving is a complex task requiring visual, motor, and cognitive demands impacted by aging as well as agerelated medical conditions. Furthermore, interactions among the driver, the vehicle, and the environment put the older driver at varying risk for involvement in automobile crashes (see Figure 29.1). Cognitive impairment is arguably the most important risk factor for impaired driving in the elderly. In a survey of medical reports to the State of Missouri licensing agency, dementia/cognitive impairment was the most common reason for reporting older drivers, accounting for 45% of reports (Meuser et al., 2009). The literature on older adults with dementia indicates that some drivers with a dementing illness continue to drive, many well into the disease process (Carr et al., 1991; Odenheimer, 1993; Ott et al., 2008). An estimated 4% of current drivers over 75 years have a dementing illness (Foley et al., 2000). Results from one study that performed a cognitive screen

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Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

Primary visual function

Disease Aging

AD

Cognition: - Executive - Attention - Visual perception

Driving ability: - Road test performance

Motor skills

External factors: - Environment - Other drivers

Motor vehicle crashes and traffic violations

Time Figure 29.1 Multifactorial model of driving impairment in older drivers. AD, Alzheimer’s disease. Source: Ott & Daiello (2010).

Reproduced with permission of Future Medicine Ltd.

on older adults during driver license renewal found that almost 20% of those over 80 years were impaired (Stutts et al., 1998). Taken together, these studies probably underestimate the actual number of demented drivers on the road because some older adults with memory loss may not renew their license and continue driving and/or are inaccurately reported as having stopped driving. A number of editorials and review articles have addressed the issue of driving in older people and those with dementia (AMA, 2003; Brown and Ott, 2004; Breen et al., 2007; Man-Son-Hing et al., 2007; Adler and Silverstein, 2008; Marshall, 2008; Uc and Rizzo, 2008; Martin et al., 2009). Based on overall crash occurrences per year, older drivers have fewer crashes than younger drivers, largely due to reduction in driving miles. When gauged on a permile basis, however, older drivers are a significant risk group, with crash rates approaching those seen in teenage drivers (Mayhew et al., 2006). Moreover, as previously discussed, due to frailty, they are more likely to die in a motor vehicle accident than younger drivers (Kent et al., 2005; Mayhew et al., 2006). Advanced age by itself, however, should be regarded not as the problem, but rather as a proxy for physical or cognitive impairments that lead to unsafe driving. With age, right-of-way and traffic sign violations increase, and the frequency of intersection and left-turn crashes increases (Mayhew et al., 2006; Braitman et al., 2007; Abou-Raya and El Meguid, 2009). Older adults have been noted to take more hazardous actions (such as speeding, improper turning, and failure to yield)

in multivehicle crashes, compared to younger drivers (Kostyniuk et al., 2003). Older adults are also more likely to be involved in overtaking, merging, and lane change collisions (Clarke et al., 1998; McGwin and Brown, 1999). Older adults are more often found to cause or contribute to a crash (Hakamies-Blomqvist, 1993), and they are overrepresented in angle broadside/crashes (Ryan et al., 1998). These errors are generally felt to be related to changes in reaction time, visual perception, and attention. Aging effects on motor function and other disease-related factors such as eye disorders (Thiyagesh et al., 2009) add to decrements in driving ability. Mild cognitive impairment (MCI) is a syndrome that is generally regarded as a prodromal stage to AD, and all AD patients initially pass through an MCI stage. There is limited data on MCI and driving. One simulator study of drivers with mild AD and MCI found that MCI drivers were similar to controls except for a test of time to contact by rear-end collision (Frittelli et al., 2009). Another study reported that those with MCI performed less well on a road test than cognitively normal controls (Wadley et al., 2009). Due to similar but more severe deficits, drivers with dementia are at a particularly high risk for unsafe driving. Some studies suggest that drivers with dementia have decreased yearly mileage in comparison to controls. For example, Trobe and colleagues found that individuals with AD drove an average of about 5000 km annually in the 2 years before they stopped driving, compared to an average of 8000 km driven for controls (Trobe et al., 1996).

Driving Impairment in Older Adults

Other studies confirm that, as a group, older demented drivers limit their driving exposure (Dubinsky et al., 1992; Carr et al., 2000; Freund, 2006). Despite data indicating that they drive fewer miles and thus have reduced exposure, various studies have demonstrated that drivers with dementia have a 1.5–8 times greater risk of involvement in a crash, compared to age-matched controls (Retchin and Hillner, 1994; Marshall, 2008). The crash risk for a driver with AD rises above that of the highest-risk group (teenage males) beyond the third year of disease (Drachman and Swearer, 1993). Other degenerative dementias are not uncommon, and they, too, negatively impact driving fitness. In a prospective road test study of controls and mixed medical disorder patients with AD, vascular dementia, and diabetes, driving performance errors were comparable between AD and vascular dementia patients, suggesting that degree of  cognitive impairment rather than dementia diagnosis is the more important determinant of risk (Fitten et al., 1995). Disinhibited and agitated behaviors in patients with frontotemporal dementia have been shown to cause hazardous driving (de Simone et al., 2007) and may be even more dangerous than seen in drivers with AD (Tanikatsu et al., 2009). The prominent visuoperceptual and attention deficits, as well as common occurrence of visual hallucinations and fluctuating levels of alertness, should raise significant concerns about driving safety for patients with dementia with Lewy bodies. To date, driving in this group has not been studied. While advanced **Parkinson’s disease (PD) may limit driving due to reduced motor function, earlier-stage problems are more clearly related to cognitive deficits (Grace et al., 2005; Amick et al., 2007). PD patients are particularly prone to distraction (Uc et al., 2006). In one study, navigational errors and lower driver safety were associated more with impairments in cognitive and visual function than the motor severity of their disease in drivers with PD (Uc et al., 2007).

Medical assessment Older adults with cognitive impairment should be examined to rule out other diagnoses or comorbidities that can impair driving ability, many of which may be partially or totally remediable. Medical conditions that have been associated with impaired driving ability include alcohol abuse and dependence, cardiovascular disease, cerebrovascular disease, traumatic brain injury, depression, dementia, diabetes mellitus, epilepsy, use of certain medications, musculoskeletal disorders, schizophrenia, obstructive sleep apnea, and vision disorders (Marshall, 2008). In addition to dementia and cerebrovascular disease, other neurologic disorders that may significantly impact driving include brain tumor, migraine, multiple sclerosis, parkinsonian and other movement disorders, seizure disorder, sleep disorder, vertigo, and peripheral neuropathy (AMA, 2003). Classes of drugs that have been

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associated with impaired driving and should be avoided or minimized when operating a motor vehicle include sedating antihistamines, antipsychotics, tricyclic antidepressants, bowel/bladder antispasmodics, benzodiazepines, muscle relaxants, and barbiturates (AMA, 2003; Rapoport and Banina, 2007; Rapoport et al., 2008; Rapoport et al., 2009). Additional indictors of potential driving risk include history of fainting, complaints of muscle weakness, history of recent crashes or near misses, concerns of the family about driving safety, reduced driving mileage, self-reported situational avoidance, and aggressive or impulsive behavior (Iverson et al., 2010). Cognitively intact drivers may be able to assess their own driving competence. To assist them, the American Automobile Association markets a home self-assessment program called Roadwise Review. This program is performed though use of a CD-ROM and personal computer. Domains assessed include leg strength and flexibility, head and neck flexibility, visual acuity, working memory, and visual processing. Cognitively impaired drivers lack sufficient insight to judge their own driving abilities. Caregiver ratings of marginal or unsafe driving by patients with dementia should be strongly considered, but they may not recognize driving risks or may have a biased interest in preserving driving privileges if the person in question is the sole or primary provider of transportation (Brown et al., 2005; Iverson et al., 2010). Given the limitations of self-report and caregiver ratings, the physician is often called upon to help determine driving competence or the need for more detailed assessment by a driving rehabilitation specialist. Figure 29.2 summarizes recommendations for office evaluation of the older driver. The American Medical Association and the US Department of Transportation have developed a useful guide to the physician in assessing the older driver (AMA, 2003). After reviewing for the presence of the “red flag” medical conditions and medications just described, office assessments of vision, motor function, and cognition are recommended.

Sensory assessment Visual acuity requirements vary from state to state, with many requiring far visual acuity of 20/40 for licensure. Visual acuity should be measured with both eyes open or with the best eye open. Subjects should wear any corrective lenses that they normally use when driving and should stand 20 feet from a Snellen chart. For best corrected distance vision less than 20/70, referral to a driving rehabilitation specialist for a formal on-road assessment should be done. For distance vision less than 20/100, the physician should generally recommend not driving. If the state allows driving with this acuity, passage of a formal on-road test is highly recommended (AMA, 2003). Similarly, state regulations have no uniformity regarding visual field function, although many require a visual

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Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

Evaluate for mild cognitive impairment or dementia Screen for dementia using validated tool (e.g., MMSE, short blessed test). Use standard criteria to diagnose MCI or dementia. Evaluate for reversible causes of cognitive impairment. Rate dementia severity.

Is the patient driving now? (dictates urgency of evaluation) Evaluate for impairment of traffic skills, IADLs, and specific cognitive domains. Review history with caretaker.

No or questionable dementia

Impaired traffic skills, IADLs, or cognitive domains present?

Questionable or mild

Consider referral Subspecialist Neuropsychologist Driving Clinic DMV

Yes

Continue driving Monitor for progression or changes every 6 months.

Driving recommended?

Yes

Dementia present?

Moderate or severe

Patient refuses

No

Stop driving Discuss transportation alternatives. Steps for resistant drivers.

field of 100 degrees or more along the horizontal plane. A general estimate of visual field defect can be obtained at the bedside by confrontation testing, but if there are any questions, referral to an eye specialist for perimetry is recommended. Deficits in color vision do not constitute a significant crash risk. Impaired night vision requires evaluation and may necessitate night driving restriction (AMA, 2003).

Mobility assessment Musculoskeletal disorders and neuromuscular disorders may also limit driving ability. Musculoskeletal disorders of particular interest and common occurrence in older drivers include arthritis with limited cervical spine and

Figure 29.2 Approach to evaluating older

adults with cognitive impairment or dementia. Source: Carr and Ott (2010). Reproduced with permission of American Medical Association.

limb mobility and orthopedic problems such as fractures and rotator cuff injury. Position sensibility may be limited by peripheral neuropathies. Muscle power may be limited by both neuropathic and myopathic dysfunction. Therefore, office examination of the older driver should include testing of muscle strength and endurance (such as a rapid-pace walk or manual test of muscle strength), range of motion (particularly neck), and proprioception in hands and feet (AMA, 2003).

Cognitive assessment A wide variety of global and specific cognitive tests have been studied as potential screening tests to predict the likelihood of hazardous driving as measured by road test

Driving Impairment in Older Adults

performance, driving simulator performance, or motor vehicle accidents (Reger et al., 2004; Brown et al., 2005; Mathias and Lucas 2009). The ideal test or group of tests remains unclear because studies employ different subjects and different outcome measures, making comparisons difficult. Furthermore, odds ratios and correlation coefficients are provided, generally without defining specific model formulas or test cutoff values that could be used in practice (Molnar et al., 2006a). Stratifying dementia severity using the Clinical Dementia Rating (Morris, 1997) has been shown to be a useful and valid way to assess risk. This scale has been shown to be highly correlated with driving performance on road tests (Duchek et al., 2003; Ott et al., 2008) and is currently recommended by the American Academy of Neurology in its Practice Parameter (Iverson et al., 2010). Drivers with moderate dementia by this scale should be advised not to drive, while those with lesser severity of dementia warrant closer scrutiny. Global screening tests like the Mini–Mental Status Examination (cutoff 24 or less) may assist the physician in identifying dementia as a red flag condition, although this test itself cannot be used as the sole basis for decision making, due to low accuracy in predicting driving performance (Carr and Ott, 2010; Iverson et al., 2010). Formal neuropsychological testing may provide additional information regarding more specific cognitive deficits that can impact driving ability. Among the tests most commonly cited as being useful are useful field of view, visual reproduction tasks, clock drawing, trail making, and maze performance (AMA, 2003; Mathias and Lucas 2009; Carr and Ott, 2010). In one study comparing AD and Parkinson’s drivers, Parkinson’s patients distinguished themselves from other drivers with a head-turning deficiency. Drivers with neuropsychological impairment were more likely to be unsafe drivers in both disease groups, compared to controls. Driving performance in Parkinson’s patients was related to disease severity (Hoehn and Yaar stage), neuropsychological measures (Rey Osterreith Complex Figure (ROCF), Trails B, Hopkins Verbal List Learning Test (HVLT)-delay), and specific motor symptoms (axial rigidity, postural instability), but was not related to the Unified Parkinson Disease Rating Scale motor score. The ROCF and Trails B tests were useful in distinguishing safe from unsafe drivers in both patient groups (Grace et al., 2005). Neuropsychological tests, which are multifactorial in nature and require visual perception and visual-spatial judgments, are the most useful screening measures for hazardous driving in PD patients (Grace et al., 2005; Uc et al., 2005; Uc et al., 2006; Amick et al., 2007).

Daily living activities Driving may be regarded as the ultimate activity of daily living (Sherman, 2006). Given its complexity as an

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instrumental activity of daily living (IADL) and the pivotal role driving plays in the mobility and autonomy of older people, driving ranks high in importance among daily functions to assess in the office. To date, little research has been done to integrate driving into the assessment of IADL instruments. In one study of 79 drivers with dementia, total IADL scores were highly correlated with driving and had dropped by 46% in persons no longer able to drive, by 23% in persons driving only if accompanied, by 22% in persons driving alone but with difficulty, and by 17% in persons driving alone without difficulty (Ott et al., 2000).

Performance-based evaluations In obvious cases of gross neurologic impairment, such as homonymous hemianopia, hemiplegia, and moderate-tosevere dementia, or when the patient has already demonstrated serious safety problems such as at-fault crashes, the clinician can make a confident recommendation regarding driving cessation. More often, though, red flag issues raise concerns about driving safety that may warrant a performance-based evaluation to directly observe how the cognitive or other neurologic deficits directly impact driving abilities. Simulators Little data in the literature addresses specific crash characteristics of demented drivers and how their types of crash characteristics differ from matched controls or middleaged drivers (Carr, 1997). Data on driving simulation have consistently found that drivers with AD perform worse on tasks than controls (Rizzo et al., 1997; Cox et al., 1998; Rizzo et al., 2001; Freund et al., 2002; Uc et al., 2006). Based on simulator studies, drivers with AD are more likely to drive off the road, drive slower than the speed limit, apply less brake pressure when trying to stop, and take more time while attempting to make left turns (Cox et al., 1998). On the Iowa simulator, complex analysis of vehicle maneuvers related to crashes demonstrated that inattention and either slow or inappropriate responses were key factors leading to the accidents (Iverson et al., 2010). The use of driving simulators has been largely confined to research centers; however, they may see more widespread use in years to come if properly validated against real-world driving outcomes such as motor vehicle crashes and road test performance. In one study, participants (healthy controls and those with dementia) were tested on both on-road and driving simulator protocols. A strong correlation was found between the two types of driving assessment, suggesting that lower driving simulator scores (with fewer errors) are strongly related to better on-road driving abilities. Moreover, committing hazardous or lethal errors on the driving simulator was strongly related to failing the on-road test (Freund et al., 2002). Motion sickness may limit evaluations performed using driving simulators.

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Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

Road tests Performance-based road tests are another measure of driving competency. The majority of road test studies report on qualitative outcomes (such as pass/fail rates) in comparison to controls, and some studies use point systems or quantitative outcomes. As expected, demented drivers have higher failure rates on these evaluations than controls (Kapust and Weintraub, 1992; Hunt et al., 1993; Odenheimer et al., 1994; Fitten et al., 1995; Hunt et al., 1997; Duchek et al., 2003; Uc et al., 2004; Grace et al., 2005; Whelihan et al., 2005; Ott et al., 2008; Dawson et al., 2009); however, pooled data from two longitudinal studies, involving 134 drivers with dementia (Duchek et al., 2003; Ott et al., 2008), show that 88% of drivers with very mild dementia (Clinical Dementia Rating 0.5) and 69% of drivers with mild dementia (Clinical Dementia Rating 1.0) are still able to pass a formal road test. Few studies report on the actual in-traffic skills that are impaired in demented individuals. Those that do have noted frequent difficulties with lane checking and changing (Grace et al., 2005; Dawson et al., 2009), merging, making left turns, signaling to park (Grace et al., 2005), and following routes (Uc et al., 2004). A recent study suggests that the differences in serious errors on road tests between older drivers and demented drivers are more quantitative than qualitative (Dawson et al., 2009). Data from the Brown Longitudinal Study showed that the median time to discontinuance of driving for those with very mild dementia was 2 years; for those with mild dementia, it was 1 year (Ott et al., 2008). It should be noted that such studies were performed in a car and environment/route that was likely novel to the driver, typically measured only a “snapshot” or less than 1 hour of driving ability, and did not consistently assess the ability to respond in urgent/emergent traffic situations. Furthermore, test-taking anxiety may influence outcomes (Bhalla et al., 2007). It is unknown how the results of these types of performance-based road tests correlate to driving in the naturalistic setting and whether they accurately identify driving behaviors that are associated with an unacceptable safety risk. Road testing is the traditionally accepted method for states to determine driving competence, but the cost and need for repeated follow-up testing and monitoring may be prohibitive. Typically, such an evaluation costs between $350 and $500 and is not covered by insurance (Carr and Ott, 2010). Thus, other methods are being sought to reliably assess and monitor older drivers.

Social implications of driving restriction and driving retirement At the heart of the topic of driving in the elderly is the discussion about the appropriate time to restrict or eliminate driving rights altogether for a particular impaired

elderly patient. This topic is loaded with social, ethical, legal, and emotional implications and is made even more challenging by the relative lack of consensus about the right course of action. As has been examined previously in this chapter, in the absence of pathologic change, the aging driver still undergoes changes in body systems crucial to driving as the effect of pure aging. However, these changes can sometimes be corrected with assistive devices and, for a large group of elder individuals, these aging changes do not critically affect their ability to safely operate a motor vehicle. This large number of elderly drivers may continue to be safe on the road, but worsening sensory impairments and pathologic changes may render other older adults unsafe to drive. Whether the decision to restrict driving is made by the patient, the patient’s family members, or the patient’s physician, it can have far-reaching consequences with regard to the physical, social, and emotional well-being of the patient and the patient’s support system, as well as the patient–physician relationship. In this section, we consider the social impact of driving restriction, along with ethical concerns and barriers that physicians experiencing in addressing the topic of driving limitation.

Social implications The right to drive is typically seen as a sign of one’s independence, and gaining that right in adolescence is seen as a sign of responsibility and maturity. As one is deemed unable to drive for whatever reason, the removal of that privilege may be seen as an affront to one’s way of being and a negative commentary on one’s ability to care for him or herself. This can cause a fair amount of social strife for a patient and can lead to feelings of isolation and depression. In addition, it can lead to physical problems regarding neglect and inability for self-care. Of course, many older individuals make the decision to restrict driving themselves; a survey of older drivers showed that of those who made the decision to stop driving on their own, those who stopped driving independently tended to be older and female, with fewer reported health problems than respondents who continued to drive. However, those who reported self-discontinuation of driving tended in general to view their overall health as poorer than those who continued to drive, even though the nondrivers had fewer listed medical diagnoses. This discrepancy may speak to the difficulty in deciding who is fit or not fit to drive: those who have better insight may be more easily persuaded to give up the keys; those more impaired medically or cognitively may also have impaired insight into their condition, so reasoning with them may be difficult, if not futile (Dellinger et al., 2001). Reasons given for cessation of driving tend to involve medical conditions and problems in vision, but one reason of interest that appeared in a survey study of older drivers was that “there is always someone available

Driving Impairment in Older Adults

to drive me where I need to go” (Dellinger et al., 2001). This response raises an important point about the effect of restricting driving in the elderly. For many older individuals, driving may be their only means of maintaining contact with their surrounding world; they may not have an intact social support group to which they can reach for transportation assistance. Some studies have shown that older patients who no longer drive tend to rely on informal support systems for transportation, such as family and friends. Although this arrangement was not a major problem for many households, some caregivers noted that their work schedule was significantly disrupted or that they had to stop work altogether to provide transportation for the nondriving elder. Nondriving individuals who did not live with a driver and who were younger tended to report higher difficulty accessing social and recreational activities due to their mobility limitations (Taylor and Tripodes, 2001). Furthermore, elderly individuals who no longer drive may not use communal or public methods of transportation or walk to achieve their travel goals. Whether this is due to a reluctance to use public transportation or an inability to navigate the steps needed to procure such transportation (due to financial constraints or cognitive impairments, for example), it appears as though, when driving privileges are taken away, the burden falls on the elder person’s social network to provide transportation. If such a social network does not exist, the consequences of driving restriction could be profound. An elder person may become socially withdrawn because he or she cannot interact with the world as before. If the elder was continuing to work, the loss of driving privileges may have a serious economic consequence because it would interfere with the ability to work. Along with social isolation and possible economic burden, elderly individuals who have lost the ability to drive may see such a loss as a blow to their self-esteem and a comment on their ability to care for themselves independently. This, combined with the lack of socialization and decreased independence caused by lack of mobility, may precipitate depression in this population, which can further complicate a medical picture that is probably already complex. This can make treating the elderly individual more challenging, as another diagnosis has been added to the medical conditions list, and the logistics of getting the patient to the doctor’s office may become more difficult if the patient cannot drive.

Caregiver burden and concerns The patient who can no longer drive may suffer from a change of self-image, a lack of independence, and possible depression from the change in situation. Likewise, the patient’s caregivers, whether informal (as in family members and friends) or formal (as in physicians), are also affected by the issue of whether to have someone give up

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driving. As mentioned earlier, family caregivers are the ones most likely to be called upon to provide transportation services if driving is restricted, and this may cause significant burden on time and effort, as well as lost time at work and, thus, economic burden. A study analyzing perceived burden among caregivers of dementia patients showed that fulfilling transportation needs was a leading burden in terms of time spent caring for the patient and was the leading cause of caregivers feeling “out of sync” or unable to participate fully in life because of their obligation to the patient (Razani et al., 2007). This can cause impairments in the caregiver’s quality of life and can foster feelings of hostility toward the nondriving patient. Furthermore, the impaired elderly driver who does not believe he or she is unsafe and refuses to stop driving can be a source of significant stress for family members and other caregivers. The elder may perceive conversations regarding driving restrictions as offensive and may get angry or hostile, especially if the elder does not have insight into the impairment and thinks that family members are being oppressive. In situations such as these, the family often consults the physician for help in convincing the patient that he or she is not safe to drive. This can cause a significant amount of stress for the healthcare provider as well because it raises a conflict between patient autonomy and confidentiality and the physician’s obligation to warn of potential harm; the conversation itself can put a strain on the physician–patient relationship. The discussion of whether someone is fit to drive is muddied by the fact that so many elderly are fit to drive, and no battery of tests can perfectly identify which elder individual will be unsafe. Furthermore, an evaluation must be ongoing, as geriatric syndromes and aging changes are progressive: a physician must take this into account when determining driving ability at a particular point in time (Fitten, 2003; Razani et al., 2007). Physicians often have conflicting feelings about the best way to go about counseling a patient on driving and are unsure of their role in this matter with regard to patient confidentiality and public safety. When surveyed, they are reluctant to bring it up before the patient or family does, and they worry about being liable if their assessment of someone as either fit or unfit to drive is found to be erroneous. They are unsure about their obligation to report an unsafe driver to motor authorities, and they feel that assessment of the driver would be better conducted through driving tests, which are not in their purview. In addition, they feel as though the tests currently used and available to clinicians do not have adequate predictive power to identify those most at risk. Finally, they name the possible damage to the physician–patient relationship as a barrier to effective driving counseling (Bogner et al., 2004). Patients often see the evaluation for driving fitness, which includes cognitive testing, as an insult to their intelligence and an affront to their independence.

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Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

Furthermore, the physician’s need to preserve patient confidentiality and public duty to report a dangerous driver are often in conflict, and finding an acceptable resolution is difficult, given the lack of consensus about driving assessment. Thus, driving restriction in the elderly is a delicate topic made worse by a lack of consensus about assessment, a social stigma regarding elderly drivers in general, and the loss of independence and detriment to quality of life not only for those who lose their licenses, but also those who provide care for them.

