Copia De Atlas Of Pediatric Ophthalmology & Strabismus.pdf

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright Š2007 Lippincott Williams & Wilkins > Front of Book > Editors

Editors Alex V. Levin M.D., FRCSC Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children and University of Toronto, Toronto, Ontario

Thomas W. Wilson M.D. Geisinger Health System, Danville, Pennsylvania

Secondary Editors Frances Destefano Acquisitions Editor Joanne Bersin Managing Editor Kathy Neely Marketing Manager David Murphy Production Editor Stephen Druding Designer TechBooks

Compositor

Walsworth Publishing Company Printer

Contributors Andrew Budning M.D., FRCSC Assistant Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

J. Raymond Buncic M.D., C.M., FRCSC Professor and Former Ophthalmologist-in-Chief Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Linda Colpa O.C.(C) Orthoptist Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada

Dan DeAngelis M.D., FRCSC Assistant Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children and Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

Robert Devenyi M.D., FRCSC Professor Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada; Ophthalmologist-in-Chief and

Director of Retinal Services, Toronto Western Hospital, Toronto, Ontario, Canada

Brenda Gallie M.D., FRCSC Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children and Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Elise HĂŠon M.D., FRCSC Professor and Ophthalmologist-in-Chief Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Jeffrey Hurwitz M.D., FRCSC Professor and Chair Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada; Ophthalmologist-in-Chief, Mt. Sinai Hospital, Toronto, Ontario, Canada

Jerome Kazdan M.D., FRCSC Associate Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Peter Kertes M.D., C.M., FRCSC Associate Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children and Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada

Stephen P. Kraft M.D., FRCSC

Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children and The Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

Wai-Ching Lam M.D., FRCSC Associate Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children and The Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

Alex V. Levin M.D., MHSc., FRCSC Professor Departments of Paediatrics, Genetics, and Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Nasrin Najm-Tehrani M.B.B.Ch., MSc., FRCS Ed (Ophth) Assistant Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Robert Pashby M.D., FRCSC Assistant Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

David Rootman M.D. Associate Professor Toronto Western Hospital, Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada

David Smith M.D., C.M., FRCSC Assistant Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Carol Westall Ph.D., B.Sc. (Optom) Director of Visual Electrophysiology Unit; Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Thomas W. Wilson M.D. Geisinger Health System, Danville, Pennsylvania, USA

Agnes Wong M.D., Ph.D., FRCSC Associate Professor Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children and The Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright Š2007 Lippincott Williams & Wilkins > Front of Book > Preface

Preface The Hospital For Sick Children's Atlas of Pediatric Ophthalmology and Strabismus is a collection of photographs and images reprsenting the wide variety of ocular disorders experienced at our institution. The Hospital For Sick Children, now fondly known as SickKids, started in the spring of 1875 in a small house located in downtown Toronto, Ontario. Over the past 125 years, The Hospital has expanded to become one of the largest children's hospitals in the world. The mission of the hospital is to lead and partner to improve the health of children through the intregration of clinical care, education, and research. The Department of Ophthalmology and Vision Sciences is an integral part of this academic health science center, providing high quality medical and surgical care for children with complex medical diseases. The department has trained ophthalmology residents and fellows from all over the world. We had the privilege to train as pediatric ophthalmology fellows at SickKids and this book is in part a demonstration of our gratitude to those who taught us and this institution which gave us that wonderful year. Each photograph in the atlas is accompanied by a concise but comprehensive description of the ocular disorder. The first section of the atlas is dedicated to isolated ocular diseases and is subdivided based upon the anatomical location of the disease (e.g., retina, lens, optic nerve). The second portion of the atlas focuses on the ocular manifestations of systemic disease and is

organized by organ system (e.g., renal, endocrine, musculoskeletal). We hope this atlas will be an excellent resource for pediatricians, general ophthalmologists, pediatric ophthalmologists and other physicians interested in ocular disease of childhood. We believe ophthalmology trainees will find this atlas a valuable guide for examination review and in acquiring basic knowledge in pediatric ophthalmology and strabismus. As the primary pediatric academic health science center in Canada, patients come from all over the world to be cared for at The Hospital for Sick Children. We are grateful to the patients for allowing us to participate in their care and share with you the extraordinary breadth of examples of ocular disease that fill the pages of this book as a result of the work of SickKids. Alex V. Levin M.D., FRCSC Thomas W. Wilson, M.D.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright Š2007 Lippincott Williams & Wilkins > Front of Book > Acknowledgments

Acknowledgments The Editors and Contributors would like to acknowledge the outstanding contributions of Leslie MacKeen, who for 12 years was our ophthalmic imaging specialist. Many of the images herein were taken by her and it is to her that we attribute so much of the high quality. Excellence was always a characteristic of her work and we hope that this atlas will reflect in some way all that she did for our Departmental imaging unit. Many other individuals made important contributions to this book including our ophthalmic photographers and imaging specialists, Cynthia VandenHoven, Carmelina Trimboli and Lindsay Hampton, who consistently provided us with support, great images, and the willingness to go beyond the call of duty. Erica Bell, Charmaine DeSouza and Constance Johnson proved to be invaluable resources particularly in the final phases as the project came together in its final form. We would also like to thank the word processing department at Geisinger Medical Center and Linda Walters, Diane Syreika, Vicki Breech and Cindy Taylor for their assistance with the preparation of the legends. We are grateful for the support and assistance of all of our present and past residents and fellows as well as our clinic personnel and hospital volunteers without whom the patients would not be seen as efficiently and with whom the staff physicians contributing to this atlas are best able to apply their diagnostic focus. Many ophthalmologists who are no longer with our Department deserve mention for their diagnostic

contributions as well: Drs. J. Donald Morin, Ted Graham, Jack Crawford, Henry Brent, Maria Arstikaitis, Maria Musarella, Tom Pashby, William Callahan, John Cardarelli and Lois Lloyd. Special thanks go out to our Ophthalmologist-in-Chief at The Hospital For Sick Children, Dr. Elise HĂŠon and to the Chairman of the Department of Ophthalmology at Geisinger Medical Center, Dr. Herbert Ingraham for their contributions, support and leadership. We would also like to extend our most gracious appreciation to the patients and families who give us the privilege of participation in their care. This atlas would also not have been possible without the persistence of our publisher and the enormous organizational and technical contribution of our assistants Crystal Rhyno and Jason Rocha. Most of all we thank our own families for their endless support. In particular the Editors are grateful for the warm support, love and patience of Faith, Josh and Mike Levin. This atlas is also published in loving memory of Gerald E. Wilson and with gratitude to Tom's mom, wife Lori and children Mara and John for their unwavering love and encouragement. Family always has and always will come first.

TABLE OF CONTENTS

[-] Section I - Isolated Pediatric Eye Disorders [+] 1 - Strabismus [+] 2 - Lids and Adnexa [+] 3 - Lacrimal [+] 4 - Conjunctiva [+] 5 - Cornea [+] 6 - Iris and Pupils [+] 7 - Lens [+] 8 - Retina and Vitreous [+] 9 - Optic Nerve [+] 10 - Glaucoma [+] 11 - Orbit [-] Section II - Ocular Manifestations of Systemic Disease [+] 12 - Child Abuse [+] 13 - Chromosomes [+] 14 - Craniofacial [+] 15 - Dermatology [+] 16 - Endocrine [+] 17 - Gastrointestinal [+] 18 - Hematology [+] 19 - Infectious Diseases [+] 20 - Metabolic [+] 21 - Neurologic [+] 22 - Vitamins [+] 23 - Phakomatoses [+] 24 - Psychiatric

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[+] 25 - Pulmonary [+] 26 - Renal [+] 27 - Rheumatology [+] 28 - Skeletal [+] 29 - Syndromes

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 1 Strabismus

1 Strabismus Alex V. Levin Thomas W. Wilson Stephen P. Kraft David Smith Linda Calpa Strabismus can be classified into congenital or acquired forms, as well as comitant versus incomitant entities. Congenital strabismus is generally considered a misalignment that manifests within the first 6 months of life, while acquired forms have their onset after that time period. Comitant strabismus implies that the degree of misalignment is the same in all fields of gaze, contrasting with incomitant strabismus, in which the measured angle of the eye turn varies in the different fields of gaze. Incomitant strabismus can vary in the horizontal or vertical plane, or both. If a horizontal misalignment (esotropia or exotropia) differs in the upgaze and downgaze positions, this leads to pattern strabismus (including A, V, Lambda, Y, or X patterns). A misalignment, either horizontal or vertical, that changes when shifting from the right to left gaze positions generates a horizontal incomitance. Finally, if a vertical misalignment (hypertropia or

hypotropia) changes on fixating from upgaze to downgaze, this is termed a vertical incomitance. Incomitant strabismus can be classified etiologically into innervational and mechanical forms. Innervational entities include innervation deficits (paresis or palsy), which can be supranuclear, nuclear, or infranuclear. Excess innervation of muscles may also occur. Mechanical causes imply restrictions due to problems within the orbit, and these can include abnormalities in the muscles, soft tissues, or bones, as well as lesions within the socket. Restrictions can be caused by congenital disorders or they can be acquired as a result of trauma, surgery, systemic disorders, or other problems.

I. Comitant Strabismus a) Esotropia

Figure 1.1 Infantile Esotropia Infantile esotropia, also referred to as essential infantile esotropia or by the older term congenital esotropia, presents as a manifest deviation with onset before 6 months of age. The angle of deviation is usually over 30 prism diopters. The eye movements are full in the vertical and horizontal planes except for mildly limited abduction of the right eye. As these children often cross-fixate, using the adducted eye to view the contralateral field rather than abducting the ipsilateral eye, it can be difficult to elicit full abduction. A rapid Doll head maneuver or patching the nontested eye may be required to elicit abduction. Infantile esotropia is also associated with inferior oblique overaction (note left eye in upgaze; also see Fig. 1.31), dissociated vertical deviation (Figs. 1.19 and 1.20), latent nystagmus, and, less commonly, manifest nystagmus.

Figure 1.2 Alternating Fixation The top photo shows that when the right eye fixates there is a left esotropia. The bottom photo shows that when the left eye fixates a right esotropia is present. With alternating fixation the deviation switches back and forth from a left esotropia to a right esotropia. This indicates equal vision in each eye (no fixation preference). If the vision were better in one eye, then covering that eye would result in temporary fixation by the fellow eye. That eye would then revert to the esotropic position as soon as the cover was removed from the better eye as the preferred eye takes up fixation. Note also the position of the corneal light reflex (Hirschberg reflex), which is always more lateral relative to the visual axis in the esotropic eye and more central in the fixating eye.

Figure 1.3 Ciancia Variant with Cross-Fixation

One subgroup of infantile esotropia, the Ciancia variant, shows nystagmus on attempted abduction of either eye. When fixating with either eye the child adopts a face turn in order to fixate with the eye in the adducted position: In that position the nystagmus dampens. The left photo shows the child fixating with the right eye in adduction, and the right photo shows him fixating with the left eye in adduction. The marked nystagmus on lateral gaze serves to distinguish the Ciancia variant from the more common cross-fixation of infantile esotropia not associated with nystagmus.

Figure 1.4 Accommodative Esotropia with and without Glasses The top photo shows a patient with a large right esotropia. The patient has a hyperopic cycloplegic refraction of +4.00. The bottom photo shows the patient wearing glasses and the

correction, in which the eyes are straight. The esotropia is now controlled, confirming that this child has accommodative esotropia. Approximately one third of these patients will always need hyperopic correction (glasses or contact lenses) to maintain straight eyes, one third can be tapered out of their correction, and one third will need strabismus surgery because of the development of a nonaccommodative component.

Figure 1.5 Partially Accommodative Esotropia This girl is wearing glasses that correct all of her hyperopia as measured during atropine refraction. The atropine cycloplegia ensures that the full hyperopic refraction is measured. This is particularly important when correction of the nonatropine cycloplegic refraction does not lead to complete straightening of the eye. While wearing the glasses she has a small residual right esotropia, representing the nonaccommodative portion of her esodeviation. Surgery is required to correct the nonaccommodative portion of the strabismus. The child would still wear spectacles postoperatively to correct the accommodative portion of the

deviation to keep the eyes straight.

Figure 1.6 Esotropia with Convergence Excess The top photo shows the patient fixating in the distance, where there is no strabismus. The lower photo shows her fixating at one-third meter on an accommodative target: Her left eye deviates inward. This convergence excess form of esotropia can be a subtype of accommodative esotropia, due to the high accommodative convergence–to–accommodation (AC/A) ratio. Convergence excess may also occur with a normal AC/A ratio. The gradient method of determining the AC/A ratio would distinguish between the two possibilities. If the deviation is reduced to zero or close to zero at near with a reading add, this may also suggest a high AC/A ratio.

Figure 1.7 Accommodative Esotropia with High Accommodative Convergence–to–Accommodation (AC/A) Ratio Treated with Bifocals The upper image shows the child fixating on an accommodative target in the near position (one-third meter) while looking through the distance portion (upper segment) of the glasses: There is an esotropia. The lower image shows him looking at the same target, but now through the add (lower segment) at near: The deviation is eliminated. This child has a high AC/A ratio. The bifocal add is correcting the excess deviation that occurs at near. Note that the bifocal is executive style and set high enough so that the child can easily fixate through the add in the near fixation position. It is recommended that the top of the segment be set no lower than the inferior edge of the pupil when the patient is fixating in the distance.

Figure 1.8 Bifocals Set Too Low The upper image shows the bifocal set several millimeters below the lower eyelids. The child is viewing a distance target with full hyperopic correction for his accommodative esotropia: The eyes are straight. The lower image shows the child fixating through the bifocal in the near position. While the add is effective in maintaining good alignment for the excess near deviation (convergence excess, see Fig. 1.6), the child has to use an awkward chin-up head posture to be able to use the bifocal segment. Figure 1.7 demonstrates proper spectacle construction for this disorder.

Figure 1.9 Pseudoesotropia The wide flat nasal bridge and the prominent epicanthal folds in this Asian child result in covering of the nasal sclera of the left eye particularly when the child is fixating slightly in right gaze. These features combine to give the impression of an esotropia. However, the corneal light reflexes (Hirschberg reflex) are symmetrically centered in each eye, thus ruling out the presence of a manifest deviation. There is no strabismus on the cover test.

Figure 1.10 Negative Angle Kappa In this photo the patient is fixating with her right eye. However, the light reflex in that eye is located slightly temporal within the pupil when compared to the centered reflex in the left eye, giving the child the appearance of a right esotropia. A cover test will show no movement of the right eye on covering the left eye, indicating that there is no strabismus. The off-centered light reflex persists under monocular conditions in the right eye. This is due to a negative angle kappa: A disparity between the visual axis (joining target and fovea) and the anatomic pupillary axis (joining midpupil to fovea). (Compare to Fig. 1.18, positive angle kappa.)

Figure 1.11 Factitious Esotropia This photo shows a marked symmetrical convergence in a patient who has recently had cycloplegic drops placed in both eyes (note that both pupils are dilated). When the patient is asked to focus on a near target the failed attempt at accommodation induces convergence. The light reflex is symmetric in each eye, so there is no true esotropia: The eyes are aligned when fixating on the near target. Convergence spasm in hyperopic noncyclopleged patients presents with a similar clinical appearance except that the pupils are constricted due to the near synkinesis. Convergence spasm can also be associated with psychological disorders.

b) Exotropia

Figure 1.12 Basic Exotropia This child is fixating with the right eye. There is a left exotropia. The angle of deviation is the same on distance and near measurements, representing a basic exotropia. Note that the corneal light reflex (Hirschberg reflex) now appears more nasal relative to the pupil center as compared to the more central reflex in the fixating right eye. As this is a comitant deviation (same amount of deviation in all positions of gaze), the eye movements of both eyes in all directions are equal and full.

Figure 1.13 Divergence Excess Exotropia The top photo shows the patient fixating in the distance: The right eye diverges. The lower photo shows the patient fixating at near, where the eyes are straight. This patient therefore has a divergence excess exotropia. However, if after 45 minutes of occlusion of the right eye the deviation at near increases to equal, or almost equal, the distance measurement, then the patient has a simulated divergence excess exotropia. The implication is that fusional convergence is keeping the eyes straight at near. If the near deviation increases through plus lenses held over the two eyes, then it also indicates the presence of a simulated divergence excess, on the basis of accommodative convergence, which is keeping the eyes aligned at near.

Figure 1.14 Convergence Weakness Exotropia The upper photo shows a young child who has a 10 prism diopter right exotropia while fixating at distance. The lower photo shows the child fixating at near, where the right exotropia is larger. When there are little or no deviation at distance and an exodeviation at near accompanied by a decreased near point of convergence, with reduced convergence amplitudes, the convergence weakness is often termed convergence insufficiency. This form of exodeviation may respond to convergence exercises. Convergence insufficiency can also occur in the absence of an actual exodeviation.

Figure 1.15 Sensory Exotropia The photo shows a patient with a dense cataract in the left eye, which precludes binocular vision. Strabismus is common in older children and adults with long-standing sensory deprivation or vision loss due to cataracts or other eye disorders. In younger children sensory esotropia is more common with an incidence almost equal to sensory exodeviation. Sensory esotropia is rare in older children and adults. Surgical correction of sensory deviations is particularly challenging because in many cases there will be a tendency for the poorly seeing eye to drift out of alignment again.

Figure 1.16 Infantile Exotropia The photo shows an infant with a large-angle right exotropia, which presented before the age of 6 months. Infantile exotropia, also known as essential or congenital exotropia, is much rarer than infantile esotropia (Fig. 1.1). The exodeviation is usually very large, almost always over 40 prism diopters. Infantile exotropia has also been reported in association with various neurologic and developmental disorders.

Figure 1.17 Exotropia with Refractive Error The top image shows a child with a left exotropia when she does not wear her myopic spectacles. The bottom image shows that her eyes are straight when she wears her glasses. The improvement is likely due to a combination of accommodative convergence and stronger fusional convergence. Improved control of exotropia can also be seen in patients with moderate or high hyperopia who are given their hyperopic correction. Without glasses the patient may choose not to accommodate fully and the exotropia manifests due to lack of fusion and accommodative convergence. When the patient wears the hyperopic correction, fusional convergence may improve, leading to straight eyes.

Figure 1.18 Positive Angle Kappa (Pseudoexotropia) The top photo shows a patient with an apparent left exotropia. The corneal light reflex in the fixating right eye is central. The bottom photo shows the patient's right eye being covered to force fixation with the left eye, which has a vision of 6/6. However, in both images the light reflex in the left eye remains located slightly nasal within the pupil, giving the child the false appearance of a persisting left exotropia. Pseudoexotropia is particularly common following retinopathy of prematurity complicated by a temporal dragging of the macula. To fixate with the fovea, the eye must be held in a turned-out position as the disparity between the visual and anatomic pupillary axes is exaggerated.

II. Dissociated Deviations

a) Dissociated Vertical Deviation

Figure 1.19 Unilateral Dissociated Vertical Deviation (DVD) The upper image shows a right hypertropia when the left eye fixates. The middle image shows the left eye being covered to force fixation with the right eye. In the lower image, the right eye continues to fixate but there is no manifest hypotropia of the left eye, confirming the diagnosis of unilateral right DVD. In dissociated vertical deviations, one eye is moving independently of the other (nonyoked innervation) in contrast to “true” vertical deviations, in which a switch of fixation to the hypertropic eye always results in an equal downward deviation of the fellow eye (yoked innervation). DVD with a downward drift has also been rarely reported.

Figure 1.20 Bilateral Dissociated Vertical Deviation (DVD) The upper photo shows that when the patient fixates with the left eye the right eye drifts upward and outward. The lower photo shows that when she fixates with the right eye the left eye drifts upward and outward. Indirect ophthalmoscopy showed excyclotropia of the hyperdeviated eye in each instance. These findings confirm the presence of bilateral DVD. Note that there is never a hypotropia of the fixating eye when fixation is switched (Fig. 1.19). If a patient presents with a latent or manifest DVD in one eye, patching of the fellow eye for several minutes may bring out a bilateral DVD that was not apparent on initial examination. In side gaze, fixation by the adducting eye can be blocked by the nose, causing that eye to drift upward. To differentiate this from overaction of the inferior oblique (Fig. 1.31), a cross-cover test will fail to show a hypotropia of the abducting eye in DVD.

b) Dissociated Horizontal Deviation

Figure 1.21 Dissociated Horizontal Deviation (DHD) The upper image shows a child with a right exotropia when he fixates with the left eye. This horizontal deviation becomes manifest when there is a lack of visual attention or a disruption in fusion. In the lower image, the child is fixating with his right eye, yet there is no manifest exotropia of the left eye. There is a symmetric low hyperopic refractive error in the two eyes, leading to symmetric accommodative demand for the two eyes. These findings suggest a right dissociated horizontal exodeviation. Most cases of DHD are exodeviations. Dissociated esodeviations are much less common.

