Oxidative Stress & Autism A Paradigm For Effective Treatment

Oxidative Stress & Autism A Paradigm for Effective Treatment

Allen T. Lewis, MD, FAAP Medical Director, Pfeiffer Treatment Center Warrenville, Illinois

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Questions • What is autism?

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• How did it happen? • What can be done?

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An Axial Approach

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• Axis I • Axis II • Axis III • Axis IV • Axis V

Clinical Disorders Personality Disorders & Mental Retardation General Medical Conditions Psychosocial & Environmental Problems Global Assessment of Functioning

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A Preponderance of Autisms Social interaction:

• poor eye contact • inability to regulate social interaction • inability to develop age appropriate relationships

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Language:

• delay or lack of spoken language • abnormal or absence of imitative play

Symbolic or imaginative play:

• rituals • repetitive mannerisms (aka “stims”) • restricted areas of interest

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Three Strikes Drs. Hornig and Lipkin describe in animal model studies a 3 strike concept of potential cause for neurodevelopmental disorders. It is a triad of (1) genetic susceptibility in light of (2) critically timed environmental insults of (3) sufficient severity and quantity that trigger the disease process that manifests as a neurodevelopmental disorder (i.e. PDD, ASD, etc.).

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Understanding a Disease Process What does it look like? • Diagnostic criteria • Level of functioning

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• Clinical manifestations

What is broken? • Genetic & Epigenetic influences • Physiology/ Biochemistry • Review of systems

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Manifestations of an Illness

• Physical • Behavioral • Developmental • Neuropsychiatric

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Mechanisms of an Illness • Organ Systems • brain, bowel, etc.

• General metabolic processes © HRI/PTC 2008 – All Rights Reserved

• Oxidative stress & inflammation

• Individual Biochemical Pathways • trace metals, methylation, pyrrole chemistry

• Systemic, regional or local • global brain effects or specific regions.

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A Biologically Impaired Brain Primary Brain Dysfunction – Abnormalities in structure and/or maturation – Genetic predisposition for Axis 1 symptoms

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Acquired Brain Dysfunction – Metabolic, biochemical and nutritional imbalances – Oxidative stress and Metallothionein dysfunction

=> Resulting in Sensory Integration Dysfunction Disorganized processing of sensory, biochemical, or neuropsychiatric signals leading to abnormal behavior, learning and development.

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More than the Brain

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• • • • • •

Gastrointestinal Neurologic Immune Autoimmune Metabolic Biochemical

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Paradigm of Autism

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ASD is a medical illness - with a biologically impaired brain, - commonly associated with multiple medical problems and organ systems, - with genetic and acquired factors - leading to abnormal behavior, learning, and development - that is treatable.

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Why Oxidative Stress?

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What is Oxidative Stress?

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• An excess of chemical free-radicals that can damage proteins and essential fats, as well as disrupt normal cellular processes. • Oxygen free radicals are one of many free radicals that lead to oxidative damage. Nitrogen species and ionized metals are also important free radicals.

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Consequences of Ox Stress • Inflammation • Poor immune function

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• Neurodegeneration • Impaired methylation and other cellular processes • Increased sensitivity to toxic influences • Depletion of glutathione and metallothionein

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Severity of Oxidative Injury Both genetic susceptibility and the severity of the environmental insult likely determines the degree to which the injury is manifest: (1) Mild injury results in PDD or speech delay. (2) Severe injury results in lower functioning ASD or mutism.

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Timing of Oxidative Injury • Early injury => ASD

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Delayed or impaired maturation resulting in immature brain cells and developmental delay

• Late or cumulative injury => Alzheimer’s Disease Degeneration of mature cells and thereby loss of previously established normal brain function.

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Evidence of Oxidative Stress

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Vascular Damage in the Kidney

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Study of treatment-naive patients with autism vs. age matched controls: • Evidence of increased oxidative markers in the urine. • Evidence of oxidative damage to vascular tissues. Yao Y et al. Altered vascular phenotype in autism: correlation with oxidative stress. Arch Neurol. 2006 Aug;63(8):1161-4.