Legal ramifications The majority of the research and public policy directives addressing dementia and driving issues have focused on defining methods to detect unsafe drivers and remove them from the active driving pool. A number of professional societies and consensus meetings have published practice guidelines for the clinician in this regard (American Psychiatric Association, 1997; Johansson and Lundberg 1997; Small et al., 1997; Patterson et al., 1999; Dobbs et al., 2000; Alzheimers Association, 2001; AMA, 2003; Canadian Medical Association, 2006; Lyketsos et al., 2006; Iverson et al., 2010). Uniformity of opinion holds that moderately severe dementia precludes safe driving, but there is still no consensus on how to deal with seniors with questionable or mild dementia who are minimally or only mildly dependent on others for assistance with their other daily living activities.

Requirements of physicians to report elders at risk Current research indicates that many, but not all, demented individuals have difficulty in actual driving situations. The crash data taken as a whole indicate that the overall risk of this group is not elevated to the point that clinicians should work toward removing all drivers with a diagnosis of dementia from the road. That is, some demented drivers may be competent to drive in the early stages of their illness (Duchek et al., 2003; Ott et al., 2008). Licensing decisions based only on the diagnosis of dementia may unfairly penalize patients and prematurely limit independence and mobility. Thus, a diagnosis of dementia should not be the sole justification for revoking a driver’s license (Alzheimers Association, 2001). If the patient has a progressive dementia such as AD, the conversation about future driving retirement being inevitable should take place early in the discussion. If the clinician determines that the patient is currently competent to drive, monitoring over time is imperative. Review of driving risk by the clinician every 6 months has been recommended (Dubinsky et al., 2000; Duchek et al., 2003; Molnar et al., 2006b; Ott et al., 2008; Carr and Ott, 2010).

Court decisions have been divided regarding physician liability for “failure to warn” a patient not to drive when medical risk is identified. In some cases, physicians have been held liable for failure to advise patients about medications side effects, medical apparati, and medical conditions that may impair driving (AMA, 2003; Anon, 1998). Many physicians are uncertain of their legal responsibility to report unsafe drivers to the state (Miller and Morley 1993; Kelly et al., 1999). State regulations vary regarding the requirement and methods to report medically at-risk drivers. The reader is advised to review policies provided in the AMA Physician’s Guide to Assessing and Counseling Older Drivers (AMA, 2003), as well as contact local licensing authorities about specific laws and policies. At least nine states call for mandatory reporting of medically atrisk drivers. These include California, which specifically requires reporting of drivers with AD and related disorders (Reuben and St George, 1996). Only two states mandate road testing of older drivers. Seventeen states require a road test if recommended by examiner or physician or eye specialist. Seven states mandate and 16 encourage physicians to report unsafe drivers. Physicians are not required to report unsafe drivers in 21 states (Aung et al., 2004). The responsibility to the public safety to report potentially risky drivers must be balanced against the physician’s ethical responsibility to maintain patient confidentiality. Consequently, many physicians choose not to report, for fear of jeopardizing the therapeutic relationship with their patient or breaking privacy regulations under Health Insurance Portability and Accountability Act (HIPAA). Many states recommend voluntary reporting, and some (half) provide immunity from prosecution by the reported, which offers some protection to the physician. In states where no such protection exists, the physician must obtain permission for the patient to report. Thorough documentation of any discussions and recommendations in the medical record, and open discussion with the patient explaining a plan to report, are recommended, along with strict adherence to local state laws (AMA, 2003).

How to determine whom to report Using a decision tree such as the one suggested in Figure 29.2 may help the clinician make a recommendation to stop driving. Quite often, though, the safety risk for the driver is not clear, and in such cases, referral for an onroad test from a driving instructor or other driving rehabilitation specialist is particularly helpful. Another option for referral, which may include a performance-based road test, is to contact the state Department of Motor Vehicles. Most states require the physician to fill out forms that require medical information and vision testing results, and provide an opinion on whether the driver should undergo visual or on-road testing. The road test utilized is often the same test that is used for the novice or teenage driver.

Driving Impairment in Older Adults

Sometimes the physician is faced with a patient who is deemed unsafe to drive after careful assessment yet who refuses to retire from driving or get a performancebased assessment to provide assurance that the safety risk is acceptable at the time. This is particularly common among drivers with dementia who lack insight. Sufficient time to discuss the recommendation should be provided in the office visit, to allow the patient to vent anger and frustration, as well as maximize communication. The recommendation to stop driving should include counseling on alternative transportation sources. A listing of webbased resources is provided later in this chapter and may be helpful. The support and involvement of family members in both communicating this recommendation and enforcing it are key. Steps that family members can take to ensure compliance include the following: 1 Ask the physician to write a “prescription” for driving cessation. 2 Ask the physician to refer to other medical conditions as reasons to cease driving, such as vision problems, arthritis, or limited reaction time. 3 File or otherwise disable the keys. 4 Do not repair the car, or send it out for an indefinite period of time for “repairs” and arrange for its removal. 5 Remove the car by selling or donating it. 6 Disable the vehicle by removing the distributor cap or other means. 7 Involve the family lawyer in counseling. 8 Where permitted under state law, sending a referral to the Department of Motor Vehicles by formal letter may be necessary (Carr and Ott, 2010). Currently, 44 states allow a family member to report an impaired driver. The ethical guidelines of the American Medical Association address the issue of physician reporting and patient confidentiality: “[W]here clear evidence of substantial driving impairment implies a strong threat to patient and public safety, and where the physician’s advice to discontinue driving privileges is ignored, it is desirable and ethical to notify the Department of Motor Vehicles.” (AMA Policy Finder, 2000)

Conclusion Specialized training in age-related disorders that can affect safe driving allows the geriatric neurologist to be ideally positioned to provide expert consultation and counseling to patients and their families on driving interventions to promote safety and mobility.

Driving interventions to promote safety and mobility Given the evidence that many cognitively impaired drivers may still be able to drive safely for several years,

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future efforts should be made to maximize the safety and driving competence of those still actively driving with cognitive impairment due to degenerative dementia. This issue will become more compelling as the baby boom generation ages yet aims to retain a vigorous and mobile lifestyle. Early intervention via forced or voluntary driving retirement can avoid serious accidents, yet one does not want to limit driving arbitrarily based on diagnosis alone because autonomy for the elderly is an extremely important goal both socially and economically. A major question arises: when should a cognitively impaired older person stop driving? To address these questions, a large number of epidemiologic risk factor studies and neuropsychological test studies have been performed using various outcome measures of driving competence, such as motor vehicle accidents, performance on driving simulators, and on-road driving tests. However, relatively little attention has been paid to the exploration of possible interventions to prolong the time that cognitively impaired older drivers can drive safely and maintain their transportation independence. The development of uniform standards for road testing may improve outcomes. For example, in the Brown Longitudinal Study, crash rates for drivers with dementia declined to the levels of healthy controls during a period of 18 months when evaluated with road tests every 6 months (Ott et al., 2008). The costs of such detailed surveillance may be prohibitive, however, and it is unknown whether community-based road testing programs would reproduce these results. It is generally recognized that memory loss alone does not impair the critical cognitive processes needed for safe driving, but it could impact the ability of a driver to navigate without getting lost, as well as increase safety risk of crashing in challenging circumstances (Anderson et al., 2007). Family members often try to compensate by having a nonimpaired driver serve as “co-pilot.” Assistive technologies, such as user-friendly GPS devices, need to be developed to maximize independent living for people with MCI. Early studies examining the effectiveness of classroombased or on-road training programs for older drivers failed to show clear benefits. In 2007, however, Marottoli and colleagues conducted a randomized controlled trial of 126 drivers age 70 years and older assigned to safety education versus a combined classroom and on-road driving training sessions. They were able to demonstrate improved performance on a road test following the intervention for the active treatment group (Marottoli et al., 2007). In another study by this group, 178 drivers age 70 years and older were randomized to intervention with graduated exercises versus controls who received home and environment safety modules. The active treatment group maintained driving performance as assessed by a

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road test, while controls significantly declined during the study period; however, the changes in the intervention group were modest, at best, and it is unknown whether the changes would be lost over time and whether the improvement of several points on a quantitative road test evaluation would translate to a reduction in crashes (Marottoli et al., 2007). More recently, studies involving cognitive speed of processing training in normal elderly drivers have shown promising short- and long-term results in improving driving performance on road test examinations (Roenker et al., 2003; Edwards et al., 2009a; Edwards et al., 2009b. Although these studies are encouraging in terms of prospects for enhancing driver safety among older drivers, brief educational and cognitive training programs would be challenging for the cognitively impaired and unlikely to have a lasting benefit for drivers with degenerative brain disease such as AD, due to its progressive nature. Recently, a pilot study of cholinesterase inhibitor therapy in AD drivers demonstrated that cholinesterase inhibitor treatment was associated with improvements in tests of executive function and visual attention, as well as simulated driving (Daiello et al., 2010). These findings could have important implications for patients who continue to drive in the early stages of AD. The development of more effective therapies for cognitive impairment and methods to slow functional incline would have an important impact on driving and mobility in the elderly. Also needed are better road designs that accommodate the challenges to the older driver, as well as improved safety warning systems for the vehicles they drive (Ott and Daiello, 2010).

Role of the geriatric neurologist Given his or her training in the diagnosis and treatment of many of the age-related disorders that can affect safe driving, the geriatric neurologist is ideally positioned to provide expert consultation and counseling to patients and their families on this often thorny issue. The ability of the physician to predict on-road driving performance is, at best, modest and probably should not be relied upon as the sole determinant of driving privilege, except in obvious cases. In one study of drivers with dementia, accuracy of clinician ratings ranged from 62% to 78% for the instructor’s global rating of safe versus marginal or unsafe. In general, there was moderate accuracy and inter-rater reliability. Accuracy could have been improved in the least-accurate raters with greater attention to dementia duration and severity ratings, as well as less reliance on the history and physical examination. The most accurate predictors were clinicians specially trained in dementia assessment, who were not necessarily the most experienced in their years of clinical experience (Ott et al., 2005). Utilizing appropriate resources such as neuropsychologists and driving rehabilitation specialists may result in referrals for more detailed

assessment, to improve accuracy and validity of the driving assessment process. Recognizing the problem driver is only the start of the process. A treatment plan must be developed that includes medication adjustments, treatment of ocular disease, sleep disorders, and metabolic problems such as diabetes. Collaboration with primary care physicians and specialist in other fields, such as ophthalmology, sleep medicine, orthopedics, and rheumatology, is important. Education on driving alternatives and community resources should be provided, particularly when driving retirement is advised. Listed next are a number of important organizations and resources that can be incorporated into the overall care plan and mobility counseling.

Support from organizations and internet educational resources (Carr and Ott (2010)): caregiver and patient resources Association for Driver Rehabilitation Specialists (ADED) The ADED web page, which describes warning signs of driving and provides a link to the directory for locating a driving specialist. www.driver-ed.org/i4a/pages/index.cfm?pageid=104 American Occupational Therapy Association (AOTA) Information on occupational therapists and their role in driving assessment and rehabilitation. www1.aota.org/olderdriver/ Alzheimer’s Association The national association’s website on driving and dementia, with links to educational information. Local chapter websites often list available driving clinics in the area. www.alz.org/safetycenter/we_can_help_safety_driving .asp Family Caregiver Alliance (1) Fact sheet on dementia and driving. http://www.caregiver.org/caregiver/jsp/content_node .jsp?nodeid=432 (2) A review of the myriad caregiver issues related to this topic. www.caregiver.org/caregiver/jsp/content_node .jsp?nodeid=432 (3) Information on dementia and driving and the California state law. www.caregiver.org/caregiver/jsp/content_node .jsp?nodeid=433 Lennox and Addington Dementia Network Dementia and Driving—Family and Caregiver Information. www.providencecare.ca/objects/rte/File/Health_Professionals/drivinganddementia_patient.pdf MayoClinic.com Caregiver site on when to stop driving. www.mayoclinic.com/health/alzheimers/HO00046

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National Association of Social Workers Tool for locating a social worker near you. www.socialworkers.org/ The Caregiver Project Links to other websites on this topic. www.quickbrochures.net/alzheimers/alzheimersdriving.htm The Hartford Insurance company website, with links to the brochures At the Crossroads and We Need to Talk. www.thehartford.com/alzheimers/ www.thehartford.com/talkwitholderdrivers/ WebMD Dementia and driving video for caregivers. www.webmd.com/video/driving-and-dementia

Physician resources Alzheimer’s Knowledge Exchange website, with selected links on dementia and driving. www.candrive.ca/en/resources/physician-resources/ 43-driving-and-dementia.html American Family Physician Dementia and Driving handout for the office. www.aafp.org/afp/20060315/1035ph.html American Medical Association (AMA) Physician’s Guide to Assessing and Counseling Older Drivers (see “Dementia and Driving,” page 47). http://www.ama-assn.org/resources/doc/publichealth/older-drivers-chapter4.pdf Information on state licensing and reporting laws (last updated 2004). http://www.ama-assn.org/resources/doc/publichealth/older-drivers-chapter8.pdf California Department of Motor Vehicles Discussion of the California law and dementia severity. www.dmv.ca.gov/dl/driversafety/dementia.htm Dementia and Driving Toolkit: The Dementia Network of Ottawa A toolkit for clinicians who evaluate and counsel older drivers. http://docs.google.com/gview?a=v&q=cache:sU_ gDWuJOa0J:www.cma.ca/multimedia/CMA/Content_ Images/Inside_cma/WhatWePublish/Drivers_Guide/ AppendixD_e.pdf+dementia+and+driving+tookit&hl=en &gl=us Insurance Institute for Highway Safety (IIHS) Website on older driver laws for driver licensing, updated every six months. www.iihs.org/laws/olderdrivers.aspx Neurology Factors that affect when patients with Alzheimer’s should stop driving, by Deniz Erten-Lyons

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www.neurology.org/cgi/reprint/70/14/e45?maxtoshow =&HITS=10&hits=10&RESULTFORMAT=&fulltext=driv ing+and+dementia&searchid=1&FIRSTINDEX=10&sorts pec=relevance&resourcetype=HWCIT Neuropsychiatry “Driving with Dementia: What is the Physician’s Role?” A discussion of the physician’s role in this process. www.neuropsychiatryreviews.com/may02/npr_may02_ demdrivers.html Psychiatry Weekly “Psychogeriatrics: Advanced Age, Dementia, and Driving.” A discussion of the physician’s role, ethics, and communication issues. www.psychiatryweekly.com/aspx/article/articledetail. aspx?articleid=984 Talking to Seniors and Their Family about Dementia and Driving Educational pamphlet by Mark Rapaport (2007). http://docs.google.com/gview?a=v&q=cache:8BVwrfg pLOwJ:www.rgpc.ca/best/GiiC%2520Resources/GiiC/ pdfs/5%2520Talking%2520to%2520seniors%2520about% 2520driving.pdf+rappoport+dementia+driving&hl=en& gl=us VA Government Pamphlet Dementia and Driving handout. www1.va.gov/vhapublications/ViewPublication. asp?pub_ID=1162

Transportation alternatives Agency on Aging Assists in finding local resources for aging in the community. www.n4a.org/ American Public Transportation Association (APTA) Helps locate a local transportation provider in your community. www.publictransportation.org/systems/ American Administration on Aging (AOA) Eldercare locator. Assists in finding resources in your community for older adults. www.eldercare.gov Community Transportation Association (CTAA) Information on transportation in the United States. www.ctaa.org/ntrc/ ITNAmerica Novel older adult transportation system that provides 24/7 rides to seniors. www.itnamerica.org/. National Center on Senior Transportation Links to many transportation agencies. http://seniortransportation.easterseals.com/site/ PageServer?pagename=NCST2_trans_care

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Seniors on the MOVE Assists older adults with relocation to another community. www.seniorsonthemoveinc.com/

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Roenker, D.L., Cissell, G.M., Ball, K.K., et al. (2003) Speed-ofprocessing and driving simulator training result in improved driving performance. Hum Factors, 45: 218–233. Ryan, G.A., Legge, M., and Rosman, D. (1998) Age related changes in drivers’ crash risk and crash type. Accid Anal Prev, 30: 379–387. Saleh, K.L. (1993) The elderly patient in the post anesthesia care unit. Nurs Clin North Am, 28: 507–518. Sherman, F.T. (2006) Driving: the ultimate IADL. Geriatrics, 61: 9–10. Small, G.W., Rabins, P.V., Barry, P.P., et al. (1997) Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. J Am Med Assoc, 278: 1363–1371. Staats, D.O. (2008) Preventing injury in older adults. Geriatrics, 63: 12–17. Stutts, J.C., Stewart, J.R., and Martell, C. (1998) Cognitive test performance and crash risk in an older driver population. Accid Anal Prev, 30: 337–346. Tanikatsu, R., Iseki, M., Kamimura, N., et al. (2009) Are drivers with frontotemporal lobar degeneration more dangerous than those with Alzheimer’s disease? Int Psychogeriatr, 21 (Suppl. 2): S104–S105. Taylor, B.D. and Tripodes, S. (2001) The effects of driving cessation on the elderly with dementia and their caregivers. Accid Anal Prev, 33: 519–528. Thiyagesh, S.N., Farrow, T.F., Parks, R.W., et al. (2009) The neural basis of visuospatial perception in Alzheimer’s disease and healthy elderly comparison subjects: an fMRI study. Psychiatry Res, 172: 109–116. Trobe, J.D., Waller, P.F., Cook-Flannagan, C.A., et al. (1996) Crashes and violations among drivers with Alzheimer’s disease. Arch Neurol, 53: 411–416. Uc, E.Y. and Rizzo, M. (2008) Driving and neurodegenerative diseases. Curr Neurol Neurosci Rep, 8: 377–383. Uc, E.Y., Rizzo, M., Anderson, S.W., et al. (2004) Driver route-following and safety errors in early Alzheimer disease. Neurology, 63: 832–837. Uc, E.Y., Rizzo, M., Anderson, S.W., et al. (2005) Visual dysfunction in Parkinson disease without dementia. Neurology, 65: 1907–1913. Uc, E.Y., Rizzo, M., Anderson, S.W., et al. (2006) Unsafe rear-end collision avoidance in Alzheimer’s disease. J Neurol Sci, 251: 35–43. Uc, E.Y., Rizzo, M., Anderson, S.W., et al. (2006) Driving with distraction in Parkinson disease. Neurology, 67: 1774–1780. Uc, E.Y., Rizzo, M., Anderson, S.W., et al. (2006) Impaired visual search in drivers with Parkinson’s disease. Ann Neurol, 60: 407–413. Uc, E.Y., Rizzo, M., Anderson, S.W., et al. (2007) Impaired navigation in drivers with Parkinson’s disease. Brain, 130: 2433–2440. Wadley, V.G., Okonkwo, O., Crowe, M., et al. (2009) Mild cognitive impairment and everyday function: an investigation of driving performance. J Geriatr Psychiatry Neurol, 22: 87–94. Whelihan, W.M., DiCarlo, M.A., and Paul, R.H. (2005) The relationship of neuropsychological functioning to driving competence in older persons with early cognitive decline. Arch Clin Neuropsychol, 20: 217–228.

Chapter 30 Elder Abuse and Mistreatment Elliott Schulman1, Ashley Roque2, and Anna Hohler3 1

Lankenau Institute for Medical Research, Lankenau Medical Center, Wynnewood, PA, USA Boston University School of Medicine, Boston, MA, USA 3 Department of Neurology, Boston University School of Medicine, Boston, MA, USA 2

Summary • Physical, emotional, financial, and sexual abuse, along with neglect, are all types of elder abuse. • Risk factors for mistreatment include being female, advanced age, low income, comorbid medical issues, and social isolation. • Elders with dementia and cognitive impairments are more likely to become victims, perhaps due to decreased ability to communicate and defend themselves from their caregivers. • Burnout, stress, and individual factors put caregivers and nursing home staff at risk for becoming abusive. • EM screening is recommended for all geriatric patients. Accurate documentation of history and recognition of physical signs of abuse are important in identifying elder abuse. • Interventions for EM include education for both the patient and caregiver, adult protection services, support groups, and respite care.

Introduction Abuse affects all age groups, spares no sociodemographic boundaries, and can contribute to health problems ranging from depression to coronary artery disease. Abuse and neglect may be associated with migraine and pseudoseizures (Alper et al., 1993; Tietjen et al., 2007). A history of abuse may influence disease presentation and response to treatment. A significant portion of neurologic patients are elderly, a group that is at particular risk for mistreatment. Elder mistreatment (EM) is defined as abuse or neglect of either an individual over 65 years of age, or an adult who is physically or mentally disabled. As neurologists, it is imperative to identify the mistreatment and provide the appropriate resources for our patients. An estimated 1.01 million elders became victims of various types of domestic elder abuse in 1996. Women make up 68.3% of elder abuse victims (National Center on Elder Abuse, 1996). These numbers are thought to grossly underestimate the actual rates of EM. This epidemic of EM is estimated to cost Americans tens of billions of dollars annually in healthcare, social services, investigative, and legal costs (National Committee for the Prevention of Elder Abuse (NCPEA) official website). EM also influences the survival of our patients. Individuals who experience mistreatment are at a higher risk of 1 year mortality (Dong et al., 2009). Reliably assessing the prevalence of

elder abuse is difficult, as research studies suggest that only one in four elder abuse incidents is reported (Tatara, 1990). Several reasons for this exist, including under reporting because of physical or mental disability, and fear of the consequences of reporting. By recognizing this issue and addressing it as part of each evaluation, neurologists can positively influence patient care.

Definitions of elder mistreatment Elder abuse can fall into several different categories. Individuals can be placed in a disadvantaged position both by what is done to them and by what is not provided for them. Table 30.1 defines the types of abuse and neglect and provides examples.

The cycle of mistreatment Typically, EM does not occur continually, but instead occurs sporadically. The caregiver may be caring between episodes, which contributes to the lack of reporting. The abused elder may perceive that the situation will improve with time. The abuse becomes more severe as the caregiver tries to meet the ever-increasing physical and cognitive demands of the individual.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Table 30.1 Various forms of elder abuse Type

Definition

Physical abuse

Willful act carried out with the intent of causing pain or injury

Emotional abuse

Financial abuse

Sexual abuse

Elder neglect

Examples

Slapping, hitting, kicking, striking with objects, pinching, pushing, pulling hair, and physically restraining Willful act executed to Verbal aggression, threats cause emotional pain, of institutionalization, injury, or mental anguish social isolation, humiliating statements, insults Theft of checks or money, Misappropriation of elderly person’s or coercion to deprive the elderly person of assets assets for personal (such as forcible transfer of or monetary gains, or property, forgery, fraud) failure to use funds to restore health and wellbeing of the elder Nonconsensual sexual Suggestive talk, activity with an elderly forced sexual activity, person touching, or fondling with a nonconsenting or incompetent person Failure to provide adequate Failure of designated food, clothing, shelter, caregiver to meet the elderly person’s physical medical care, hygiene, social stimulation, or and mental well-being emotional support needs

Source: Adapted from Ahmad and Lachs (2002) with permission of Cleveland Clinic Journal of Medicine.

Risk factors for elder mistreatment Being female increases the risk for abuse among both older and younger individuals. Abuse of elderly females may represent a continuum of violence against females throughout the lifespan (Hightower, 2010). Elderly women have a greater chance than men of being widowed, losing social support, and not being financially independent. In many countries, women are assigned lower social statuses and have a decreased voice in decision making. All these factors may contribute to the greater incidence of risk of abuse among elder females (Daichman et al., 2010). In one study, investigators postulated that women suffer more serious injuries than men when abused; therefore, the abuse would be more likely to come to the attention of protective services. Males, on the other hand, made up the majority of those who were abandoned (National Center on Elder Abuse, 1996). The oldest elders (80 years and over) were abused and neglected at 2–3 times the rate of the general elderly population. The median age of elder abuse victims is 77.9 years. In 1996, 66.4% of the reported victims of domestic elder abuse were white, 18.7% were African American, and 10.4% Hispanic (National Center on Elder Abuse, 1996).

Neglect is the most common form of EM (55%). Physical abuse is the most common reported form of abuse (14.6%), followed by financial (12.3%), emotional (7.7%), and sexual abuse (0.3%) (National Center on Elder Abuse, 1996).

Individual risk factors of elders Individual risk factors for becoming a victim of EM include advanced age (over the age of 75) and income less than $10,000 a year (Mass.Gov, 2010; Jones et al., 1997). Comorbid medical issues in the elderly can also increase the risk of abuse. Common medical problems that increase the risk of abuse include depression, frailty, physical impairment, and dementia (Jones et al., 1997; Utley, 1999; Cooper et al., 2009). Elderly who experience depression are at increased risk of abuse because depression may cause a decrease in self-care and self-protection (Halphen and Dyer, 2010). One study found that elders with dementia were ten times more likely to be the victims of abuse than other elders (Cooney et al., 2006). Cognitive impairment may decrease elderly patients’ abilities to defend themselves, remove themselves from an abusive situation, or make them unable to communicate the abuse to others. Elderly persons with cognitive and physical impairment are increasingly reliant on their caregivers for help with performing activities of daily living. Increased reliance can cause informal caretakers to experience significant stress that increases the risk that they will abuse the elderly patient under their care (American Psychological Association, 2003). Social isolation has also been shown to put the elderly at an increased risk for mistreatment. In these situations, the abuser prevents the elder from interacting with others, and the elder becomes completely dependent on the abuser. This may stop the elder from reporting the abuse due to fear of institutionalization or abandonment (Jayawardena and Liao, 2006; Halphen and Dyer, 2010).