III. Incomitant Strabismus: Patterns

a) A-pattern Strabismus

Figure 1.22 A-pattern Exotropia with Overaction of the Superior Obliques The photos show the nine diagnostic positions of a patient with an exotropia in primary position (center photo). The exotropia increases significantly on direct downgaze, while on upward gaze the deviation is much smaller. The overactions of the superior obliques are evident on gazes into the down-right and down-left positions. There is mild underaction of both inferior oblique muscles evident in the upper right and upper left photos.

Figure 1.23 A-pattern Exotropia without Overaction of the Superior Obliques This patient has a small exotropia in primary position (center photo) that is larger on downgaze and less on upgaze. There is no overaction of the superior oblique muscles (lower right and lower left images).

Figure 1.24 Head Posture with A-pattern Exotropia The left photo shows the child with a chin-down head posture, viewing straight ahead with eyes in upgaze. The top right photo shows normal alignment in the upgaze position while the bottom right photo shows a large exotropia on downgaze. The chin-down position allows the child to maintain binocular vision.

Figure 1.25 A-pattern Esotropia with Overaction of the Superior Obliques This patient shows an esotropia in primary position (center photo). The esotropia is markedly reduced on downgaze and increases significantly on upgaze. The superior obliques are overacting as seen in the lower right and lower left gaze positions where the adducting eye is relatively hypotropic. The inferior oblique muscles are underacting, as seen in the upper right and upper left gaze positions where the adducting eye is also relatively hypotropic.

Figure 1.26 A-pattern Esotropia without Overaction of the Superior Obliques This patient has an esotropia in primary position (center photo) that is markedly reduced on downgaze and increases significantly on upgaze. However, the superior and inferior oblique muscle actions are normal.

Figure 1.27 Head Posture with A-pattern Esotropia The photos show the chin-up posture adopted by a child with A-pattern esotropia. The esotropia is reduced somewhat by wearing his hyperopic glasses (partially accommodative esotropia, Fig. 1.5). As a result, the chin position with spectacles on (left photo) is less severe than the chin-up posturing without glasses (right photo). The anomalous head posture enables the child to retain fusion as the deviation is least in the downgaze field.

b) V-pattern Strabismus

Figure 1.28 V-pattern Exotropia with Overaction of the Inferior Obliques These photos show a patient with exotropia in primary position (center photo). The exodeviation is greatest on upgaze and is almost eliminated on downgaze. The inferior oblique muscles are overacting as seen in the upper right and upper left gaze positions where the adducting eye is relatively hypertropic. In addition, there is some underaction of both superior obliques, as seen in the lower right and lower left gaze positions where the adducting eye is also relatively hypertropic.

Figure 1.29 V-pattern Exotropia without Overaction of the Inferior Obliques This child has exotropia in primary position (center photo). The exodeviation is greatest on upgaze and reduces to zero on downgaze. The inferior oblique muscles are acting normally as seen in the upper right and upper left images.

Figure 1.30 Head Posture with V-pattern Exotropia The left photo shows the chin-up posture adopted by this child with V-pattern exotropia. The top right photo shows the child's large exotropia on upgaze. The lower right photo shows the normal alignment in downgaze. With the chin elevated the child is able to view straight ahead with eyes in downgaze, thus maintaining normal ocular alignment and good binocular vision.

Figure 1.31 V-pattern Esotropia with Overaction of the Inferior Obliques This child has a small esotropia in primary position (center photo). The esodeviation is greatest on downgaze and reduces to zero on upgaze. The inferior oblique muscles are overacting, as seen in the upper right and upper left gaze positions where the adducting eye is hypertropic. In addition, there is some underaction of both superior obliques as seen in the lower right and lower left gaze positions where the adducting eye is, again, hypertropic.

Figure 1.32 V-pattern Esotropia without Overaction of the Inferior Obliques This child's small esotropia in primary position (center photo) increases on downgaze and decreases on upgaze. The inferior oblique muscles are acting normally, as are the superior obliques.

Figure 1.33 Head Posture with V-pattern Esotropia The photo shows an older boy with an extreme chin-down posture due to V-pattern esotropia caused by bilateral superior oblique paresis. There was a large esotropia in primary position, which increased in downgaze, associated with excyclotropia. Only in his preferred head position, where he is fixating in extreme upgaze, can he regain fusion.

b) Other-pattern Strabismus

Figure 1.34 Y-pattern Strabismus This patient has straight eyes in primary position (center photo) and in downgaze. There is a large exotropia in upgaze. On looking up and to the right (upper left photo), the left eye is abducted, and on looking up and to the left (upper right photo), the right eye is abducted. Y-pattern strabismus can be caused by tightness or inferior malposition of the lateral rectus muscles or, occasionally, by overaction of the inferior obliques.

Figure 1.35 Lambda-pattern Strabismus This patient has a small exotropia in primary position (center photo) that measures the same in upgaze. There is a much larger exotropia in the downgaze position. On looking down and to the right (lower left photo) and down and to the left (lower right photo), the superior obliques appear to overact. However, this pattern can also be caused by superior malpositions of the lateral rectus muscles.

Figure 1.36 X-pattern Strabismus This patient has an exotropia in primary position (center photo), which increases significantly on both upgaze and downgaze. There is mild limitation of adduction of each eye (center right and center left photos). There are apparent overactions of both the superior and inferior obliques in each eye, although this feature can also be caused by overrotation of the globes within the orbits due to a lack of full adduction. This pattern is most commonly seen in longstanding exotropia where the lateral rectus muscles have become contractured, a condition termed the tight lateral rectus syndrome.

IV. Incomitant Strabismus: Paretic a) Grading Ocular Muscle Actions

Figure 1.37 Grading Abduction Deficits (Courtesy of W.E. Scott, MD) This composite figure shows various degrees of abduction limitation in the left eye ranging from normal abduction (grade 0) to complete failure of abduction (grade –4). The upper right picture shows normal abduction (0). The upper left picture shows some lateral rectus weakness (–1), consistent with approximately 25% limitation. In the lower panel, from left to right, the photos show 50% limitation (– 2), 75% limitation (–3), and total (100%) limitation (–4). The designations for adduction limitations (not shown) are done in a similar fashion. Limitations of adduction or abduction must be correlated with monocular movements of the eyes (ductions) to ensure that there is no pseudolimitation brought on by fixation with the fellow eye.

Figure 1.38 Grading Inferior Oblique Actions (Courtesy of W.E. Scott, MD) This figure shows nine grades of right inferior oblique action. The center photo shows normal (0) action. The underactions are mild (grade -1, left center), 50% limitation (-2, lower left), 75% limitation (-3, lower center), and total limitation (-4, lower right). The overactions are mild (+1, right center), moderate (+2, upper right), severe (+3, upper center), and complete (+4, upper left). Another way to grade under- and overaction of the oblique muscles is to equate one grade with 1 mm of difference in the inferior limbus (for inferior oblique grading) and superior limbus (for superior oblique grading) between the eyes. For example, if in adduction the right inferior limbus is 2 mm higher than the left inferior limbus, then the right eye is designated to have +2 overaction.

Figure 1.39 Grading Superior Oblique Actions (Courtesy of W.E. Scott, MD) This figure shows the nine grades of right superior oblique action: four grades of overaction (+1 to +4), normal action (0), and four grades of underaction (-1 to -4). The superior oblique action is graded in the same fashion and in the same array as for the inferior oblique (Fig. 1.38). Note that in cases of extreme overaction, the affected eye abducts in downgaze in addition to extreme depression (upper left photo).

b) Third Nerve Paresis (Oculomotor Nerve Paresis)

Figure 1-40 A: Complete Third Nerve Palsy This patient with a right third nerve palsy is fixating with his left eye in the primary position. There is severe right ptosis.

Figure 1-40 B: Complete Third Nerve Palsy This figure shows the nine diagnostic positions of gaze, with the ptotic right upper eyelid held up to show the eye movements. In the center image of the figure, he shows a right large-angle exotropia and right hypotropia. The right pupil is dilated and nonreactive with loss of accommodation due to paresis of the parasympathetic fibers, which originate in the Edinger-Westphal nucleus in the midbrain and travel to the eye with the inferior division of cranial nerve III. There are complete adduction and elevation deficits, and the depression of the eye is limited. The origin of the third nerve palsy is likely intracranial as all branches are involved. Possible causes include trauma, tumor, and vascular malformation. New onset of a nontraumatic third nerve palsy should lead to neurologic evaluation. When the pupil is spared the cause is usually due to a vasculopathic cause such as diabetes, but a neurologic assessment is still recommended.

Figure 1.41 Congenital Third Nerve Palsy A 3-month-old infant with congenital third nerve palsy shows an exotropia and hypotropia of the right eye along with ptosis. In children who are otherwise normal, birth trauma or intrauterine insults are the likeliest causes. Amblyopia is commonly seen in these children.

Figure 1.42 Paresis of Inferior Division of Third Cranial Nerve Photos of nine diagnostic positions show a right eye with an exotropia along with a right hypertropia (rather than a hypotropia) in primary position (center photo). The eye has mildly limited adduction and a severe limitation of depression. Elevation is slightly limited only in the adducted position, as the superior rectus muscle still functions. There is no ptosis. The pupil is slightly dilated. This is most often caused by viral illness, neoplasm, or trauma.

Figure 1.43 Paresis of Superior Division of Third Nerve This patient with a paresis of the superior division of the left third nerve has a left hypotropia in primary position (center photo). There is also left ptosis due to paresis of the levator palpebrae. The eye is unable to elevate in all upgaze fields due to the paretic left superior rectus muscle. Causes include meningitis and trauma.

Figure 1.44 Aberrant Regeneration of Third Nerve: Pseudo von Graefe Sign This patient has a chronic right third nerve paresis with right ptosis. On attempted adduction and depression of the right eye the right upper eyelid elevates, indicating aberrant regeneration between the right levator palpebrae muscle and the inferior division of the involved third nerve: Stimulation of the inferior division through attempted use of the inferior or medial rectus results in simultaneous contraction of the levator palpebrae. The aberrant innervation can occur within several weeks of the insult to the nerve. Causes include trauma or a space-occupying lesion, such as a tumor or aneurysm in the cavernous sinus.

Figure 1.45 Aberrant Regeneration of the Third Nerve: Pupil Involvement This patient has old bilateral third nerve paresis, in which the right paresis has almost recovered. There is aberrant regeneration in the right eye involving the pupil: The pupil is dilated, but it constricts on gaze to the left and on downward gaze, indicating aberrant regeneration between the pupil constrictor fibers and the nerves to the medial and inferior rectus muscles (inferior division of third cranial nerve). If the history does not suggest trauma as a cause, then investigation for a tumor or aneurysm should be undertaken.

c) Fourth Nerve Paresis (Superior Oblique Paresis)

Figure 1.46 Three-step Test (Including Bielschowsky Headtilt Test) The top image shows an incomitant vertical deviation in the horizontal plane, with a left hypertropia in primary position (upper center photo). The causative weak vertical muscle can be one of the depressors of the left eye (superior oblique or inferior rectus), or one of the elevators of the right eye (inferior oblique or superior rectus). The deviation decreases in left gaze and increases in right gaze, thus isolating the possible weak muscles to the left superior oblique or the right superior rectus as these muscles have their principal vertical actions on right gaze. In the bottom images, we see the same patient on head tilt to the right and left shoulders. There is no hypertropia on tilting to the patient's right, but there is a large left hypertropia on tilting to the left. This indicates a positive head-tilt test. It is also termed a positive Bielschowsky head-tilt test, or a significant head-tilt difference. The findings isolate the candidate muscle to an incyclotorter of the left eye (which still implicates the left superior oblique) or one of the excyclotorters of the right eye (neither of which was a candidate muscle). Therefore, of the two candidate muscles

isolated in the second step, the left superior oblique is confirmed as the weak muscle.

Figure 1.47 Unilateral Superior Oblique Paresis This patient has a left hypertropia that worsens in the right gaze position and decreases in left gaze. There is a V pattern with an esotropia in downgaze. The left superior oblique muscle is underacting, and its antagonist, the left inferior oblique muscle, is overacting. In the lower panel the center photo shows the compensatory head posture consisting of a right head tilt and slight right face turn. The right and left images in the bottom panel show the positive head-tilt test, with a left hypertropia on left tilt that vanishes on right tilt, confirming the diagnosis of a left superior oblique paresis. Superior oblique palsy may be congenital or acquired. Patients with congenital superior

oblique palsy may not be diagnosed until they are no longer able to maintain fusion and begin to experience diplopia and/or show a manifest strabismus in the primary position. Old photographs may show long-standing compensatory head tilt and facial asymmetry. These patients may have markedly enlarged vertical fusional amplitudes. Common causes of acquired fourth cranial nerve palsy include head trauma and intracranial tumors.

Figure 1.48 Bilateral Superior Oblique Paresis Bilateral superior oblique paresis may be suspected in the presence of a reversing hypertropia: A right hypertropia on left gaze and a left hypertropia on right gaze. These deviations are most noticeable on downgaze to the right and left. There is large V pattern, with an esotropia in downgaze and exotropia in upgaze. Both superior oblique muscles are underacting. The bottom left photo shows right hypertropia

on right head tilt, while the bottom right photo shows a left hypertropia on left head tilt, thus confirming the diagnosis of bilateral superior oblique paresis. In the primary position the eyes may be orthotropic or a hypertropia in the eye with an asymmetrically worse superior oblique palsy may be seen. Differential diagnoses include alternating skew deviation (Fig. 1.68), craniofacial syndromes with exorbitism (Chapter 14: Craniofacial), primary overaction of the inferior obliques (Fig. 1.28), and bilateral dissociated vertical deviation (Fig. 1.20).

Figure 1.49 Fallen Eye Syndrome This patient has a left superior oblique paresis. When the patient fixates with the paretic left eye, it causes a right hypotropia that is incomitant. The right eye becomes significantly more hypotropic on right gaze (the field of action of the left superior oblique), and this down-drift is

termed a “fallen eye.” The presence of a fallen eye may indicate an oblique muscle problem in the fixating eye. If the patient fixates with the nonparetic eye, the hypertropia in the paretic eye (the primary deviation) may be less than the hypotropia seen when fixing with the paretic eye (the secondary deviation).

Figure 1.50 Fundus Excyclotropia The upper two photos show bilateral fundus excyclotropia, with the foveae lying at levels below the lower edges of the optic discs. Normally the foveal reflexes lie at levels even with the lower one third of the disc. The lower two photos show reorientation of the foveae close to their normal positions following bilateral modified Harada-Ito procedures to correct the excyclotropia. This reorientation can be observed on the operating room table as the procedure is

performed.

d) Sixth Nerve Palsy (Lateral Rectus Paresis)

Figure 1.51 Total Unilateral Sixth Nerve Palsy The upper image shows a child with a left sixth nerve palsy adopting a large left face turn in order to maintain fusion by placing his eyes in right gaze to maintain alignment. In the bottom images, the child's head is being held in the primary position where there is a left esotropia. The deviation increases markedly in left gaze due to the failure of abduction. The angle decreases almost to zero in right gaze. In children, common causes of a sixth cranial nerve palsy include increased intracranial pressure from tumor or trauma and inflammation of the petrous portion of the temporal

bone following otitis media (Gradenigo syndrome). Sixth cranial nerve palsy must be distinguished from Duane syndrome (Fig. 1.59).

Figure 1.52 Partial Unilateral Sixth Nerve Paresis The photos of the horizontal gaze positions show a partial limitation of abduction of the left eye, consistent with a partial sixth nerve paresis. As in a complete sixth cranial nerve palsy, there is an esotropia in primary position (center photo), which is incomitant, increasing on ipsilateral gaze (lower photo) and decreasing on contralateral gaze (upper photo). The patient may adopt a face turn to the affected side, but the degree of face turn will be less than that seen in a complete sixth cranial nerve paresis (Fig. 1.51). Likewise, the esotropia in primary position will also be smaller.

Figure 1.53 Bilateral Sixth Nerve Palsy The presence of a very large bilateral esotropia in primary position (center photo) with a complete failure of abduction of each eye on side gazes (upper and lower photos) is a characteristic of a bilateral sixth nerve palsy. The differential diagnoses include infantile esotropia (Fig. 1.1), in which abduction can be improved significantly by Doll eye maneuvers; bilateral Duane syndrome (Fig. 1.60), in which the primary position esotropia is much smaller and characteristic co-contraction on adduction is seen in both eyes; strabismus fixus following a history of long-standing esotropia; the Ciancia variant of the infantile esotropia syndrome (Fig. 1.3); and factitious esotropia (Fig. 1.11). The patient may adopt a face turn to either side not to attain fusion, but rather to see straight ahead with an eye that otherwise cannot abduct well enough to get to the midline (primary position).

c) Multiple Cranial Nerve Paresis

Figure 1.54 Combined Fourth and Sixth Nerve Pareses In primary position (center photo) this patient has a right esotropia and right hypertropia. There is a limitation of abduction due to a right sixth nerve paresis (center left), along with limitation of depression in the adducted position (bottom right) due to the concurrent right fourth nerve paresis. The right inferior oblique muscle is overacting (upper right). The three-step test (Fig. 1.46) cannot be applied if the third cranial nerve is one of the affected nerves. The presence of multiple simultaneous cranial nerve palsies should lead one to consider meningeal processes (meningitis, meningeal carcinomatosis), severe brain injury, demyelinating disease, and Arnold Chiari malformation as possible causes. Myasthenia gravis, orbital trauma, and

Graves disease can lead to unusual eye movement patterns that mimic multiple cranial nerve palsies.

f) Double Elevator Paresis

Figure 1.55 Double Elevator Paresis The top photo shows a young child with a right hypotropia and ptosis. The lower six views show limitation of elevation of the right eye in all of the upgaze fields (upper row) and a comitant right hypotropia in the horizontal plane (lower row). Although this entity is commonly referred to as a double elevator palsy (DEP), it is more appropriately called a monocular elevation deficit, as the cause can be an inferior rectus restriction, a supranuclear deficit of elevation (the classic form of DEP), a superior rectus paresis, or a paresis of both elevators. The child adopted a chin-up position (top center inset image) to attain fusion.

Figure 1.56 Pseudoptosis In the upper image a patient with a left monocular elevation deficit is fixating with normal right eye. There is a left hypotropia and ptosis. In the lower image, the patient is fixating with the paretic left eye. The upper eyelid is now almost at its normal position. This confirms that the ptosis seen in the top photo is mainly a pseudoptosis due to the hypotropic position of the eye rather than a true paresis of the levator palpebrae, which is not involved in this child's monocular elevation deficit. The lid position is best addressed by repair of the strabismus rather than ptosis surgery.

Figure 1.57 Bell Phenomenon Although this patient has a right monocular elevation deficit, the single bottom image demonstrates the intact Bell phenomenon in that eye: Full upgaze in response to an attempt to open forcibly closed eyelids. This confirms that the elevators of the right eye are, in fact, functioning and that there is no mechanical restriction to upgaze. This suggests that the elevation deficit is of supranuclear origin as seen in the classic double elevator palsy (Fig. 1.55). Note that the Bell phenomenon is an involuntary movement of the eye, as opposed to the voluntary ductions and versions.

g) Inferior Oblique Paresis

Figure 1-5 A: Inferior Oblique Paresis Figure A shows a patient with a left hypertropia in primary position (center image). The hypertropia worsens in left gaze and decreases in right gaze. There is an A-pattern esotropia. The right inferior oblique muscle is underacting (upper right image) and its antagonist, the right superior oblique, is overacting (bottom right image).