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Implications of Vascular Study

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• Increased oxidative damage of fats, vascular tissues, and other molecules may be present in many tissues and organs of the body, i.e. brain, bowel. • Antioxidant therapy may be helpful for patients with ASD.

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WBC/Leukocyte Study

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Study of treatment-naive patients with autism vs. age matched control: • Increased oxidative stress in the white blood cell (WBC). • Increased inflammation. • Decreased immune function. • Significant disturbance in methylation. Suh J et al. Altered Sulfur Amino Acid Metabolism in Immune Cells of Children Diagnosed with Autism. Am J Biochem Biotechnol. 2008 4(2); 105-113.

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Implications of WBC Study • Similar disturbances in cellular function extend beyond the kidney to another tissue. • Oxidative stress plays an important role in the disruption of normal cellular processes. • Biochemical abnormalities exist in autism.

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Neuroinflammation

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Study of autism and control brain tissue for evidence of immune-mediated differences. • Evidence of active neuroinflammation of the cerebral cortex, white matter and cerebellum of autism brain tissue. • Evidence of a proinflammatory response in the cerebrospinal fluid of patients with autism. Vargas D et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 57 (1); 67-81.

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Oxidative Injured Brain

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Study of autism brain samples for evidence of oxidative injury in comparison to control brain samples. • Direct evidence of oxidative damage was found in all samples of autism brain and in no control sample. Evans T el at. The Autistic Phenotype Exhibits a remarkably Localized Modification of Brain Protein by Products of Free Radical-Induced Lipid Oxidation. Am J Biochem Biotechnol 2008. 4(2); 61-72.

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Implications of Ox Brain Injury • Oxidative injury of proteins in the brain would likely be associated with neurologic abnormalities. • Oxidative injury of brain tissue likely plays a role in autism. • A better understanding of oxidative injury in the brain and other tissues is needed and would likely lead to improvements in the treatment of autism.

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What can be done?

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Goals of Treatment

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• • • •

Identification of broken systems. Restoration of normal function. Protection from re-injury. Promotion of normal physical, emotional, and mental health. • Thereby, establish more normal learning and development.

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Pieces of the Autism Puzzle

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• • • • •

Neurologic Psychiatric Gastrointestinal Immunologic Biochemical

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Nutrients and Neurotransmission

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The Brain is a Chemical Factory • Zinc is required for GABA synthesis • Vitamin B6 is required for Serotonin (5-HT) synthesis • Copper (Cu++) is a cofactor in the conversion of Dopamine (DA) to Norepinephrine (NE) • The Methyl:Folate ratio impacts the levels of Dopamine, Norepinephrine and Serotonin

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Biochemical Individuality Matters

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Due to genetics and epigenetic influences individuals may be - deficient in several nutrients, as well as - overloaded in others. Multiple vitamins are rarely effective, as they may - contribute to nutrient excess for those with pre-existing overload (i.e. copper, folate) and/or - induce another nutrient imbalance.

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Targeted Treatment with Nutrients

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•

Genetic nutrient deficiency may require many times the RDA to achieve normalization/optimization.

• Genetic overloads may require biochemical therapy to eliminate the nutrient excess. • Treatment focuses on correcting specific imbalances that manifest with specific clinical symptoms.

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Differential Diagnosis of Biochemistry • Pyrrole Disorder • Disordered Metal Metabolism - Copper Excess - Zinc Deficiency • Folic Acid-responsive Methylation (aka Low Histamine)

• Methionine-responsive Methylation (aka High Histamine)

• Metallothionein dysfunction Bringing Balance to the World – One Person

Pyrrole Disorder

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Clinical Features:

Metabolic Consequences:

• • • •

• • •

Anxiety Fear Mood Swings Stress Intolerance:

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Emotional, biochemical, & physical

• •

Misperceptions Sensory issues: Light, sound, and tactile

•

• • •

Increased oxidative stress Vitamin B-6 Deficiency Impaired serotonin synthesis Zinc deficiency Low blood arachindonic acid levels Physiologic stress

Increased risk of PTSD related triggers

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Copper Excess

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Clinical Features:

Metabolic Consequences:

• • • • • •

• •

Hyperactivity Temper Tantrums Learning problems Agitation Tinnitus Depression (dysthymic or refractory)