Caregiver risk factors Caregivers who have disabling conditions, such as addiction to alcohol or drugs, sociopathic personalities, or a history of mental illness, have higher rates of being perpetrators of abuse. Those with dementia, mental retardation, and a history of experiencing abuse and violence themselves are also more likely to be abusers (Jones et al., 1997). Numerous studies have shown that caregivers who are financially dependent on the abused also show a greater risk for becoming abusers (Jones et al., 1997; Utley, 1999; Halphen and Dyer, 2010). Caregivers who have employment problems, personal illness, or low income may take out their frustrations on the elders under their care, leading to mistreatment (Jones et al., 1997).

Elder Abuse and Mistreatment

In almost 90% of EM episodes with a known perpetrator, the perpetrator is a family member. Two thirds of the perpetrators are adult children or spouses (National Center on Elder Abuse, 1996). Overall, men were the perpetrators of abuse and neglect 52.5% of the time. Of the cases of abuse and neglect, males were the most frequent perpetrators of abandonment (83.4%), physical abuse (62.6%), emotional abuse (60.1%), and financial/material exploitation (59%). The age category with the most perpetrators was those from 41 to 59 years (38.4%), followed by those less than 40 years of age (27.4%) (National Center on Elder Abuse, 1996). Verbal abuse was associated with a poor premorbid relationship and social isolation of the caregiver. The longer the caregiver had been tending to the elderly, the higher the risk of physical abuse (Cooney and Mortimer, 1995). Neglectful situations arise more commonly when there is a lack of resources.

Caregiver burnout “Burnout” may be a risk factor for physical abuse (Cooney and Mortimer, 1995). Evidence suggests that those who physically abused elders were under mental distress (Cooney and Mortimer, 1995; Cooper et al., 2009). The longer the caregiver is taking care of the elderly individual, the higher the risk of physical abuse. Often informal caregivers take complete responsibility for an elderly patient without appropriate training. They are not educated on the disease process, what behaviors to expect, how to deal with difficult behavior, or the resources that are available to them. As a result, they may have difficulty meeting both their own needs and the needs of the patient. These caregivers often feel hopeless, frustrated, angry, and “burned out,” which can lead them to use physical force or other abusive behaviors (American Psychological Association, 2003). It is important to determine the degree of assistance the elderly require. Caregivers should be carefully questioned regarding whether they are overwhelmed, have a social support system, or have adequate free time for themselves (Cooper et al., 2009).

Special situations Nursing homes Nursing home residents are at higher risk of EM because of cognitive impairment and physical limitations. In addition, many are unable to report abuse, for fear of reprisal (Lindbloom et al., 2007). A 1987 survey of nursing home staff found that 36% had witnessed at least one episode of physical abuse in the preceding 12 months, and 40% had committed at least one episode of psychological or verbal abuse over this time period (Pillemer and Moore, 1989). Psychological

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abuse is likely to be more prevalent than physical abuse and may take the form of isolation or intimidation (Tarbox,  1983). Neglect may manifest as malnutrition and dehydration. Often caregivers experience almost daily abuse, including verbal and physical assault (Pillemer and Moore, 1989). When staffing was inadequate, caregivers were more likely to be abusive to nursing home residents. Burnout was another risk factor for abuse. Workers at risk for being abusive were often stressed, while those who ignored the yelling or pushing by residents had positive work experiences and had a stable personal life (Shaw, 1998). The following list provides some abuser characteristics. Characteristics of abusers in nursing homes • Lower job satisfaction • Workload stress • Burnout • History of domestic violence or mental illness • Drug or alcohol abuse • Inadequate staffing (Lindbloom et al., 2007)

Screening for abuse The American Medical Association (AMA) recommends that all physicians routinely inquire about the mistreatment of elderly patients (American Medical Association, 1982). If there is a suspicion of abuse, the patient and caregiver should be interviewed separately. The patient will feel more comfortable talking about their relationship with the caregiver and will be less likely to fear retribution from the caregiver (Swagerty and Brickley, 2005). AMA guidelines are listed here. AMA guidelines for screening (1982) 1 Are you alone a lot? 2 Has anyone ever failed to help you take care of yourself when you needed help? 3 Are you afraid of anyone at home? 4 Have you ever signed any documents that you did not understand? 5 Has anyone ever threatened you? 6 Has anyone ever touched you without your consent? 7 Has anyone at home ever hurt you? Reports of abuse occurring in 5% of the elderly probably understate the prevalence (Figure 30.1). This suggests that only the most serious abuse is being detected or reported (Cooper et al., 2008). Research studies have been undertaken to determine the most effective screening strategy. A consensus has not yet been reached, but several of the available methods have been tested for accuracy. In fast-paced settings, such as emergency rooms or busy outpatient clinics, brief instruments to assess potential

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Table 30.2 Red flags for abuse Reported abuse

Unidentified and unreported abuse

Type of abuse

Signs and symptoms

All types

Frequent unexplained crying Unexplained fear or suspicion of persons in the home Bruises, lacerations Bone fractures Laboratory findings of medication overdose or underutilization of prescribed drugs Bruises around breasts or genital area Unexplained venereal disease Signs of agitated or emotional upset Sudden change in behavior Extreme withdrawal and noncommunication or nonresponsiveness Dehydration Malnutrition Untreated bedsores Poor personal hygiene Unattended or untreated health problems

Physical

Sexual Emotional/ psychological Figure 30.1 Iceberg table. Source: NEAIS study, pp. 2–4; www

.ncea.aoa.gov/Main_Site/Library/Statistics_Research/National_ Incident.aspx.

mistreatment are generally used to determine whether further assessment is required. Comprehensive assessment protocols and guidelines are designed for settings such as the Adult Protective Services (APS) and ombudsman interviews, in which more in-depth assessment is performed (Fulmer et al., 2004). In general, patients respond more readily to questionnaires that are then reviewed during the office visit (Glass et al., 2001). Before screening the patient for abuse, the physician should inform the patient of any mandatory requirement to report abuse to protective agencies (Boston Medical Center, 2009). An elderly person is 2–3 times more likely to visit a healthcare professional than someone of a younger age. Therefore, the healthcare field provides an opportune setting for identifying and intervening in elder abuse (Swagerty et al., 1999). However, identifying victims of EM is usually difficult. Healthcare professionals, social service agencies, and police departments often assume the responsibility of identifying, reporting, and intervening in elder abuse (Fulmer et al., 2004). In spite of this, many healthcare professionals experience difficulty in identifying the victims of elder abuse and feel uncomfortable intervening in cases of abuse. Table 30.2 lists some typical signs of abuse. In one study, 90% of physicians reported that EM was difficult to detect, and only 2% of all cases of suspected EM were reported by physicians (Fulmer et al., 2004). Clinicians should have specific training on how to assess for elder abuse and how to refer or report these cases (Campbell et al., 2000). Because of the limited number of elders who report abuse to authorities, the AMA recommends EM screening for all geriatric patients. Two important factors in identifying elder abuse are taking an accurate history and recognizing physical signs of abuse (Swagerty et al., 1999). When taking a history, the physician should try to get a good sense of the patient’s daily life. Several important

Neglect

features should be obtained from the history (Swagerty et al., 1999). • Medical problems/diagnoses • Detailed description of home environment (adequacy of food, shelter, supplies, medication, and so on) • Accurate description of events related to injury or trauma (instances of rough handling, confinement, or verbal or emotional abuse) • History of prior violence • Description of prior injuries and events surrounding them • Description of berating, threats, or emotional abuse • Improper care of medical problems, untreated injuries, poor hygiene, or prolonged period before presenting for medical attention • Depression or other mental illness • Extent of confusion or dementia • Drug or alcohol abuse • Quality/nature of relationships with caregivers • Other social contact, the patient has, besides the caregiver

Documentation and legal requirements In the 1990s, elder abuse became a criminal offense. With some variation among states, certain types of emotional elder abuse and elder neglect are subject to criminal prosecution, depending on the perpetrator’s conduct, intent, and the victim’s injuries. States differ on who is required to report suspected elder abuse although the list of mandatory reporters is growing. Typically, medical personnel, nursing home workers, peace officers, emergency personnel, public officials, social workers, counselors, and clergy are listed as mandatory reporters, and that responsibility is spreading to financial institutions and other entities that work with seniors.

Elder Abuse and Mistreatment

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Reporting Reporting suspected elder abuse is mandatory in all states except Colorado, New Jersey, New York, North Dakota, South Dakota, and Wisconsin. In Delaware, Indiana, Kentucky, New Mexico, North Carolina, Rhode Island, Texas, and Wyoming, anyone who suspects EM is required to report the abuse. In other states, only people of certain occupations, including healthcare workers, are considered mandatory reporters. Even if the patient is competent and requests that the abuse not be reported, the physician is required to report abuse under the mandatory reporting laws. Reporting abuse is not considered a breach of patient confidentiality. In 28 states, failure to report suspected abuse is punishable by law (Jayawardena and Liao, 2006; Halphen and Dyer, 2010). Health professionals are required to report abuse if they have a reasonable cause to believe it is occurring. Suspicion of abuse is an adequate threshold to report to protective agencies. Also, in most states, reporters are protected from civil and criminal litigation (Jayawardena and Liao, 2006). If the patient is being abused by the caregiver or someone in the general community, the report should be made to the local APS. Initially, a verbal report should be made immediately by calling the Elder Abuse Hotline. A written report of abuse should then be sent to the appropriate agency within 48 hours. Physician’s offices and hospitals generally keep copies of the Elder Abuse Mandated Reporting Form on file. If the suspected abuse is occurring in a long-term care institution, the report should be made to the ombudsman by calling the Department of Public Health. If there is concern that immediate action is required to prevent further harm, the reporter should notify law enforcement and protective agencies (Jayawardena and Liao, 2006; Halphen and Dyer, 2010). A referral to social work may also be appropriate to ensure ongoing assessment and support of the elder. The physician should inform patients that they have a duty to report the abuse to protective agencies and should involve patients in the reporting process as much as possible. Information pertaining to the suspected abuse should be recorded in the medical record.

5 Specific details of any mandated reports, including name of reporter, type of report, and date of reporting, where applicable. 6 Copies of reports themselves should not be included in the medical record. Great care must be taken in recording information pertaining to the abuse. Summaries and general statements are not considered strong evidence by law enforcement agencies. If there is any physical evidence of abuse, it is best to take photographs. If photographic evidence is not possible, it is best to draw the injuries and provide a record of color, induration, and size (Halphen and Dyer, 2010).

Documentation of abuse in the medical record 1 Complete, objective details of injuries/conditions based on clinical findings and observations. 2 Patient’s account of injuries/conditions. Use direct quotes in quotation marks whenever possible, including specifics of incident(s). 3 Medical, nursing, and social work assessments. 4 Treatment and discharge plans, including referrals to medical, nursing, or social work staff. Do not include names of any confidential shelters or details of any safety planning.

Intervention for caregivers: education and support

Interventions for the abused Education Competent elders have the right to reject the services offered by protective agencies (Mass.Gov, 2010). If this occurs, the physician’s main role is to educate the elder on how to live as safely as possible. The physician should gather information on the patient’s unmet needs and refer the patient to the appropriate resources. Patients who experience abuse can be referred to local support groups, individual counseling, safety planning services, and crisis intervention services (Chez, 1999). Patients should be given the number for the National Domestic Violence Helpline. In elder abuse situations when the victim is deemed incompetent and is at the risk of serious harm, intervention is court-ordered (Mass.Gov, 2010). Adult protective services Interventions provided by the APS include receiving reports of adult abuse, exploitation, or neglect; investigating these reports and subsequent case planning; and monitoring. The APS may also provide or arrange for the provision of medical, social, economic, legal, housing, law enforcement, or other protective, emergency, or supportive services (National Center on Elder Abuse About Adult Protective Services). It is APS policy that interventions be as unrestrictive as possible; thus, in-home and community-based services are preferred to placement in a longterm care center (Mass.Gov, 2010).

Instruction in behavior management techniques All caregivers should be instructed in how to handle difficult situations that may arise. Research has shown that the behaviors that are most troubling to caregivers are wandering, personality changes, paranoia, and aggressive behavior. Classes, groups, and materials have all been developed to provide caretakers with techniques on

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Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

dealing with these difficult situations. These behaviors are usually the result of pain and discomfort, being experienced by the elder. If caregivers are taught to recognize this, they can respond appropriately by eliminating the source of discomfort (Nerenberg, 2002). While communicating with the abuser, the physician should not pass judgment on him or her. After being accused of EM, abusers may react with feelings of denial, guilt, blame, frustration, lack of understanding, and indifference. Educational services should include reducing stress by improving coping skills. These include an understanding of developmental changes with aging (Chez, 1999). Knowledge of the progression, prognosis, and treatment of disease may ease the caregiver’s anxiety (Nerenberg, 2002). Caregivers should also be educated on the importance of receiving treatment for mental health and substance abuse (Jones et al., 1997). The patient and caregiver should both be informed on what is considered abuse and the laws/regulations on elder abuse. Knowing these laws may stop some caregivers from becoming abusers (Chez, 1999). A vital step in preventing caregiver stress and burnout is ensuring that caregivers are made aware of the various resources available to them. Numerous materials, fact sheets, brochures, articles, courses, and websites provide information and training to caregivers. Fifteen states have comprehensive state-funded caregiver support programs. These programs offer respite care and referral sources, family consultation, support groups, care management, education, and training. In 2000, the Older Americans Act Amendments enacted the National Family Caregiver Support Program (NFCSP), which increased the amount of support services available to informal caregivers. Another helpful resource for elder caregivers is the support group. These groups are organized by both private and public sponsors and provide an environment for caregivers to meet and discuss the difficulties associated with caring for elderly patients. These groups help caregivers understand the behaviors that frustrate them, identify their “triggers,” and instruct them on stress-reducing practices. Caregivers learn to work through the negative feelings they have about their roles in caring for the elderly (Nerenberg, 2002).

programs provide temporary care for several days in residential care facilities, nursing homes, or hospitals (Nerenberg, 2002).

Respite care Respite care is another intervention to prevent burnout and stress in caregivers and is a central part of the social policy enacted to help prevent elder abuse. Respite care provides relief or rest for informal caregivers and reduces stress (de la Cuesta-Benjumea, 2010). Numerous respite services are available to caregivers. Included in some of these programs are volunteers or employees who provide relief to the caregivers. Adult day care centers also give elders opportunities to participate in social, recreational, or therapeutic programs. Other

Summary

Case management Case management is a model for providing services that was developed for persons with various medical and social needs. A case manager performs comprehensive “functional assessments” on patients to determine the types of interventions and assistance they require. They then help coordinate the patient’s care, assisting the patient and the family in accessing the resources and services they require (Table 30.3). They closely monitor the patient and intervene as necessary (Nerenberg, 2002).

Table 30.3 Addressing caregiver burnout Risk factors for caregiver burnout

Caregiver resuscitation

Caregiver unclear on patient prognosis and expectations for disease progression Caregiver lack of financial resources Caregiver lack of social support and respite Patient with significant behavioral, cognitive, or physical disabilities

Regular evaluation of situation by provider Financial resources optimized Respite care coordination Optimization of medication, treatment, and assistant devices

Source: Hohler (2010).

Future directions Researchers can contribute to the current understanding of caregiver stress and its relationship to abuse in the following ways. 1 Improve the reliability and validity of studies on the relationship between caregiver stress and elder abuse. 2 Conduct research on the impact of providing support to caregivers and its effect on EM, and identifying effective caregiver coping strategies (Nerenberg, 2002).

Abuse is a common problem in the elderly that will likely increase as the population ages. By providing education to caregivers and the abused, improving identification of abuse, and intervening in EM cases, physicians act as advocates for the elderly patient. Physicians should take on the role of empowering elders to advocate for themselves and to protect their rights (Daichman et al., 2010). Research is needed in this field to improve our understanding of the development and prevention of EM.

Elder Abuse and Mistreatment

Vignettes Case 1 A 75-year-old woman is brought to the emergency department (ED) from her nursing home for fever. She has a history of a left middle cerebral artery stroke with right-sided weakness and mild aphasia. On examination, she reports that she lies in bed most of the day, as the nursing home is understaffed. She requires assistance to get to the bathroom and is not always able to get help. She has frequent accidents as a result. She complains of pain on her backside. The attending ED calls the facility, where they report that she has had fever, confusion, and agitation for the past 3 days. When asked to clarify her medications, the nurse reports that she has missed several doses of her BP meds. The nurse reports that she has been in bed most of the day for the past 2 weeks because “it takes a lot of work to sit her up and walk her.” BP is 210/90, HR is 110, and is febrile. On examination, the patient is alert and oriented to person and place, but has difficulty with the date. She has some difficulty remembering her medications but thinks they may have been missed on several occasions. She is able to follow commands but has some difficulty with attention. She has some difficulty with naming and slowness with repetition. She is noted to have right-sided weakness of her face and arm, with some increase in tone on the right. She is able to stand with assistance. A stage 4 decubitus ulcer is noted on her backside that appears infected. This patient is suffering from neglect. She is missing her medications and is not being assisted in her toileting. As a result, she is hypertensive and has a decubitus ulcer that is infected. The ED staff should document the situation, including the call to the nursing home, and should contact the ombudsman to report the nursing facility. Case 2 An 82-year-old Parkinson’s patient is dropped off in the ED by her son. She is an accurate historian, with no evidence of dementia or delusions. She lives with her son, who is her primary caretaker. Her son controls the finances and does not provide her with enough care and supervision at home. She is left to sit much of the day, without assistance to the bathroom. She has fallen numerous times and sustained a recent contusion to the head. She reports that her son yells at her and tells her to clean herself and fix her own meals. He provides minimal gait assistance, stating that she needs to “learn how to walk.” He has witnessed many falls and does not assist her. Her Parkinson’s disease symptoms are progressing rapidly. This case illustrates how neglect can have a direct impact on the physical health of the patient. A thorough discussion with the patient about neglect is imperative, and an investigation by elder protective services is required. This

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patient will need to be cared for in an environment where her physical and emotional needs can be met.

Case 3 An 85-year-old male is brought to the ED for a fall. He is experiencing impaired cognition and difficulty ambulating. He reports that his son pushed him in the house during an argument; he fell and hit his head. His son reports that the patient was being loud and was frustrating him, and he wanted him to be quiet. The patient has moderate Alzheimer’s disease. The patient has a head CT scan performed that reveals a right subdural hemorrhage. This case illustrates physical abuse that is likely a result of caregiver burnout. The case should be reported to Elder Services, and the caregiver should be counseled about burnout and given resources and education. The patient should be transferred to a safe environment.

Appendix Additional screening instrument Hwalek-Sengstock Elder Abuse Screening Test (H-S/ EAST) (Hwalek et al., 1991) 1 Do you have anyone who spends time with you, taking you shopping or to the doctor? 2 Are you helping to support someone? 3 Are you sad or lonely often? 4 Who makes decisions about your life, such as how you should live or where you should live? 5 Do you feel uncomfortable with anyone in your family? 6 Can you take your own medication and get around by yourself? 7 Do you feel that nobody wants you around? 8 Does anyone in your family drink a lot? 9 Does someone in your family make you stay in bed or tell you, you are sick when you know you are not? 10 Has anyone forced you to do things you did not want to do? 11 Has anyone taken things that belong to you without your consent? 12 Do you trust most of the people in your family? 13 Does anyone tell you that you give them too much trouble? 14 Do you have enough privacy at home? 15 Has anyone close to you tried to hurt you or harm you recently?

Resources For those being abused National Center on Elder Abuse 302-831-3525 www.ncea.aoa.gov

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For healthcare professionals American Academy of Neurology online CME training “Recognizing Abuse in Your Neurology Patients” w w w. a a n . c o m / e d u c a t i o n / w e b c m e / i n d e x . c f m ? event=program:info&program_id=5 CDC Elder Maltreatment www.cdc.gov/violenceprevention/eldermaltreatment/ National Institute of Justice/Elder Abuse http://www.ojp.usdoj.gov/nij/topics/crime/elderabuse/welcome.htm For caregivers ThisCaringHome.org www.thiscaringhome.org

References Ahmad, M. and Lachs, M. (2002) Elder abuse and neglect: what physicians can and should do. Clev Clin J Med, 69 (10): 801–808. Alper, K., Devinsky, O., et al. (1993) Non-epileptic seizures and childhood sexual and physical abuse. Neurology, 43 (10): 1950–1953. American Medical Association. (1982) Diagnostic and Treatment Guidelines on Elder Abuse and Neglect. Chicago: American Medical Association. American Psychological Association. (2003) Elder Abuse and Neglect: In search of solutions. www.apa.org/pi/aging/resources/guides/ elder-abuse.aspx [accessed on August 24, 2010]. Boston Medical Center. (2009) Victims of abuse/neglect and mandatory reporting. Policy, 3: 16. Campbell, J.K., Penzien, D.B., et al. (2000) For the U.S. Headache Consortium. Evidenced-based guidelines for migraine headache: Behavioral and physical treatment. www.aan.com. Chez, R. (1999) Elder abuse, the continuum of family violence. Prim Care Update Ob Gyns, 6 (4): 132–134. Cooney, C., Howard, R., et al. (2006) Abuse of vulnerable people with dementia by their carers: can we identify those most at risk?. Int J Geriatr Psychiatry, 21 (6): 564–571. Cooney, C. and Mortimer, A. (1995) Elder abuse and dementia: a pilot study. Int J Soc Psychiatry, 41 (4): 276–283. Cooper, C., Selwood, A., et al. (2009) The determinants of family carers’ abusive behaviour to people with dementia: results of the CARD study. J Affect Disord, 121 (1–2): 136–142. Cooper, C., Selwood, A., et al. (2008) The prevalence of elder abuse and neglect: a systematic review. Age Ageing, 37 (2): 151–160. Daichman, L., Aguas, S., et al. (2010) Elder abuse. In: V. Patel, A. Woodward, V. Feigin, S. Quah, and K. Heggenhougen (eds), Mental and Neurological Public Health: A Global Perspective. San Diego, CA: Academic Press. de la Cuesta-Benjumea, C. (2010) The legitimacy of rest: conditions for the relief of burden in advanced dementia care-giving. J Adv Nurs, 66 (5): 988–998. Dong, X.Q., Simon, M., et al. (2009) Elder self-neglect and abuse and mortality risk in a community-dwelling population. J Am Med Assoc, 302 (5): 517–526. Fulmer, T., Guadagno, L., et al. (2004) Progress in elder abuse screening and assessment instruments. J Am Geriatr Soc, 52 (2): 297–304.