Figure 1-58 B: Inferior Oblique Paresis Figure B shows the Bielschowsky head-tilt test, with the left hypertropia worsening on left head tilt and lessening on right head tilt. This result confirms the right inferior oblique muscle, an excyclotorter of the right eye, as the weak vertical muscle. Inferior oblique palsy is generally an idiopathic condition, but congenital, traumatic, and vascular causes have rarely been reported.

h) Duane Retraction Syndrome

Figure 1.59 Unilateral Duane Syndrome Type I Duane syndrome is one of the strabismus entities now grouped under the category of congenital cranial disinnervation disorders (CCDDs), which include Moebius syndrome (Fig. 1.73) and congenital fibrosis syndrome (Fig. 1.66). These disorders are all caused by the development of anomalous innervational patterns due to cranial nerve maldevelopment that arises during embryogenesis. This patient has a left esotropia in primary position (center image). She has almost complete failure of abduction of the left eye. On adduction of the affected eye, the eyelid fissure narrows noticeably (center left image), due to retraction of the globe into the orbit. As a result of maldevelopment of the left sixth cranial nerve, reinnervation of the lateral rectus with aberrant fibers from the third cranial nerve causes both the lateral and medial rectus to contract simultaneously on adduction. The adduction of the eye appears full, thus confirming this Duane syndrome as type I.

Figure 1.60 Bilateral Duane Syndrome Type I This patient has bilateral limitations of abduction and bilateral narrowing of the eyelid fissures with globe retraction on adduction to either side (center row). The adduction of each eye is almost full, confirming the diagnosis of bilateral type I Duane syndrome. Notice the near absence of esotropia in primary position (center image), unlike the large esotropia seen in bilateral sixth cranial nerve palsy (Fig. 1.53). In Duane syndrome, neuroimaging and urgent management are rarely required. Several chromosomal aberrations and loci have been associated with Duane syndrome. It may be inherited in an autosomal dominant pattern.

Figure 1.61 Unilateral Duane Syndrome Type II This patient has a Duane syndrome of the left eye that produces an incomitant exotropia. The center row of images shows a left exotropia in primary position (center) with limitation of adduction of the left eye and marked retraction causing narrowing of the eyelid fissure, while abduction is full. There is a significant upshoot (upper-left image) and downshoot (bottom-left image) in the adducted position. These findings are consistent with a Type II Duane syndrome. This is the least common among the three classic types of Duane syndrome.

Figure 1.62 Unilateral Duane Syndrome Type III This patient has markedly limited adduction and abduction of the left eye and narrowing of the palpebral fissure on adduction of that eye, consistent with a type III Duane syndrome. The eyes are orthotropic or only minimally misaligned in the primary position. As a result, the patient does not adopt an anomalous head position. In all forms of Duane syndrome, children become unconsciously adept at turning their head from side to side to compensate for their deficient horizontal ductions. As a result, particularly when there is no anomalous head position or strabismus in the primary position, Duane syndrome often goes undiagnosed until later childhood.

Figure 1.63 Up-shoot and Down-shoot Phenomena in Duane Syndrome Up-shooting (left image) and down-shooting (right image) in adduction can be seen in all types of Duane syndrome and represent slippage of a tight contracted lateral rectus over the globe or a coinnervation phenomenon involving the lateral and superior rectus or lateral and inferior rectus muscles or, rarely, the lateral rectus and inferior oblique muscles.

V. Incomitant Strabismus: Restrictive a) Brown Syndrome

Figure 1.64 Unilateral Brown Syndrome The images show a child with a right congenital idiopathic Brown syndrome. There is a total failure of elevation of the right eye in the adducted position (upper right photo), due to lack of laxity in the superior oblique tendon and its surrounding soft tissues. There is also limited elevation in the straight upward gaze position (upper center image). The action of the right superior oblique in its gaze field (adducted downgaze, lower right image) is normal. There is a V-pattern exotropia. The child may adopt a chin-up position to maintain fusion. Brown syndrome may also be acquired due to trauma or inflammation (e.g., juvenile rheumatoid arthritis). In the latter circumstance, the area of the trochlea may be swollen and tender to palpation.

Figure 1.65 Bilateral Congenital Brown Syndrome This patient with bilateral congenital Brown syndrome has markedly limited elevation in the adducted position of both eyes (upper left and upper right images). Each eye shows a mild down-drift (hypotropia) on adduction (center right and left images). There is a V pattern with a large exotropia in the upgaze position (top center image), due to the restrictive anomalies in both superior oblique tendons. The patient may adopt a chin-up position to obtain fusion.

b) Congenital Fibrosis Syndrome

Figure 1.66 Congenital Fibrosis Syndrome Type 1 (CFEOM Type 1) These images show a patient with the most common form of congenital fibrosis syndrome, or CFEOM type 1. The patient is unable to elevate either eye above the midline. In primary position the eyes are ptotic and exotropic; the child is more comfortable fixating in downgaze. The patient will likely use an extreme chin lift in the primary position with or without a face turn. The presence of amblyopia or asymmetry will affect the choice of face position. This syndrome is one example of the group of primary congenital innervational disorders that can lead to severe mechanical restrictions, and which collectively are known as the congenital cranial disinnervation disorders (CCDDs). Other entities included among the CCDDs are Duane syndrome (Figs. 1.59, 1.60, 1.61, 1.62 and 1.63) and Moebius syndrome (Fig. 1.73). Mutations in the kinesin gene (K1F21A) on chromosome 12 result in maldevelopment of the third cranial nerve nuclei and the CFEOM type 1 phenotype, which is transmitted in an autosomal dominant pattern.

Figure 1.67 Congenital Fibrosis Syndrome Type 2 (CFEOM Type 2) These images show a patient with a large exotropia in primary position and limited adduction in each eye. There are also limitations of elevation and depression in both eyes. CFEOM type 2 is due to mutations in the ARIX gene at 11q13, which encodes a transcription factor involved with the development of the nuclei for cranial nerves III and IV. Patients may also show bilateral miosis. There is also another form of this disorder, CFEOM type 3 (not pictured), mapped to 16q24, for which the gene has not yet been cloned.

VI. Supranuclear Disorders with Strabismus

a) Skew Deviation

Figure 1.68 Alternating Hypertropia Skew deviations are incomitant deviations, which may or may not conform to patterns seen in other established strabismus disorders, due to central nervous system disease. In this patient with a cerebellar tumor, there is a right hypertropia on right gaze (center left image) and a left hypertropia on left gaze (center right image). This should not be confused with the alternating hypertropia of bilateral superior oblique paresis (Fig. 1.48). In the patient pictured here, there is apparent overaction of both superior oblique muscles. However, skew deviation can also manifest itself with apparent underaction of the superior obliques. The patient also had ataxia and nystagmus.

b) Internuclear Ophthalmoplegia

Figure 1.69 Internuclear Ophthalmoplegia with Exotropia The images show the horizontal versions of a patient with a left internuclear ophthalmoplegia (INO) caused by a demyelinating disorder. There is a left exotropia in primary position (center image) and limited adduction of the left eye (left image). Clinically, the patient showed a jerk nystagmus of the right eye in the right gaze direction. INO can occur with or without an exotropia in primary position. The lesion is located in the medial longitudinal fasciculus on the left side, which contains an interconnecting neuron joining the right sixth nerve nucleus with the left medial rectus subnucleus.

Figure 1.70 Wall-eyed Bilateral Internuclear Ophthalmoplegia (WEBINO) Syndrome This patient has bilateral internuclear ophthalmoplegia and a large exotropia, or WEBINO syndrome, caused by a cerebrovascular occlusive event. There is markedly limited adduction of each eye. There was a jerk nystagmus of the abducting eye on both lateral gazes. Such cases arise due to damage to both medial longitudinal fasciculi, leading to disconnection between both sixth nerve nuclei and their connections to the contralateral medial rectus subnuclei. This syndrome is caused by extensive lesions in the brainstem.

VII. Miscellaneous Disorders

a) Ophthalmoplegias

Figure 1.71 Fisher Syndrome Fisher syndrome is an infrequent variant of the GuillainBarré syndrome, consisting of a triad of ataxia, areflexia, and ophthalmoplegia without concurrent peripheral neuropathy. This patient has Fisher syndrome following an upper respiratory illness, which is the most common cause. The differential diagnoses include brainstem stroke, pituitary apoplexy, diphtheria, and cerebral sinus thrombosis. There is a partial ophthalmoplegia that includes limited abduction in the right eye and limited abduction, elevation, and adduction in the left eye. There is a mild ptosis of the left upper eyelid.

Figure 1.72 Chronic Progressive External Ophthalmoplegia (CPEO) This woman has bilateral limited horizontal and vertical ductions and ptosis due to CPEO. The elevation and adduction of each eye are most severely affected. The most common subset of CPEO is the Kearns-Sayre syndrome, which has an onset in the first or second decade of life and is due to deletions in mitochondrial DNA. Patients show a progressive ptosis and external ophthalmoplegia, and they develop a salt-and-pepper pigmentary retinopathy and cardiac conduction deficits. This patient did not show any evidence of retinopathy or heart conduction problems.

b) Moebius Syndrome

Figure 1.73 Moebius Syndrome The center image shows the presence of a small right esotropia in primary position and hypoplastic facial muscles. The seventh cranial nerves were weak on both sides (facial diplegia). There is complete failure of abduction of both eyes, but the vertical ductions are normal. Moebius syndrome is another strabismus entity in the overall category of congenital cranial disinnervation disorders, which include Duane syndrome (Figs. 1.59, 1.60, 1.61, 1.62 and 1.63) and congenital fibrosis syndrome (Figs. 1.66 and 1.67). In addition to the eye muscle and facial nerve anomalies, any of the lower cranial nerves can be involved.

Figure 1.74 Moebius Syndrome—Nonocular Findings Moebius syndrome may be associated with limb anomalies such as the abnormal right forearm (phocomelia) shown here (left photo). The patient also had a hypoplasia of the ipsilateral pectoralis muscle (Poland syndrome). One or both sides of the tongue may appear crenulated due to hypoplasia of the 12th cranial nerve (hypoglossal nerve). In this patient the left side of the tongue is affected (right photo). Several chromosomal loci have been associated with Moebius syndrome. It may be inherited as an autosomal disorder with variable expression.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 2 - Lids and Adnexa

2 Lids and Adnexa Alex V. Levin Thomas W. Wilson Robert Pashby Dan DeAngelis The lids and adnexa are composed of the anterior and posterior lamella. The anterior lamella is composed of the skin, subcutaneous tissue (which is the thinnest in the body), cilia, and orbicularis muscle. The posterior lamella consists of the orbital septum, tarsus (including meibomian glands), and conjunctiva. Embryologically, the upper eyelids are derived from the frontonasal process and the lower eyelid is derived from the maxillary process of the face. The eyelids fuse at approximately 7 weeks' gestation and typically open by the sixth month of gestation. The events that lead to eyelid separation in utero are thought to be related to either keratinization of the eyelid margin or secretions by the primitive meibomian glands. Proper development of the eyelids and adnexa is dependent on normal fusion of the eyelids. Inadequate fusion of the eyelids can result in eyelid colobomas and deficiencies in the adnexal structures, namely the cilia and tarsus. Similarly, abnormal separation of the

eyelids can result in persistent bands to the globe or the opposing lid. Early in the development of the adnexa, the meibomian glands are pluripotential structures that most commonly develop into glandular elements. However, they also have the potential to develop into follicular structures. If this occurs, then cilia are seen emerging from the posterior half of the eyelid margin, in the meibomian orifices. Thus, the patient will have an extra accessory row of anatomically normal eyelashes, which can cause significant ocular irritation. The normal eyelid crease is formed by the projection of the levator fibers anteriorly, as they interdigitate among the fibers of the orbicularis oculi muscle. Congenital ptosis is caused by a dystrophic change in the levator muscle, resulting in a muscle that is variably functional. As such, the fibrosis in the muscle fibers results in an absent lid crease and in lid retraction on downgaze, both prominent features of congenital ptosis. Lid abnormalities may occur in isolation or as part of systemic syndromes and disease processes. The underlying globe may also be abnormal. Lid and adnexal malformations may also be unilateral or bilateral. An understanding of these congenital and acquired lid disorders may assist the physician in understanding coexisting ocular and systemic abnormalities.

Figure 2.1 Cryptophthalmia Cryptophthalmia is complete or partial fusion of the eyelids usually with aberrant or no eyelashes. The underlying eye is typically microphthalmic and often fused to the overlying eyelid skin. Attempts to repair the skin defect often involve corneal transplantation with poor visual prognosis. The nasolacrimal system is usually absent or malformed. Cryptophthalmos can be either unilateral or bilateral. Autosomal recessive, and less commonly autosomal dominant, inheritance has been reported. Most cases are sporadic. Approximately one fourth of cases are isolated and the rest are associated with other malformations. Fraser syndrome is the association of cryptophthalmos (not obligatory), syndactyly, and abnormalities of the urogenital system. Some cases are due to mutations in the FRAS1 gene at 4q21.

Figure 2.2 Ankyloblepharon Ankyloblepharon is complete or partial fusion of the eyelid margins. Unlike cryptophthalmus, the globe is usually normal and proper lid structures are recognizable. Most often the connections are thin bands as shown in these images. The skin adjoining the lids is called filiform adnatum. Although the strands look thin, one should not separate the lids by manual traction. Treatment is by surgical separation of the eyelid margins. Rarely, ankyloblepharon can be part of systemic conditions such as Hay-Wells syndrome. More often it is a sporadic nongenetic anomaly.

Figure 2.3 Blepharophimosis Blepharophimosis syndrome (BPES) is a combination of congenital ptosis, epicanthus inversus, and short horizontal palpebral fissure length with telecanthus (increased distance between the medial canthi). Ectropion may also be seen. As shown here, the patient may use a chin lift in the straightahead viewing position. There is an autosomal dominant inheritance. Type 1 BPES is also characterized by female infertility and is due to abnormalities in the FOXL2 gene at 3q22. Type 2 BPES is due to abnormalities in the same locus but with no systemic abnormalities. Another locus for isolated BPES is proposed on chromosome 7q. Treatment options include a resection of the medial canthal skin (Roveda procedure) and ptosis surgery.

Figure 2.4 Epicanthus There are four types of epicanthal folds: supraciliaris (upper photo), palpebralis (not pictured), tarsalis (lower photo), and inversus (see Fig. 2.3). Although epicanthus inversus is more common in blepharophimosis, epicanthus is otherwise generally a nonspecific minor malformation often seen in normal individuals. Epicanthus is more prevalent in certain ethnic groups.

Figure 2.5 Coloboma Eyelid coloboma is a defect in the upper or lower eyelid margin. The most common location is in the nasal half of the upper lid and may be isolated or seen in association with Goldenhar syndrome. Characteristic lower eyelid colobomas are associated with Treacher Collins syndrome or mandibulofacial dysostosis (Chapter 14: Craniofacial, Figs. 14.14, 14.15 and 14.16), where the medial aspect of the lid downslopes gradually, followed by a sharp uprise to the normal lateral margin. When the medial aspect of the lid is involved with coloboma, the lacrimal puncta and canaliculus may be absent and the caruncle abnormal. As seen in this image, lid coloboma may also be associated with a form of symblepharon where conjunctiva and/or lid tissue may be attached to the globe with or without scarring of the cornea.

Figure 2.6 Epiblepharon Epiblepharon is caused by a horizontal fold of skin under the medial lower eyelid, which rotates the eyelashes toward the globe. It is more common in some Asian children, but may be seen in any ethnic group. Epiblepharon can often resolve with midfacial growth. Surgery is indicated for corneal irritation and scarring due to trichiasis. A horizontal strip of skin and orbicularis corresponding to the fold is removed in order to reorient the eyelashes. It is important not to include the epicanthal folds with the resection. This entity is not considered a major malformation and is often seen in the otherwise normal general population.

Figure 2.7 Telecanthus and Hypertelorism Telecanthus is an increased distance between the medial canthi and should be distinguished from hypertelorism, which is an increased distance between the orbits. Hypertelorism is diagnosed using the Mustardé index: ICD/IPD >0.55 (where ICD = inner canthal distance and IPD = measured interpupillary distance). Hypertelorism is a radiologic diagnosis, measuring the interlacrimal distance. This patient has both telecanthus and hypertelorism. Telecanthus without hypertelorism is seen in blepharophimosis syndrome (Fig. 2.3). In telecanthus, the lower lid puncta is often displaced lateral to the medial limbus in primary gaze.

Figure 2.8 Lid Retraction The differential diagnoses of eyelid retraction include the “setting sun” sign of hydrocephalus, Marcus-Gunn jaw wink, Parinaud dorsal midbrain syndrome, neonatal Graves disease, and cranial nerve III palsy with aberrant regeneration. Pseudo eyelid retraction can be caused by proptosis or restriction to upgaze on the ipsilateral side causing overfiring of the superior rectus and subsequent levator palpebra contraction and contralateral ptosis. This photograph was taken just after turning off the lights in a normal child who is demonstrating a common normal infant reflex of upper lid retraction, often associated with tonic downgaze. When the lights are turned back on, the lids will return to their usual position.

Figure 2.9 Congenital Ptosis Congenital ptosis is caused by dysgenesis of the levator palpebral muscle. There is typically no lid crease and a decreased ability to relax the levator in downgaze. It may be unilateral or bilateral. Treatment options include levator resection for patients with mild ptosis and good levator function. Frontalis suspension using fascia lata or artificial materials is recommended for children with severe ptosis with poor levator function. Congenital ptosis may be seen in a wide variety of genetic syndromes but is usually an isolated anomaly.

Figure 2.10 Marcus-Gunn Jaw Wink Marcus-Gunn jaw wink is caused by synkinesis between nerves supplying the muscles of mastication (pterygoid) and the levator palpebral muscle. Patients will often have ptosis but with jaw manipulation will have upward movement of the affected eyelid. Treatment is tailored toward either the synkinesis or the ptosis. A complete levator disinsertion and frontalis resuspension unilaterally or bilaterally address the synkinesis. Unilateral frontalis suspension can be used if the ptosis alone is more problematic. Marcus-Gunn jaw wink is seen in approximately 2% of all congenital ptosis.

Figure 2.11 Congenital Tarsal Kink Tarsal kink is caused by a folding of the upper eyelid tarsal plate back onto itself. Although the eyelid appears to be everted, reversion is not easily performed in part due to edema and/or fibrosis. This entity should be differentiated from a floppy eyelid as might be seen in trisomy 21 (Chapter 13: Chromosomes, Fig. 13.7). Treatment would include mechanical unfolding of the tarsal plate and taping the eyelid in its normal position or surgical incision along the tarsal plate.

Figure 2.12 Congenital Ectropion Congenital ectropion is an outward turning of the eyelid margin at birth. It is associated with blepharophimosis, buphthalmos, orbital tumor, and anterior lamellar deficiencies but may also be an isolated unilateral or bilateral abnormality. Ocular surface desiccation tends to be less of a problem in infants and young children, but lubrication is recommended. The palpebral conjunctiva can appear quite injected, as demonstrated here. Chemosis may also be seen.

Figure 2.13 Congenital Entropion Congenital entropion is an inward turning of the eyelid margin. It is associated with epiblepharon (Fig. 2.6), microphthalmia, anophthalmia, or enophthalmos. Trichiasis may result in chronic corneal epithelial erosion, pannus, or ulcer. Some children become remarkably symptom free, which can contribute to a delay in diagnosis of such complications. Topical lubrication is recommended until definitive surgical cure.

Figure 2.14 Distichiasis Distichiasis is an extra row of eyelashes on the inferior eyelid. The lashes extend from the opening of the meibomian glands. Distichiasis can be associated with the autosomal dominant distichiasis-lymphedema syndrome, due to mutations in the FOXC2 gene at 16q24.3. Patients may also have cleft palate, diabetes, ptosis, or renal disease. Treatment would include eyelid margin splitting with cryotherapy to the hair follicles.

Figure 2.15 Ectopic Lashes Isolated lashes or clumps of lashes can be seen exiting from a meibomian gland without a more complete row as seen in distichiasis (Fig. 2.14). Ectopic hair follicles are located within the eyelid. This abnormality is an isolated anomaly not usually associated with a genetic syndrome. It is usually unilateral and occurs on an otherwise normal lid.

Figure 2.16 Trichomegaly Trichomegaly can be a primary or secondary disorder. In the former, it may be an isolated abnormality or a manifestation of numerous syndromes such as Cornelia de Lange syndrome (Chapter 29: Syndromes, Fig. 29.2). It is almost always bilateral and occurs on otherwise normal lids. There are no normative values for lash length, leaving this to be a subjective diagnosis. Prostaglandin analogs used to treat glaucoma are a common cause of trichomegaly, as demonstrated here. Upper lashes tend to be more affected.