•

Post-partum Depression

•

•

Increased oxidative stress Increased inflammatory responses and stresses Increased Norepinephrine effects due to increased conversion from Dopamine Increased strain on zinc requirements

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Zinc Deficiency

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Clinical Features:

Metabolic Consequences:

• •

•

• • • • • • •

Explosive temper Poor memory and mental lethargy Poor and delayed growth Frequent infections Poor wound healing Acne Diarrhea Hypogeusia White spots on finger nails

• • • •

Reduced defense against oxidative stress Decreased GABA formation Altered copper homeostasis Impaired cell-mediated immunity Poor energy

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Low Blood Histamine

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Clinical Features:

Metabolic Consequences:

• • • • • • •

• • •

Generalized anxiety Depression Panic Agitation & paranoia Racing thoughts Underachievement Good response to benzodiazepine medication • History of significant side effects with SSRI or antihistaminic medications

Folate deficiency Over-methylation Tendency to high dopamine, serotonin and norepinephrine

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Elevated Blood Histamine

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Clinical Features:

Metabolic Consequences:

• • • • • • • •

• • •

ADHD OCD, perfectionism Blank mind Rumination Addictive behavior Seasonal allergies Migraine headaches A history of good response to SSRI medication.

•

Methyl Deficiency Under-methylation Low levels of dopamine and serotonin. Intolerance to higher doses of folic acid.

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Metallothionein

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Short, linear, cysteine-rich proteins present in all tissues of the body that are required for trace metal metabolism and other functions: •

MT I & II are present in all tissues and regulate zinc and copper; thereby cell transcription, immune function and more. Furthermore, MT I & II are in high concentrations in the intestinal and blood-brain barriers protecting the body and brain from penetration of toxic metals.

•

MT III is present mainly in the brain and acts as a neuronalgrowth-inhibitory factor in the development, organization, and apoptosis of brain cells.

•

MT IV is present primarily in the GI tract and regulates stomach acid pH, and taste/texture discrimination by the tongue.

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Metallothionein Dysfunction Disturbances in zinc and copper are directly related to MT dysfunction.

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Quantitative depletion: Zinc is one of the primary inducers of MT; therefore, zinc depletion leads to lower levels of MT, decreased zinc transport and zinc delivery to target tissues. Functional Impairment: Excess copper displaces zinc from MT and thereby reduces zinc availability to tissues.

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MT Dysfunction in Autism Brain Structure and Function

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• impaired pruning during development • impaired functioning in tissues with high MT concentrations - Purkinjie cells, hippocampus, amygdala, pineal body and inferior olives.

Impaired immune modulation and T cell function Impaired digestive enzyme function Impaired functioning of the Blood Brain Barrier and the barrier function of the bowel wall Impaired or crippled protection from oxidative stress

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Increased Oxidative Stress

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Pro-oxidant Influences:

Overwhelmed Defenses:

• • • • •

• • •

Elevated Copper Emotional Stress Environmental toxins Immune abnormalities Physical injury

• •

Glutathione Deficiency Zinc deficiency Impaired metallothionein function Selenium deficiency Malnutrition

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Pfeiffer Research on ASD

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The Pfeiffer Treatment Center has evaluated approximately 20,000 patients, 5,500 with ASD, since 1989. Analysis of this data has shown: – – – – –

Undermethylation in Autism, 1999. Elevated copper/zinc in autism, 2000 Elevated unbound copper in autism, 2001 Metallothionein deficiency in autism, 2001 & 2003 Confirmation of these biochemical imbalances in treatmentnaïve patients with autism, 2003 – Oxidative Stress in Autism, 2006 & 2008

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Pfeiffer Assessment • Comprehensive medical evaluation focusing on the differential diagnosis of biochemistry and associated medical conditions. • Thorough laboratory assessment of biochemistry and other conditions if needed. • Development of individualized nutrient program to address biochemical needs. • Monitoring of response to treatment and reassessment every 6-12 months.

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Contact Information

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Allen T. Lewis, MD, FAAP Medical Director Pfeiffer Treatment Center 4575 Weaver Parkway

630-505-0300 630-836-0667 (fax)

Warrenville, IL 60555

[email protected]

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