Glass, N., Dearwater, S., et al. (2001) Intimate partner violence screening and intervention: data from eleven Pennsylvania and California community hospital emergency departments. J Emerg Nurs, 27 (2): 141–149. Halphen, J. and Dyer, C. (2010) Elder mistreatment: abuse, neglect, and financial exploitation. UptoDate.com website. Hightower, J. (2010) Abuse later in life: when and how does gender matter? In: G. Gutman and C. Spencer (eds), Aging, Ageism and Abuse: Moving from Awareness to Action, pp. 17–29. Vancouver, Canada: Elsevier. www.elsevierdirect.com/ISBN/9780123815088/ Aging-Ageism-and-Abuse [accessed on August 24, 2010] Hohler, A. (2010) Abuse and Violence in Neurological Care. www. bu.edu/parkinsonsdisease/ [accessed on August 24, 2010]. Hwalek, M.A., Scott, R.O., et al. (1991) Validation of the HwalekSengstock abuse screening test. J Appl Gerontol, 10 (4): 406–418. Jayawardena, K.M. and Liao, S. (2006) Elder abuse at end of life. J Palliat Med, 9 (1): 127–136. Jones, J.S., Holstege, C., et al. (1997) Elder abuse and neglect: understanding the causes and potential risk factors. Am J Emerg Med, 15 (6): 579–583. Lindbloom, E.J., Brandt, J., et al. (2007) Elder mistreatment in the nursing home: a systematic review. J Am Med Dir Assoc, 8 (9): 610–616. Mass.Gov. (2010) Protective Services Program. www.mass.gov/? pageID=eldersterminal&L=2&L0=Home&L1=Service+Organiz ations+and+Advocates&sid=Eelders&b=terminalcontent&f=pr otective_services&csid=Eelders> [accessed on August 24, 2010]. National Center on Elder Abuse. (1996) National Elder Abuse Incidence Study, Executive Summary. This Informational report was researched and written by Toshio Tatara, Ph.D. and Lisa M. Kuzmeskus, M.A. for the National Center on Elder Abuse Grant No. 90-am-0660 Washington, DC: National Center on Elder Abuse (update by the National Center on Elder Abuse, March, 1999) National Center on Elder Abuse About Adult Protective Services. (2010) www.ncea.aoa.gov/ncearoot/Main_Site/Find_Help/ APS/About_APS.aspx [accessed on August 24, 2010]. National Committee for the Prevention of Elder Abuse (NCPEA). (2010) www.preventelderabuse.org/ [accessed on August 24, 2010] Nerenberg, L. (2002) Caregiver Stress and Elder Abuse, NCEA. Washington, D.C.: Institute on Aging. Pillemer, K. and Moore, D.W. (1989) Abuse of patients in nursing homes: findings from a survey of staff. Gerontologist, 29 (3): 314–320. Shaw, M.M.C. (1998) Nursing home resident abuse by staff: exploring the dynamics. J Elder Abuse Negl, 9 (4): 1–21. Swagerty, D. and Brickley, R. (2005) American Medical Directors Association and American Society of Consultant Pharmacists joint position statement on the Beers List of Potentially Inappropriate Medications in Older Adults. J Am Med Dir Assoc, 6 (1): 80–86. Swagerty, D.L. Jr., Takahashi, P.Y., et al. (1999) Elder mistreatment. Am Fam Physician, 59 (10): 2804–2808. Tarbox, A. (1983) The elderly in nursing homes: psychological aspects of neglect. Clin Gerontol, 1 (4): 39–52. Tatara, T. (1990) Summaries of National Elder Abuse Data: An Exploratory Study of State Statistics Based on a Survey of State Adult Protective Service and Aging Agencies. National Aging Resource Center on Elder Abuse (NARCEA). www.ncea.aoa.gov/ main_site/library/cane/CANE_Series/CANE_EAScope.aspx Tietjen, G.E., Brandes, J.L., et al. (2007) History of childhood maltreatment is associated with comorbid depression in women with migraine. Neurology, 69 (10): 959–968. Utley, R. (1999) Screening and intervention in elder abuse. Home Care Provid, 4 (5): 198–201.

Chapter 31 Advocacy in Geriatric Neurology Glenn Finney1 and Anil K. Nair2 1 2

Department of Neurology, McKnight Brain Institute, Gainesville, FL, USA Clinic for Cognitive Disorders and Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA

Summary • Initial milestones for senior advocacy include the creation of social security, the establishment of the AARP (American Association of Retired Persons), and the passage of Medicare. • Prominent patient advocacy organizations include The American Heart Association, The National Parkinson Foundation, Parkinson’s Action Network, and The Alzheimer’s Association. Advocacy for elder abuse is also developing. • The federal legislative process is reviewed. • Learning about your legislators’ backgrounds and beliefs as well as thoroughly researching your legislative proposal is essential to successful advocacy. • A list of talking points to consider when meeting with legislature on the topic of geriatric neurology is included.

Introduction Before the twentieth century, most of the elderly in our society were cared for quietly at home by their families. Quiescence, followed by senescence, was the expectation of people as they entered the so-called “golden years.” However, the twentieth century saw a disruption of many of the traditional ways of looking at family and aging, both for good and for ill. The aging of the baby boomer generation at the beginning of the twenty-first century brought to the forefront the efforts of the preceding century in advocacy for and by senior citizens in America. As an increasing percentage of our total population consists of people aged 55 and older, issues of economic security and health become dominant. Many of the changes and actions of the twentieth century have set the stage for senior advocacy in the twenty-first century. This chapter provides a brief overview of some of the highlights of legislative and nongovernmental organization advocacy for the elders of our society.

Beginnings: senior advocacy and social security Advocacy by and for seniors in America is difficult to trace to its beginnings, although the first landmark legislative triumph for the geriatric population could

arguably be the passage of the Social Security Act in 1935. Although various pension schemes had been around as far back as the American Revolutionary War, this landmark piece of legislation was the first program designed to protect the elderly from penury in their senior years. It was a response to sky-high poverty rates of more than 50% among seniors (Patterson, 1981). Some cite President Franklin Delano Roosevelt’s championing of social security as part of the New Deal as the first instance of presidential advocacy for the elderly (Achenbaum, 1986). Frances Perkins, President Roosevelt’s Secretary of Labor, was the chief architect of the plan for social security and was herself in her mid-50s at its passage (Downey, 2009). This part of the New Deal faced head on the growing predicament of a population that was beginning to outlive the traditional age of work and the grave threat of poverty faced by seniors who had made enough through the years for their immediate needs but had nothing left for years—sometimes decades—of retired life. They had no incoming stream of revenue, and their traditional form of supportive care, children and other relatives, was stretched to the breaking point by the widespread financial devastation of the Great Depression. While the national and global economy recovered from the economic upheaval, something about the relationship of family, society, and the elderly fundamentally changed.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Rise of organized senior advocacy: advent of the American Association of Retired Persons

the 1980s on, the more assertive stance that elder advocates assumed in the 1970s remained a part of elder advocacy.

AARP started out as the American Association of Retired Persons. Founded for retired people aged 50 and older, it was designed to advocate on issues for retired seniors. It was formed in 1958 by the retired educator Ethel Percy Andrus, having evolved from Andrus’s National Retired Teachers Association, founded in 1947 (Ohles et al., 1997). In 1999, as part of the organization’s recognition that some seniors continued to work well past 50 years of age; the association changed its name officially to its initials AARP. AARP claims around 40 million members and is one of the largest and best-known senior advocacy organizations in America. This kind of action, with seniors banding together to promote their rights and care for their own needs, was a watershed in elder advocacy. Seniors refused to accept retirement and aging as the end of a productive, active life, but rather sought the rights and the tools to continue being prosperous and active well after the traditional age for such matters.

Elders win prescription drug support

Passage of Medicare: a major geriatric advocacy milestone Multiple attempts to develop a national health insurance program were made throughout the twentieth century, only to fail each time. However, one initiative that did succeed transformed the landscape of health care for the elderly: Medicare. Enacted through the Social Security Act of 1965 as part of President Lyndon Baines Johnson’s Great Society program, Medicare was the first program to provide comprehensive health coverage for senior citizens. The bill was signed into law at the Truman Library, with former President Harry S. Truman and his wife in attendance; the Trumans then received the first Medicare cards, in recognition of the President’s leadership in health care during his presidency (Centers for Medicare & Medicaid Services History).

The rising of rights movements The 1970s saw several advocacy movements come to the fore of American life. On the elder front, 1970 saw the birth of the Gray Panthers, founded by Maggie Kuhn in that year when she was forced to retire at the age of 65 (Centers for Medicare & Medicaid Services). Indeed, a hot topic for senior advocacy throughout the 1970s was the fight against age discrimination, especially in the workplace. This new militancy and legally aggressive stance by the aged reflected the zeitgeist of the late 1960s and 1970s. Although the approach of advocacy groups mellowed appreciably from

Medicare’s ability to provide health care was greatly augmented by the passage of the Medicare Prescription Drug, Improvement, and Modernization Act, signed into law by President George Walker Bush on December 8, 2003. Although this act significantly expanded coverage for care to seniors, the budgetary compromises required to gain passage of the bill left a “donut hole” in which seniors were often forced to pay thousands of dollars a year for prescription drugs. This problem was exacerbated by the dissolution of previously offered prescription drug plans for the elderly in favor of the so-called Part D plans (referring to the prescription drug benefit’s designation as Part D of Medicare). Physicians and seniors often struggled to find ways to cover the last several months’ worth of medications as the end of the year slowly came. Some pharmaceutical companies provided relief for patients in the donut hole, but these often were strictly limited by finances, making them no real solution to the problem. However, seniors continued to advocate for closing the donut hole. On March 23, 2010, President Barack Hussein Obama signed the Patient Protection and Affordability Care Act of 2010 (PPACA), which included a number of provisions designed to gradually close the donut hole for prescription drugs for seniors.

Ongoing areas of Medicare advocacy in 2010 Closing the prescription “donut hole” remains a large part of the present elder advocacy activities (Brown, 1998). Other elder advocacy issues that are commonly championed in relation to Medicare are access to care, especially ensuring availability and lack of barriers to specialty care or care by a physician of the elder’s choice, and control of premiums on Medicare that are financially hazardous to seniors on a fixed income. Another rising area of advocacy interest is provision of a long-term care benefit for seniors requiring skilled nursing care.

Patient advocacy organizations Formed during the twentieth century, most of the prominent patient advocacy organizations addressing diseases of aging started with mandates for education and research into the diseases afflicting the elderly. Over time, many branched out into patient outreach and services and, of course, became more active in advocating to state

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and federal governments for the needs of seniors afflicted with or at risk for these diseases.

Have a heart One of the earliest examples of a patient advocacy organization dealing with a disease that disproportionately strikes the elderly is the American Heart Association (AHA). Founded in New York City in 1915 as the Association for the Prevention and Relief of Heart Disease, its main purpose at the time was to redress ignorance and change perception of heart disease. At that time, heart disease was viewed as unavoidable, and the only treatment was believed to be bed rest. The AHA made great strides over the many decades of its existence. In the mid 1990s, it focused on the challenge of stroke by forming a new division, the American Stroke Association. The dedication of the AHA to stroke prevention became perhaps most evident with its selection of a neurologist, Ralph L. Sacco, MD, MS, FAAN, FAHA, as its president-elect in 2009 (American Heart Association). The American Stroke Association partners with many other organizations in its efforts, including the American Academy of Neurology.

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known as the Alzheimer’s Association. The Alzheimer’s Association has several advocacy avenues for seniors and those who care for them, including a yearly Alzheimer’s Health Policy Forum in Washington, D.C. (Alz.org.). Another active Alzheimer’s patient advocacy group is the Alzheimer’s Foundation of America, which was founded as a consortium of organizations to ensure quality of care and excellence in service for Alzheimer’s disease (Alzheimer’s Foundation of America).

Emerging threat to elderly: elder abuse An emerging area of senior advocacy is in the area of elder abuse. At the turn of the century, in part because of the aging of the baby boom generation, it became more obvious that some seniors were being abused by caregivers, often spouses or adult children, but sometimes other care providers (Cooper et al., 2008). Health-care education and provision of resources through the US government’s Administration on Aging have been the front line of advocacy on this sensitive issue, but more is likely to develop in future.

The federal legislative process: how a bill becomes a law

Senior advocacy on the move The National Parkinson Foundation (NPF) is one of the oldest patient advocacy groups to address diseases of the elderly—in this case, Parkinson’s disease and related disorders. Founded sometime before 1957 by Mrs. Jeanne C. Levey in Dade County, Florida, the foundation lost its original charter in a flood of the Dade County Courthouse. The NPF subsequently received a state charter in Florida in 1957, which the organization uses as its official year of incorporation (Parkinson.org.). In 1991, Joan Samuelson founded a new network to specifically advocate for more attention from the federal government for Parkinson’s disease, the Parkinson’s Action Network (PAN). It has been an active advocacy group for this disease that impacts a disproportionate number of seniors and has teamed up in the past both with other patient advocacy groups and with the American Academy of Neurology (Parkinson’s Action Network PANs History).

Elder advocacy on my mind The neurodegenerative disease that affects the largest number of elders is Alzheimer’s disease. The first patient advocacy group for Alzheimer’s disease was incorporated on April 10, 1980, under the name of the Alzheimer’s Disease and Related Disorders Association. It later came to be

Although Article One of the US Constitution establishes and defines the legislative branch of the federal government, it does not specify an exact protocol for creating laws. Instead, the two chambers of Congress—the House of Representatives and the Senate—have come to develop and use a very similar process for passing bills into laws. Along each step of this process, numerous opportunities arise to defeat a bill. Simple inaction can (and often does) “kill” a bill. Once a bill has been defeated, it cannot be reintroduced to Congress until the next congressional session. Notably, only 10% of bills introduced to Congress even make it out of committees for a full chamber vote, and only 5% of the total bills introduced become laws, although congressional productivity varies considerably year to year. The Process (House and Senate) • Only a member of Congress may introduce a bill. A sponsor introduces a bill; additional members may sign on as cosponsors. • Bills are referred to committees and subcommittees with jurisdiction over the bill subject. Because committees conduct research and hold hearings on the bills referred to them, they also represent a prime opportunity for advocacy involvement. • The House and the Senate have very different floor protocols. In the House, for example, discussion per legislator is

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often limited and must be germane to the bill at hand. In the Senate, however, entire bills can be amended to other bills. Bills may also be filibustered—that is, one senator can talk about a bill until time runs out, thereby “killing” the bill. • Conference committees consist of legislators from both the House and the Senate. Bills are sent to a conference committee when both chambers approve different versions of the same bill. After a conference committee reconciles the differences, the bill is sent back to both chambers for a final vote, but it can be amended. • A bill passed by both the House and the Senate then becomes a law if the president signs it. If the president vetoes a bill, that bill may still become a law if a two-thirds majority in both chambers votes to override the veto. A pocket veto occurs when the president does not sign the bill within ten days and Congress adjourns during that time. A pocket veto cannot be overridden. • A bill may be “killed” at any point during this process. A bill makes it to the next step only if it has survived or bypassed the previous one.

Keys to effective advocacy Learn about your legislators Before meeting with your members of Congress, it is best to learn about their background, political beliefs, and top issues. Learn your legislator’s background • Visit congress.org or similar websites to gather information about offcials. • Each legislator’s profile contains the following information: Length in office Residence Marital status Previous occupation Previous political experience Education Age Birthplace Religion Percentage of votes received in their last election Washington, D. C., address Local office address Current committee appointments • Take the time to review all this information, as it may be crucial to making a lasting connection during your visit. Note: The AHDA finds the biographical information supplied by www.congress.org to be useful but does not endorse the editorial content posted on this website. Learn your legislator’s political beliefs and top issues One of the best ways to learn about your members of Congress is to review their official website. A Google search of

their name typically finds the right website. If not, you can search using the appropriate link below: • US House of Representatives: www.house.gov On the website, the “Search for your legislator by zip code” function is located in the top-left corner of your screen. • US Senate Select your state using the “Find Your Senators” dropdown menu in the top-right corner of your screen. • Official websites for members of Congress are geared toward informing their constituents about their top issues and promoting past successes. To be an effective advocate, one has to reach the listener and make the audience care enough to take the action you want. An advocate should also understand the context and follow the rules of the legislative process, including no harsh words, surprises, or assumptions. In speaking with a legislator, start with common ground. Demonstrate passion and commitment to the issues, and be both credible and knowledgeable about the issue.

Effective advocacy during a legislative visit Legislative visits offer a more substantial opportunity to present a case for your issue. For that reason, legislative advocacy requires a bit more preparation. The first step is to understand what legislative outcome your action plan requires. Are you trying to get a new legislation passed? Are you asking for funding? Are you trying to modify an existing proposal or law? When you know what you are trying to achieve, you need to do some research. Are other individuals or groups interested in the same objective? Can you support existing legislation? Have other efforts been undertaken in the past? It is important to assess potential partnerships and know the context in which you will be making your request. When you know what you want and have done your research, the next step is to know how your local system of government works so that you direct your efforts appropriately. After you have identified your legislative targets, you are ready to get to work! You have many media for communicating your request—phone, e-mail, letters, faxes, and in-person meetings. It is important to consider which medium will best communicate your point while making the best use of your own time. Sometimes a quick phone call or e-mail is ideal. At other times, it may be worthwhile to meet with your legislator in person. Whatever your course, use the following resources to help you. If you live outside the United States, you may need to spend some additional time researching your own state or national system to determine where legislative advocacy is appropriate. In addition, many of these techniques may work in other settings (educational systems, medical and academic centers, and so on) where direct advocacy is needed.

Advocacy in Geriatric Neurology

Being an effective advocate depends on being professional, courteous, positive, direct, clear, concise, factual, credible, and specific. Always do your homework. Find out where a bill is in the legislative process. Always follow up with information you have promised. Visit or call a legislator with an offer to be of assistance in the future. Follow the KISS rule: keep fact sheets, letters, and testimony short. Be sure to include contact information on fact sheets and letters. Stay in contact with your legislator—it is the key to establishing a relationship of mutual trust. Treat members of the legislature as friends and intelligent citizens. Attend legislative hearings, committee meetings, budget mark-up sessions, and floor votes on your issues, if appropriate. Always, always be truthful and reasonable, and realize that everyone thinks their issue is the most important one being considered. Thank legislators for meeting with you and for their consideration, even if your comments are not well received. Treat members of the legislature as you would like to be treated. It is common sense what not to do at these visits. Do not give inaccurate information or purposely lie. Never be rude to a legislator and/or his or her aide. Do not make moral judgments based on a vote or an issue. Do not hold grudges or be argumentative or abrasive. Do not interrupt when someone is obviously busy. Do not cover more than one subject in a contact unless asked. Do not blame legislators for all the things that go wrong in government. Do not be offended if someone forgets your name or who you are, even if it is just 5 minutes after your visit.

Talking points Use the same key messages you would for press contacts when you have the opportunity to meet with a legislator and/or his or her staff. Unlike a media interview, however, legislative visits offer a more substantive opportunity to present a case for your issue. For that reason, legislative advocacy requires a bit more preparation. Have talking points memorized when you meet a legislator. Talking points to consider when meeting government officials about geriatric neurologic care are legion. The main points are summarized next.

Geriatric neurology talking points Congress should appropriate more funds for geriatric neurology: • To improve the integration and coordination of geriatric neurology, mental health, and rehabilitative services • To provide specialized geriatric care, especially including the development of primary geriatric neurology centers at the federal and state levels • For community-based research in geriatric neurology, with emphasis on clinical research based on the community for prevention and treatment, including exploration into the causes of geographic and racial disparities in geriatric neurologic care delivery

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• To improve reimbursement practices for geriatric neurologic care (particularly on-call reimbursement for neurologists) to promote specialized care. Congress should promote public awareness campaigns regarding geriatric neurologic diagnosis, prevention, and treatment. Congress should support public and professional education regarding geriatric neurologist as a primary or principal care provider for the elderly. Neurologists receive training in the delivery and interpretation of diagnostic imaging tests. Neurologists are the experts in the clinical use of neuroimaging, receiving extensive training in the anatomy, physiology, and pathology of the nervous system. Based on this training and daily clinical experience, neurologists are in the best position to define and interpret appropriate neuroimaging studies. Neurologists provide their patients with high-quality imaging and diagnosis. No credible evidence indicates that imaging by neurologists is being conducted inappropriately or is resulting in inaccurate diagnoses. In fact, a study reported in the Journal of the American Medical Association (JAMA) in April 1998 showed that neurologists were asked to interpret computed tomography (CT) scans for signs of stroke performed as well as radiologists. Restricting neurologists’ diagnostic testing privileges would reduce patient access to timely, convenient testing, and disrupt the important continuity of care. The American College of Radiology (ACR) asserts that there is a shortage of radiologists. In certain parts of the country, patients already face long waiting periods for critical imaging studies. Restricting neurologists’ ability to provide imaging services could substantially aggravate this problem, resulting in significant delays and reduced quality of care. Restricting imaging self-referral access will not lower health care costs. JAMA published a study in September 1995 showing that reduced reimbursement for self-referred services did not result in a lower rate of self-referral. Even though physicians received less money for their services, they continued to provide the tests—because their patients needed the service, regardless of the price. National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) has greatly aided in the understanding and treatment of neurologic disorders. Since Congress doubled funding for NIH, NINDSsupported research has led to the identification of more than 100 genes associated with neurologic diseases.

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Therapeutic strategies based on gene discoveries that are already moving into human clinical testing include ones for ALS, Huntington’s disease, ataxias, and muscular dystrophy. Recent NIH/NINDS appropriations have severely impaired its ability to sustain these advances. Federal research funding has been inadequate for some disabling neurologic disorders. For example, funding has been especially poor for migraine and other primary headache disorders when considering disease prevalence, disease-associated disability, and disease-associated economic burden. Migraine afflicts 36 million Americans. One in 25 Americans experiences prolonged headaches 15 or more days per month. Few federal expenditures have paid off more than support of the NIH and NINDS. A recent comprehensive review of all Phase III clinical trials supported by the NINDS found that, estimated conservatively, the economic benefit in the United States from just eight of these trials exceeded $15 billion over the course of 10 years. The study also found that new discoveries from the trials were responsible for an estimated additional 470,000 healthy years of life. These programs prove their worth every day. Congress should increase NIH funding. This is the amount authorized by Congress when it reauthorized the NIH in 2006. Funding is also needed to complete Phase II of the Porter Neuroscience Research Center. Even with recent funding issues, the NIH continues to streamline and improve research efforts. Examples include Phase I of the John Edward Porter Neuroscience Research Center, which houses neuroscientists from 11 NIH Institutes and Centers that have intramural neuroscience programs.

Sustainable growth rate talking points Physicians are the only providers subject to the Medicare Sustainable Growth Rate (SGR). The SGR cuts payments to physicians if growth in Medicare patients’ use of services exceeds the annual growth in the US gross domestic product (GDP). Medicare payments have not kept pace with physician costs since 2001. Multiple studies have shown that physician acceptance of new Medicare patients is declining. Further

cuts in annual updates will result in physicians taking fewer new Medicare patients and fewer physicians participating in Medicare. Both of these effects will have a negative impact on access to care for Medicare beneficiaries. Ask to support legislation to avert pending Medicare physician payment cuts. Ask the legislator to support the MedPAC’s recommendation that Medicare physician reimbursement be based on the Medical Economic Index, which measures annual practice cost increases. Paying physicians according to the actual costs associated with treating patients is necessary to maintain consistent access to providers. The AAN also asks that the policy of including the cost of physician-administered drugs in the SGR be eliminated, as these drugs are clearly not “physician services” as defined by the law.

References Achenbaum, A. (1986) Social Security Visions and Revisions. New York: Cambridge University Press. Alz.org. About Us. www.alz.org/about_us_about_us_.asp. Alzheimer’s Foundation of America. About AFA. www.alz.org/ about_us_about_us_.asp (accessed on September 01, 2012). American Heart Association. History of the American Heart Association. www.americanheart.org/presenter.jhtml?identifier=10860 (accessed on September 01, 2012). Brown, D. (1998) Senior power. Social Policy, 28 (3): 43–45. Centers for Medicare & Medicaid Services. History. www.cms. gov/History/ (accessed on September 01, 2012). Centers for Medicare & Medicaid Services. Prescription Drug Coverage—General Overview. www.cms.gov/PrescriptionDrugCovGenIn/01_Overview.asp (accessed on September 01, 2012). Cooper, C., Selwood, A. and Livingston, G. (2008) The prevalence of elder abuse and neglect: a systematic review. Age Ageing, 37 (2): 151–160. Downey, K. (2009) The Woman Behind the New Deal: The Life of Frances Perkins, FDR’s Secretary of Labor and His Moral Conscience. New York: Nan A. Talese/Doubleday. Ohles, F., Ohles, S.M. and Ramsay, J.G. (1997) Biographical Dictionary of Modern American Educators. Westport, CT: Greenwood Publishing Group. Parkinson.org. History and Network. www.parkinson.org/AboutUs/History-and-Network (accessed on September 01, 2012). Parkinson’s Action Network PAN’s History. www.parkinsonsaction.org (accessed on September 01, 2012). Patterson, J.T. (1981) America’s Struggle Against Poverty, 1900--1980. Cambridge, MA: Harvard University Press.