Figure 2.17 Capillary Hemangioma—Nonamblyogenic Capillary hemangiomas are the most common adnexal tumor in children. This child has a large capillary hemangioma on the upper eyelid. The lesion is not occluding the visual axis and cycloplegic refraction did not reveal anisometropia or astigmatism. As a result, amblyopia is unlikely. However, hemangiomas typically grow rapidly in the first year of life, after which they may regress completely (70% by 7 years of age). A lesion that may appear at birth as not much more than a macule may become amblyogenic within months. Periodic follow-up throughout the first 2 years of life is essential.

Figure 2.18 Capillary Hemangioma—Amblyogenic This child has an extensive capillary with complete secondary ptosis. Urgent treatment is required to restore the visual axis and prevent permanent visual loss due to amblyopia. Larger lesions such as this can be associated with excessive platelet and fibrinogen consumption (Kasabach-Merritt syndrome). Although treatment with intralesional or topical steroids might be useful in less extensive amblyogenic capillary hemangioma, a lesion of this size will often require systemic treatment with steroids, systemic steroids, and/or α-interferon. Subsequent patching therapy will be necessary after the tumor size has been reduced.

Figure 2.19 Capillary Hemangioma This is the same patient pictured in Figure 2.18. Note the extensive hemangioma extending into the orbit causing significant proptosis, optic nerve compression with unilateral disc swelling, retinal vascular congestion, and peripapillary hemorrhage. Intralesional steroids are contraindicated due to fear of spread to the optic nerve and retinal circulation. Surgical options are few and rarely indicated.

Figure 2.20 Cavernous Hemangioma Cavernous hemangioma is a deeper blood vessel tumor in the lids and is not associated with the overlying “strawberry” capillary hemangioma of the skin (Fig. 2.18). It often has a bluish color. This tumor can cause significant globe displacement, as shown here, and secondary astigmatic or strabismic amblyopia. The diagnosis can be confirmed by surgical excision. Change in size with age does not occur. Differential diagnoses include lymphangioma, capillary hemangioma, rhabdomyosarcoma, teratoma, or histiocytic lesion. Cavernous hemangioma is painless and usually isolated to the lid.

Figure 2.21 Acute External Hordeolum External hordeolum, also known as sty, is an acute inflammatory mass at the eyelid margin resulting from obstruction of a gland of Moll/Zeis. Significant pain, redness, and edema are typical. The lesion may drain at the lid margin, through the skin, or through the palpebral conjunctiva. Treatment includes a combination of warm compresses, lid hygiene (e.g., baby shampoo eyelash scrubs), topical antibiotics, and, rarely, possible surgical drainage.

Figure 2.22 Internal Hordeolum An internal hordeolum, also known as chalazion, may be acute or, as shown here, a chronic nodular lesion within the eyelid. It is the result of a granulomatous response to sebaceous material trapped within the eyelid from prior blockage (acute phase) of a meibomian gland. Surgical removal may be necessary, although long-term use of lid hygiene can be effective. Recurrent hordeolum involving all four lids at various times is common.

Figure 2.23 Blepharitis Significant scales and collarettes are seen at the base of the eyelashes in this child with chronic blepharitis: An idiopathic condition in which there is suboptimal flow of the meibomian glands. Blepharitis predisposes to hordeolum. Conjunctival and corneal desiccation and inflammation due to deficient tear film or from staphylococcal immune keratitis (Chapter 5: Cornea, Fig. 5.26) can lead to scarring and visual impairment. Treatment includes topical antibiotics, warm compresses, lid hygiene, and, occasionally, topical steroids to control the surface inflammation. Oral antibiotics such as erythromycin may be used, especially when associated with rosacea.

Figure 2.24 Benign Papilloma Benign papillomas are common adult eyelid lesions, but they can also occur in children. The tumor is similar to the skin in color and can be sessile (as seen in this photo) or pedunculated. Surgical removal may be required, usually for cosmetic reasons, but symptoms may also be present. Verrucae vulgaris is included in the differential diagnoses but is rare in childhood.

Figure 2.25 Pilomatrixoma Pilomatrixoma is a benign tumor arising from matrix hair cells in the lid. They present in childhood or young adulthood. This lesion is more common in patients with Down syndrome (Chapter 13: Chromosomes, Fig. 13.7). As seen in this photo, a single lesion located near the eyebrow is typical. Subcutaneous lesions may have white lobular areas or a bluish appearance. Complete surgical excision is recommended.

Figure 2.26 Giant Hairy Nevus Giant hairy nevus, also known as nevomelanocytic nevus, is a large pigmented lesion involving the trunk, scalp, face, or extremities. The risk of malignant transformation increases with larger lesions. Hair may be present at birth and does not increase or decrease the risk of malignant transformation. The normal lashes are also often abnormally directed. Although surgical excision is recommended, extensive reconstructive surgery may be required.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 3 Lacrimal

3 Lacrimal Alex V. Levin Thomas W. Wilson Dan Deangelis Robert Pashby Jeffery Hurwitz The lacrimal system includes the lacrimal gland, upper and lower lid puncta, upper and lower lid canaliculus, lacrimal sac, and nasolacrimal duct. The lacrimal gland is responsible for the production of the middle (aqueous) layer of the tear film. It is innervated by the lacrimal branch of the middle division trigeminal nerve. The superficial layer of the tear film is contributed by the meibomian glands of the lids (see Chapter 2: Lids and Adnexa). The inner layer of the tear film is made by the conjunctival goblet cells (see Chapter 4: Conjunctiva). As the tear film is produced continuously, it must have a place to drain. The nasolacrimal system collects the tears via the puncta, which must be patent and lie in apposition to the surface of the globe so that they may collect the tear film drainage. If there is inadequate drainage, epiphora will occur. Flow of tears into the nasolacrimal system is facilitated by the orbicularis muscle and other muscles

surrounding the sac creating a pumping mechanism. If the lids are hypotonic, malpositioned, or floppy (see Chapter 2: Lids and Adnexa), epiphora may result as the tears are unable to gain access to the puncta. Each punctum lies at the peak of an elevated papilla. There is a vertical path of approximately 2 mm followed by a 90-degree turn into the canaliculus. The upper and lower canaliculi join at the medial canthus to form the common canaliculus, which then enters the lacrimal sac. The lacrimal sac is located in a bony sulcus in the anterior medial orbital wall such that only its upper third is exposed. The remainder of the sac and the nasolacrimal duct lie within the bone of the anterior orbit and face. The nasolacrimal duct opens into the nose as the inferior meatus under the ipsilateral inferior turbinate. Disease within the nose may also cause obstruction. Although nasolacrimal system abnormalities are commonly isolated, they may also be seen in a wide variety of syndromes, particularly those that affect midline disorders or the lids. Dysfunction can also occur secondary to trauma, tumor, and infection. Likewise, the lacrimal gland can be affected by infection, tumor, or external influences such as radiation. Lacrimal gland dysfunction may also occur in Sjögren and other autoimmune diseases (see Chapter 27: Rheumatology). Dysfunction of the lacrimal gland results in dry eye.

Figure 3.1 Punctal Atresia Punctal atresia is complete absence of the lacrimal punctum. There is usually no papilla, although a small indentation in the area where the punctum should be may occur. Patients usually have symptoms of epiphora without significant discharge. Treatment is usually not necessary for absence of the upper punctum as shown here. Lower lid punctal atresia is more likely to be symptomatic. Treatment options include surgical cannulation and placement of silicone tubes for several months. If no canaliculus can be found, then a conjunctival-lacrimal sac tube (Jones tube) may be necessary.

Figure 3.2 Punctal Membrane A punctal membrane is a grayish membrane over the normal punctum. There is typically a papilla, although the puncta may not be easy to recognize or may be stenotic. Symptoms will likely include epiphora and scant discharge, especially if the lower puncta is involved. Surgical penetration of the membrane and probing will often relieve the symptoms of epiphora. As the puncta are derived from surface ectoderm, unlike the mesoderm-derived nasolacrimal duct, the distal system is usually intact.

Figure 3.3 Lacrimal Sac Fistula Lacrimal sac fistula is a direct connection between the nasolacrimal sac and the skin in the area of the medial canthus. The fistula appears as a small hole in the skin below the medial canthus (arrow) through which tears may emanate. Treatment options include simple probing to relieve any resistance to normal tear flow or elimination of the fistula with cautery. This patient required a nasolacrimal duct tube, which can be seen crossing from the lower to upper puncta and was tied within the nose.

Figure 3.4 Nasolacrimal Duct Obstruction Nasolacrimal duct obstruction presents with epiphora and mucous discharge starting at or shortly after birth. The obstruction is in the distal nasolacrimal duct. There is an absence of conjunctival injection, cornea cloudiness, or buphthalmos, thus ruling out glaucoma or infection. The poor drainage will allow for the mucoid components of the tear film (inner and outer layers) to precipitate out and appear as a discharge, which is usually worse on waking from sleep. This child has copious discharge with a strand extending between the lids. Tearing, wet lower lid lashes, and chronic skin changes in the lower lid subciliary area are common. Treatment includes nasolacrimal sac massage in the area of the lacrimal fossa, and nasolacrimal duct probing.

Figure 3.5 Lacrimal Sac Mucocele Lacrimal sac mucocele, also known as dacryocystocele or amniotocele, results from a completely imperforate inferior meatus resulting in an inability of the nasolacrimal duct to drain tears and necrotic debris from the coring out of the mesoderm during embryonic formation of the duct. A “ball valve” effect is created proximally, resulting in the outpouching of the lacrimal sac, which presents as a small bluish mass (arrow) below the medial canthal tendon. The medial canthus may be deflected upward, as seen in the right image of a child with a left infected mucocele. Treatment is recommended before infection occurs.

Figure 3.6 Lacrimal Mucocele The membrane covering the entrance of the nasolacrimal duct into the nose is often distended, creating a cystlike structure underneath the inferior turbinate, as seen in the left image endoscopically and in the right image by computed tomography scan (arrow). As infants often present during the first 2 weeks of life, respiratory problems may be noted, especially in breast-fed babies when on the ipsilateral breast (i.e., baby with right mucocele feeding on the mother's right breast) as the nipple compresses the nares on the unaffected side. We recommend nasal endoscopy in all cases of lacrimal sac mucocele to ensure that the nasal cyst is extirpated.

Figure 3.7 Dacryocystitis Dacryocystitis is an infectious enlargement of the nasolacrimal sac. In infancy, over 95% of patients will have an underlying lacrimal sac mucocele. Beyond the first few weeks of life, mucocele is unlikely, but history may reveal pre-existing nasolacrimal duct obstruction. We recommend treatment with intravenous antibiotics. After the infection has been reduced, we recommend probing and, in the first month of life, nasal endoscopy to search for and remove a cyst under the inferior turbinate (see Fig. 3.6). The infected sac should not be incised percutaneously.

Figure 3.8 Dacryoadenitis Dacryoadenitis is the term for infection or inflammation of the lacrimal gland, as seen in this child's right eyelid. The enlarged lacrimal gland will present as a swelling of the lateral upper lid and may, as demonstrated here, extend from the upper fornix onto the surface of the globe. Common infectious causes in children include mononucleosis, rubeola, or herpes zoster. Noninfectious causes include pseudotumor and lymphoma.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 4 Conjunctiva

4 Conjunctiva Alex V. Levin Thomas W. Wilson David Rootman Jerome Kazdan The conjunctiva is derived from surface ectoderm and has an important role in maintaining ocular surface integrity. Goblet cells within the conjunctiva provide the inner layer of the trilaminar tear film for lubrication and surface wetting. Tumors of the conjunctiva are often benign but must be observed for possible malignant transformation. Conjunctival findings may assist in the diagnosis of systemic diseases, and conjunctival biopsy can be a useful diagnostic tool. As the conjunctival epithelium is contiguous with the corneal epithelium and vascular supply to the limbus is brought in part by the conjunctiva, it is not uncommon for conjunctival disease to coexist with corneal disease or anterior segment inflammation (iritis). The conjunctiva also extends upward and downward to form the superior and inferior fornices where it reflects out onto the inner surface of the lids. Bulbar conjunctiva, which overlies the globe, may or may not be affected in some disorders. The same is true

for palpebral conjunctiva. The fornices may serve as repositories for chemical or particular matter, and therefore, lid eversion is an essential part of complete conjunctival examination. Defects or foreign bodies in the conjunctiva can be detected by topical fluorescein staining, whereas rose bengal can be used to detect devitalized conjunctival epithelial cells.

Figure 4.1 Amelanotic Nevus In childhood, most conjunctival nevi initially appear amelanotic and show little or no active melanin production until the pubertal years. Microcysts within the lesion are common. Prominent vessels leading to the lesion with telangiectasia within the nevus may also be seen. Conjunctival nevi are most commonly located in the perilimbal area in the interpalpebral fissure. Even though conjunctival nevi have a low chance of malignant transformation, nevi that are increasing in size or become more inflamed should be excised with cryotherapy at the base of the lesion.

Figure 4.2 Melanotic Nevus Conjunctival nevi consist of melanocytic nevus cells classified based upon location within the epithelium. The nevus cells can be located in the epithelium (junctional nevus), subepithelium, or both layers (compound nevus). Most of the lesions are located near the limbus, are slightly raised, and can contain a variable amount of pigment. Lesions should be followed by serial photography. Although rare, malignant transformation can occur, especially in the teenage years. Signs of transformation include growth, formation of an elevated mass, increased feed vasculature, and extension into contiguous structures.

Figure 4.3 Caruncle Nevus A nevus located within the caruncle typically presents during puberty, contains small cysts, and does significantly change in size. The caruncle is an extension of the conjunctival tissue and serves little purpose in terms of ocular health. Surgical excision is recommended for pigmented lesions that are changing in size, gaining pigmentation, or associated with inflammation.

Figure 4.4 Axenfeld Loops Axenfeld loops are areas of pigmentation surrounding an intrascleral nerve or blood vessel. They are typically located a few millimeters posterior to the limbus and appear as variably sized, slate gray, pigmented patches circumferentially equidistant from the limbus. Under high magnification, the pigment appears as rectangular deposits at the level of the episclera. These lesions are a normal variant, benign, and of no ophthalmic concern.

Figure 4.5 Ocular Melanosis Ocular melanosis is a form of episcleral pigmentation, usually slate gray, that tends to occur as broad patches with no anatomic correlate, unlike Axenfeld loops (see Fig. 4.4). This form of episcleral pigmentation is seen in darkly pigmented individuals and is not associated with malignant transformation. The lesions may be uni- or bilateral. Pigmentation does not move with the conjunctiva.

Figure 4.6 Oculodermal Melanocytosis The combination of ocular melanosis (see Fig. 4.5) and similar skin pigmentation, known as nevus of Ota, is called oculodermal melanocytosis. The skin has a bluish gray appearance. Other uveal structures, including the iris and retinal pigment epithelium, can have increased pigmentation (Fig. 4.7). Nevus of Ota is more common in darkly pigmented individuals and is typically unilateral. It is more common in certain ethnic groups, particularly in far eastern Asia. When found in the Caucasian population it has a higher incidence of associated malignancy, including choroidal melanoma.

Figure 4.7 Iris Melanosis Iris melanosis is often associated with oculodermal melanocytosis (see Figs. 4.5 and 4.6). The usual iris crypts are missing, particularly in the peripheral two thirds of the iris. Instead, the iris appears flat with or without a large number of tiny bumps following no particular pattern. The iris tends to be chocolate brown, particularly when compared to the other eye. Gonioscopy is normal and there is no increased association with glaucoma. However, eyes with iris melanosis in the presence of oculodermal melanocytosis may have a higher risk of ocular melanoma. Malignant transformation is very rare in childhood.

Figure 4.8 Conjunctival Hemangioma Conjunctival hemangioma is a benign tumor presenting with bright red vascularized lesion of the conjunctiva, usually in the inferior fornix. This patient has a diffuse conjunctival hemangioma associated with deeper orbital involvement (see Chapter 11: Orbit, Fig. 11.4), always a consideration with conjunctival hemangioma. Treatment is indicated only for reconstructing appearance, as this tumor is rarely visually significant. The hemangioma may be sessile or polypoid. In the latter case it should be distinguished from pyogenic granuloma (Fig. 4.9). Although topical steroids may be tried, definitive treatment requires surgery or thermocautery. Surgical intervention should be restricted to the anterior portion of the tumor only.

Figure 4.9 Pyogenic Granuloma Pyogenic granuloma is a fibrovascular proliferation following inflammation (hordeolum), surgery (strabismus, chalazion removal, or scleral buckle), trauma, or foreign body. The typical lesion is bright red, pedunculated, and highly vascular. It may be so friable that it bleeds when touched. Treatment includes a trial of topical steroids. If that fails, surgical removal with cauterization or cryotherapy of the lesion base after excision is usually effective. Recurrence following surgical removal is not uncommon. Malignant transformation does not occur.

Figure 4.10 Viral Conjunctivitis Adenoviral conjunctivitis is the most common viral conjunctivitis. The epidemic keratoconjunctivitis type is highly contagious. Patients will commonly have upper respiratory illness and a history of contact with another infected individual. The conjunctiva is significantly hyperemic with a watery mucoid discharge. Follicles of the conjunctiva are common. A tender preauricular node (note right temporal swelling) supports the diagnosis but is not pathognomonic of viral conjunctivitis. Dramatic lid swelling can occur. Treatment is confined to lubrication, cool compresses, and comfort measures.

Figure 4.11 Pseudomembrane Pseudomembranes are white or gray-white collections of leukocytes and inflammatory debris on the palpebral conjunctiva that are not attached to the underlying tissues and therefore do not bleed when removed. They are particularly common in epidemic keratoconjunctivitis (see Fig. 4.10), but may also be seen in conjunctivitis caused by a number of viral and bacterial organisms. They must be differentiated from true membranes as seen in Stevens Johnson syndrome (see Chapter 15: Dermatology, Fig. 15.11).

Figure 4.12 Subepithelial Infiltrates Subepithelial corneal infiltrates are not uncommon sequelae of epidemic keratoconjunctivitis but may also result from other infectious causes. They appear as gray amorphous small infiltrates below the corneal epithelium with no particular pattern of distribution. Pain and photophobia are characteristic. Although they are responsive to topical steroids, it may be difficult to stop the steroids once begun. Symptomatic relief is preferred. The lesions usually appear toward the end of the active viral illness and persist after all other signs of viral conjunctivitis have resolved. The infiltrates shown here are somewhat larger and fewer in number than those seen with adenovirus. This should lead to investigation for possible Epstein-Barr virus conjunctivitis/keratitis.

Figure 4.13 Neonatal Gonorrhea Conjunctivitis Gonococcal conjunctivitis of the newborn commonly presents with severe injection, chemosis, lid swelling, and large amounts of purulent discharge. Neisseria gonorrhoeae is one of few known pathogens that can penetrate an intact cornea epithelium. Therefore, suspected ocular gonorrhea is considered an ophthalmic emergency. Even if conjunctival swab Gram stain is inconclusive, the presence of purulent conjunctivitis in a neonate should result in the initiation of systemic treatment with antibiotics, preferably cephalosporins, immediately after appropriate cultures are taken. Treatment should include topical antibiotics, frequent saline lavage, a search for other sexually transmitted diseases that may have been acquired pre- or perinatally, and similar testing of the mother and her partner(s). Gonorrhea conjunctivitis in older children should raise concerns about possible covert sexual abuse.

Figure 4.14 Chlamydia Conjunctivitis Chlamydia trachomatis is a common cause of infectious ophthalmia neonatorum. The conjunctiva is very erythematous, with the palpebral conjunctiva being affected more severely than the bulbar conjunctiva. Unlike adult or childhood trachomatis conjunctivitis, there are no follicles or limbal infiltrates present. Systemic involvement includes a pneumonitis, which can occur weeks or months after the ocular infection. Therefore, systemic treatment with erythromycin is necessary to eradicate the Chlamydia trachomatis from the nasopharynx. This conjunctival scraping taken from a patient with Chlamydia trachomatis shows intracytoplasmic inclusion bodies on Giemsa stain.

Figure 4.15 Phlyctenule Conjunctival phlyctenule is a discreet raised area of inflammation of the bulbar conjunctiva in the intrapalpebral fissure. The lesions are typically a yellowish white nodule that is surrounded by conjunctival hyperemia. Phlyctenules are frequently located at or a few millimeters posterior to the limbus. Rarely, the lesion may be on the cornea with blood vessels extending from the limbus to the lesion. The most common cause is staphylococcal hypersensitivity in the setting of blepharitis (see Chapter 2: Lids and Adnexa, Fig. 2.23). Tuberculosis should also be considered. Treatment should be directed toward the underlying blepharitis. Lid hygiene and topical antibiotics should be started with or without a short course of topical steroids.