Index

α-synuclein 209, 314–315, 320 AAION see arteritic anterior ischemic optic neuropathy AAMI see age-associated memory impairment AARP see American Association of Retired Persons AARS see Apparent Affect Rating Scale abnormal motor movements 80 abstract thinking 92 acamprosate 607 ACC-001 580 acetylcholinesterase inhibitors (AChEIs) 352, 508, 557–558, 561–564 ACI-24 581 acoustic neuroma 533 acquired immunodeficiency syndrome see HIV/AIDS acquired neuropathies 501–507 ACS see delirium activities of daily living (ADLs) Alzheimer’s disease 201 driving impairment 688 mild cognitive impairment 188 acute angle-closure glaucoma 406, 491 acute confessional state 303–304 acute confusional state (ACS) see delirium acute inflammatory demyelinating polyradiculoneuropathy (AIDP) 501–502 acute intracranial thrombotic stroke 530 acute motor sensory axonal neuropathy (AMSAN) 501–502 acute symptomatic seizures 373 acute viral encephalitides 464–465 acyclovir 432 AD see Alzheimer’s disease AD8 screening interview 91, 94–95 adenocarcinoma 533 ADLs see activities of daily living

ADPKD see autosomal dominant polycystic kidney disease Adult Protective Services (APS) 701, 702 advanced glycation end products (AGEs) 10, 13–14, 30 advocacy 706–711 Alzheimer’s disease 708 American Association of Retired Persons 707 American Heart Association 708 concepts and definitions 706 diagnostic testing 710 elder abuse and mistreatment 708 federal legislative process 708–709 historical development 707 keys to effective advocacy 709–711 learning about legislators 709 legislative visits 709–710 Medicare and Medicaid 707, 711 NIH/NINDS support 710–711 Parkinson’s disease 708 patient advocacy organizations 707–708 prescription drug support 707 senior advocacy and social security 706 sustainable growth rate 711 talking points 710–711 understanding and treatment of neurologic disorders 710–711 AEDs see antiepileptic drugs affect assessment 88, 92–93 affitopes 580–581 age-associated memory impairment (AAMI) 187 age-related macular degeneration (AMD) 75, 403–404 AGEs see advanced glycation end products aggression Alzheimer’s disease 201 behavioral problems 619–620 psychopharmacology 591–592

aging ancient versus modern environments 28–31 antagonistic pleiotropy 4, 8 apoptosis 15 autophagy 10, 14–15 brain size and neuronal loss 38–39 brain tumors 58–61 cardiovascular disease 24–26 cellular senescence 15–16 central nervous system infections 474 cerebrovascular disease 5, 23, 40, 42, 52–56, 301–302 cognitive changes in aging 28 cognitive reserve 123 concepts and definitions 3–5, 37–38 dementia and cognitive impairment 26–27, 40–52 demographic shifts 6–7 depression 295–297, 298 dietary or calorie restriction 4–5, 9–10, 15, 17–23, 32 diseases of aging 5–6, 24–32 disposable soma theory of aging 8–9 driving impairment 682–684 economic impacts 6–7 endocrine dyscrasia 16–17 evolutionary perspectives 4, 7–10, 17–18, 28–31 exercise and lifestyle 22–23, 669, 674–675 existential aspects of aging 298 expressive art therapies 628–629 functional changes to nervous system 37–67 gait disorders 127–128 genetic theories 9–10, 19 glycation, AGEs and AGE receptors 10, 13–14, 30 health care implications 3–36 historical perspectives 7–10

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

713

714

Index

aging (Continued) immunosenescence 474 infections and inflammation of the CNS 62–63 inflammation 13 lifestyle perspectives 5, 22–23, 28–31, 32 macroscopic changes 40 microscopic vascular pathology 40 mitochondria 10–13 mortality rates 5–6, 9 movement disorders 27–28, 56–58 normal aging and disease 38, 39–40 obesity 5, 23 oxidative stress 4, 9, 10–13 pharmacodynamics 590 pharmacokinetics 586–590 phenotypes of aging 10–17 polyphenols 23–24 prevention of diseases of aging 6–7, 32–33 promotion of diseases of aging 28–32 psychopharmacology 584, 586–590 sarcopenia 15 sensory disorders 395–396, 400 sleep disorders 348 synaptic and dendritic changes 39 trauma 63 vertigo and dizziness 378 white matter changes 39 agitation 591–592 agoraphobia 602 agraphias 91–92 AHA see American Heart Association AHEI see Alternate Healthy Eating Index AICA see anterior inferior cerebellar artery AIDP see acute inflammatory demyelinating polyradiculoneuropathy AIDS see HIV/AIDS AION see anterior ischemic optic neuropathy alcohol dependence 606–607 diet and nutrition 649, 652, 657 gait disorders 131 withdrawal 607–608 alprazolam 600 ALS see amyotrophic lateral sclerosis Alternate Healthy Eating Index (AHEI) 653 Alzheimer’s disease (AD) 200–207 advocacy 708 aging 26–27, 39–40, 41–43 amyloid hypothesis 572–581 amyloid imaging 162–168

behavioral problems 615–616, 622–623 biomarkers 204 changes in normal aging 39–40 clinical features and diagnostic evaluation 200–203 clinical laboratory investigations 172, 173, 202 cognitive reserve 118–120, 122–123 concepts and definitions 184–185, 200 cortical atrophy 140–141 delirium 477–478 depression 297 diagnostic criteria 42–43, 202–205, 555 diet and nutrition 645, 646–651 differential diagnosis 189–195, 201, 203–205, 208, 212–213, 245, 283–285, 334–335 driving impairment 685–686, 688, 693 elder abuse and mistreatment 704 epidemiology 205 epilepsy 370 evidence-based pharmacologic treatment 555–560 exercise and lifestyle 667–671, 673–675, 676 expressive art therapies 630–639 functional imaging 146–156 genetics 205–206 hippocampal atrophy 138–140 immunotherapy 554, 572–583 macroscopic appearance 41 medical foods 560 microscopic findings 41–42 neurologic examination 201–202 neuropsychology 111 olfactory disorders 440 preclinical stage 203 primary prevention or treatment 556–557 prodromal features 195 secondary prevention or treatment 555, 557–560 sleep disorders 351–352 structural neuroimaging 138–141 symptomatic therapy 557–558 symptoms 200–201 ventricular enlargement 141 visual disorders 419 white matter changes 141 amaurosis fugax 406–407 aMCI see amnestic mild cognitive impairment AMD see age-related macular degeneration American Association of Retired Persons (AARP) 707 American Heart Association (AHA) 708

amnestic mild cognitive impairment (aMCI) aging 44, 48 amyloid imaging 164, 167 concepts and definitions 184, 187, 189–190 diagnostic criteria 188, 191 gait disorders 127 predictors of outcomes 193–195, 196 structural neuroimaging 140–141 treatment 195 AMPK signalling pathway 18–21 AMSAN see acute motor sensory axonal neuropathy amyloid hypothesis amyloid-β plaques and neurofibrillary tangles 39–40, 41–42 exercise and lifestyle 668–669 immunotherapy 572–581 amyloid imaging 137, 162–169 biomarkers 162–163 (11)C labeled agents 137, 163 case studies 165–167 concepts and definitions 137, 162–163 (18)F labeled agents 137, 164–165 mild cognitive impairment 192 amyloid precursor protein (APP) 206, 572 amyotrophic lateral sclerosis (ALS) 493 aging 50–51, 57 diagnostic criteria 494 differential diagnosis 334–335 epidemiology and clinical features 494 neurologic examination 73 treatment and prognosis 494–495 AN1792 573–577 anaplastic astrocytomas 59 aneurysms 519, 521–527 anhedonia 290–291, 295 animal prion diseases 276–277 anosmia 75 anoxic encephalopathy 55 antagonistic pleiotropy 4, 8 antecedent control model 621 anterior inferior cerebellar artery (AICA) 426–427 anterior ischemic optic neuropathy (AION) 408–412 anterior odontoid screw fixation 537–538 anti-amyloid-β 572–581 antibiotics 461–462 antidepressants 593–597 adverse effects and drug interactions 594–595 clinical usage 595–597, 602–603, 607, 609 indications 595 pharmacokinetics and pharmacodynamics 593–594

Index

antiepileptic drugs (AEDs) 374–375 antihypertensive therapy 307 antioxidants aging 11, 12–13, 23–24 diet and nutrition 646–647, 651, 653–654 anti-platelet therapy 307 antipsychotics 590–593 adverse effects and drug interactions 591 clinical usage 591–593 indications 591 pharmacokinetics and pharmacodynamics 590–591 anxiety dementia with Lewy bodies 218 Mental Status Examination 93 Parkinson’s disease 317 Parkinson’s disease dementia 218 psychopharmacology 597–603 anxiolytics 597–603 adverse effects and drug interactions 598–599 clinical usage 599–600, 608 indications 599 monitoring treatment 600 pharmacokinetics and pharmacodynamics 597–598 apathy 93 aphasias neurologic examination 73–74, 89, 91 neuropsychology 103 ApoE see apolipoprotein E apolipoprotein E (ApoE) gene 173, 192–193 apoptosis 15 APP gene 206, 572 Apparent Affect Rating Scale (AARS) 634 aprosodia 73 APS see Adult Protective Services aqueductal stenosis (AS) 281 argyrophilic grain disease 352 aripiprazole 563 arrhythmias 362 art therapy 632–636 arterial spin labeling (ASL) 154, 156 arteriosclerosis 40, 53 arteriovenous malformation (AVM) 522–523 arteritic anterior ischemic optic neuropathy (AAION) 408, 410–412 AS see aqueductal stenosis aseptic meningitides 462–463 ASL see arterial spin labeling aspirin 307, 565 astrocytomas 58–59 astrogliosis 371

ataxia 128, 131, 132 atherosclerosis 26, 40, 52–53 atlantoaxial subluxations 386 attention 90, 101–102 atypical pain 546 audiometry 398, 422, 433–434 auditory agnosia 436 auditory disorders 398–399, 419–436 central hearing disorders 436 cerumen impaction 419–420 clinical laboratory investigations 398 conductive hearing disturbances 419–422 herpes zoster oticus 429–432 neurologic examination 77–78 noise-induced hearing loss 423–425 objective tinnitus 420–421 ototoxicity 432–433 presbycusis 423 sensorineural hearing disturbances 422–436 subjective tinnitus 423, 424, 433–436 sudden deafness 423, 425–428 superficial siderosis 428–429 auditory hallucinations 436 automatic speech 102 autonomic dysfunction 362–363 autonomic failure 318, 319, 362–363 autophagy 10, 14–15 autosomal dominant polycystic kidney disease (ADPKD) 522 AVM see arteriovenous malformation

β-blockers 326–327 β-carotene 646, 654–655 bacterial brain abscesses 466–467 bacterial meningitidis 62, 460–462, 463 BAER see brainstem auditory evoked response balance cerebrovascular disease 302 normal pressure hydrocephalus 282–283 vertigo and dizziness 378–394 ballooned neurons 48–49 bapineuzumab 576–579 basilar impression 386 Bayes’ theorem 171–172 BBB see blood–brain barrier BCB see blood–cerebrospinal fluid barriers BDNF see brain-derived neurotrophic factor behavioral problems 613–627 aggravating factors 617–620 Alzheimer’s disease 615–616, 622–623 antecedent control 621

715

behavior assessment 88 caregiving 619–622 clinical repercussions 614 common behavioral problems 614 concepts and definitions 613 confusion 618 delirium 618 disinhibition 107–108, 201 environmental interventions 621 environmental stressors 619 evidence-based treatment research 622 family/caregiver education and training 621–622 frontotemporal dementia 616–617, 623–624 good care/comfort care model 620 individualized approaches to treatment 622 learning theory 621 Lewy body dementia 616, 623 management techniques 702–703 medication-induced 618 nonpharmacologic treatment 620–624 pain 619 Parkinson’s disease 617, 624 prevalence rates 613–614 primary progressive aphasia 261–262 psychosocial interventions 622 rationale for nonpharmacologic approaches 614–615 unmet needs 620–621 vascular dementia 616, 623 behavioral variant frontotemporal dementia (bvFTD) aging 48 behavioral problems 616–617 clinical features 239–240 clinical–pathologic correlation 244 concepts and definitions 185, 239 diagnostic criteria 246 differential diagnosis 239 functional imaging 151 structural neuroimaging 141 benign paroxysmal positional vertigo (BPPV) 379–381 bent spine syndrome 129 benzodiazepines 597–603, 608, 609–610 BF-227 163 bibliotherapy 637–639 bilateral vestibular loss (BVL) 384–385 Binswanger syndrome 227, 230–231 biometrics 72 blood-oxygenation-level-dependent imaging (BOLD) 154–155 blood–brain barrier (BBB) 459, 474 blood–cerebrospinal fluid barriers (BCB) 459

716

Index

body mass index (BMI) 23 BOLD see blood-oxygenation-leveldependent imaging Bonnet syndrome 413–414, 415–416 botulinum toxin 327–328 BPPV see benign paroxysmal positional vertigo brachial plexopathy 499–500 brain-derived neurotrophic factor (BDNF) 288, 668 brain reserve model 118–120 brain size 38–39 brain tumors see neurooncology brainstem auditory evoked response (BAER) testing 425, 427–428, 434 brainstem strokes 386–388 branch retinal artery occlusion (BRAO) 407–408 Broca’s aphasia 73–74, 103 bupropion 609 burning mouth syndrome 442 burnout 700, 703 buspirone 597–600 bvFTD see behavioral variant FTD BVL see bilateral vestibular loss (11)C labeled agents 137, 163 C-reactive protein (CRP) 175, 176, 411–412 CAA see cerebral amyloid angiopathy CAD-106 581 CADASIL 225, 227–228, 230–231 caffeine 649, 652 calcium 652, 657–658 calculation abilities 92 calorie restriction see dietary or calorie restriction CAM see confusion assessment method camptocormia 316–317 canalolith-repositioning procedures 381 cancer neuromuscular disorders 499–500, 510–511 neurosurgical care 539 see also neurooncology carbamazepine 374–375, 543 cardiac syncope 361–362, 365 cardiovascular disease (CVD) aging 24–26 diet and nutrition 646, 656, 658 exercise and lifestyle 668 physical examination 73 caregiving behavioral problems 619–622 burnout 700, 703 driving impairment 690–691 elder abuse and mistreatment 699–700, 702–703

carotid angioplasty and stenting (CAS) 307–308, 530 carotid endarterectomy (CEA) 307–308, 528–530 carotid occlusive disease 528–530 carotid sinus hypersensitivity (CSH) 216, 361 carotid surgery 307–308 cART see combination antiretroviral therapy CAS see carotid angioplasty and stenting case management 703 cataracts 75, 401 catatonia 602 catechins 654–655 cautious gait 129 CBD see corticobasal degeneration CBGD see corticobasal ganglionic degeneration CDR see Clinical Dementia Rating CEA see carotid endarterectomy cellular senescence 15–16 central gustatory disturbances 441–443 central hearing disorders 436 central nervous system (CNS) infections 459–476 acute viral encephalitides 464–465 blood–brain barrier 459, 474 concepts and definitions 459–460 cutaneous herpes zoster and complicated zoster syndromes 469–470 HIV/AIDS in the aging population 471–473 immunosenescence 474 infectious meningitidis 460–464 intracranial abscesses 466–468 myelitides and spinal canal infections 468–469 septic encephalopathy 470–471 central nervous system (CNS) lesions 385–386, 436 central nervous system (CNS) lymphoma 533 central olfactory disturbances 438–440 central retinal artery occlusion (CRAO) 407–408 central visual disturbances 414–419 cerebellar ataxia syndromes 389–390 cerebellar examination 82–83 cerebellar strokes 386–388 cerebellar tremor 329 cerebral amyloid angiopathy (CAA) aging 40, 42, 53–55 immunotherapy 572, 579 cerebral aneurysms 527 cerebral injury 178–179

cerebral perfusion 668 cerebrolysin 566 cerebrospinal fluid (CSF) central nervous system infections 460–464, 468–469 chronic subdural hematomas 520–521 clinical laboratory investigations 172–179 dementia with Lewy bodies 213 frontotemporal dementia 246 immunotherapy 577 mild cognitive impairment 192, 194 normal pressure hydrocephalus 281–282, 532–533 Parkinson’s disease 320 prion diseases 272–273 vertigo and dizziness 391–392 cerebrovascular accidents (CVAs) neurologic examination 73, 76–77, 83 neuropsychology 104, 107 cerebrovascular disease (CVD) 301–311 aging 5, 23, 40, 42, 52–56, 301–302 Alzheimer’s disease 200, 210 atypical presentations 302–303 biologic changes with aging 301–302 clinical laboratory investigations 170, 175–176 clinical presentations 302 concepts and definitions 301 depression 296 gustatory disorders 442 hospitalization 302, 303 Mental Status Examination 87–88 neurologic examination 74 normal pressure hydrocephalus 282 specific diseases 303–309 treatment and outcome data 306–309 vascular cognitive impairment 224–235 vascular depression hypothesis 309 see also individual disorders cerumen impaction 419–420 cervical venous hum 421 cervicogenic headache 485, 490–491 characteristic model of memory 105 Charcot–Marie–Tooth (CMT) syndrome 506–507 CHEIs see cholinesterase inhibitors chemotherapy 464, 534, 535–536 CHF see congestive heart failure Chiari malformations 386 CHMP-2B gene 245 cholesterol-lowering agents 513–514 cholinesterase inhibitors (CHEIs) 215–219 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 503 chronic subdural hematomas 519, 520–521

Index

chronic traumatic encephalopathy 63 chronic wasting disease (CWD) 276–277 CIND see cognitive impairment no dementia CIPD see chronic inflammatory demyelinating polyradiculoneuropathy circadian rhythms 347, 348 CJD see Jakob–Creutzfeldt disease CK-BB see creatine kinase Clinical Dementia Rating (CDR) scale 94, 187, 190 clinical laboratory investigations 170–180 Alzheimer’s disease 172, 173, 202 Bayes’ theorem 171–172 body fluids used 172 cerebral injury 178–179 cerebrovascular disorders 175–176 concepts and definitions 170–171 delirium 177, 481 depression 176–177 epilepsy 373 frontotemporal lobar degeneration 172, 173–174 genetic disorders 178 headaches 176 hemorrhage 175 HIV/AIDS 177 infarction 175 Jakob–Creutzfeldt disease and prion disorders 172, 174 laboratory test interpretation 171–172 Lewy body disease 172, 173 normal pressure hydrocephalus 174 paraneoplastic disorders 177–178 Parkinson-plus syndromes 174–175 Parkinson’s disease 173, 174 secondary dementia 172–173 sensory disorders 398 syncope 363–364 vascular cognitive impairment 172, 173 vasculitis 175–176 clock-drawing test 92, 108–110 clonus 82 clopidogrel 565 clorazepam 564 closed-angle glaucoma 405 closed head injury 370 Clostridium botulinum toxin 422 clozapine 563 cluster headaches 485, 488 CMT see Charcot–Marie–Tooth CMV see cytomegalovirus CNS see central nervous system coenzyme Q10 652–653 coffee 649, 652, 655–656 cognitive impairment see individual disorders

cognitive impairment no dementia (CIND) 187, 188, 224–226 cognitive rehabilitation 675 cognitive reserve 118–125 brain reserve model 118–120 concepts and definitions 118–121 exercise and lifestyle 673–674 implications for diagnosis and prevention 123 neural markers in healthy elderly and Alzheimer’s patients 122 neural markers in healthy young and older adults 121–122 neural markers in young, healthy adults 121 cognitive status assessment see Mental Status Examination; neuropsychology cognitive training 674–675 coiled bodies 336–337 combination antiretroviral therapy (cART) 463, 471–473 communication 88–89, 102–104 competency 100 complicated zoster syndromes 469–470 comprehension 102–103 compression fractures 519, 539–542 computed tomography angiography (CTA) 523–524, 528–529, 531 computed tomography (CT) aneurysms 523–525 auditory disorders 421, 429 central nervous system infections 461, 466, 469 chronic subdural hematomas 520–521 compression fractures 540 infarction 175 neuromuscular disorders 498 normal pressure hydrocephalus 282, 532–533 odontoid fractures 536–537 stroke 528 concentration 90, 101–102 concrete thinking 107 conditioning 105 conduction aphasia 104 conductive disturbances auditory 419–422 gustatory 440–441 olfactory 437 visual 400–402 confusion 618 confusion assessment method (CAM) 481 congestive heart failure (CHF) 362 consciousness level 87 construction skills 92 coordination tests 82–83

717

cortical atrophy 140–141 cortical deafness 436 corticobasal degeneration (CBD) 343–345 aging 48–50 clinical features 343–344 concepts and definitions 313, 343 diagnostic testing 344 differential diagnosis 334–335, 343, 344 epidemiology 343 neuropathology 345 structural neuroimaging 142 treatment 344–345 corticobasal ganglionic degeneration (CBGD) 112–113, 174–175, 352 corticobasal syndrome (CBS) 239, 242 corticosteroids 508–509, 514–515 corticotropin-releasing factor (CRF) 288, 292–295 CR see dietary or calorie restriction cranial nerves 74–78 cranial neuropathies 76 craniocervical junction syndromes 386 CRAO see central retinal artery occlusion creatine kinase (CK-BB) activity 179 creative aging 628–629 CRF see corticotropin-releasing factor CRP see C-reactive protein cryptococcal meningitis 464 cryptococcosis 62 CSF see cerebrospinal fluid CSH see carotid sinus hypersensitivity CT see computed tomography cutaneous herpes zoster 469–470 CVAs see cerebrovascular accidents CVD see cardiovascular disease CWD see chronic wasting disease cyclophosphamides 509, 511 cyclosporines 511 cytochrome P450 (CYP450) 587–589, 594, 599 cytomegalovirus (CMV) 464–465 DA see dopamine dairy products 652, 657 dance therapies 636–637 Dandy’s syndrome 384–385 DASH see Dietary Approaches to Stop Hypertension DAT see dopamine transporter DBS see deep brain stimulation de Kooning, Willem 635 declarative memory 105 decompressive hemicraniectomy 531 deep brain stimulation (DBS) Parkinson’s disease 320, 546–550 progressive supranuclear palsy 339 tremor disorders 328

718

Index

deep tendon reflexes 81–82 default mode network (DMN) 155–156 delirium 477–484 behavioral problems 618 cerebrovascular disease 302, 303–304 clinical laboratory investigations 177, 481 clinical presentations 481–482 concepts and definitions 477 confusion assessment method 481 diagnostic criteria 479, 481 epidemiology 477–478 etiology 480–481 future directions and research 483 medication-induced delirium 480 neuropsychology 113 pathophysiology 478 psychopharmacology 592 risk factors 478–480 treatment 482–483 visual disorders 419 dementia with Lewy bodies (DLB) 208–223 aging 40, 46–47 clinical features 208, 214, 217–219 clinical laboratory investigations 173 cognition and function 215–216 concepts and definitions 185, 208 diagnostic criteria 47, 209–214 differential diagnosis 203–205, 208–214, 317–318, 334–335 dopamine transporter SPECT imaging 211 evidence-based pharmacologic treatment 561–562 falls and dysautonomia 219 fluctuating cognition 210, 218 frequency 209 functional imaging 151–152 genetics 214–215 improving diagnostic accuracy 210–211 microscopic and macroscopic appearances 46–47 mood disorders 218 neurochemistry 209 neuropathology 208–209 neuropsychology 112 olfactory disorders 439 parkinsonism 218–219 predictors of treatment response 216–219 psychopharmacology 592 REM sleep behavior disorder 210–211 revised consensus diagnostic criteria 211–214 severe neuroleptic sensitivity 211 sleep disorders 353

structural neuroimaging 142 treatment 215–219 visual disorders 418–419 dementias see individual disorders dendrites 39 depression 287–300 aging 295–297, 298 Alzheimer’s disease 297 cerebrovascular disease 309 clinical laboratory investigations 176–177 common factors promoting late-life depression 295–297 dementia with Lewy bodies 218 diagnostic criteria 290–291 epidemiology 287 evolutionary perspectives 289–290 exercise and lifestyle 672 existential aspects of aging 298 inflammation 296–297 interactive depressive matrix 293–294 lifestyle perspectives 298 mechanistic integration 288–289 media representations 288 Mental Status Examination 92–93 mild cognitive impairment 191 monoamine deficiency hypothesis 291–292 multifaceted separation-distress hypothesis 289 neuropsychology 113 neuroscientific overview 291–292 pain 296 Parkinson’s disease 317, 319 Parkinson’s disease dementia 218 problem space of depression 287–289 psychopharmacology 593–597 social brains 292–295 syndrome versus chemical imbalance 288 treatment 297–298 dermatomal sense 81 dermatomyositis 510–511 dexamethasone 462 DHA see docosahexaenoic acid diabetes mellitus neuromuscular disorders 500–501, 505–506 syncope 363 vascular cognitive impairment 232 diabetic amyotrophy 500–501 diabetic neuropathies 505–506 diet and nutrition 645–666 alcohol 649, 652, 657 Alzheimer’s disease 645, 646–651 antioxidants 646–647, 651, 653–654 B vitamins 647, 650, 651, 653, 656

coenzyme Q10 652–653 coffee, tea and caffeine 649, 652, 655–656 concepts and definitions 645–646 dairy products 652, 657 dietary patterns 649–650, 653, 658–659 fish and unsaturated fatty acids 647–648, 650, 651–653, 655, 658–659 fruit, vegetables and fiber 647, 650, 651, 655, 656–657 Parkinson’s disease 645, 651–653 stroke 645, 653–659 Dietary Approaches to Stop Hypertension (DASH) 650–651, 658–659 dietary or calorie restriction (DR/CR) aging 4–5, 9–10, 15, 17–23, 32 calorie restriction mimetics 20–22, 32 evolutionary and animal models 17–19 genes and pathways 19 mammalian target of rapamycin 18–22 variants and mutants 22 diffuse Lewy body disease (DLBD) 27–28 diffusion tensor imaging (DTI) 142 diffusion-weighted imaging (DWI) central nervous system infections 466–467 degenerative dementias 141 prion diseases 273–274 stroke 528 digital subtraction angiography (DSA) 523–524 disability 127 discrimination tests 81 disease modifying treatment 246–247 disequilibrium see balance; vertigo and dizziness disinhibition 107–108, 201 disposable soma theory of aging 8–9 disulfuram 607 Dix–Hallpike maneuver 379–380 dizziness see vertigo and dizziness DLB see dementia with Lewy bodies DLDB see diffuse Lewy body disease DMN see default mode network docosahexaenoic acid (DHA) 647–648, 651 donepezil 195, 216, 558–563, 566 dopamine (DA) neurons 17 dopamine transporter (DAT) imaging 211, 344 DR/CR see dietary or calorie restriction drama therapies 636–637 driving impairment 681–697 activities of daily living 688 aging drivers 682–684 caregiver burden and concerns 690–691