Figure 4.16 Parinaud Oculoglandular Syndrome Parinaud oculoglandular syndrome is a granulomatous conjunctivitis that typically is unilateral and has associated neck lymphadenopathy. Patients will often present with conjunctivitis and associated fever and rash. Note the typical yellow conjunctival lesions. Possible causes include cat scratch disease, tularemia, and sporotrichosis. Diagnosis is confirmed with a conjunctival biopsy, and the treatment is to target the underlying infection.

Figure 4.17 Allergic Chemosis Allergic chemosis can be caused by environmental allergens or topical medications. The conjunctiva is thickened and has a clear, “boggy” appearance. The area of swelling can occur rapidly and dramatically. Treatment includes topical lubrication, topical vasoconstrictor/antihistamines, and steroids if necessary. The inciting agent is rarely found. The chemosis may be uni- or bilateral. Other causes of chemosis include infection, paralysis (e.g., in ventilated intensive care unit patients), trauma, cranial vault surgery (especially craniofacial procedures involving a bicoronal flap), and hypoalbuminemia.

Figure 4.18 Vernal Papillary Conjunctivitis Vernal conjunctivitis is a seasonal inflammation of the conjunctiva most commonly found in young boys. It is typically bilateral and presents with severe itching, photophobia with significant injection of the conjunctiva, and a thick, white mucous discharge. Giant papillae are commonly found on the upper tarsus and resemble “cobblestones.” Small white dots (Trantas dots) may be seen in the limbal area. Treatment of vernal conjunctivitis includes topical steroids and mast cell stabilizers. Topical antihistamines and cold compresses also can be helpful in relieving the symptoms.

Figure 4.19 Shield Ulcer Shield ulcers typically occur in the superior half of the cornea and have an oval shape. A combination of mechanical irritation and the toxic effects of the inflammatory mediators from the vernal conjunctivitis causes the ulcers. Treatment should be aimed at reducing the vernal response with topical mast cell stabilizers and steroids. Bandage contact lenses with or without antibiotic coverage may be indicated.

Figure 4.20 Limbal Vernal Limbal vernal occurs more commonly in the African and Asian population and clinically is seen as small gelatinous elevations circumferentially at the limbus. Like vernal conjunctivitis (see Fig. 4.18), it is seasonal and may be associated with tearing, itching, and red eye, and small white dots (Trantas dots) may be seen in the limbal area. The elevated areas may have some pigmentation, as shown here. Topical steroids and mast cell stabilizers are the treatment of choice.

Figure 4.21 Conjunctival Lymphoid Hyperplasia Children will often have an increased number and size of follicles in the lower fornix and on the lower palpebral conjunctiva without significant erythema or symptoms. This reaction is similar to other areas of lymphoid hyperplasia (tonsils or lymph nodes) that occurs in particular from approximately 2 to 10 years of age. This benign asymptomatic condition requires no intervention. Care must be taken not to confuse this with the follicular reaction of other disorders, such as viral conjunctivitis (see Fig. 4.10).

Figure 4.22 Ligneous Conjunctivitis Ligneous conjunctivitis is a chronic membranous conjunctivitis mainly affecting the pediatric population. It will often coincide with a systemic illness including otitis media, respiratory infection, and sinusitis. The palpebral conjunctiva is severely injected and white, woodlike structures extend from the conjunctival surfaces. Treatment is very difficult and a wide variety of agents have been used. Autologous plasminogen drops may have particular benefit.

However, some cases will spontaneously resolve. Removal of the lesions results in conjunctival bleeding and recurrences are common. The lesion may cause severe corneal damage.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 5 Cornea

5 Cornea Alex V. Levin Thomas W. Wilson David Rootman Jerome Kazdan The cornea develops from surface ectoderm (corneal epithelium) and neural crest cells (corneal stroma and endothelium). Developmental anomalies can result from inherited or spontaneous genetic mutations and insults during embryogenesis. Acquired disease can result from infection or other environmental or local contiguous processes. Multiple genes are involved in corneal formation. Mutations in these genes may result in isolated corneal malformation or associated abnormalities of the anterior and posterior segment. As the most important refracting portion of the eye, corneal disease is likely to have a significant effect on vision. In the developing visual system of a child, superimposed amblyopia will almost certainly accompany most corneal disease. As the cornea has afferent neural pain fibers carried by the trigeminal nerve, photophobia and pain are also common symptoms of corneal disease. Its location does allow for topical treatment to be

effective in many types of disease, but some corneal problems are not amenable to medical therapy. Corneal transplantation is available to clear the visual axis and relieve symptoms, but this process requires long-term follow-up and treatment, which itself can be uncomfortable and amblyogenic. In the setting of congenital obstruction of the visual axis, the poor success of infantile corneal transplantation has to be carefully weighed against the value of clearing the visual axis as soon as possible.

Figure 5.1 Peters Anomaly Peters anomaly is due to defective separation of the lens, a surface ectoderm derivative, from the surface ectoderm during the fourth to seventh week of gestation. The resulting corneal opacity (left image), which is usually central, is associated with a defect in the posterior cornea (Descemet membrane and endothelium) to which the iris and/or lens remains attached (right image). The lens is often cataractous. It is bilateral in 80% of patients, and glaucoma is present in 50% of patients. When patients have associated heart defects, cleft palate, and skeletal anomalies, the syndrome is referred to as Peters Plus (Krause-Kivlin syndrome). Although most cases are sporadic,

involvement of the PAX6, CYP1B1, and PITX2 has also been occasionally described.

Figure 5.2 Sclerocornea Sclerocornea is an opacification of the cornea, which is contiguous with the sclera. There is often associated microcornea, microphthalmia, or cornea plana. Visual prognosis is guarded even with early transplantation due to the associated ocular developmental abnormalities. Extensive vascularization may also contribute to corneal graft failure. Although the intraocular pressure may appear to be elevated by tonometry and glaucoma is associated, one must be careful to consider that the increased rigidity and thickness of the cornea may result in artifactitious measured pressure elevation.

Figure 5.3 Corneal Dermoid Corneal dermoids are round or oval vascular masses attached to the corneal surface. They often protrude, as seen here. They consist of ectodermally derived tissue and may contain hair and sweat glands within the corneal stroma. Therefore, these lesions are classified as choristomas. The lesions are most commonly located at the inferotemporal limbus but may also occur in the conjunctiva or central cornea. Astigmatic or occlusion amblyopia is a concern. Systemic associations include Goldenhar syndrome (Chapter 14: Craniofacial, Figs. 14.18, 14.19, 14.20 and 14.21). Lamellar keratoplasty and penetrating keratoplasty are performed for superficial and deep lesions, respectively. When isolated, this is usually a sporadic nongenetic anomaly.

Figure 5.4 Microcornea Microcornea is a corneal horizontal diameter of less than 10 mm after 2 years of age. Normative values for younger ages are also available. Microcornea can occur unilaterally or bilaterally and is associated with other ocular disorders including cataract, glaucoma, and coloboma. Note that microcornea can occur in the absence of microphthalmia (shortened axial length). There are numerous syndromic and chromosomal associations. Although vision is usually reduced, mild microcornea can be associated with vision as good as 6/12 in some patients.

Figure 5.5 Megalocornea Megalocornea is an increased horizontal diameter of greater than 13 mm by age 2 years. The intraocular pressure, cornea thickness, and endothelial density are typically normal. X-linked recessive transmission is typical, with affected males often having bilateral corneal diameters in excess of 14 mm and carrier females having diameters of 12 to 14 mm. Radial iris transillumination may be present. One characteristic sign, pictured here, is the ability to see the iridocorneal angle structures without gonioscopy. This can also be seen in some cases of buphthalmos due to infantile glaucoma, but there is no corneal edema or opacity in Xlinked megalocornea. An autosomal recessive form (Neuhauser syndrome) associated with mental retardation is less common.

Figure 5.6 Congenital Cornea Ectasia Congenital corneal ectasia is a thinning and protrusion of the central cornea, if not a descemetocele or frank perforation at birth. Uveal tissue often lines the endothelial surface of the abnormal cornea. There is typically microphthalmia and increased intraocular pressure due to angle anomalies. Ectasia may be a manifestation of Peters anomaly (Fig. 5.1), congenital infections (e.g., cytomegalovirus, Chapter 19: Infectious Diseases, Figs. 19.9, 19.10 and 19.11), or an isolated ocular anomaly. Treatment includes urgent penetrating keratoplasty for tectonic support. Given the young age at which this procedure is required, the success rate is low.

Figure 5.7 Prominent Corneal Nerves Increased visibility of corneal nerves in children is seen with neurofibromatosis type I, congenital glaucoma, keratoconus, multiple endocrine neoplasia type IIB, ichthyosis, corneal infection with herpes virus or acanthamoeba, leprosy, tuberculosis, and Refsum disease. The visual acuity is not typically affected by the corneal nerves but can be reduced by the associated ocular conditions. Corneal nerves are normally visible up to 2 mm anterior to the limbus.

Figure 5.8 Vertically Oval Cornea The normal cornea is typically oval with a wider horizontal diameter. When the cornea is vertically oval, it is otherwise normal and the vision is unaffected. Associated conditions include microphthalmia, interstitial keratitis, and Turner syndrome. No treatment is indicated.

Figure 5.9 Cornea Plana Cornea plana is an abnormally flat anterior corneal surface with corneal curvatures less than 40 diopters and often less than 36. The peripheral cornea is similar to sclera and may be more opaque than usual with features of sclerocornea (Fig. 5.2). Central cornea may also have decreased clarity. Most cases are sporadic, although autosomal dominant and autosomal recessive forms due to mutations in the keratocan gene at 12q also occur, as does association with systemic syndromes such as Ehlers-Danlos and Marfan.

Figure 5.10 Meesman Corneal Dystrophy Meesman dystropy is an abnormality of the corneal epithelium. Small intraepithelial vesicles can be detected within the first decade. Patients become symptomatic later in life and experience significant photophobia, tearing, and foreign body sensation. Treatment modalities include bandage contact lenses and artificial tears. Patients rarely require keratoplasty. Meesman dystrophy is inherited as an autosomal dominant disorder and is likely due to mutations in genes for the corneal keratins K3 and K12 located at 17q12 and 12q13, respectively. These proteins are involved with corneal epithelial cell cytoskeleton.

Figure 5.11 Reis-Buckler Dystrophy Reis-Buckler corneal dystrophy, also known as corneal dystrophy of Bowman layer type 1, is an autosomal dominant anterior corneal dystrophy, which is linked, like many other corneal dystrophies, to 5q31. Clinically, this dystrophy is characterized by multiple small discrete opacities with a geographic distribution seen centrally just under the epithelium. The peripheral cornea is usually spared. Secondary involvement of the anterior stroma or overlying epithelium may occur. Patients suffer from recurrent erosions. Histologically, the cornea shows scarring and thickening of collagen in the area of the Bowman membrane with abnormalities of the epithelial cells.

Figure 5.12 Schnyder Crystalline Corneal Dystrophy Schnyder corneal dystrophy presents in the first few years of life with bilateral central discoid lesions composed of small polychromatic crystals. The needlelike opacities are concentrated in the anterior stroma and can increase in density over time. The condition is autosomal dominant and has been mapped to 1p34.1-36. Histopathology reveals cholesterol and fat deposits within the keratocytes and the extracellular matrix. Phototherapeutic keratoplasty or penetrating keratoplasty may be required to restore visual acuity.

Figure 5.13 Granular Corneal Dystrophy (Groenouw Type I Corneal Dystrophy) Granular stromal dystrophy is a progressive degeneration of the corneal stroma. It is an autosomal dominant disorder caused by mutations in the keratoepithelin gene at 5q31. Signs typically appear in the first decade of life. The opacities resemble “bread crumbs” and are concentrated in the visual axis. The opacities have sharp borders with clear cornea between the lesions. On pathology, the lesions consist of hyaline degeneration and stain with Masson trichrome stain.

Figure 5.14 Lattice Stromal Dystrophy Lattice stromal dystrophy is a progressive deposition of amyloid material within the corneal stroma. It is inherited as an autosomal dominant trait and typically appears within the first decade of life. Patients usually present with decreased vision or pain secondary to recurrent corneal erosions. Clinically the cornea storage diseases, birth trauma with forceps injury, and sclerocornea are also included in the differential diagnoses. Pathologically there is endothelial degeneration with an abnormal Descemet membrane. The anterior banded zone of Descemet is normal; however, the posterior part of Descemet shows increased thickness. Treatment would include corneal transplant.

Figure 5.15 Macular Corneal Dystrophy (MCD) Macular corneal dystrophy is an autosomal recessive disorder due to mutations in a sulfotransferase gene at 16p22. Onset occurs in the first decade and the disorder is progressive with the development of punctuate gray opacities. Patients experience recurrent attacks of photophobia due to recurrent erosions. Special stains on corneal specimens show acid mucopolysaccharides in corneal fibroblasts. The disorder is divided into two types: MCD type I, which has almost no sulfated keratan sulfate in the serum and cornea; and MCD type II, in which sulfated keratin sulfate is normal.

Figure 5.16 Congenital Hereditary Endothelial Dystrophy (CHED) Congenital hereditary endothelial dystrophy is an autosomal recessive abnormality of the corneal endothelium. Patients typically present at birth with cloudy cornea. Autosomal recessive and autosomal dominant inheritance patterns have been reported. The autosomal dominant form develops in the first few years of life with increasing photophobia and epiphora. Because the cornea is clear for the first year of

life, nystagmus typically is not present. The autosomal recessive form has significant corneal edema at birth, and nystagmus is common. Pathologic examination reveals a normal anterior banded layer of Descemet membrane and an abnormal posterior layer. Treatment includes corneal transplant. Differential diagnoses include sclerocornea, congenital glaucoma, trauma due to forceps injury, corneal ulcer, metabolic diseases, and dermoid.

Figure 5.17 Posterior Polymorphous Dystrophy Posterior polymorphous dystrophy is an autosomal dominant posterior corneal abnormality. The abnormal gene has been mapped to chromosome 20Q11. It is typically bilateral and presents with irregular blisterlike opacities in the area of the Descemet membrane. Peripheral anterior synechiae can form causing corectopia, iris atrophy, and glaucoma. The pathologic examination of the posterior cornea shows an

endothelium with similar morphologic and immunopathologic resemblance to corneal epithelium.

Figure 5.18 Keratoglobus Keratoglobus is a generalized corneal ectasia secondary to an abnormality of corneal collagen. Keratoglobus is a bilateral condition that presents at birth with myopia and astigmatism. Unlike congenital corneal ectasia (Fig. 5.6), there is a generalized protrusion of the globe with thinning of the corneal stroma and localized absence of the Bowman membrane. The thinning is greatest in the periphery, which makes penetrating keratoplasty difficult. The cornea is usually clear, although edema may result from a progressive break in the Descemet membrane. Corneal diameter is normal. The cornea may be particularly susceptible to rupture from even minor trauma.

Figure 5.19 Keratoconus Keratoconus is an abnormality in corneal collagen. Keratoconus typically presents in the second decade of life and can be either rapidly or slowly progressive. Clinical signs include a corneal protuberance in the shape of a cone, the apex of which is progressively thin. Keratoconus is an autosomal dominant disorder that has been mapped to multiple loci with one known gene, VSX1 at 20p11.2. Keratoconus is associated with increased visualization of corneal nerves (Fig. 5.7) and iron lines caused by pigment deposition within the epithelial and Bowman layer (Fleischer ring). It is more common in children with Down syndrome, atopy, Leber congenital amaurosis, and perhaps eye rubbing.

Figure 5.20 Keratoconus—Acute Corneal Hydrops and Munson Sign If the Descemet membrane is ruptured due to progressive thinning at the apex of the cone, the cornea can rapidly fill with fluid, causing a rapid decrease in vision due to corneal edema (left image). This acute corneal hydrops may improve with no treatment but may also require emergency corneal grafting. Subsequent scarring in the visual axis after the acute hydrops resolves is another indication for transplantation. This scarring can be seen in the right image, which also demonstrates a Munson sign: A conical deviation in the lower lid in downgaze due to the corneal cone.

Figure 5.21 Corneal Forceps Injury A corneal injury can occur when forceps are inadvertently applied to the face, with the edge of a forceps blade across the open or closed lid, during delivery. Breaks in the Descemet membrane are the direct result of pressure placed on the cornea and are typically linear. They appear as parallel lines representing the two edges of the scrolled Descemet membrane. Corneal edema and permanent scarring can lead to photophobia, astigmatism, and vision loss. However, improvement usually occurs over time and transplantation is rarely needed. There may be associated injury to the periocular tissues such as ecchymosis and laceration, and/or facial nerve palsy. The lesion is virtually always unilateral.

Figure 5.22 Band Keratopathy Band keratopathy is caused by deposition of calcium within the Bowman layer of the cornea. The deposits are grayishwhite and are concentrated within the interpalpebral area. The absence of the Bowman layer in the peripheral cornea creates a clear zone at the corneal–limbal junction. As seen in the photo, pinpoint clear areas can be seen throughout the opacity and represent areas where the corneal nerves pass through the Bowman layer. Potential causes include chronic inflammation (e.g., uveitis, keratitis), hypercalcemia, toxins, and skin diseases. Treatment modalities include chelation with ethylenediaminetetraacetic acid and/or mechanical scraping.

Figure 5.23 Exposure Keratopathy Corneal exposure can occur with reduced corneal lubrication or inadequate eyelid closure. Decreased lubrication can be secondary to inadequate tear quality or quantity (e.g., blepharitis, damage to the lacrimal gland from radiation, tumor or trauma, and Sjögren syndrome). Inadequate eyelid closure can be the result of lower lid ectropion, proptosis, lagophthalmos, or facial nerve palsy. A neurotrophic/anesthetic cornea will be more susceptible to changes secondary to exposure. The cornea in the photo has chronic exposure with keratinization of the corneal surface and vascularization. Progressive damage can ultimately lead to perforation. Treatment modalities include aggressive tear replacement with drops and ointment, elimination of eyelid apposition abnormalities, tarsorrhaphy, and nighttime closure with tape.

Figure 5.24 Thygeson Superficial Punctate Keratitis Thygeson superficial punctate keratitis is a focal keratitis without conjunctival or stromal involvement. It is usually recurrent and bilateral. Patients typically present with foreign body sensation with photophobia and increased tearing. On slit-lamp examination there are multiple slightly raised, white/gray dots. They are concentrated centrally and may stain with fluorescein during the acute attack (Fig. 5.25). There is no associated conjunctivitis or subepithelial infiltrate. The episode lasts 4 to 6 weeks and then typically recurs several times a year. Treatment options include topical steroids and a bandage contact lens.

Figure 5.25 Thygeson Superficial Punctate Keratopathy The cause of this remarkably asymptomatic disorder is largely unknown. It is characterized by mild foreign body sensation and multiple elevated white or gray-white round intraepithelial opacities that stain with fluorescein. The remainder of the eye examination is normal. The lesions usually resolve spontaneously, but recurrences and chronicity are common. Artificial lubrication, and in more severe cases topical steroids, are used as treatment.

Figure 5.26 Staphylococcal Hypersensitivity Immune Keratitis Staphylococcal hypersensitivity immune keratitis is a type IV immune response on the periphery of the cornea. The small raised white dots located near the limbus will often stain with fluorescein. Excessive amounts of staphylococcal species, usually coagulase negative and otherwise nonpathogenic, are the causative agent. Blepharitis and meibomian plugging are commonly found (Chapter 2: Lids and Adnexa, Fig. 2.23). Treatment includes lid hygiene, warm compresses, and topical antibiotics to address the lid margin disease, but a short course of topical steroids will rapidly resolve the keratitis.

Figure 5.27 Corneal Phlyctenule Corneal phlyctenules are inflammatory lesions located just anterior to the limbus. A type IV hypersensitivity reaction to staphylococcus species is the most common cause and may also be associated with conjunctival phlyctenule (Chapter 4: Conjunctiva, Fig. 4.15). Corneal phlyctenule may also be due to tuberculosis or, in immunocompromised patients, sporotrichosis. The lesions can become ulcerated on the surface and result in scarring of the peripheral cornea. Treatment of the underlying blepharitis (Chapter 2: Lids and Adnexa, Fig. 2.23) with lid hygiene and topical antibiotics is essential. Topical steroids are indicated for severely inflamed lesions or lesions not responding to conservative therapy.