Index

clinical assessment of older drivers 684–689 cognitive changes and assessment 683–686, 687–688 concepts and definitions 681–682 driving restriction and driving retirement 689–691 interventions to promote safety and mobility 692–693 legal ramifications 691–692 medical assessment 686 mobility/strength changes and assessment 684, 687 performance-based evaluations 688 physician decision on whom to report 691–692 physician requirements to report at risk elders 691 road tests 689 road traffic accident statistics 681–682 role of geriatric neurologist 693 sensory changes and assessment 682–683, 686–687 simulators 688 social implications 689–690 support and resources 693–695 drug-induced tremor 328–329 DSA see digital subtraction angiography DTI see diffusion tensor imaging DWI see diffusion-weighted imaging dysarthria 73 dysautonomia 219 dyskinesias 316–317, 319 dysmetria 82–83 dysphasias 102 dystonias 316–317, 333–334, 343 EBT see evidence-based treatment ECG see electrocardiography ECT see electroconvulsive therapy education 673–674, 702–703 EEG see electroencephalography eicosapentaenoic acid (EPA) 647–648, 651 Einstein Aging Study 127–128 ELD see external lumbar drainage elder abuse and mistreatment 698–705 advocacy 708 caregivers 699–700, 702–703 case management 703 case studies 704 concepts and definitions 698–699 cycle of mistreatment 698 documentation and legal requirements 701–702 future directions 703 incidence and prevalence 698 interventions 702–703

neglect 699–701 nursing homes 700 reporting 702 resources 704–705 risk factors 699–700 screening for abuse 700–701, 704 signs and symptoms 701 special situations 700 electrocardiography (ECG) 360, 363–364 electroconvulsive therapy (ECT) 596, 602 electroencephalography (EEG) corticobasal degeneration 344 epilepsy 372–373 prion diseases 272 sleep disorders 346–347 syncope 360, 364 electrolytes 657–658 electromyography (EMG) 347 electrooculography (EOG) 347 elimination half-life 590 EMG see electromyography emotional abuse 699–701 encoding 105–106 end-of-life care 6–7 endocrine dyscrasia 16–17 endothelial nitric oxide synthase (eNOS) 25–26 environmental interventions model 621 environmental stressors 619 EOG see electrooculography EPA see eicosapentaenoic acid ependymomas 60 epilepsy 369–377 clinical diagnosis 371 clinical laboratory investigations 373 clinical studies of drug therapy 374–375 concepts and definitions 369 differential diagnosis 359–360, 372–373 epidemiology 369–370 etiology of geriatric epilepsy 370–371 mechanisms of seizures 371 syndromes and seizure classification 373 treatment 374–375 epileptic vertigo 385–386 epileptic visual hallucinations 415 episodic ataxia syndromes 390 episodic memory 104–106, 105 Epworth sleepiness scale (ESS) 347 erythrocyte sedimentation rate (ESR) 176, 411–412 ESS see Epworth sleepiness scale essential tremor (ET) concepts and definitions 312–313, 325–326 differential diagnosis 314, 325–326

719

pathophysiology 326 treatment 326–328 ethical issues 195–196 evidence-based pharmacologic treatment Alzheimer’s disease 555–560 concepts and definitions 554 dementia with Lewy bodies 561–562 frontotemporal dementia 561 medical foods 560 overall approach to pharmacotherapy of dementia 562–564 Parkinson’s disease dementia 566–567 primary prevention or treatment 555–557 pseudobulbar affect 567–568 secondary prevention or treatment 555, 557–560 symptomatic therapy 557–558 vascular dementia 565–566 evidence-based treatment (EBT) 622 evolutionary perspectives aging 4, 7–10, 28–31 depression 289–290 executive function Alzheimer’s disease 200 Mental Status Examination 92 neuropsychology 106–108 exercise and lifestyle 667–680 aging 5, 22–23, 28–31, 32 cognitive rehabilitation 675 concepts and definitions 667 depression 298 disease progression 670–671 education and lifetime cognitive experiences 673–674 impact of exercise in older age 669–670 later-life cognitive experiences and cognitive training 674–675 lifetime exercise and dementia 668–669 lifetime social support and dementia risk 676 mental exercise 672–675 non-AD dementia syndromes 671–672 physical exercise 667–672 potential modifying factors 672 primary prevention 668–669, 673–674, 676 secondary prevention 669–670, 674– 675, 676 social interaction 675–676 tertiary prevention 670–671, 675, 676 expressive art therapies 628–641 Alzheimer’s disease 630–639 art therapy 632–636 concepts and definitions 628–629 creative aging 628–629 dance/movement and drama therapies 636–637

720

Index

expressive art therapies (Continued) frontotemporal dementia 633, 635–636 music therapy 629–632 Parkinson’s disease 637 poetry/bibliotherapy, storytelling and reminiscence 637–639 expressive speech 102 external lumbar drainage (ELD) 532–533 extracellular amyloid deposition 572 extraocular movements 76 extraparenchymal abscesses 468 (18)F labeled agents 137, 164–165 facial droop/asymmetry 77 facial movement 77 facial pain syndromes 519, 542–546 facial recognition 110 falls cerebrovascular disease 302 dementia with Lewy bodies 219 gait disorders 126–127, 129 Parkinson’s disease dementia 219 syncope 365 familial Jakob–Creutzfeldt disease (fCJD) 174, 267, 270, 274 fatal familial insomnia (FFI) 267, 270, 274–275, 353 fCJD see familial Jakob–Creutzfeldt disease FDDNP 164 FDG-PET see positron emission tomography federal legislative process 708–709 FFI see fatal familial insomnia fiber 647, 656–657 financial abuse 699–700 fish 647–648, 650, 655 FLAIR see fluid attenuated inversion recovery flavonoid 654–655 florbetaben 165 florbetapir 164–165 fluctuating cognition 210, 218 fluid attenuated inversion recovery (FLAIR) 273–274, 466, 535 fluoxetine 564 flutemetamol 164 fMRI see functional magnetic resonance imaging focal motor neuron disease 495–496 folic acid 647, 656 Folstein Minimental State examination 283–284 fragile X ataxia tremor syndrome (FXTAS) 389–390 frontal gait 128, 131 frontal lobe injuries 108

frontotemporal dementia (FTD) 239–250 behavioral problems 616–617, 623–624 clinical–pathologic correlation 243–245 concepts and definitions 185, 239 diagnostic criteria 245–246 differential diagnosis 190, 203–205, 239 epidemiology 239 evidence-based pharmacologic treatment 561 expressive art therapies 633, 635–636 functional imaging 240–241 genetics 245 neuropsychology 111–112, 241 pathology 242–245 sleep disorders 352 structural neuroimaging 141–142, 240–241 subtypes 239–245 treatment 246–247 see also individual spectrum disorders frontotemporal lobar degeneration (FTLD) aging 40–41, 48–51 ALS-dementia 51 amyotrophic lateral sclerosis 50–51, 57 clinical laboratory investigations 172, 173–174 corticobasal degeneration 48–50 differential diagnosis 239, 245–246 FTLD-tau and tauopathies 48, 243, 246 FTLD-ubiquitin 50–51 functional imaging 151 Pick’s disease 48 progressive supranuclear palsy 49–50 fruit 647, 650, 651, 655 FTD see frontotemporal dementia FTLD see frontotemporal lobar degeneration functional disorders 129 functional imaging 136–137, 146–161 Alzheimer’s disease 146–156, 162–168 cognitive reserve 120, 121–123 concepts and definitions 136–137, 146 corticobasal degeneration 344 dementia with Lewy bodies 151–152, 211, 212–213 frontotemporal dementia 240–241 frontotemporal lobar dementia 151 mild cognitive impairment 147–149, 162–167, 192–193 normal pressure hydrocephalus 282 Parkinson’s disease 315 primary progressive aphasia 254–255, 257–258, 259–260 progressive supranuclear palsy 338 vascular dementia 152 see also individual techniques

functional limitations 100 functional magnetic resonance imaging (fMRI) cognitive reserve 121–122 dementia 137, 146, 154–156 mild cognitive impairment 192–193 perfusion fMRI using arterial spin labeling 156 response to memory tasks 155 resting state fMRI 155–156 fungal meningitides 463 fused in sarcoma (FUS) pathology 243 FXTAS see fragile X ataxia tremor syndrome gamma-aminobutyric acid (GABA) 288, 292 gabapentin 327 GAD see generalized anxiety disorder gag reflex 78 gait disorders 126–135 adverse outcomes 126–127, 129 aging of walking 127–128 case discussions 131–133 clinical classification 128–129 epidemiology 126 etiology, diagnosis and workup 130–131 expressive art therapies 632 historical perspective 126 neurologic examination 83–84 normal pressure hydrocephalus 282–283 performance-based tests 130 progressive supranuclear palsy 333 psychogenic gait disorders 129 quantitative assessment 129 timed gait 129–130 walking while talking 130 galantamine 558, 559–563 gantenerumab 580 GBM see glioblastomas multiforme GCA see giant cell arteritis gender 672 general appearance 88 generalized anxiety disorder (GAD) 600, 602 genetic testing 173, 178 genetics aging 9–10, 19 Alzheimer’s disease 205–206 clinical laboratory investigations 178 dementia with Lewy bodies 214–215 frontotemporal dementia 245 Parkinson’s disease dementia 214–215 prion diseases 267, 270, 274–275 progressive supranuclear palsy 337–338

Index

genome-wide association studies (GWAS) 206 Gerstmann–Sträussler–Scheinker (GSS) 267, 270, 274 GFR see glomerular filtration rate giant cell arteritis (GCA) 410–412, 485, 489–490 glaucoma 75, 404–406, 491 glial neoplasms 58–60 glioblastomas 59 glioblastomas multiforme (GBM) 533–534 gliosis 371 globus pallidus interna (GPI) 550 glomerular filtration rate (GFR) 590 glycation 10, 13–14, 30 good care/comfort care model 620 GPI see globus pallidus interna grasp strength 632 GSS see Gerstmann–Sträussler–Scheinker Guillain–Barré syndrome 501–502 gustatory disorders 398–399, 440–443 burning mouth syndrome 442 central gustatory disturbances 441–443 cerebrovascular disease 442 clinical laboratory investigations 398 conductive gustatory disturbances 440–441 Parkinson’s disease 442–443 presbygeusia 441–442 sensorineural gustatory disturbances 441–443 HAD see HIV-associated dementia hallucinatory misperceptions 396–397 haloperidol 482, 592 HAND see HIV-associated neurocognitive disorders HD see Huntington’s disease head injuries 370 head and neck examination 72 headache 485–492 classification 486 clinical approaches 486–487 clinical laboratory investigations 176 concepts and definitions 485–486 etiology 486 migraine 390–391, 414–415, 485, 487 neurooncology 534 primary headache disorders 485–489 secondary headache disorders 485–486, 489–491 treatment 487–491 hearing see auditory disorders Heidenhain variant of Jakob–Creutzfeldt disease 415 hemicrania continua 485, 488–489

hemiparetic gait 131, 133 hemorrhage 175, 386–388, 427 hemorrhagic stroke 490, 527–528 hereditary motor and sensor neuropathy (HMSN) 506–507 herpes simplex virus (HSV) 62, 464–465 herpes zoster oticus 429–432 HHV see human herpes viruses higher-level gait disorders 128 hippocampal atrophy 138–140 HIV-associated dementia (HAD) 471–472 HIV-associated neurocognitive disorders (HAND) 471–473 HIV/AIDS central nervous system infections 459, 463, 465, 471–473 clinical laboratory investigations 177 delirium 479 HMSN see hereditary motor and sensor neuropathy hospitalization 302, 303 house-drawing test 109–110 HPA see hypothalamic-pituitary-adrenal HPG see hypothalamic–pituitary–gonadal HSV see herpes simplex virus human herpes viruses (HHV) 464–465 human immunodeficiency virus see HIV/AIDS Huntington’s disease (HD) 57–58 hyperlipidemia 307 hypertension 231–232, 307 hyperviscosity syndrome 427 hypnic headaches 485, 489 hypoglossal nerve 78 hypoglycemia 360 hypophonia 334 hyposmia 439 hypothalamic-pituitary-adrenal (HPA) axis 288, 292, 294 hypothalamic–pituitary–gonadal (HPG) axis 8, 16–17 hypotonia 79 hypoxic encephalopathy 55 IADLs see instrumental activities of daily living iatrogenic Jakob–Creutzfeldt disease (iCJD) 174, 270, 275–276 IC see intracranial ICP see intracranial pressure ictal hallucinations 397 ideomotor apraxia 344 idiopathic polyneuropathy 506 idiopathic vestibulopathy 381–383 illusory misperceptions 396–397 imbalance see balance; vertigo and dizziness

721

immediate memory 104 immunosenescence 474 immunotherapy active immunotherapies in clinical development 580–581 active versus passive immunotherapy 572, 575–581 Alzheimer’s disease 554, 572–583 AN1792 573–577 bapineuzumab 576–579 clinical experience with anti-amyloid-β 573 clinical experience with passive immunization 576–580 concepts and definitions 554 follow-up studies 574 future directions 581 mechanisms of anti-amyloid-β immunotherapy 575–576 passive immunotherapies in clinical development 579–580 preclinical studies with anti-amyloid-β 572–573 second-generation immunotherapies 574 vasogenic edema 578–579 impulse-control disorders 317 IMRT see intensity modulated radiation treatment incidental PSP 337 inclusion body myositis 512–513 incontinence 302 infarction 54–55, 175 infectious diseases aging 6, 62–63 auditory disorders 427, 430–432 bacterial meningitis 62 central nervous system infections 459–476 cryptococcosis 62 epilepsy 371 toxoplasmosis 62 vertigo and dizziness 381, 383 viral infections 62 infectious meningitidis 460–464 inflammation aging 13, 62–63 depression 296–297 exercise and lifestyle 668 informant assessment 90–91, 94–95 Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) 91, 95 initiation 107 insight 89

722

Index

insomnia fatal familial insomnia 267, 270, 274–275, 353 psychopharmacology 600, 603 instrumental activities of daily living (IADLs) 688 insulin-signaling pathways 668 intelligence quotient (IQ) 119–121 intensity modulated radiation treatment (IMRT) 535 interleukins 13, 16, 23 internal carotid artery (ICA) 522 intracerebral hematoma 531 intracranial abscesses 466–468 intracranial aneurysms 522–525 intracranial pressure (ICP) 460, 462–463, 465–466 intracranial thrombotic stroke 530 intraparenchymal hemorrhages 55 intravenous immunoglobulin (IVIG) 580 IQ see intelligence quotient IQCODE see Informant Questionnaire on Cognitive Decline in the Elderly ischemic stroke 490, 527–528 isolated, apparently unprovoked epileptic events 373 IVIG see intravenous immunoglobulin Jakob–Creutzfeldt disease (CJD) aging 41, 51 clinical aspects 269–271 clinical laboratory investigations 172, 174 concepts and definitions 268–269 diagnostic criteria 271 diagnostic tests for sCJD 272–274 differential diagnosis 278 familial CJD 174, 267, 270, 274 genetic prion diseases 267, 270, 274–275 history of CJD nomenclature 267–268 iatrogenic CJD 174, 270, 275–276 molecular classification of sCJD 277–278 molecular and pathologic findings 277 overview of human prion diseases 267 prion decontamination 276 proteinase-sensitive proteinopathy 278 sleep disorders 353 sporadic CJD 174, 267, 269–274, 277–278 structural neuroimaging 142–143 treatment 278 variant CJD 51, 174, 270, 275–276 visual disorders 415 judgment 92 kinetic/action tremor 324 Kooning, Willem de 635

Kuru 270, 275 kyphoplasty 540–542 laboratory investigations see clinical laboratory investigations Lambert–Eaton myasthenic syndrome (LEMS) 509–510 lamotrigine 374–375 language and speech corticobasal degeneration 344 Mental Status Examination 88–89, 91–92 neurologic examination 73, 73–74 neuropsychology 102–104 primary progressive aphasia 253–254, 256–262 late-life migrainous accompaniments 414–415 late-onset hereditary myopathies 515 LDL see low density lipoprotein learning theory 621 LEMS see Lambert–Eaton myasthenic syndrome level of consciousness 87 levetiracetam 375 levodopa evidence-based pharmacologic treatment 564 Parkinson’s disease 317, 318–319, 320–321 progressive supranuclear palsy 334, 338–339 Lewy body dementia (LBD) behavioral problems 616, 623 clinical laboratory investigations 172, 173 differential diagnosis 190, 213–214 see also individual spectrum disorders life expectancy 5–6, 9 lifestyle see diet and nutrition; exercise and lifestyle light touch 81 lipopolysaccharides (LPS) 470–471 lithium 488 logopenic variant primary progressive aphasia (lvPPA) 251–252, 253, 258–260 longstanding overt ventriculomegaly in adults (LOVA) 281, 285 long-term memory 104–105 loudness 73 LOVA see longstanding overt ventriculomegaly in adults low density lipoprotein (LDL) 25 lower-level gait disorders 128 LPS see lipopolysaccharides LRRK2 mutations 315, 338 lumbosacral plexopathy 500–501

macular degeneration 75 magnesium 658 magnetic resonance angiography (MRA) 490–491, 523–524 magnetic resonance imaging (MRI) Alzheimer’s disease 138–141, 146 auditory disorders 427, 429, 434 central nervous system infections 468–469 chronic subdural hematomas 520–521 compression fractures 540 corticobasal degeneration 344 dementia with Lewy bodies 213 epilepsy 372–373 exercise and lifestyle 668, 670 infarction 175 mild cognitive impairment 192–193 neuromuscular disorders 498 neurooncology 534–535 normal pressure hydrocephalus 282–283, 532–533 odontoid fractures 536–537 Parkinson’s disease 547 prion diseases 273–274 progressive supranuclear palsy 338 stroke 528 major depressive disorder (MDD) 290–291 malignant gliomas 533–534, 536 mammalian target of rapamycin (mTOR) 9, 10–12, 16, 18–22 MAOIs see monoamine oxidase inhibitors MAPT gene 243, 245, 337–338 MAV see migraine-associated vertigo maxillomandibular advancement (MMA) procedure 351 MCA see middle cerebral artery MCI see mild cognitive impairment MDD see major depressive disorder mean wakefulness test (MWT) 347 media representations of depression 288 medical foods 560 Medicare and Medicaid 7, 707, 711 medication history 72 medication-induced behavioral problems 618 medication-induced delirium 480 medication-induced visual hallucinations 415 medication overuse headache (MOH) 485, 489 Mediterranean diet 649–650, 659 medullary strokes 78 memantine 216–217, 557–558, 560–562, 566–567 memory Alzheimer’s disease 200 cerebrovascular disease 302

Index

functional imaging 155 Mental Status Examination 90–91, 92–93 neuropsychology 104–106 normal pressure hydrocephalus 283 Meniere’s disease 383–384 meningiomas 60–61, 533 Mental Status Examination 87–97 abstract thinking 92 attention, working memory and concentration 90 behavior 88 calculation abilities 92 cognitive assessment 90–95 concepts and definitions 73, 85, 87 executive function 92 general appearance 88 informant-based tools 90–91, 94–95 insight 89 judgment and problem-solving 92 language 91–92 level of consciousness 87 memory 90–91, 92–93 mood and affect 88, 92–93 movement 88 observational and neuropsychiatric assessment 87–89 orientation 90 perceptual disturbances 89 performance-based tools 90–91, 93–94 speech and communication 88–89 thought form/content 89 vascular cognitive impairment 226 visuospatial and construction skills 92 word list generation 92–93 metastatic lesions 60 MG see myasthenia gravis microvascular decompression (MVD) 545–546 MID see multi-infarct dementia middle cerebral artery (MCA) 522, 530–531 migraine 414–415, 485, 487 migraine-associated vertigo (MAV) 390–391 mild cognitive impairment (MCI) aging 40–41, 44 amyloid imaging 162–167 biomarkers 191–193, 196 concepts and definitions 184, 187–189 diagnostic criteria 188, 190–191 diet and nutrition 650 differential diagnosis 184, 188–193, 201 driving impairment 685–686, 692 evidence-based pharmacologic treatment 556, 557 exercise and lifestyle 669–670, 673, 675

functional imaging 147–149, 192–193 future directions 196 gait disorders 127 immunotherapy 581 neurologic examination 72 neuropsychology 110–111, 113–114 pathologic changes 191 predictors of outcomes 193–195 societal impacts and ethical issues 195–196 structural neuroimaging 192–193 subtypes 184, 187–188, 189–190 treatment 184, 195 Mini Cognitive Assessment Instrument (Mini-Cog) 91, 93 mini-mental state examination (MMSE) expressive art therapies 631 Mental Status Examination 91, 93 mild cognitive impairment 188 neuropsychology 99, 102 mitochondria 10–13 mixed pathology in dementia 47–48 MLST see Multiple Sleep Latency Test MMA see maxillomandibular advancement MMSE see mini-mental state examination MNDs see motor neuron diseases MoCA see Montreal Cognitive Assessment modality model of memory 105 modified Rankin scale (mRS) 306 MOH see medication overuse headache monoamine deficiency hypothesis 291–292 monoamine oxidase inhibitors (MAOIs) 318–319, 594–596 monoclonal antibodies 580 monounsaturated fatty acids (MUFAs) 647–648, 651 Montreal Cognitive Assessment (MoCA) 74, 91, 94, 165–167 mood disorders dementia with Lewy bodies 218 expressive art therapies 632 Mental Status Examination 88, 92–93 Parkinson’s disease 317 Parkinson’s disease dementia 218 psychopharmacology 603–605 see also depression mood stabilizers 603–605 adverse effects and drug interactions 604 clinical usage 604–605 indications 604 pharmacokinetics and pharmacodynamics 603–604 mortality rates 5–6, 9 motion sickness 382

723

motor examination 78–80 motor neuron diseases (MNDs) 493–497 amyotrophic lateral sclerosis 493, 494–495 clinical features 242 diagnostic criteria 494–496 differential diagnosis 239, 256 epidemiology and clinical features 494–496 focal motor neuron disease 495–496 functional imaging 151 olfactory disorders 440 pathophysiology 493–494, 496 post-polio syndrome 496–497 primary lateral sclerosis 493, 495 progressive muscular atrophy 493, 495 treatment 494–497 movement assessment 88 movement disorders see individual disorders movement therapies 636–637 MRA see magnetic resonance angiography MRI see magnetic resonance imaging mRS see modified Rankin scale MS see multiple sclerosis MSA see multiple system atrophy mTOR see mammalian target of rapamycin MUFAs see monounsaturated fatty acids multi-infarct dementia (MID) 44–45 multiple sclerosis (MS) 388 Multiple Sleep Latency Test (MSLT) 347, 354 multiple system atrophy (MSA) aging 56–57 clinical laboratory investigations 174–175 differential diagnosis 334–335 sleep disorders 353 syncope 362–363 muscle bulk 78 muscle disorders 510–513 muscle strength 79–80 muscle tone 78–79 music therapy 629–632 MVD see microvascular decompression MWT see mean wakefulness test myasthenia gravis (MG) 507–509 myelitides 468–469 myeloneuropathy 132 myocardial scintigraphy 212 NAION see nonarteritic anterior ischemic optic neuropathy naltrexone 607 naMCI see nonamnestic mild cognitive impairment