Figure 5.28 Radiation Keratitis Radiation keratitis occurs when the eye is in the field of radiation for ocular, orbital, sinus, or brain tumors. In addition to corneal dysfunction, there is contributing meibomian gland dysfunction and loss of conjunctival goblet cells with or without lacrimal gland hyposecretion, all of which lead to dry eye and corneal vascularization. The inferior third of the cornea is usually the most affected site. Artificial lubrication is essential to prevent progression. Left untreated, severe corneal vascularization, scarring, and even perforation may result.

Figure 5.29 Filamentary Keratitis Corneal filaments are strands of mucus and corneal epithelium attached to the surface of the cornea. Filamentary keratitis is a clinical finding caused by dry eye, recurrent erosion, exposure keratopathy, radiation keratopathy, neurotrophic keratopathy, and herpes simplex virus. Treatment includes debridement, tear supplements, bandage contact lenses, and mucolytic agents (Nacetylcysteine). The filaments can be quite prominent despite minimal symptoms.

Figure 5.30 Herpes Simplex Virus—Primary Infection The left image shows a patient with primary herpes simplex virus (HSV) infection of the periocular structures. The vesicular lesions on the face are most commonly the result of direct exposure to an infected individual. Clinical features may include vesicular dermatitis, blepharoconjunctivitis, and keratitis. Conjunctival follicles and pseudomembranes (Chapter 4: Conjunctiva, Fig. 4.11) are common. Keratitis occurs in 50% of patients with primary HSV. In the right image, the corneal findings are different from recurrent HSV and include a diffuse epitheliopathy without branching dendrites (as shown in the image). Treatment with antiviral agents is indicated for blepharitis, conjunctivitis, and keratitis. Ocular surface medication is not needed if the eye is not red.

Figure 5.31 Herpes Simplex Virus— Recurrent Infection Recurrent herpes simplex virus is a reactivation of the latent virus stored within the trigeminal ganglion. The primary disease could have previously involved the periocular structures or the mouth. A diffuse epithelial punctuate keratopathy is the first sign of corneal involvement that may progress into corneal dendrites, as demonstrated here with topical fluorescein staining. The lesions may be painful, but after recurrent infections, corneal sensation is reduced. Treatment includes debridement, topical antivirals, and, in infants or vision-threatening lesions, systemic antivirals.

Figure 5.32 Varicella Zoster Herpes zoster is caused by reactivation of the varicella virus following earlier chickenpox. The photograph demonstrates the typical vesicular lesions respecting the distribution of the trigeminal nerve. Children with zoster should undergo an evaluation for underlying immunosuppression. Ocular manifestations include keratitis, uveitis, scleritis, conjunctivitis, and chorioretinitis. Treatment includes topical steroids and systemic acyclovir. Postzoster neuralgia can also occur in children.

Figure 5.33 Acanthamoeba Keratitis Radial keratitis is pathognomonic for acanthamoeba keratitis. Acanthamoeba keratitis is caused by protozoa and is seen most commonly in contact lens wearers. Patients present with severe photophobia and pain. Clinical findings include a follicular conjunctivitis, preauricular node, ring corneal infiltrate, and radial keratitis (enlarged corneal nerves with surrounding infiltrates). Diagnosis is made by culturing the acanthamoeba on Escherichia coli nonnutrient agar. Cysts and trophozoites can be identified on smears with calcofluor white. Treatment includes neomycin, the antifungal agents containing imidazole and triazole, the antiseptic solution chlorhexidine, the swimming pool cleaner Brolene, and polymyxin B.

Figure 5.34 Bacterial Bacterial corneal ulcers in children can be caused by trauma, contact lens overwear, exposure keratopathy, and congenital malformations. Aphakic children in silicone contact lenses rarely get ulcers. Teenagers with poor cosmetic soft contact lens hygiene are particularly susceptible. Corneal cultures and stains should be obtained to isolate the organism, even if examination under anesthesia is needed. Broad-spectrum antibiotics should be started topically and then tailored to cover the identified organisms. The white corneal infiltrate is usually surrounded by stromal edema and overlying corneal epithelial defects.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 6 - Iris and Pupils

6 Iris and Pupils Alex V. Levin Thomas W. Wilson J. Raymond Buncic David Rootman The iris is formed during ocular development by an extension of the optic vesicle (neuroectoderm) forward as the posterior pigmented and nonpigmented iris epithelium, and an influx of neural crest cells forming the iris stroma. The iris sphincter and dilator muscles differentiate from the epithelial layers. Mesoderm contributes the endothelial lining of the vessels. Abnormalities of embryogenesis can lead to iris anomalies including coloboma, persistent pupillary membranes, aniridia, and Axenfeld-Reiger syndrome. Iris findings can often give clues to underlying systemic diseases including Down syndrome (Brushfield spots), neurofibromatosis type 1 (Lisch nodules), Williams syndrome (stellate iris), and Hirschsprung syndrome (sector iris heterochromia). Abnormalities of the iris are also associated with other ocular abnormalities in diseases such as aniridia, albinism, and coloboma. Iris abnormalities can be the first clues of an underlying systemic disease or genetic disorder.

Figure 6.1 Aniridia Aniridia is an autosomal dominant abnormality of ocular development caused by a defect in the PAX6 gene located at chromosome 11p13. The association of Wilms tumor, sporadic aniridia, genitourinary abnormalities, and mental retardation is termed WAGR syndrome and is due to contiguous gene deletion in this region. Patients with aniridia will often present with nystagmus, photophobia, and decreased vision. Clinical findings include complete or partial absence of the iris, keratitis, cataract, macular hypo- plasia, and optic nerve hypoplasia. Glaucoma is present in approximately one third of patients with aniridia and cataracts in approximately 50%.

Figure 6.2 Aniridia—Glaucoma Glaucoma is a common association with aniridia. One fourth to one third of patients with aniridia will develop angle closure glaucoma in the first decade of life. The possible mechanisms include aplasia of the Schlemm canal, goniodysgenesis, or migration of the rudimentary iris stump forward, as shown here, resulting in obstruction of the trabecular meshwork. Medical treatment is often not successful and glaucoma surgery is required to control the intraocular pressure.

Figure 6.3 Aniridia—Macular Hypoplasia Aniridia is often associated with nystagmus and visual loss. The most common cause of vision loss in a patient with otherwise clear media is macular and optic nerve hypoplasia. This photograph shows abnormal macula throughout the deeply depressed light reflex centrally. The retinal blood vessels also do not respect the foveal avascular zone. The optic nerve in this photograph also appears hypoplastic.

Figure 6.4 Gillespie Syndrome Gillespie syndrome is the association of aniridia and cerebellar ataxia and mental retardation. Aniridia associated with Gillespie syndrome is not caused by mutations of the PAX6 gene, and is therefore not associated with Wilms syndrome. The disorder is autosomal recessive. Note the typical scalloped pupil margin and more robust iris stump as compared to classic aniridia (Fig. 6.1).

Figure 6.5 Congenital Iris-Lens- Pupillary Membrane Syndrome This photograph demonstrates secondary congenital miosis from a traction band extending across the borders of the pupil. White fibrous material seen centrally represents a remnant of the tunica vasculosa lentis. This form of persistent fetal vasculature (Chapter 7: Lens, Fig. 7.2) is characterized by corectopia and a high risk for glaucoma. The membrane may also extend behind the iris. Surgical pupilloplasty would be necessary in cases where the visual axis is significantly obstructed.

Figure 6.6 Physiologic Anisocoria To be considered physiologic, the relative difference in the pupil sizes should be the same in light and dark conditions. There should be full extraocular movements and no evidence of ptosis. Old photographs are often helpful to determine the chronicity of the anisocoria. Further workup including neuroimaging, cocaine testing, and evaluation for neuroblastoma should be considered with any other neurologic or associated ocular findings.

Figure 6.7 Iris Pupillary Cysts Congenital cysts of the iris pigment epithelium are commonly detected on red reflex testing by the pediatrician. This photograph shows a group of cysts that are not obscuring the visual axis. Glaucoma is not typically associated with these cysts. The cysts tend to be multiple and are not large enough to occlude the visual axis. The cysts may rupture or collapse over time. Chronic use of phospholine iodide can cause similar cysts and will resolve with discontinuation of the medication. Cysts that occlude the visual axis can be disrupted with neodymium YAG capsulotomy or anterior segment surgery.

Figure 6.8 Congenital Iris Ectropion Uvea Congenital ectropion uvea is an abnormal migration of posterior pigment epithelial into the anterior iris surface. The patient will often present with concerns regarding anisocoria or iris pigmentation. Clinical examination shows an irregular pigmented mass on the anterior surface of the iris with distortion of the pupil and corectopia. Secondary glaucoma will commonly present, requiring surgical treatment. The disorder is almost always unilateral and nonheritable. Histology shows a residual contractile cellular lining attached to the leading edge of the ectropion and possibly covering the trabecular meshwork.

Figure 6.9 Polycoria Polycoria is a rare congenital abnormality with more than one pupil. True polycoria must have two completely separate iris margins. Pseudopolycoria is more common and caused by defects in the iris stroma or traction bands dividing the normal pupillary opening.

Figure 6.10 Corectopia Corectopia is a pupil that is not centered within the iris stroma. Mild corectopia as seen in this photograph will not affect the visual development; however, it may lead to the misdiagnosis of esotropia. On the Hirschberg light reflex test, the patient will have a light reflex on temporal iris, indicating a possible esotropia. Cover testing will determine the presence of an underlying strabismus. Severe corectopia may be associated with ectopia lentis and is referred to as ectopia lentis et pupillae (Chapter 7: Lens, Fig. 7.18). If the lens is not dislocated, these patients will often have no visual problems. A cosmetic contact lens could be used in this patient if there are cosmetic concerns.

Figure 6.11 Iris Coloboma Iris colobomas are abnormalities of ocular development due to incomplete closure of the optic cup. Incomplete closures anteriorly lead to iris colobomas and incomplete closures posteriorly lead to choroidal and optic nerve colobomas. Colobomas are typically located inferonasally, which corresponds to the location of the embryonic fissure of the developing optic cup. Several syndromes have associated coloboma. CHARGE association is the combination of coloboma, heart defects, atresia choanae, retarded growth and development, genitourinary abnormalities, and ear anomalies. Partial trisomy 22 (cat eye syndrome), trisomy 13 (Patau syndrome), and trisomy 18 (Edwards syndrome) are all associated with iris coloboma.

Figure 6.12 Persistent Pupillary Membrane Persistent pupillary membrane is a common finding on careful slit-lamp examination. Persistent membranes are the result of incomplete regression of the primitive vascular supply in the developing eye with failure of dissolution of the surrounding neural crest derived iris stroma that normally covers the pupil in utero. The annular vessel within the optic cup provides the vascular supply for the anterior lens surface. If this vascular network does not involute completely, a resultant pupillary membrane will form. Pupillary membranes vary greatly in size, configuration, and severity. Even more severe membranes, as shown in the right image, may prove to be visually insignificant and dissolve with time, presumably due to the normal contraction and dilation of the pupil with changes in ambient light. Topical phenylephrine 2.5% can stretch the membrane and open the visual axis dramatically in some patients as shown on the left.

Figure 6.13 Persistent Pupillary Membrane with Cataract There can be attachment of the pupillary membrane to the anterior lens surface with a small cataract in the area of the attachment. This type of cataract is usually eccentric to the visual axis and rarely visually significant. Growth is uncommon. Note that the base of the iris strands are arising from the iris collarette, thus distinguishing this from posterior synechia (Fig. 6.24), where the attachment is to the pupil margin.

Figure 6.14 Iris Hypoplasia Iris hypoplasia is characterized by a flat underdeveloped anterior iris leaflet with thin stroma. The iris sphincter is bared and easily identified around the pupil. Iris hypoplasia is associated with glaucoma and inherited as an autosomal dominant disorder. It can be caused by mutations in the PITX2 gene at 4q25. Patients identified with iris hypoplasia require periodic screening for early detection of glaucoma.

Figure 6.15 Axenfeld-Rieger Syndrome Axenfeld-Rieger syndrome is a rare congenital anomaly of the iris and anterior chamber angle structures. It is typically bilateral and inherited as an autosomal dominant trait. Approximately 50% of the patients will develop secondary glaucoma. Clinical manifestations include a prominent Schwalbe line with iris strands extending from the Schwalbe line to the iris surface. As seen in this photograph, there may be significant thinning of the iris stroma and formation of iris defects.

Figure 6.16 Axenfeld-Rieger Syndrome The glaucoma seen in approximately 50% of patients with Axenfeld-Rieger syndrome typically presents in early childhood and is the most likely caused by iridogoniodysgenesis rather than blockage of the trabecular meshwork by the iridocorneal strands seen here on gonioscopy. Medical management is often unsuccessful and surgery is often required. Several theories have been proposed to explain pathogenesis. This is an autosomal dominant developmental disorder of neural crest migration and may be due to mutations in the FOXC1 gene at 6p25 or PITX2 gene at 4q25. Another locus on chromosome 13q14 is also known.

Figure 6.17 Axenfeld-Reiger Syndrome This syndrome has associated systemic abnormalities, including facial and dental anomalies. Facial abnormalities include midfacial and maxillary hypoplasia with prominence of the lower lip as compared to the upper lip. Telecanthus with a flat nasal bridge is a common facial feature. Dental anomalies include a decreased number of teeth (hypodontia), decreased size (microdontia), and absence of teeth (anodontia) (left image). There is an increased rate of umbilical hernias or incomplete involution of the umbilicus, as seen in the right image. Deafness, structural cardiac anomalies, and cerebellar atrophy have been associated.

Figure 6.18 Iris Mamillations Iris mamillations are formed elevations of normal iris tissue found on the anterior surface of the iris. They may be bilateral or unilateral and should be differentiated from Lisch nodules, which are more scattered, amorphous, and generally not the same color as the iris. Mamillations are always multiple and clustered with a decrease in the usual iris crypts and valleys. There is a rare association with glaucoma.

Figure 6.19 Iris Hemangioma The left photograph is a localized hemangioma of the iris. Histopathologically, there may be capillary and cavernous configurations. Patients may present with a discoloration on the iris. Spontaneous hyphema (right image) may occur. Treatment for small solitary tumors would include surgical removal or systemic steroids. Diffuse iris hemangiomas occur in Sturge-Weber syndrome.

Figure 6.20 Iris Nevus Iris nevi are small areas of pigmentation on the anterior surface of the iris. They are nonprogressive in size and do not distort the pupil. They are well circumscribed and typically found in the first years of life. They may be single or multiple. Iris nevi may also be referred to as iris freckles.

Figure 6.21 Sector Iris Heterochromia Sector iris heterochromia is often incorrectly referred to as sector iris nevus. Note that the iris architecture is normal throughout. Compare this to Figure 6.20, where the architecture changes in the location of the iris. Sector iris nevus is actually an abnormal migration of neural crest cells and thus a deficiency of melanocytes. The abnormal portion of the iris is the hypopigmented sector. This may be associated with other disorders of abnormal neural crest migration such as Hirschsprung disease (Chapter 17: Gastrointestinal, Fig. 17.4). Patients with sector iris nevus should specifically be asked about constipation and large stools.

Figure 6.22 Horner Syndrome Horner syndrome caused by sympathetic chain denervation of the pupil dilator muscle, Müeller muscle, and sweat glands of the face results in the classic triad of miosis, ptosis, and anhidrosis. Other clinical abnormalities can include a decreased amplitude of accommodation, lower intraocular pressure, and elevated lower lid (upside-down ptosis). The anisocoria is greater in dim illumination than bright. The amount of ptosis is typically small, between 1 and 2 mm. In the pharmacologic test of Horner syndrome, 4% cocaine drops fail to dilate the abnormal smaller pupil but do dilate the normal one. Hydroxyamphetamine testing fails to dilate the pupil in peripheral (third-order) lesions. Heterochromia in congenital cases reflects failure of the sympathetic supply to the neural crest cells for pigmentation, and may be very subtle. Causes include traumatic birthing traction on the brachial plexus (Klumpke palsy). Urinary homovanillic acid and vanillylmandelic acid are elevated in neuroblastoma. Congenital heart surgery, central venous line placement in the subclavian or external jugular vein, and other paravertebral anomalies are other causes.

Figure 6.23 Iris Melanoma Iris melanoma is a rare uveal tumor in children. The tumors are slow growing and are unlikely to metastasize early in the disease. Patients may present with a noticeable brown mass on the iris or hyphema. These tumors are extremely rare in the black population. Differential diagnoses include iris nevi and ectropion uveae. The most common histologic form of iris melanoma is spindle cell. Other histopathologic cell types are mixed and epithelioid. Treatment remains controversial, but many experts advocate enucleation.

Figure 6.24 Posterior Synechiae Posterior synechiae are adhesions between the pupil margin and anterior lens capsule secondary to inflammation of the iris with adherence to the anterior capsule of the lens. The pupil is often restricted to one position, and iris bombe with pupillary block and acute angle closure glaucoma can occur. The risk of posterior synechiae can be reduced with control of the intraocular inflammation and daily mydriatic agents. This child also has a cataract due to his uveitis. The iris should be freed from the anterior lens capsule at the time of surgery.

Figure 6.25 Congenital Absence of the Pupil Sphincter and Dilator This rare anomaly is usually an isolated unilateral or bilateral disorder but may also be seen in central hypoventilation syndrome (Ondine curse). The iris is fixed and middilated. Note that there is no collarette and the stroma is rather featureless. This is not visually significant, but hypoaccommodation may require optical correction and bifocals.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 7 Lens

7 Lens Alex V. Levin Thomas W. Wilson David Rootman The lens of the eye is derived from surface ectoderm, which invaginates into the optic vesicle during embryogenesis. This newly formed lens vesicle contains an outer capsule and is lined with primary lens epithelium. The posterior fibers elongate anteriorly to fill the vesicle. Secondary lens fibers emanate from the equatorial lens and migrate anteriorly and posteriorly to form the Y sutures. The primary lens fibers that are encircled by these secondary fibers are compacted to form the embryonic nucleus. The secondary fibers interior to the Y sutures make up the fetal nucleus. Additional fibers are laid down exterior to the Y sutures, forming the cortex. This complicated process is regulated by a variety of genes with differential expression in terms of location and time of development. The morphology of pediatric cataracts often reflects these stages of differentiation. Significant amblyopia and subsequent vision loss can occur from these opacities. Early surgery with optical correction is crucial for visual development. Cataracts can be isolated genetic or nongenetic conditions or the

result of systemic disease and systemic medications, in particular steroids. Cataracts may also be part of congenital syndromes. Heritable cataracts may be unilateral or bilateral. Attention must be paid to cataract morphology as this will provide information on cause, heritability, and management strategies. Some small cataracts may be managed medically, whereas more significant visual axis obstruction will require surgery. The lens is suspended on the anterior vitreous face behind the pupil by the zonules (suspensory ligaments). A wide variety of systemic disorders, covered elsewhere in this atlas, may be associated with zonular weakness or dehiscence resulting in ectopia lentis. This chapter will focus on the causes of isolated ectopia lentis due to ocular malformation. Buphthalmos (Chapter 10: Glaucoma, Fig. 10.1) can also cause ectopia lentis. Isolated autosomal dominant and autosomal recessive forms may also be observed.

Figure 7.1 Mittendorf Dot Mittendorf dot is a small, gray or white opacity on the posterior capsule of the lens. It is the area where the hyaloid artery system attaches to the lens during ocular development. The opacity is not vision threatening and typically does not progress. A hyaloid remnant is seen here with some radiating persistent fetal circulation on the posterior surface of the lens.

Figure 7.2 Tunica Vasculosa Lentis Tunica vasculosa lentis is the primitive vasculature that envelops the developing lens of the fetus as the forward extension of the hyaloid system. This fine network of vessels regresses starting at 28 to 30 weeks of gestation, but regression may be delayed by systemic illness. It clears centrally first and can be an accurate marker of gestational

age. It is not visually significant. The left image is taken in a premature baby that is younger than the child on the right.

Figure 7.3 Anterior Subcapsular Cataract Anterior subcapsular cataract is an opacity that lies on the posterior surface of the anterior lens capsule. It is often traumatic in cause but may be an isolated heritable opacity or associated with Alport syndrome (often in the anterior lenticonus, not shown here) or atopic dermatitis. There may be a central focal white opacification of the anterior capsule, shown here, with the gray base of posterior subcapsular opacity. The latter may enlarge and become visually significant. However, if the opacity remains small (<3 mm), medical management with pharmacologic dilation of the pupil and patching of the other eye may result in good vision outcomes.

Figure 7.4 Anterior Dot Polar Cataract Anterior dot polar cataracts are small white opacities located centrally on the anterior lens capsule. Two thirds are unilateral. Although usually visually insignificant, other ocular findings may include amblyopia, anisometropia, persistent pupillary membrane, and strabismus. Progression is uncommon but patients should be examined at regular intervals, especially in the first year of life. Autosomal inheritance may be observed.

Figure 7.5 Anterior “Tractional” Cataract This lens opacity is always associated with a persistent pupillary membrane strand to which it is attached. This is a remnant of the neural crest–derived iris stroma network that covers the pupil during ocular development. The opacity in the lens capsule, with or without an underlying anterior subcapsular opacity, is usually eccentric to the visual axis and therefore visually insignificant. Enlargement of the subcapsular component is rare but follow-up is recommended, especially in the first year of life. The pupillary membrane strand often lyses spontaneously over time. This is a nongenetic unilateral lens opacity.

Figure 7.6 Cerulean Cataract Cerulean cataract, also known as “blue dot” cataract, may be an isolated heritable cataract or associated with systemic disorders such as Down syndrome. The multiple opacities appear as small, bluish-white amorphous dots located in the cortical material of the lens. More coalescence of the opacity may be seen in the nucleus, at the sutures, or in the posterior cortex. Crystallin gene mutations (CRYBB2, CRYGD) have been associated with autosomal dominant forms of cerulean cataract.

Figure 7.7 Lamellar Cataract Lamellar cataracts are opacities outside the lens nucleus and are contained within the cortex. The central lens is often clear. The cortical fibers are laid down in concentric layers. At the point where the cataractogenic event occurs, one layer becomes opacified. As seen here, arclike opacities, which appear to be perpendicular to the lamellar opacity (arrow), arc around the lamella. These are called cortical riders. Lamellar cataracts are often progressive and many will require surgical removal, although the opacity may seem more severe than the visual acuity.

Figure 7.8 Embryonal Nuclear Cataract Embryonal cataracts involve the most central portion of the lens nucleus. They are typically not progressive but can be visually significant. The embryonic nucleus is formed within the first 2 months of gestation as primary lens fibers extend forward from the back of the lens vesicle and are then compressed into a central core by surrounding secondary lens fibers. These cataracts are often genetic and bilateral. If they disrupt the central 3 mm of the retinoscopy reflex, then surgery is usually indicated.

Figure 7.9 Fetal Nuclear Cataract A fetal nuclear cataract is a lens opacity involving the fetal nucleus, which is the portion of the lens delimited anteriorly and posteriorly by the Y sutures. It contains a central core, the embryonal nucleus, which is also often opacified as well. Although the fetal cataract is typically nonprogressive, it can cause visual loss and require surgery. Nuclear cataract, especially when associated with microphthalmia, significantly increases the risk of aphakic glaucoma following cataract surgery.

Figure 7.10 Pulverulent Cataract Cataract centralis pulverulenta consists of a small central grayish globular opacity containing small white granules. There is also often a multitude of tiny dustlike opacities throughout the cortex as well as the nucleus. The opacities may be confined to one or more lamellae and may be of different sizes in different parts of the lens. It is located within the fetal nucleus and has an autosomal dominant inheritance. Many genes have been associated with both autosomal recessive and autosomal dominant pulverulent cataracts.

Figure 7.11 Sutural Cataract Sutural cataracts occur at the Y sutures, which are formed from developing secondary lens fibers as they surround the embryonal nucleus. These lens opacities may progress but are not usually visually significant. They are usually isolated ocular abnormalities and may be inherited as an autosomal dominant condition due to mutations in the crystalline genes CRYBB2 or CRYBA1.

Figure 7.12 Posterior Subcapsular Cataract (PSC) The posterior subcapsular cataract is an opacity on the anterior surface of the posterior capsule. This type of cataract is associated with chronic steroid use, radiation exposure, inflammation, and trauma. PSC can also be an isolated heritable ocular abnormality, usually autosomal dominant. It is often visually significant, requiring surgical correction. However, in childhood the vision is often surprisingly better than one might expect from the examiner's view of the opacity.

Figure 7.13 Posterior Lenticonus Posterior lenticonus is lens opacity secondary to absence or thinning of the posterior lens capsule with progressive overlying cortical opacification. As shown here, there is a characteristic posterior bowing of the lens capsule. Speckled white opacities on the posterior capsule surrounding the defective area may be seen. Because of its location, posterior lenticonus is commonly visually significant, requiring either refractive correction or surgical removal, even if there is no opacity within the bowed portion of the posterior capsule.

Figure 7.14 Persistent Fetal Circulation (PFC) Formerly known as persistent hyperplastic primary vitreous (PHPV), PFC is due to a persistence of the primitive hyaloid vasculature of the developing eye. The fibrovascular stalk extends from the posterior lens posterior to the optic nerve. This patient demonstrates the characteristic vascularized posterior capsular plaque associated with pulled-in ciliary processes. Poor pupillary dilation and microphthalmia with a shallow anterior chamber are also frequent. If unilateral, this is a nongenetic disorder. In less than 10% of cases, bilateral PFC may be seen. These children have a higher incidence of developmental delay and other systemic malformations.

Figure 7.15 Persistent Fetal Circulation The remnant of the fetal hyaloid vasculature is seen extending from the posterior lens capsule (left image) to the optic nerve (right image). The stalk may or may not have patent vasculature. During surgical removal, this blood vessel will often bleed, requiring electrocautery. The posterior stalk can be associated with distortion and detachment of the macula. Retinal distortion is seen in the right image. This may preclude visual rehabilitation after cataract surgery.

Figure 7.16 Persistent Fetal Circulation Persistent fetal circulation is a persistence of the anterior hyaloid system. The hyaloid system normally flares out over the anterior vitreous face on its way to envelop the lens. When normal regression does not occur, a fibrovascular opacification occurs and appears on ultrasound biomicroscopy as a double linear echo (arrows). This membrane may insert at the ora and result in retinal traction, if not dialysis, during surgery. Involvement of a vitreoretinal surgeon may be appropriate for cataract surgery.

Figure 7.17 Total Cataract The entire lens is opacified in this photograph. Surgical removal should be performed as soon as possible in an attempt to restore the vision. View of the posterior pole is not possible and therefore B-scan ultrasound is advised. Many of the cataracts pictured in this chapter can progress to a total white cataract. Therefore, the surgeon must be prepared to encounter such problems as posterior lenticonus or other types of primary cataract opacities.

Figure 7.18 Ectopia Lentis et Pupillae Ectopia lentis et pupillae is a developmental abnormality where the lens is dislocated in one direction and the pupil is displaced in the opposite direction. The pupil tends to be oval and dilates poorly. There may be zonular deficiency in the quadrant toward which the pupil is displaced, thus resulting in the lens moving in the opposite direction. An autosomal recessive inheritance pattern has been reported. An adequate visual axis may be obtained in some cases with pharmacologic dilation of the pupil, but surgery would be required if the lens is displaced significantly.

Figure 7.19 Ectopia Lentis in Persistent Fetal Circulation This slide demonstrates an ectopic lens secondary to persistent fetal circulation (formerly known as persistent hyperplastic primary vitreous [Fig. 7.14]). Note the opacity on the posterior pole of the lens. Presumably due to the contraction of the fibrovascular membrane, the lens has shifted laterally and slightly superiorly. The ciliary body can be seen nasally. Surgery would be needed to clear the visual axis.

Figure 7.20 Microspherophakia In microspherophakia, the lenses are small and round. This may be a primary disorder of lens size or a secondary finding due to weak zonules. The entire lens is visible through the dilated pupil. Dislocation of the lens into the anterior chamber and pupillary block glaucoma can occur. Associated systemic conditions include Weil Marchesani syndrome, in which patients will demonstrate skeletal abnormalities including short stature with a large thorax, short spadelike hands, brachycephaly, and a depressed nasal bridge. This syndrome may be inherited as an autosomal dominant (mutations in the fibrilin-1 gene, FBN1, at 15q21.1, which also is responsible for Marfan syndrome [Chapter 28: Skeletal, Fig. 28.8]) or autosomal recessive (mutations in the ADAMTS10 gene at 19p13.3-13.2) disease.

Figure 7.21 Dislocated Lens in Anterior Chamber In this photograph, the lens is dislocated into the anterior chamber causing papillary block glaucoma. This may result in iritis, corneal edema, and pupillary block. The latter is due to the strong attachments between the pediatric anterior vitreous face and the back of the lens. As a result, when the lens comes forward, vitreous is dragged through the pupil. If the pupil constricts around the vitreous, block occurs and intraocular pressure can be dramatically high. Although the lens may float back behind the pupil with pharmacologic dilation in the supine position followed by pharmacologic miosis, surgery is usually recommended to prevent recurrences. Complete forward dislocation is more common in disorders where zonules break (e.g., homocystinuria, Chapter 20: Metabolic, Fig. 20.3) or in microspherophakia (Fig. 7.20), as opposed to disorders where the zonules stretch, as in Marfan syndrome (Chapter 28: Skeletal, Fig. 28.8).

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 8 Retina and Vitreous

8 Retina and Vitreous Elise Héon Nasrin Najm-Tehrani Brenda Gallie Wai-Ching Lam Peter Kertes Robert Devenyi Carol Westall Thomas W. Wilson Alex V The retina develops from the neuroectodermal cells of the optic cup around 4 weeks of gestation. Retinal development occurs in parallel with the development of other organ systems and therefore, explains why retinal diseases of childhood are often associated with disorders of the ear, kidney, or central nervous system. Primary care providers should be informed of the possibility of an underlying syndrome in all children with retinal disease. The retina matures from the center to the periphery. The photoreceptors, essential to the processing of light, start to develop between 4 and 12 weeks of gestational age. The macula

becomes recognizable between 24 and 26 weeks and the fovea will continue to mature after birth until 4 years of age. The retina is a fragile multilayered tissue where light is processed. The major step in the processing of light is called phototransduction, which takes place in the photoreceptors. The integrity of a photoreceptor requires a healthy surrounding, including the retinal pigmented epithelium (RPE) and inner sensory retina. Anomalies at any of these levels may lead to photoreceptor dysfunction and visual loss. This is usually the basis of the complex field of retinal dystrophies. Likewise, abnormalities of the choroid, the vasculature of which nourishes the outer retina, may also lead to retinal degener- ation. For most retinal and choroidal dystrophies, there is no treatment available, but this will change with the great influx of genetic knowledge about these conditions and the rapid progress of retinal gene and pharmacologic therapy. Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinal vessels in premature babies. It is characterized by arrest of the normal process of retinal vessel growth with resultant arteriovenous shunts and development of abnormal new vessels that may eventually lead to tractional retinal detachment and blindness. The disease is detected through a screening program for premature babies who are at risk and involves regular examination of the retina. The guidelines for inclusion in screening programs vary slightly between countries depending on local variations in incidence of ROP and neonatal care, but the infants at highest risk are those of low gestational age (<32 weeks) and low birth weight (<1,500 g). In these infants screening for ROP should start at 4 to 6 weeks after birth and continue at regular intervals until retinal vascularization has reached the temporal periphery (zone 3). The use of wide angle digital imaging has greatly improved our ability to observe and record the course of retinal maturation and document progression of disease, which allows for comparison between patient examinations and better communication between ophthalmologists and other health care providers. Fortunately, in the majority of

cases ROP regresses spontaneously; however, in a small percentage the disease will progress with development of severe stages of ROP, with major visual consequences. Retinoblastoma is the most common malignant tumor of childhood, but it is quite rare at an incidence of 1 in 15,000 live births. Retinoblastoma can be hereditary or nonhereditary. If left untreated, it can be fatal. For retinoblastoma and ROP, one must remember that the earliest diagnosis will produce the most favorable outcome.

Figure 8.1 Macular Hypoplasia Macular hypoplasia can be seen as an isolated autosomal dominant or autosomal recessive disorder. It may also be seen in association with albinism, aniridia, or other developmental disorders of the eye. The hypoplasia is characterized by the absence of the usual reflection from the macular mound and a poorly developed fovea. Retinal

vessels coursing through the central macula are common. In the absence of proper macular differentiation, the blood vessel pattern may not develop properly. Visual acuity is difficult to predict on the basis of macular appearance, but the presence of anomalous vessels that do not respect the horizontal meridian portends a worse prognosis.

Figure 8.2 Congenital Hypertrophy of the Retinal Pigmented Epithelium (CHRPE) Congenital hypertrophy of the pigment epithelium may be isolated or associated with systemic disorders such as neurofibromatosis (see Chapter 23: Phakomatoses) or familial adenomatous polyposis (FAP). When FAP is associated with benign soft tissue and bony tumors, the condition is called Gardner syndrome. When brain tumors are present, the patient is said to have Turcot syndrome. FAP is associated with a very high risk for colonic cancer.

Patients with more than two CHRPE lesions in one eye, bilateral CHRPE, or a family history of colon cancer should be screened with periodic colonoscopy starting in childhood. CHRPE lesions are usually asymptomatic unless the macula is involved. Lesions can be of various size and shape. They may have a hypopigmented ring (shown here) or a “tail.”

Figure 8.3 Bear Tracks These congenital hyperpigmented areas of the retinal pigmented epithelium are clustered in a pattern that has similarity to the footprints of a bear. They tend to cluster in one quadrant, usually unilaterally, and increase in number and area covered from posterior to anterior. Unlike congenital hypertrophy of the pigment epithelium (Fig. 8.2), they are not associated with systemic disease and usually do not have hypopigmented edges or tails. There may be one or

more clusters, each typically with a larger lesion surrounded by one or more smaller lesions.

Figure 8.4 Congenital Retinal Macrovessel This rare benign vascular anomaly (arrow) is not associated with leakage or systemic disease (as might be seen in the capillary hemangioma of von Hippel-Lindau disease, Chapter 23: Phakomatoses, Fig. 23.12). Even though these vessels may appear in areas of retina not usually vascularized in this fashion, as shown here, unlike the anomalous vessels of macular hypoplasia (Fig. 8.1), congenital macrovessels are

typically associated with normal retinal development and function.

Figure 8.5 Immature Retina The retina is often not fully vascularized until 36 weeks gestation. The nasal retina vascularizes before the temporal periphery. In this premature child, the retinal vessels taper without clear demarcation of the peripheral avascular retina (asterisk). The choroidal vessels visible through the thin avascular retina are easily mistaken for retinal vessels by the inexperienced examiner. The macular area is featureless, the foveal reflex is blunted, and the fovea cannot be located easily. In this case, an arteriovenous loop is visible joining the superior temporal retinal arteriole to the venule

(arrow). The extent of vascularization of the retina is just as far as the border of zone 1 and zone 2. According to the International Classification of Retinopathy of Prematurity, the zones of retinopathy of prematurity in the developing retina are as follows: • Zone 1 is a circle centered on the optic disc, the radius of which is twice the distance between the disc and the fovea. • Zone 2 is a circle centered on the optic disc, the radius of which is equal to the distance between the disc and the nasal ora. • Zone 3 is the remaining crescent-shaped area bounded by the outer boundary of zone 2 and the ora serrata, the widest part of which is in the temporal retina. This crescent tapers as it approaches the nasal ora.

Figure 8.6 Stage 1 Retinopathy of Prematurity in Zone 2 These images demonstrate a demarcation line between vascularized and nonvascularized (asterisk) retina. The left image is that of a darkly pigmented fundus. The right image is

that of a Caucasian infant. There is a “hold up” in the normal growth of the retinal vessels. The white line demarcating the extent of retinal vascularization is flat and thin. The vessels posterior to the demarcation line are dilated rather than tapered, and there is prominence of branching just behind the demarcation line. Although no treatment is indicated and the prognosis for resolution is excellent, careful follow-up, perhaps no later than 2 weeks, is required.

Figure 8.7 Stage 2 Retinopathy of Prematurity (ROP) With progression of ROP the demarcation line will become elevated, gain volume, and form a ridge (arrow). The distinction between stage 1 and stage 2 is much better appreciated in a three-dimensional view of the retina, using

scleral depression to look at the ridge in profile (i.e., tangentially). It may be more difficult to distinguish between stage 1 (Fig. 8.6) and 2 on two-dimensional imaging. Note the associated vascular changes including peripheral vessel dilation, tortuosity, and hyperacute branching. Also note the few peripapillary intraretinal hemorrhages as sometimes seen in active disease following examination.

Figure 8.8 Stage 3 Retinopathy of Prematurity—Mild With further progression of disease, there is development of neovascularization within the extra-retinal proliferation. As a result, the extra-retinal proliferation changes color from white to pink and becomes broader. The neovascularization is above the plane of the retina and can extend posteriorly over the retinal surface or centrally into the vitreous. The

extra-retinal proliferation can become more irregular in outline with development of neovascularization. There is notable vascular dilation and tortuosity close to the extraretinal proliferation, which may extend posteriorly to the posterior pole. Stage 3 may be mild, moderate, or severe as defined by the number of clock hours and the degree of neovascularization. Hemorrhage can be seen here along the anterior border of the extra-retinal proliferation (arrow).

Figure 8.9 Stage 3 Retinopathy of Prematurity— Moderate As stage 3 becomes more advanced, the neovascularization is more marked and the extra-retinal proliferation more pink in color. The retinal vessels are obscured as they lead up to the extra-retinal proliferation by the posterior extension of extraretinal (i.e., preretinal) neovascularization over the surface of the retina. Note also the increasing dilation and

tortuosity of the retinal vessels.

Figure 8.10 Stage 3 Retinopathy of Prematurity (ROP)— Severe This image shows severe stage 3 ROP as characterized by a broad neovascularized extraretinal ridge with a ragged posterior border with clearly visible popcorns (Fig. 8.12). There is hemorrhage along the anterior border of the ridge (arrow). The stage 3 ROP extended for 360 degrees (12 clock hours) in this baby. The retinal vessels in the posterior pole around the optic disc are clearly dilated and tortuous.

Figure 8.11 Stage 3 Retinopathy of Prematurity (ROP)— Severe These images show high magnification of severe stage 3 ROP. In the left image the photographer has focused on the extraretinal neovascularization, which is above the plane of the retina: The retinal vessels leading up to the extra-retinal proliferation are not in focus. In the right image of the same area the photographer has focused on the retinal vessels behind the extra-retinal proliferation, and therefore the neovascular extra-retinal proliferation is out of focus. The white area anterior to the extra-retinal proliferation (asterisks) shows the near confluent diode laser treatment to the vascular retina.

Figure 8.12 “Popcorn” Retinopathy of Prematurity (ROP) “Popcorn” ROP is a term used to refer to isolated clumps of new vessels posterior to the ridge. They are clearly seen to be on the surface of the retina and obscure the underlying retinal vessels. Development of “popcorn” may be seen in association with stage 2 ROP. The clumps may coalesce and eventually result in progression to stage 3. Popcorns can also occur later in the course of ROP and be associated with the regression phase and peripheral advancement of stage 2. In this image, the popcorns are seen posterior to an area of severe stage 3 associated with some bleeding along the neovascular extra-retinal proliferation. Near confluent laser treatment was applied to the avascular retina (appearing here as white areas, asterisk) and resulted in regression of the disease.

Figure 8.13 Stage 4a Retinopathy of Prematurity (ROP) Following diode laser treatment in this eye with severe ROP, regression of the acute neovascular process was achieved. However, there is significant cicatricial change with resultant straightening of the temporal vascular arcades and temporal ectopia (“dragging”) of the fovea. In the more peripheral inferotemporal retina (bottom left section of image), the retina is elevated (and out of focus). Stage 4a ROP is defined by this partial retinal detachment not involving the macula. In this case, the retinal detachment improved spontaneously without any treatment.

Figure 8.14 Stage 4b Retinopathy of Prematurity (ROP) In stage 4b ROP, the partial retinal detachment involves the macula. Note the significant cicatrization and temporal dragging of both temporal and nasal vessels and tractional retinal detachment, which has involved the fovea. The macular architecture is almost unrecognizable and the fovea can no longer be clearly identified. The visual prognosis for stage 4b ROP is very poor, with significant risk of progression to further retinal detachment over time without surgical intervention.

Figure 8.15 Stage 5 Retinopathy of Prematurity (ROP) In stage 5 ROP, the retina is completely detached. Note the marked dilation of the retinal vessels and obscuration of the optic disc due to the funnel-shaped total retinal detachment. The retina has a glassy appearance. Progressive fibrosis will result in closure of the funnel over time. This degree of severity of disease is no longer amenable to laser treatment, and surgical treatment to release tractional retinal detachment by vitrectomy is often not successful. The visual prognosis is dismal.