724

Index

naming tests 91 NART see National Adult Reading Test National Parkinson Foundation (NPF) 708 natural selection 8, 289–290 NAV4694 165 nerve root diseases 493, 497–499 neural compensation 120 neurally mediated syncope 361 neuritic plaques 42–43 neurodegenerative disease aging 14–15, 26–27 Alzheimer’s disease 203 depression 297 epilepsy 370 gait disorders 131 olfactory disorders 439–440 structural neuroimaging 136, 138–145 see also individual disorders neurofibrillary tangles (NFTs) 39–40, 41–42, 336 neurofibromas 61 neurogenesis 668 neuroimaging see amyloid imaging; functional imaging; structural neuroimaging neuroleptic sensitivity 211, 217–218 neurologic examination 71–84 Alzheimer’s disease 201–202 coordination and cerebellar examination 82–83 cranial nerves 74–78 focus on function 71–72 gait and posture 83–84 language evaluation 73–74 mental status testing 73 motor examination 78–80 physical examination 71, 72–73 reflexes 81–82 sensory examination 80–81 speech evaluation 73 neurologic gaits 128 neuromuscular disorders 493–516 acquired neuropathies 501–507 amyotrophic lateral sclerosis 493, 494–495 brachial and lumbosacral plexus diseases 499–501 cholesterol-lowering agents 513–514 chronic inflammatory demyelinating polyradiculoneuropathy 503 concepts and definitions 493 dermatomyositis 510–511 diabetic neuropathies 505–506 focal motor neuron disease 495–496 Guillain–Barré syndrome 501–502 hereditary motor and sensor neuropathy 506–507

idiopathic polyneuropathy 506 inclusion body myositis 512–513 Lambert–Eaton myasthenic syndrome 509–510 late-onset hereditary myopathies 515 muscle disorders 510–513 myasthenia gravis 507–509 nerve root diseases 493, 497–499 neuromuscular junction disorders 507–510 paraneoplastic neuropathy 504–505 paraproteinemic polyneuropathy 503–504 peripheral nerve disorders 501 polymyositis 511–512 post-polio syndrome 496–497 primary lateral sclerosis 493, 495 progressive muscular atrophy 493, 495 specific toxins 513–515 steroid myopathy 514–515 toxic neuropathies 505, 513 see also motor neuron diseases neuromuscular junction disorders 507–510 neuronal achromasia 48–49 neuronal loss 38–39 neurooncology aging 58–61 glial neoplasms 58–60 meningiomas 60–61 metastatic lesions 60 neurofibromas 61 neurosurgical care 519, 533–536 primary CNS lymphomas 60 Schwannomas 61 neuropathic gait 131, 132 neuropathic tremor 329 neuropsychiatric symptoms dementia with Lewy bodies 217–218 Mental Status Examination 87–89 Parkinson’s disease 317–318 Parkinson’s disease dementia 217–218 neuropsychology 98–117 attention, orientation and concentration 101–102 cognitive disorders 110–113 cognitive domains 101–113 concepts and definitions 85–86, 98 diagnosis 100 executive abilities 106–108 frontotemporal dementia 241 functional limitations 100 interpretation of results 99 language and communication 102–104 normative data 98 preclinical diagnosis of dementia 113–114

standardized assessment 98–99 treatment 100–101 utility of neuropsychological assessment 99–101 vascular cognitive impairment 226–227 verbal and episodic memory 104–106 visuospatial abilities 108–110 neurosurgical care 519–553 acute intracranial thrombotic stroke 530 aneurysms 519, 521–527 carotid occlusive disease 528–530 chronic subdural hematomas 519, 520–521 compression fractures 519, 539–542 concepts and definitions 519–520 decompressive hemicraniectomy 531 neurooncology 519, 533–536 normal pressure hydrocephalus 531–533 odontoid fractures 519, 536–539 pain 519, 542–546 Parkinson’s disease 519, 546–550 spontaneous intracerebral hematoma 531 stroke 519, 527–528 trigeminal neuralgia 519, 542–546 neurotrophic growth factors 668 NFTs see neurofibrillary tangles nfvPPA see nonfluent/agrammatic variant primary progressive aphasia nicotine dependence 608–609 noise-induced hearing loss (NIHL) 423–425, 434, 436 nonamnestic mild cognitive impairment (naMCI) aging 44 concepts and definitions 184, 187, 189–190 gait disorders 127 predictors of outcomes 193–195 nonarteritic anterior ischemic optic neuropathy (NAION) 408–410 nondeclarative memory 105 nonepileptic seizures (NES) 360, 372–373 nonfluent aphasia 344, 632 nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) 239, 241–242, 244, 252–256 nonrapid eye movement (NREM) sleep 346, 347, 352 nonsteroidal anti-inflammatory drugs (NSAIDs) 485, 487, 498–499 normal aging 38, 39–40 exercise and lifestyle 669, 674–675 sensory disorders 396 sleep disorders 348

Index

normal pressure hydrocephalus (NPH) 281–286 classification of hydrocephalus 281 clinical laboratory investigations 174 concepts and definitions 186, 281 demographics 281 diagnostic criteria 284 differential diagnosis 283–285 gait disorders 131, 133 neuroimaging 282 neurosurgical care 531–533 pathophysiology 281–282 prognostication 284 symptoms 282–283 treatment 284–285, 286–287 vertigo and dizziness 391–392 normative data 98 NPF see National Parkinson Foundation NPH see normal pressure hydrocephalus NREM see nonrapid eye movement NSAIDs see nonsteroidal antiinflammatory drugs Nuedexta 564, 567–568 nursing homes 700 nutrition see diet and nutrition obesity 5, 23 objective tinnitus 420–421 observational assessment 87–89 obsessive–compulsive disorder (OCD) 602 obstructive sleep apnea (OSA) 318, 350–351, 353–354 OCD see obsessive–compulsive disorder odontoid fractures 519, 536–539 office testing 398 olfactory disorders 398–399, 436–440 central olfactory disturbances 438–440 clinical laboratory investigations 398 conductive olfactory disturbances 437 neurologic examination 75 Parkinson’s disease 318, 439 presbyosmia 438 sensorineural olfactory disturbances 437 oligodendrogliomas 59–60 omega-3 fatty acids 647–648, 650, 651–652 open-angle glaucoma 405 optic nerve 75 oral candidiasis 440–441 orientation 90, 101–102 orthostatic hypotension 362, 364–365, 392–393 orthostatic tremor 325, 328 OS see oxidative stress OSA see obstructive sleep apnea otogenic dizziness 379, 392

ototoxicity 432–433 oxcarbazepine 375 oxidative stress (OS) 4, 9, 10–13 oxytocin 293 PACNS see primary angiitis of the CNS Pagnini–McClure maneuver 380 pain atypical pain 546 behavioral problems 619 depression 296 medical therapy 543 microvascular decompression 545–546 natural history 542–543 neurologic examination 81 neurosurgical care 519, 542–546 percutaneous procedures 543–544 stereotactic radiosurgery 544–545 PAN see Parkinson’s Action Network panic attacks/disorder 602 PAP see positive airway pressure paraneoplastic LEMS 510 paraneoplastic neurologic syndromes (PNS) 177–178 paraneoplastic neuropathy 504–505 paraproteinemic polyneuropathy 503–504 parkinsonism Alzheimer’s disease 201 dementia with Lewy bodies 218–219 gait disorders 130, 132–133 normal pressure hydrocephalus 283 Parkinson’s disease dementia 218–219 sleep disorders 353 tremor disorders 328 visual disorders 416 parkinsonism–dementia complex (PDC) 334–335 Parkinson-plus syndromes 174–175 see also individual spectrum disorders Parkinson’s Action Network (PAN) 708 Parkinson’s disease dementia (PDD) behavioral problems 617, 624 clinical features 214, 217–219 clinical laboratory investigations 173 cognition and function 215–216 differential diagnosis 212–214, 283–285, 317–318 evidence-based pharmacologic treatment 566–567 falls and dysautonomia 219 genetics 214–215 mood disorders 218 neuropsychology 112 predictors of treatment response 216–219 sleep disorders 353

725

structural neuroimaging 142, 142–143 treatment 215–219 Parkinson’s disease (PD) advocacy 708 aging 27–28, 56 behavioral problems 617, 624 clinical features 214, 315–317 clinical laboratory investigations 173, 174 concepts and definitions 312, 314 deep brain stimulation 320, 546–550 diet and nutrition 645, 651–653 differential diagnosis 208, 212–214, 314, 317–318, 325–326, 334–335, 343 driving impairment 688 elder abuse and mistreatment 704 epidemiology 314 exercise and lifestyle 671–672 expressive art therapies 637 functional imaging 315 future directions 321 gustatory disorders 442–443 lesion surgery 320 neurologic examination 73 neuropsychiatric symptoms 317–318 neurosurgical care 519, 546–550 nonmotor features 318 olfactory disorders 318, 439 pathogenesis 314–315 prodromal features 315 psychopharmacology 592, 601–602 syncope 362–363 treatment 318–320 visual disorders 416–418 paroxetine 564 paroxysmal hemicranias 485, 488–489 PAS see Predementia Alzheimer’s Disease Scale patient advocacy organizations 707–708 PBA see pseudobulbar affect PD see Parkinson’s disease PDC see parkinsonism–dementia complex PDD see Parkinson’s disease dementia Peabody Picture Vocabulary Test (PPVT) 120 penlight shadow test 398 pentoxyfylline 565–566 perceptual disturbances 89 percutaneous procedures 543–544 performance testing 90–91, 93–94, 130, 688 perfusion fMRI 156 periodic lateralized epileptiform discharges (PLEDs) 465 periodic limb movements of sleep (PLMS) 349–350, 352–354

726

Index

peripheral nerve disorders 501 peripheral nervous system (PNS) infections 459 personality change 201 PET see positron emission tomography PGRN mutations 245 phenotypes of aging 10–17 PHN see postherpetic neuralgia phonation 73 physical abuse 699–701 physical examination biometrics 72 cardiovascular assessment 73 head and neck examination 72 medications 72 neurologic examination 71, 72–73 physical exercise 667–672 PiB 163 PICA see posterior inferior cerebellar artery Pick’s disease see behavioral variant FTD PIGD see postural instability gait disorder pinhole test 400 PINK1 mutations 315 PLEDs see periodic lateralized epileptiform discharges PLMS see periodic limb movements of sleep PLS see primary lateral sclerosis PMA see progressive muscular atrophy PML see progressive multifocal leukoencephalopathy PMR see polymyalgia rheumatica PNS see paraneoplastic neurologic syndromes; peripheral nervous system poetry 637–639 point-to-point movements 83 polymerase chain reaction (PCR) 461–463, 465, 468–469 polymyalgia rheumatica (PMR) 410 polymyositis 511–512 polypharmacy 480–481 polyphenols 23–24 polysomnography (PSG) 347 polyunsaturated fatty acids (PUFAs) 647–648, 650, 651–653, 658–659 ponezumab 579–580 position sense 81 positive airway pressure (PAP) therapy 351, 354 positive spontaneous visual phenomena with blindness 413–414 positron emission tomography (PET) Alzheimer’s disease 137, 146–152, 154 amyloid imaging 162–168

clinical applications 152 dementia with Lewy bodies 151–152, 212–213 frontotemporal lobar dementia 151 immunotherapy 577–578 mild cognitive impairment 147–149, 192–193 physiologic and pathologic brain processes 146–149 presymptomatic AD risk evaluation 149–150 progressive supranuclear palsy 338 SPECT comparison 154 vascular dementia 152 posterior inferior cerebellar artery (PICA) 426–427, 522, 526 posterior odontoid screw fixation 538–539 posterior probability 171 posterior vitreous detachment (PVD) 401–402 postherpetic neuralgia (PHN) 469–470 post-polio syndrome 496–497 post-stroke dementia (PSD) 230–231 post-traumatic stress disorder (PTSD) 602–603 postural hypotension 392–393 postural instability gait disorder (PIGD) 316–317, 319 postural tremor 324 posture 83–84 potassium 658 PPVT see Peabody Picture Vocabulary Test preclinical silent vascular brain injury 230 Predementia Alzheimer’s Disease Scale (PAS) 194 prednisone 511 pregabalin 327 presbycusis 423 presbygeusia 441–442 presbyopia 75, 400–401 presbyosmia 438 prescription drug support 707 presenilin proteins 206 PRGN mutations 338 primary angiitis of the CNS (PACNS) 175–176 primary CNS lymphomas 60 primary headache disorders 485–489 primary lateral sclerosis (PLS) 493, 495 primary progressive aphasia (PPA) 251–266 assessment of speech–language function 260–261 associated cognitive, behavioral and neurologic deficits 254, 257, 259

behavioral problems 617 clinical features and neurobiologic correlates 241–242, 252 concepts and definitions 185, 239, 251 diagnostic criteria 251–252 differential diagnosis 239 functional imaging 151, 254–255, 257–258, 259–260 logopenic variant 251–253, 258–260 neurologic examination 73–74 neuropathology 255–256, 258 neuropsychology 111–112 nonfluent agrammatic variant 239, 241–242, 244, 252–256 semantic variant 239, 241–244, 252–253, 256–258 speech–language profile 253–254, 256–262 structural neuroimaging 141–142, 254–255, 257–258, 259–260 treatment 261–262 primary writing tremor 328 primidone 326 priming phenomena 105 primitive reflexes 82 prion diseases 267–280 animal prion diseases 276–277 clinical aspects 269–271 clinical laboratory investigations 172, 174 concepts and definitions 186, 267, 268–269 diagnostic criteria 271 diagnostic tests for sCJD 272–274 differential diagnosis 278 epidemiology 267 genetics 267, 270, 274–275 history of CJD nomenclature 267–268 molecular classification of sCJD 277–278 molecular and pathologic findings 277 overview of human prion diseases 267 prion decontamination 276 proteinase-sensitive proteinopathy 278 sleep disorders 353 treatment 278 see also Jakob–Creutzfeldt disease prior probability 171 PRNP gene 267–269, 274–275, 415 problem-solving 92 procedural memory 105 progressive cortical atrophy 616 progressive multifocal leukoencephalopathy (PML) 62 progressive muscular atrophy (PMA) 493, 495

Index

progressive supranuclear palsy (PSP) 49–50, 332–342 biochemistry 337 clinical features 242 clinical laboratory investigations 174–175 clinical–pathologic correlation 244–245 clinical presentation 332–334 concepts and definitions 313 diagnostic criteria 332–333 differential diagnosis 239, 334–335, 343 epidemiology 332 functional imaging 338 genetics 337–338 historical perspective 332 incidental PSP 337 macroscopic pathology 336 microscopic pathology 336–337 mixed pathology 337 neurologic examination 73 neuropathology 336–337 neuropsychology 112 prognosis 339 sleep disorders 352 structural neuroimaging 142, 338 treatment 247, 338–339 variants 334 proinflammatory cytokines 13, 16–17, 23 proliferative vitreoretinopathy (PVR) 402 pronator drift 80 propranolol 326–327 proteinase-sensitive proteinopathy (PSPr) 278 PSD see post-stroke dementia pseudobulbar affect (PBA) 567–568 PSG see polysomnography PSP see progressive supranuclear palsy PSPr see proteinase-sensitive proteinopathy psychiatric disorders 392 psychodrama 637 psychogenic gait disorders 129 psychogenic nonepileptic seizures 372–373 psychogenic pseudosyncope 360 psychogenic tremor 329 psychopharmacology 584–612 adverse effects and drug interactions 585–586, 591 aging 584, 586–590 antidepressants 593–597, 602–603, 607, 609 antipsychotics 590–593 anxiolytics and sedative–hypnotic drugs 597–603, 608 clearance and excretion 590 diagnostic criteria 584

distribution 587 elimination half-life 590 metabolism 587–589 mood stabilizers 603–605 pharmacodynamics 590, 591 pharmacokinetics 586–591 screening for psychotropic use 585 substance-related disorders 605–610 treatment adherence 586 treatment effectiveness 584–585 treatment initiation 586 psychosis 590–593 psychosocial interventions 622 PTSD see post-traumatic stress disorder public awareness campaigns 710 PUFAs see polyunsaturated fatty acids pulsatile tinnitus 420–421 pupillary reactions 76 pure word deafness 436 PVD see posterior vitreous detachment PVR see proliferative vitreoretinopathy quetiapine 563 radiation therapy (RT) 500, 534–536 radiculopathies 493, 497–499 radionuclide cisternography 532 rapid alternating movements 83 rapid eye movement behavior disorder (RBD) 353 dementia with Lewy bodies 210–211 epilepsy 372 olfactory disorders 439 Parkinson’s disease 315, 319–320 progressive supranuclear palsy 334 visual disorders 417 rapid eye movement (REM) sleep 346, 347–348, 352 rapid eye movement sleep without atonia (RSWA) 315, 319–320, 334 RAS see Rhythmic Auditory Stimulation RBD see rapid eye movement behavior disorder reactive oxygen species (ROS) 10–13 reading assessment 91 recurrent stroke 232–233 reflexes 81–82 release hallucinations 397 REM see rapid eye movement reminiscence 637–639 remote memory 105 repetition 91, 103 respite care 703 resting tremor 324 restless leg syndrome (RLS) 348–349, 353–354 retinal artery occlusion 407–408

727

retrieval 105–106 retrochiasmal visual field defects 415–416 Rhythmic Auditory Stimulation (RAS) 632 rigidity 79 risk prognostication scores 365 rivastigmine 559–563, 566 RLS see restless leg syndrome road tests 689 Romberg test 83 ROS see reactive oxygen species RSWA see rapid eye movement sleep without atonia RT see radiation therapy SAH see subarachnoid hemorrhage Saint Louis University Mental Status (SLUMS) 91, 94 saliva 441 sarcopenia 15 SASP see senescence-associated secretory phenotype SBT see short blessed test Schwannomas 61 sCJD see sporadic Jakob–Creutzfeldt disease SDH see subdural hematomas secondary dementia 172–173 secondary headache disorders 485–486, 489–491 sedative–hypnotic drugs 597–603 adverse effects and drug interactions 598–599 clinical usage 599–600 indications 599 monitoring treatment 600 pharmacokinetics and pharmacodynamics 597–598 seizures 359–360, 370–373, 534 selective serotonin reuptake inhibitors (SSRIs) depression in the elderly 297 Parkinson’s disease 319 psychopharmacology 594–597, 602–603, 607 self-monitoring and assessment 107 semantic dementia (SD) behavioral problems 617 expressive art therapies 635–636 neuropsychology 111–112 structural neuroimaging 141–142 semantic memory 105 semantic variant primary progressive aphasia (svPPA) 239, 241–244, 252, 256–258 Semont liberatory maneuver 381 senescence-associated secretory phenotype (SASP) 30

728

Index

senile cataracts 401 senior advocacy see advocacy sensorineural disturbances auditory 422–436 gustatory 441–443 olfactory 437 visual 402–414 sensory ataxia syndromes 388–389 sensory disorders 395–458 aging 395–396, 400 auditory disorders 398–399, 419–436 categorization by modality and level of dysfunction 399 clinical laboratory investigations 398 concepts and definitions 395–398 distortions and other misperceptions 396–398 driving impairment 682–683 gustatory disorders 398–399, 440–443 neurologic examination 80–81 olfactory disorders 398–399, 436–440 sensorineural disorders 396 sensory deficits 396 visual disorders 75, 398–419 septic encephalopathy 470–471 serotonin-selective reuptake inhibitors (SSRIs) 177 sertraline 564 SES see socioeconomic status severe neuroleptic sensitivity 211 sexual abuse 699–701 SGR see sustainable growth rate short blessed test (SBT) 91, 93–94 short-lasting unilateral neuralgias with conjunctival tearing (SUNCT) 485, 488–489 short-term memory 104 shunt valves 284–285, 286–287 SIADH see syndrome of inappropriate antidiuretic hormone sight see visual disorders single photon emission computed tomography (SPECT) corticobasal degeneration 344 dementia 137, 152–154 dementia with Lewy bodies 211, 212–213 mild cognitive impairment 192–193 PET comparison 154 visual disorders 413 sirtuins (SIRT) 12, 21–22 situation-related seizures 373 SIVD see subcortical ischemic vascular dementia sleep disorders 346–356 Alzheimer’s disease 351–352 circadian rhythms 347, 348

clinical approaches 353–354 concepts and definitions 346–347 disorders of sleep in the elderly 348–351 epilepsy 372 fatal familial insomnia 267, 270, 274–275, 353 insomnia 600, 603 napping and excessive daytime sleepiness 348, 354 nonrapid eye movement sleep 346, 347, 352 normal aging 348 obstructive sleep apnea 318, 350–351, 353–354 Parkinson’s disease 315, 318, 319–320 periodic limb movements of sleep 349–350, 352–354 prion diseases 267, 270, 274–275, 353 psychopharmacology 600, 603 rapid eye movement sleep 346, 347–348, 352 restless leg syndrome 348–349, 353–354 sleep architecture 347, 348 slow-wave sleep 346, 347, 352 synucleinopathies 218 tauopathies 334, 352 treatment 349, 351 see also rapid eye movement behavior disorder slow-wave sleep (SWS) 346, 347, 352 SLUMS see Saint Louis University Mental Status small vessel disease 40, 53, 172 smell see olfactory disorders social anxiety disorder 603 social brains 292–295 social interaction driving impairment 689–690 exercise and lifestyle 675–676 expressive art therapies 630–631, 632 social security 6–7, 706 societal impacts 195–196, 690–691 socioeconomic status (SES) 119 SOD see superoxide dismutases sodium restriction 384 solanezumab 579 spasticity 78–79, 128–129 spatial cognition 109 SPECT see single photon emission computed tomography speech see language and speech spinal accessory nerve 78 spinal canal infections 468–469 spontaneous intracerebral hematoma 531 sporadic Jakob–Creutzfeldt disease (sCJD) 174, 267, 269–274, 277–278

SSRIs see serotonin-selective reuptake inhibitors stage model of memory 105–106 standardized neuropsychological assessment 98–99 statins 513–514 stereotactic radiosurgery 544–545 steroid myopathy 514–515 STN see subthalamic nucleus storage 105–106 storytelling 637–639 stress 294–295, 672 striatal deformities 316 stroke bottom of form 305 carotid surgery, endarterectomy and stenting 307–308 cerebrovascular disease 304–309 classifications 305 diet and nutrition 645, 653–659 epilepsy 371 etiology and clinical subtypes 305 expressive art therapies 631–632 headache 490 neurologic examination 75 neurosurgical care 519, 527–528 novel therapies 308–309 outcome data 306–307 risk factors 304 stroke care 305–306, 307 vascular cognitive impairment 224, 230–233 vertigo and dizziness 386–388 structural neuroimaging Alzheimer’s disease 138–141 cognitive reserve 120, 121–123 concepts and definitions 136 cortical atrophy 140–141 corticobasal degeneration 344 degenerative dementias 136, 138–145 dementia with Lewy bodies 142, 213 frontotemporal dementia 141–142, 240–241 hippocampal atrophy 138–140 mild cognitive impairment 192–193 normal pressure hydrocephalus 282 parkinsonian dementias and Jakob– Creutzfeldt disease 142–143 Parkinson’s disease dementia 142 primary progressive aphasia 254–255, 257–258, 259–260 progressive supranuclear palsy 338 vascular cognitive impairment 227 ventricular enlargement 141 white matter changes 141 see also individual techniques

Index

subarachnoid hemorrhage (SAH) 55–56, 522–527 subcortical ischemic vascular dementia (SIVD) 45, 225 subcortical vascular dementia (SVD) 227, 230–231 subdural hematomas (SDH) 63, 519, 520–521 subependymomas 60 subjective light touch 81 subjective tinnitus 423, 424, 433–436 substance-related disorders alcohol dependence 606–607 alcohol withdrawal 607–608 benzodiazepine dependence 609–610 concepts and definitions 605 diagnosis 606 nicotine dependence 608–609 psychopharmacology 605–610 subthalamic nucleus (STN) 549–550 sudden deafness 423, 425–428 SUNCT see short-lasting unilateral neuralgias with conjunctival tearing superficial siderosis 428–429 superoxide dismutases (SOD) 10–11 survival 127 sustainable growth rate (SGR) 711 svPPA see semantic variant primary progressive aphasia swallowing 632 SWS see slow-wave sleep symptomatic localization-related epilepsy 373 synapses 39 syncope 357–368 autonomic dysfunction 362–363 cardiac syncope 361–362, 365 clinical features 358–359 clinical laboratory investigations 363–364 definition and classification 357 differential diagnosis 359, 372 elderly patients 365 epidemiology 357–358 epilepsy and/or seizures 359–360 neurally mediated syncope 361 nonepileptic seizures 360 postsyncopal symptoms 359 prodromal features 358–359 prognosis and economic impact 364 psychogenic pseudosyncope 360 risk prognostication scores 365 symptoms 359 treatment 364–365 types 357–358, 361–363 syndrome of inappropriate antidiuretic hormone (SIADH) 470

tacrine 558 tai chi 637 task-specific tremor 325 taste see gustatory disorders tauopathies aging 48 corticobasal degeneration 345 frontotemporal dementia 243, 246 sleep disorders 352 TBI see traumatic brain injury TCAs see tricyclic antidepressants TDP-43 protein 243–244 tea 649, 652, 655 temperature sense 81 temporal model of memory 104–105 tension-type headaches 485, 488 TGN see trigeminal neuralgia thalamotomy 320 thought form/content 89 thrombolysis 306–307 TIAs see transient ischemic attacks ticlopidine 565 tilt table testing 360, 362–364 timed gait 129–130 TimeSlips 639 tinnitus 420–421, 423, 424, 433–436 TLOC see transient loss of consciousness TN see trigeminal neuralgia TNF-α see tumor necrosis factor topiramate 327, 375 TOR signalling pathway 18–21 toxic neuropathies 505, 513 toxoplasmosis 62 Trail Making Test A/B 99 transient global amnesia (TGA) 372 transient ischemic attacks (TIAs) cerebrovascular diseases 307–308 differential diagnosis 372 syncope 360, 361 vertigo and dizziness 387 visual disorders 414–415 transient loss of consciousness (TLOC) 357–359, 365 transmissible spongiform encephalopathies (TSEs) 268 trauma 63 traumatic brain injury (TBI) 178–179 treatment adherence 586 treatment effectiveness 584–585 tremor disorders 324–331 cerebellar tremor 329 clinical characterization of tremor 324–325 concepts and definitions 312–313, 324 drug-induced tremor 328–329 essential tremor 312–313, 314, 325–327 orthostatic tremor 325, 328

729

parkinsonism 328 Parkinson’s disease 315–317, 319 pathophysiology 326 primary writing tremor 328 psychogenic tremor 329 treatment 319, 326–329 tricyclic antidepressants (TCAs) 487, 594–596 trigeminal nerve injuries 76–77 trigeminal neuralgia (TGN) 485, 491, 519, 542–546 tuberculous meningitis 463–464 tufted astrocytes 336–337 tumor necrosis factor (TNF-α) 13, 16–17, 23 tumors see cancer; neurooncology tuning fork tests 398 UB-311 581 ubiquitin 50–51 UFAs see unsaturated fatty acids undetermined epilepsy 373 unilateral pulsatile tinnitus 420–421 unmet needs model 620–621 unsaturated fatty acids (UFAs) 647–648, 650, 651–653, 655, 658–659 urinary symptoms 283 V-950 581 valosin-containing protein (VCP) 244, 245 valproate 328–329 variant Jakob–Creutzfeldt disease (vCJD) 51, 174, 270, 275–276 varicella-zoster virus (VZV) 430–432, 469–470 vascular cognitive impairment (VCI) 224–238 aging 40, 44–46 clinical laboratory investigations 172, 173 concepts and definitions 185, 224–225 diagnostic criteria 227–230 differential diagnosis 190 epidemiology 225–226 evaluation 226–227 historical perspective 224–225 infarct size, number and location 44–45 Mental Status Examination 226 microscopic infarcts 45–46 neuropathology 40, 227 neuropsychology 226–227 primary prevention and risk factors 231–232 prognosis/outcome 234 recurrent stroke and cognitive decline 232–233

730

Index

vascular cognitive impairment (VCI) (Continued) secondary prevention 232–233 structural neuroimaging 227 subcortical ischemic vascular dementia 45 subtypes 227, 230–231 treatment 231–234 vascular dementia (VaD) behavioral problems 616, 623 concepts and definitions 224–225 differential diagnosis 190, 229–231 epidemiology 225–226 evidence-based pharmacologic treatment 565–566 exercise and lifestyle 671 functional imaging 152 neuropsychology 113 prognosis/outcome 234 treatment 233–234 vascular depression hypothesis 309 vascular parkinsonism 315, 335 vasculitis 54, 63, 175–176 vasogenic edema 578–579 VCI see vascular cognitive impairment vCJD see variant Jakob–Creutzfeldt disease VCP see valosin-containing protein vegetables 647, 650, 651, 655 velnacrine 559 venlafaxine 563 venous hum 421 ventral intermediate nucleus (VIM) 549 ventricular enlargement 141 verbal episodic memory 106 verbal memory 104–106 vertebroplasty 540–542 vertical gaze palsy 332–333 vertigo and dizziness 378–394 aging 378 benign paroxysmal positional vertigo 379–381 bilateral vestibular loss 384–385 cerebellar ataxia syndromes 389–390 CNS structural lesions 385–386 craniocervical junction syndromes 386 diagnosis and diagnostic tests 380, 382, 384–385, 387–391, 393 differential diagnosis 380–382, 384–388, 390–392 epileptic vertigo 385–386 episodic ataxia syndromes 390 mechanisms 379–382, 384–390

Meniere’s disease 383–384 migraine-associated vertigo 390–391 multiple sclerosis 388 normal pressure hydrocephalus 391–392 otogenic dizziness 379, 392 postural or orthostatic hypotension 392–393 prognosis 381 psychological causes of dizziness 392 sensory ataxia syndromes 388–389 symptoms 379, 382–385, 387–393 treatment 381–393 types and classification of dizziness 378–379 vascular causes 386–388 vestibular neuritis 381–383 very low density lipoprotein (VLDL) 25 vestibular neuritis 381–383 VH see visual hallucinations vibration sense 80–81 vicious circle hypothesis 11 videonystagmography (VNG) 382 VIM see ventral intermediate nucleus viral encephalitides 464–465 viral infections 62 viral meningitides 462–463 visual disorders 398–419 age-related macular degeneration 75, 403–404 Alzheimer’s disease 419 amaurosis fugax 406–407 anterior ischemic optic neuropathy 408–412 central visual disturbances 414–419 clinical laboratory investigations 398 conductive visual disturbances 400–402 delirium 419 dementia with Lewy bodies 418–419 distortions and other misperceptions 397–398 glaucoma 404–406 hallucinations due to central pathology 415–416 Heidenhain variant of Jakob– Creutzfeldt disease 415 late-life migrainous accompaniments 414–415 neurologic examination 75, 75–76 parkinsonism 416 Parkinson’s disease 416–418 positive spontaneous visual phenomena with blindness 413–414

posterior vitreous detachment 401–402 presbyopia 400–401 retinal artery occlusion 407–408 senile cataracts 401 sensorineural visual disturbances 402–414 visual hallucinations (VH) 397–398 Alzheimer’s disease 419 Bonnet syndrome 413–414, 415–416 delirium 419 dementia with Lewy bodies 418–419 due to central pathology 415–419 epileptic VHs 415 medication-induced 415 Parkinson’s disease 317, 319, 416–418 retrochiasmal visual field defects 415–416 visuoperception 108–109 visuospatial abilities 92, 108–110 vitamins and vitamin supplementation 298, 646–647, 650–651, 653–656, 658 VLDL see very low density lipoprotein VZV see varicella-zoster virus WAIS see Wechsler Adult Inventory Scale walking while talking (WWT) 130 WAT see Word Accentuation Test Wechsler Adult Inventory Scale (WAIS) 120, 121–122 Wechsler Memory Scale (WMS) 188 weight loss 318 Welander distal myopathy 515 Wernicke’s aphasia 73–74, 104 Wernicke–Korsakoff syndrome (WKS) 41, 51–52 West Nile virus (WNV) 464–465 whispered voice test 398 white matter 39, 141 Wide Range Achievement Test (WRAT) 120 WKS see Wernicke–Korsakoff syndrome WNV see West Nile virus Word Accentuation Test (WAT) 120 word list generation 92–93 working memory 90, 104 WRAT see Wide Range Achievement Test WWT see walking while talking xerostomia 441 Z-scores 98 zidovudine 513

Figure 2.1 Apical dendrite (arrow head) and cell body (arrow) of

pyramidal neuron, hippocampus CA1, mouse brain (Golgi stain).

Figure 2.2 Dendritic spines, mouse brain, hippocampus CA1

(Golgi stain).

Figure 2.3 Activated cortical microglia in older person without

cognitive impairment; antibody to class II major histocompatibility antigen (MHCII). (a)

(b)

Figure 2.4 Alzheimer’s disease brain showing

(a) narrowing of gyri and widened sulci, and hippocampal atrophy with enlargement of lateral ventricles, especially temporal horn (b).

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

(a)

(b)

Figure 2.5 Neurofibrillary tangles:

(a) hippocampus CA1 (modified Bielschowsky stain); (b) frontal cortex (immunohistochemistry with antibodies to paired helical filament).

Figure 2.6 Ghost tangles, hippocampus CA1 (modified Bielschowsky

silver stain). (a)

(b)

Figure 2.7 Neuritic plaque

pathology in AD. (a) Three NPs in the neocortex on H&E stain are difficult to see. (b) The same NPs are easily visualized on modified Bielschowsky silver stain. (a)

(b)

(c)

(d) Figure 2.8 Amyloid pathology

in AD. (a) Numerous amyloid immunostained plaques in the cortex at low power. (b) Leptomeningeal arterioles also may show amyloid deposition. (c, d) Higher power of plaque pathology using amyloid immunostain.

(a)

(b)

Figure 2.9 An old lacunar infarct in the

anterior thalamic nucleus: (a) gross coronal brain slab; (b) histologic appearance of old infarct with few macrophages and cavitation.

(a)

(b)

Figure 2.10 Subcortical ischemic vascular

disease. Both (a) gross and (b) histologic brain sections show lacunar infarcts and enlarged perivascular spaces predominantly in the caudate in a person with vascular parkinsonism.

(a)

Figure 2.11 Substantia nigra

neurons with multiple LBs: (a) classic dense concentric appearance with peripheral halo on H&E; (b) LB halo stains darker using antibodies to α-synuclein.

(b)

(a)

(b)

(c)

Figure 2.12 Cortical LBs in the superior

temporal cortex. (a) H&E stain shows an eosinophilic cytoplasmic inclusion without a clearly defined halo. (b) Low-magnification view showing numerous α-synucleinimmunostained cortical LBs. (c) Cortical LBs may stain uniformly or show a peripheral halo with α-synuclein immunostain.

Figure 2.13 Corticobasal degeneration: ballooned neuron (neuronal

achromasia) on H&E stain.

Figure 2.14 Tau-immunopositive astrocytic plaques are

characteristic of CBD (AT8 immunohistochemistry).

(a)

(b)

(c)

Figure 2.15 Progressive supranuclear

palsy: neurofibrillary tangle (NFT) pathology. (a) Globose NFT with basophilic filamentous appearance (H&E). (b) NFT in SN highlighted with tau immunohistochemistry. (c) Antibody to 4-repeat tau isoforms labels two NFT.

(a)

(b)

Figure 2.16 PSP: astrocytic pathology.

(a) Tau-immunoreactive tufted astrocyte in the subthalamic nucleus (AT8 antibody). (b) Coiled bodies that immunolabel with antibodies specific to 4-repeat tau.

(a)

Figure 2.17 FTLD-TDP: TDP-43 immunoreactive

inclusions in the neurons of the dentate layer of hippocampus. (a) Low magnification shows diffuse nuclear staining and numerous TDP-43 positive inclusions (arrows). (b) High magnification shows cytoplasm inclusions with nuclear clearing in affected neurons.

(b)

Figure 2.18 Atherosclerosis, the Circle of Willis. Note the

Figure 2.19 Fusiform aneurysm of the basilar artery. Artery is

asymmetric involvement of vertebral arteries, extension into basilar artery, and posterior cerebral arteries.

dilated and tortuous and may compress and distort the brain stem.

Figure 2.20 Arteriolosclerosis: hyaline thickening of two small

vessels in the deep white matter. Note that the upper vessel appears occluded.

(a)

(b)

Figure 2.21 Cerebral amyloid

(c)

(d)

angiopathy. (a) Cortex involves small-size and medium-size arteries, arterioles, and capillaries (arrows; small arrow also shows dysphoric change). (b) Leptomeninges vessels. (c) Amyloid alternating with amyloid-free regions. (d) “Double-barrel” appearance from separation of endothelium from the affected muscularis. (a–c, Aβ immunostain.)

Figure 2.22 Charcot–Bouchard aneurysm; note the

markedly thinned region of the vessel wall.

(a)

Figure 2.23 Amyotrophic

lateral sclerosis. (a) Pallor of the lateral corticospinal tracts of spinal cord on myelin stain. (b) Low and (c) high magnification show CD8 immunostained macrophages indicative of degeneration.

Figure 2.24 Amyotrophic lateral sclerosis anterior horn cell with a

Bunina body.

(b)

(c)

(a)

(b)

(c)

Figure 2.25 Amyotrophic lateral sclerosis.

Hyaline inclusions in an anterior horn motor neuron on H&E (a) and ubiquitin (b). (c) Skein-like inclusions in the anterior horn cells in ALS also stain with antibodies to ubiquitin.

Figure 2.27 Glioblastoma: histologic appearance of

pseudopalisading necrosis.

Figure 2.26 Glioblastoma multiforme: gross appearance with

variegated necrotic-appearing mass without definite borders.

Figure 2.28 Metastatic adenocarcinoma: cortical lesion appears well

demarcated and necrotic.

Figure 7.3 3D hippocampal atrophy maps showing the amount of atrophy (in %) accumulated over a 3-year period in cognitively normal elderly patients who remained cognitively normal for 6 years or longer since baseline (NL–NL) and cognitively normal elderly patients who were diagnosed with amnestic MCI at 3 years and AD at 6 years (NL–MCIAD).

Figure 7.4 Cortical atrophy in AD. Relative to patients with amnestic MCI, patients with very mild AD show extensive cortical atrophy of the entorhinal, parahippocampal, inferior, and lateral temporal cortices, with disease changes spreading next to the parietal and frontal association cortices (left column). The pattern is strikingly similar to the amyloid deposition described in Braak and Braak amyloid stage B (right column).

92 AD < 104 NC

48 mm

40 mm

32 mm

24 mm

16 mm

8 mm

0 mm

−8 mm

184 MCI < 104 NC

48 mm

40 mm

32 mm

24 mm

16 mm

8 mm

0.005

0 mm

−8 mm

7 e-16 p value

Figure 7.7 FDG PET in 92 AD

and 184 MCI participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; Mueller et al., 2006; Jack et al., 2008a), compared with 104 cognitively normal elderly controls. Top images show typical patterns of glucose hypometabolism in Alzheimer’s disease (AD), compared with normal. Bottom images show similar AD-like patterns, but to a less spatial and intensity extent in MCI. See Langbaum et al. (2009) for methodology details.

(a)

48 mm

40 mm

32 mm

24 mm

16 mm

8 mm

0 mm

−8 mm

48 mm

40 mm

32 mm

24 mm

16 mm

8 mm

0 mm

−8 mm

(b)

0.005

1 e-15 p value

Figure 7.8 FDG PET in 298 participants with varying degrees of MCI and AD, and cognitively normal elderly from ADNI ( Mueller et al., 2006; Jack et al., 2008a). (a) Areas of correlated FDG PET binding representing glucose hypometabolism associated with CDR scores. (b) Areas of correlated FDG PET binding representing glucose hypometabolism associated with MMSE scores. Regions associated with cognitive impairment are similar to those associated with a diagnosis of clinical AD (Figure 7.7). See Langbaum et al., 2009 for methodology details.

Left lateral Parietal Prefrontal

Temporal

Right lateral Parietal Prefrontal

Temporal

Figure 7.9 Regions of the brain with

abnormally low CMRgl in young adult carriers of two copies of the APOE ε4-allele and their relationship to brain regions with abnormally low CMRgl in patients with probable AD. Purple areas are regions in which CMRgl was abnormally low only in patients with AD. Bright blue areas are regions in which CMRgl was abnormally low in both the young adult e4 carriers and patients with probable AD. The muted blue areas are regions in which CMRgl was abnormally low only in the ε4 carriers. Source: Reiman et al. (2004). Reproduced with permission from National Academy of Sciences. (a)

Figure 7.10 Individual FDG-PET

scans in a patient with (a) normal cognition, (b) MCI, (c) AD, (d) bvFTLD, and (e) DLB. Images on the left are individual FDGPET CMRgl binding, showing areas of significant glucose hypometabolism compared with normal controls (blue). An automated algorithm was used to transform individual patient images into the dimensions of a standard brain and compute statistical maps of significantly reduced glucose metabolism relative to 67 normal control subjects (mean age 64 years). Redoutlined regions represent areas of mean hypometabolism seen in FDG-PET scans from 14 patients with AD (mean age 64 years), compared with the same 67 normal controls. On the right are raw FDG-PET color maps from the same corresponding patients. Here we can see the use of FDGPET for identifying diseasespecific patterns of glucose metabolism for clinical use in individual patients, to assist with diagnostic decision-making.

(b)

(c)

(d)

(e)

Left medial Cingulate

Right medial Cingulate

Amyloid negative

L A

P R

Amyloid positive

L A

P R

Figure 7.13 Falsely colored amyloid images

for cases 1, 2 and 3. Top row is images from Ms. JW, middle row from Mr. PS and bottom row from Ms. EC. Even though there images further highlight the significant differences in accumulation of amyloid, it is recommended that black and white images be used in diagnostic visual evaluation and rating of amyloid images. This is to minimize machine and operator factors involved in producing false color images leading to greater inter rater variability.

Amyloid positive

L A

P R

(a) “Refolding” model PrPC

PrPSc

(b) “Seeding” model PrPC

Figure 9.11 Voxel-based morphometry (VBM) demonstrating the

topographic distribution of left-hemisphere cortical atrophy in three PPA cohorts (red = nonfluent/agrammatic, blue = semantic, and green = logopenic). Courtesy of S.M. Wilson and M.L. Gorno-Tempini.

Very, very slow

PrPSc

Rapid

Rapid

Figure 9.12 Models for the conformational conversion of PrPC to PrPSc.

(a) The “refolding” model. The conformational change is kinetically controlled, a high-activation energy barrier preventing spontaneous conversion at detectable rates. Interaction with exogenously introduced PrPSc causes PrPC to undergo an induced conformational change to yield PrPSc. This reaction could be facilitated by an enzyme or chaperone. In the case of certain mutations in PrPC, spontaneous conversion to PrPSc may occur as a rare event, explaining why familial CJD or GSS arises spontaneously, albeit late in life. Sporadic CJD may come about when an extremely rare event (occurring in about one in a million individuals per year) leads to spontaneous conversion of PrPC to PrPSc. (b) The “seeding” model. PrPC and PrPSc (or a PrPSc-like molecule, light) are in equilibrium, with PrPC strongly favored. PrPSc is stabilized only when it adds onto a crystal-like seed or aggregate of PrPSc (dark). Seed formation is rare; however, once a seed is present, monomer addition ensues rapidly. To explain exponential conversion rates, aggregates must be continuously fragmented, generating increasing surfaces for accretion. Reproduced from Weissmann C et al. (2002).

(a)

Codons 1

PrPC

–8

23

–M 129V

50

100

150

Cu2+ β1

(b)

PrPSC

E219K

PrPSC

Type Type 1 2 82

97

(c)

αA

200

Y αB β1

231 254

Protein X Y

αc

GPI

S-S

Y αB

Protein X Y

αc

S-S

GPI

Cell membrane

PRNP

P1 D2L

(d) Figure 9.13 The prion protein. (a) The prion protein gene (PRNP) is located on the short arm of the human chromosome 20. The nonpathogenic

polymorphism includes deletion of one of the octarepeat segments, methionine–valine polymorphism at the 129 position, and glutamine– lysine polymorphism at position 219. (b) Post-translational modification truncates the cellular prion protein (PrPC) at positions 23 and 231 and glycosylates (Y) at positions 181 and 197. The phosphatidylinositol glycolipid (GPI) attached to serine at position 231 anchors the C-terminus to the cellular membrane. The intracellular N-terminus contains five octarepeat segments, P(Q/H)GGG(G/-)WGQ (blue blocks), that can bind copper ions. The central part of the protein contains one short α-helical segment (α-helix A encompassing residues 144–157 [green block]), flanked by two short β-strands (red blocks): β1(129–131) and β2(161–163). The secondary structure of the C-terminus is dominated by two long α-helical domains: α-helix B (residues 172–193) and α-helix C (residues 200–227), which are connected by a disulfide bond. The blue arrows indicate binding sites of the protein X within α-helices B and C. The dashed frame marks a segment between positions 90 and 150, which is crucial for the binding of PrPC to PrPSc. (c) PrPSc has increased β-sheet content (red dashed block). (d) Unlike PrPSc, which is anchored to the membrane, GSS amyloidogenic peptides are truncated and excreted into the cellular space, where they aggregate and fibrillize into GSS amyloid deposits. This example is an 8-kDa PrP fragment associated with the most common GSS/P102L mutation. A synthetic form of this peptide (90–150 residues), exposed to acetonitrile treatment to increase β-sheet content, is the only synthetically generated peptide that, when injected intracerebrally into P102L-transgenic mice, is able to induce the GSS disease. Source: Geschwind (2011). Reproduced with permission from Elsevier.

Figure 9.14 Neuropathology of prion disease. (a) In sCJD, some brain areas may have no (hippocampal end plate, left), mild (subiculum, middle),

or severe (temporal cortex, right) spongiform change. Haematoxylin and eosin (H&E) stain. (b) Cortical sections immunostained for PrPSc in sCJD: synaptic (left), patchy/perivacuolar (middle), or plaque type (right) patterns of PrPSc deposition. (c) Large Kuru-type plaque, H&E stain. (d) Typical “florid” plaques in vCJD, H&E stain. Source: Budka (2003). Reproduced with permission from Oxford University Press.

Trigeminal (Gasserian) ganglion

Figure 22.17 Schematic of the trigeminal nerve and its three divisions, V1, V2, and V3, and their respective sensory territories. Ophthalmic

(blue V1); maxillary (red V2); mandibular (pink V3). © Barrow Neurological Institute.

Figure 22.25 Schematic of the commonly used targets for DBS, including the globus pallidus interna, subthalamic nucleus, and ventral

intermediate nucleus of the thalamus and adjacent structures. © Barrow Neurological Institute.

Bapineuzumab treated patients

Screen (a)

Week 78 –0.09

Screen

Week 78

(b)

–0.33 4.0

(c)

0.06

0.25

Placebo treated patients

(d)

0.0 11C-PIB PET images in two bapineuzumab-treated (a, b) and two placebo-treated (c, d) patients. Average 11C-PIB PET changes from baseline to week 78 are shown at the top center of each panel for each patient (a–d). The scale bar shows the PiB uptake ratios relative to the cerebellum. Source: Rinne et al. (2010). Reproduced with permission from Elsevier.

Figure 23.7

Left hippocampus

Right hippocampus

5.2

5.2

5.1

5.1 Volume (mm3)

Hippocampus Volume (mm3)

(a)

5 4.9 4.8 4.7 4.6

Caudate nucleus

6 months

4.8 4.7 4.6

1 year

4.8

5.2

Volume (mm3)

5.3

4.7 4.6

4.4

Baseline

Thalamus

6 months

Baseline

6 months

1 year

Right caudate nucleus

4.9

4.5

(c)

4.9

Left caudate nucleus

Volume (mm3)

(b)

Baseline

5

1 year

5.1 5 4.9 4.8

Baseline

6 months

1 year

Thalamus

Volume (mm3)

15.00

Exercise

14.50

Stretching

14.00 13.50 13.00 Baseline

6 months

1 year

Figure 28.1 Brain region examined using MRI, and graphs demonstrating 1-year effects of aerobic exercise versus a stretching control in

cognitively healthy older adults (n = 120). (a) Example of hippocampus segmentation and graphs demonstrating an increase in hippocampus volume for the aerobic exercise group and a decrease in volume for the stretching control group. The Time by Group interaction was significant (p < 0.001) for both left and right regions. (b) Example of caudate nucleus segmentation and graphs demonstrating the changes in volume for both groups. Although the exercise group showed an attenuation of decline, this did not reach significance (both p > 0.10). (c) Example of thalamus segmentation and graph demonstrating the change in volume for both groups. None of the changes were significant for the thalamus. Error bars represent SEM. Source: Erickson et al. (2011). Reproduced with permission of National Academy of Sciences.

(a)

2

3

4

1

(b)

5

Change in segment 1 (genu) Younger

Older

Δ Mean diffusivity*

0.01 0

–0.01

–0.02 –0.03

(c)

Younger

Older

Δ Fractional anisotropy

0.02 0.01

0 Figure 28.3 Midsagittal slice showing corpus callosum subsegmented

–0.01 –0.02 Intervention *10–9m2/s

Control

(a) and 6-month cognitive training-induced improvements over baseline in genu (likely connecting prefrontal regions) in white matter microstructure, as measured by mean free diffusion of water (b) and directional rate (anisotropy) of water diffusion (c) for younger and older adults (n = 32). *units of measurement for Mean Diffusivity. Source: Lovden et al. (2010). Reproduced with permission of Elsevier.