Figure 8.16 Retinopathy of Prematurity (ROP)—Plus Disease Plus disease is a feature that may or may not be present in cases of retinopathy of prematurity and is used to grade severity. This image shows posterior pole retinal vascular dilation and tortuosity in all four quadrants of the major vascular arcades around the optic disc. Development of plus disease in the course of progression of disease is a significant finding and portends a worse prognosis. When trying to determine if a patient has plus disease by photographic images, it is important to look at the retinal vasculature at the same level of magnification when comparing images.

Figure 8.17 Retinopathy of Prematurity (ROP)—Anterior Plus Disease Severe plus disease in the posterior segment may be accompanied by iris vascular engorgement, poor pupillary dilation, and vitreous haze. The accompanying iris vessel engorgement and poor dilation of the pupil are particularly problematic in that not only do they herald development of severe retinopathy of prematurity, but they also prevent adequate visualization of the fundus for examination and performing treatment if needed. Although uncommon, spontaneous hyphema may also occur. In the absence of iris vascular engorgement, one should not make the diagnosis of plus disease based on poor pupillary dilation alone. Rather, improper or ineffective installation of mydriatics may be the cause.

Figure 8.18 Retinopathy of Prematurity (ROP)—Pre-plus Disease With the usual recommended serial examinations, progression of the changes in the vessels around the optic disc may be observed over time. The degree of vascular dilation and tortuosity shown here is not severe enough to be labeled as plus disease (Fig. 8.16) but is greater than normal. There is mild dilation of the retinal venules and mild tortuosity of the retinal arterioles. The term pre-plus disease is used to describe this intermediate stage.

Figure 8.19 Aggressive Posterior Retinopathy of Prematurity (AP-ROP) This less common form of ROP, also known as “rush” disease, is seen more frequently in the very-low-birthweight and low-gestational-age babies. It is located in zone 1 or posterior zone 2 and is often rapidly progressive with prominence of plus disease (Fig. 8.16) and frequently progresses to stage 5 (Fig. 8.15) without treatment. It often does not progress through the classical stages 1 to 3 of ROP and may be associated with islands of avascular retina within the vascularized retina. In this image there is lack of clear evidence of ROP temporally yet severe stage 3 nasally. There is no clear white demarcation line temporally, but there is evidence of extension nasally of neovascularization into the vitreous that has resulted in blurring and a pink appearance of the ridge.

Figure 8.20 Zone 1 Retinopathy of Prematurity (ROP) ROP is also graded by zones. One of the most severe forms of ROP includes presence of disease within zone 1, also known as rush disease (see Fig. 8.19). Zone 1 is an area subtended by a circle centered on the optic disc. The diameter of the circle is equal to twice the distance between the center of the optic disc and the fovea. In this image, avascular retina (note that choroidal vessels can still be seen under the avascular retina, asterisk) is visible within zone 1. The vessels of the superior and inferior temporal arcades are joined together in the form of an arteriovenous loop. Dilation and tortuosity of these vessels extend as far posteriorly as the optic disc.

Figure 8.21 Nasal–Temporal Asymmetry of Retinal Vascularization These images, taken to show the extent of retinal vascularization nasally and temporally in the two eyes of an infant, can be compared to demonstrate this frequently observed phenomenon. Comparing the distance between the furthest extent of vascularization of the retina on the temporal and nasal sides of the optic disc, further progression of vascularization temporal to the disc is evident when compared with the retina on the nasal side of the optic disc.

Figure 8.22 Retinopathy of Prematurity Treatment This image demonstrates moderate stage 3 disease (Fig. 8.9) that has been treated by diode laser to the avascular retina (multiple white areas on right side of image). A common problem is to “skip” areas (left image) of avascular retina, particularly in the trough between the neovascular ridge and the area of avascular retina brought into view by indentation. Photography of the treated retina at the end of the laser procedure can help to identify these skipped areas. Timely “fill-in” laser treatment to these areas will help result in resolution of active disease (right image).

Figure 8.23 Regressed Retinopathy of Prematurity (ROP) ROP may also regress spontaneously. Regression occurs when the ridge resolves and vessels (arrow) cross into the former avascular retina. Pigmentary changes, as seen here, may also be observed. This regression can occur without retinal detachment or overlying vitreous change.

Figure 8.24 Retinal Dysplasia Retinal dysplasia may occur as an isolated autosomal recessive X-linked disorder or in association with systemic findings. It most often appears as congenital nonattachment of the retina, as shown in this prenatal ultrasound (left image). This must be differentiated from congenital/infantile retinal detachment, where an otherwise normally differentiated retina is detached, for example, by traction or trauma. Walker-Warburg syndrome is also known as HARD +/- E: Hydrocephalus, agyria (i.e., lissencephaly, right image), retinal dysplasia +/- encephalocele (and/or Dandy-Walker malformation). Patients are usually severely developmentally delayed.

Figure 8.25 Walker-Warburg Syndrome Affected patients may also have anterior segment dysgenesis with microphthalmia; cataract and glaucoma may be present, as shown here. Peters anomaly (Chapter 5: Cornea, Fig. 5.1) has also been observed. Differential diagnosis of retinal dysplasia includes Norrie disease. Any case of retinal nonattachment may have secondary changes in the anterior segment, in particular shallowing and closed angle glaucoma.

Figure 8.26 Norrie Disease Norrie disease is an X-linked recessive disorder characterized by retinal dysplasia, hearing loss, developmental delay, and psychiatric disturbances in later childhood or young adulthood, but without developmental brain anomalies or anterior segment anomalies. The retina presents as nonattached in infancy, often leading to bilateral phthisis. Note the disorganized appearance of the dysplastic nonattached retina on this B-scan image. The gene that is mutated in this disorder, located at Xp11.4, may also play a role in X-linked recessive familial exudative vitreoretinopathy (Fig. 8.38) and Coats disease (Fig. 8.40).

Figure 27 Best Disease Best disease, or vitelliform macular dystrophy, is an autosomal dominant macular dystrophy characterized by mutations in the Bestrophin gene (VMD2) located on chromosome 11. Best disease has great clinical variability between families and within families. The visual impairment depends on the localization and size of the retinal lesions. The

electrooculogram is usually diagnostic with Arden ratio values usually below 1.5. The retinal lesions evolve through several stages, which can include a normal retina progressing to (A) RPE mottling or a yellow foveal dot, (B) the vitelliform stage (“egg yoke”), (C) the “scrambled egg” stage, (D) the pseudohypopyon stage, and finally (E) scar.

Figure 28 Stargardt Disease Stargardt disease is an autosomal recessive maculopathy due to mutations in the ABCA4 gene located on chromosome 1. This is the most common form of macular degeneration in childhood. The phenotype variability can be quite broad at the level of fundus appearance and natural history. The maculopathy can

present with or without pisciform flecks (A) and is usually relentlessly progressive. If there is foveal sparing the visual acuity can remain quite good. Most cases present with a phenotype in between these two images where the macula has a beaten metal appearance with some fleck deposits, not necessarily pisciform (B). The arteriovenous phase intravenous angiogram shows the typical choroidal silence, seen to some degree in 80% to 85% of cases (C).

Figure 29 Retinitis Pigmentosa Retinitis pigmentosa is a genetically and clinically heterogeneous group of disorders for which over 50% of the involved genes have been identified. The disease is

characterized by a progressive rod–cone dystrophy detected by electroretinogram recording over time, leading to night blindness and constricted visual field. The photoreceptor degeneration is accompanied by “bone spicule”–like pigmentation around the equator of the retina (A, age 39 years; B, age 50 years). Other signs include narrowing of retinal vessels (C, D, E) and developing pallor of the optic nerve. Some patients may show little pigmentation (D, E) but usually some degree of choriocapillaris atrophy or retinal pigmented epithelium dropout, specifically around the equator. Some atypical cases will present with very coarse pigmentation (E). Patients with retinitis pigmentosa may lose some central vision due to macular edema (F).

Figure 8.30 Retinitis Pigmentosa Sine Pigmento Some cases of retinitis pigmentosa tend to only develop

pigment very late in the course of the disease or not at all. It is not surprising to see an absence of pigment in children, which can be misleading if electrophysiology assessment is not available.

Figure 8.31 Unilateral Retinitis Pigmentosa Unilateral retinitis pigmentosa is uncommon and should be considered acquired, for example, due to trauma or infection, until proven otherwise. In older individuals one must rule out a possible vascular ischemic cause, in particular due to decreased carotid flow ipsilateral to the affected eye. At all ages a viral, immunologic cause must also be ruled out.

Figure 8.32 Bardet-Biedl Syndrome The cardinal features of the autosomal recessive Bardet-Biedl syndrome include retinal dystrophy, obesity, polydactyly, hypogonadism, learning disabilities, and kidney anomalies, among other features. The expression is variable between families and often within families. Multiple genes have been implicated, and oligogenic (e.g., triallelic) inheritance has also been proposed in some cases. There is usually no bone spicule pigmentation in the early stages of the disease. The retinopathy is more characterized by an equatorial depigmentation and mottling. There may be a geographic type of macular atrophy developing in the teenage years or adulthood. This patient shows a common finger shape with brachydactyly. This patient also had a sixth digit on the ulnar side that was removed (not shown).

Figure 33 Leber Congenital Amaurosis (LCA) LCA is a congenital form or very-early-onset form of retinitis pigmentosa that leads to severe visual impairment. Nystagmus is usually present. The fundus appearance can be quite variable

and normal looking in the earliest stages (A). Approximately 10% of cases will have a colobomalike lesion (B, E). The retinopathy usually shows a combination of “bone spicule”–like pigmentation, mottling, and marked retinal vascular attenuation (B, C). Not infrequently, the pigmentation can be coarser, mimicking “leopard spots” (D, E).

Figure 8.34 Juvenile X-linked Retinoschisis (XLRS) Peripheral schisis may be isolated, posttraumatic, or a sign of XLRS. The schisis may progress to a retinal detachment. XLRS also usually shows a macular schisis, at least in the early stages, and a negative wave scotopic electroretinogram (awave greater than b-wave) in response to a standard bright flash. The gene XLRS1 has been cloned and is available for molecular testing.

Figure 8.35 Cone–Rod Dystrophy Cone–rod dystrophies are characterized by a predominant dysfunction of the cones over the rods (cone system electroretinogram reduction greater than rod system). Usually the visual field deficit shows a central scotoma and the patient retains peripheral islands of visual. The diagnosis is made primarily on the basis of electrophysiology. Macular changes are usually present to a variable degree of severity (left image) and equatorial pigmentation eventually manifests (right image).

Figure 8.36 Gyrate Atrophy Gyrate atrophy is an autosomal recessive retinal dystrophy due to a decrease in the enzymatic activity of ornithine amino transferase. This is usually an ocular condition only. The disease starts as discrete, round, atrophic patches of the retinal pigment epithelium and choroid that then coalesce to form the classic scalloped lesions (left image). The macula is spared until late. “Bone spicule”–like pigmentation may develop in the areas of atrophy (right image). As in other rod–cone dystrophies, posterior subcapsular cataracts can develop at an early age (Chapter 7: Lens, Fig. 7.12). An arginine-deficient diet may slow the progression of the disease.

Figure 37 Choroideremia Choroideremia is an X-linked disorder affecting both rods and cones because of a defect in the REP1 gene. Molecular testing of the REP1 protein is available. In all cases the central visual acuity is well preserved until quite late in the course of the disease. The fundus of an 8-year-old boy with early choriocapillary atrophy with bone spicule pigmentation is shown (A). The choriocapillaris atrophy is more obvious on intravenous fluorescein angiography. The carrier female can be manifest to a variable degree, showing mild equatorial mottling (B) or more pigmentary changes (C). The late stage in affected males shows almost total choriocapillary atrophy with a minimal residual macular island (D).

Figure 38 Familial Exudative Vitreoretinopathy (FEVR) FEVR is a genetically heterogeneous disorder of great variability in its clinical manifestation. It may be autosomal dominant or X-linked recessive. Two genes have been identified and are available for genetic testing (FZD4 and LRP5). It may mimic retinopathy of prematurity in a nonpremature child. The mild disease (A, B) shows dragging and straightening of the peripheral retinal vessels. The intravenous fluorescein angiography is very useful in establishing the diagnosis as it

emphasizes the perfusion and vascular anomalies (C, D). There may be a peripheral avascular zone of retina with vascular incompetence, hemorrhage, and leakage at the edge of the vascularized retina. Treatment is conducted by laser or cryotherapy and is aimed at obliterating the avascular retina and incompetent vessels. Neovascularization and traction retinal detachment may also occur.

Figure 39 Pathologic High Myopia High myopia may be isolated or syndromic. It may be sporadic

or inherited. Isolated high myopia is often autosomal dominant. Typical changes include choroidal sclerosis (A), a staphyloma of the posterior pole, and peripapillary atrophy (B) with or without tilting of the disc. Severe myopia can also be associated with anomalies of the posterior pole such as vascular anomalies, hemorrhages (C), and lacquer cracks. One must always rule out any possibly associated connective tissue disorders such as Stickler or Marfan syndrome (see Chapter 28: Skeletal). High myopia itself can reduce electroretinogram amplitudes, and axial length must be taken into account in the analysis.

Figure 8.40 Coats Disease Coats disease is a sporadic disorder characterized by a defect of retinal vascular development that results in vessel leakage, subretinal exudation, and retinal detachment. Coats disease is usually diagnosed in childhood because of unilateral decreased vision. The disease mostly affects males and shows vascular telangiectasis, lipid exudation, macular exudates, and areas of capillary nonperfusion with adjacent

webs of filigree-like capillaries. Treatment includes laser photocoagulation, cryotherapy, and surgery, depending on the stage of the disease. Enucleation may be required for blind painful eyes that are candidates for other therapies. The left image shows typical yellow subretinal and intraretinal exudates encroaching on the fovea. The right image shows the retina anterior to the exudate with dilated telangiectatic vessels. These vessels leak proteins to give rise to the exudation. The vascular anomalies are sometimes referred to as “light bulbs.” (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.41 Coats Disease—Intravenous Fluorescein Angiogram

Angiogram of the patient pictured in Fig. 8.40 shows dilated tortuous vessels, an area of ischemic retina, and arteriovenous shunts. Many arterioles end in macroaneurysm-like dilations surrounded by avascular areas or complete vascular closure. The pathogenesis of Coats disease may include arteriovenous shunts resulting in increased pressure on the veins (blue), causing them to become telangiectatic and leaky. Arrows indicate shunts. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.42 Retinoblastoma Group A The International Intraocular Retinoblastoma Classification (IIRC) was recently designed to classify intraocular

retinoblastoma and predict the most likely prognosis with the current primary treatments available. Chemotherapy has now largely replaced radiotherapy as the primary mode of treatment for retinoblastoma. This eye would be classified as IIRC Group A: All tumors ≤3 mm in maximum dimension and ≥3 mm from the fovea and ≥1.5 mm from the optic disc. The arrow indicates the early tumor, which was treated successfully with 532 nm laser. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.43 Retinoblastoma Group A The arrows indicate the multiple tumors in the eyes of this

patient with a germline mutation. Retinoblastoma tumors are a manifestation of the “two-hit” hypothesis, whereby a second genetic event is required on the allele not carrying the germline mutation in the RB gene, thus resulting in loss of heterozygosity. Alternatively, in the absence of a germline mutation, two mutational events can occur after fertilization in retinal cells. In this case, since all the tumors (arrows) are away from the fovea and optic nerve in this patient, laser photocoagulation would be the treatment of choice. The red arrow shows a tumor immediately following treatment with 532-nm laser. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.44 Retinoblastoma Group B This eye would be classified as International Intraocular Retinoblastoma Classification Group B: Bilateral multifocal retinoblastoma, here occurring in a premature infant, compromising both macula and optic nerve. The hemorrhages seen on the tumor surface are in part related to vaginal birth. This infant was treated with stereotactic radiation to the posterior pole of both eyes, since focal

therapy would be blinding and the liver and kidney function was not mature to allow for a full dose of chemotherapy.

Figure 8.45 Retinoblastoma Group C Retinoblastoma may cause vitreous seeding (Group C). This eye would be classified as International Intraocular Retinoblastoma Classification Group C: Retinoblastoma with discrete vitreous seeding close to tumor. The tumor is too large to be managed with focal therapy alone and requires chemotherapy to shrink the tumor, followed by focal therapy (laser and/or cryotherapy). (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.46 Retinoblastoma Group D Retinoblastoma may present as total retinal detachment; shown here is an International Intraocular Retinoblastoma Classification Group D eye: Massive or diffuse with total exudative retinal detachment. There is a large tumor that may respond to chemotherapy using cyclosporine followed by carboplatin, vincristine, and VM26. Six or more cycles of chemotherapy and repeated focal therapy would be necessary. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.47 Retinoblastoma Group D This eye would be classified as International Intraocular Retinoblastoma Classification Group D: Diffuse subretinal or vitreous seeding, present or past, may cause implanted retinoblastoma (arrow), which can be difficult to distinguish from new primary retinoblastoma. Management of such an eye requires chemotherapy followed by focal therapy. Cryotherapy to normal retina less than 48 hours prior to systemic chemotherapy can increase the concentration of carboplatin in the vitreous, particularly important for eyes with vitreous seeding. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.48 Retinoblastoma Group D This eye is classified as International Intraocular Retinoblastoma Classification Group D: Retinoblastoma with massive or diffuse exudative retinal detachment. Chemotherapy is required to shrink the tumor, followed by focal therapy. Arrows show shallow detachment with subretinal tumor or exudate. Retinal detachments associated with active retinoblastoma usually resolve with a successful response to chemotherapy, as the main tumor mass also shrinks. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.49 Retinoblastoma Group E: Tumor Touching the Lens This eye would be classified as International Intraocular Retinoblastoma Classification Group E: Retinoblastoma tumor touching the lens. The arrow in the right image shows the lens capsule. Such eyes are not effectively treated with chemotherapy and focal therapy, since residual tumor on the back of the lens cannot be treated with focal therapy. Group E eyes require enucleation, as advanced tumor has the potential for extraocular disease.

Figure 8.50 Retinoblastoma Group E: Neovascularization of the Iris This eye would be classified as International Intraocular Retinoblastoma Classification Group E: Neovascular glaucoma. Neovascularization is evident with fine new vessels seen on the surface of the iris. An eye with retinoblastoma and neovascular glaucoma requires removal, since the potential for metastatic spread is increased. Elevated intraocular pressure also increases the risk that tumor has invaded the optic nerve past the lamina cribosa. Histopathologic assessment of the nerve and globe will determine the need for additional treatment. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.51 Retinoblastoma Group E: Optic Nerve Infiltration Enucleation of an eye with increased intraocular pressure and suspicious imaging of the optic nerve on computed tomography scan and magnetic resonance imaging is important to establish the extent of disease. Following enucleation, histopathology in this eye reveals retinoblastoma infiltrating the optic nerve. This has a significant negative effect on survival prognosis. Chemotherapy may be required following enucleating if the margin is positive. These cases must be assessed with a lumbar puncture. Prophylactic chemotherapy and/or radiation may be required. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.52 Retinoblastoma Group E: Anterior Chamber Retinoblastoma This eye would be classified as International Intraocular Retinoblastoma Classification Group E: Retinoblastoma with anterior chamber seeding. In addition to enucleation, children with such advanced disease require metastatic workup, including bone scan and regular bone marrow and lumbar puncture to determine the presence or absence of extraocular disease. In some cases, treatment may be advised prior to demonstration of extraocular disease. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.53 Retinoblastoma Following External Beam Radiation Facial deformity is the result of bilateral external beam radiotherapy administered in infancy for bilateral retinoblastoma. The right eye was later enucleated. The left eye has radiation cataract. Whenever possible, it is desirable to avoid external beam radiation of treating retinoblastoma.

Figure 8.54 Trilateral Retinoblastoma Primitive neuroectodermal tumor (PNET) in association with bilateral retinoblastoma presented in this child first as a brain tumor. Usually the intracranial tumor originates in the pineal gland. Since external beam radiation of infants is now rarely used as primary treatment for retinoblastoma, replaced by chemotherapy, the frequency of trilateral retinoblastoma has decreased markedly. Treatment of trilateral retinoblastoma includes extensive therapy including systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with stem cell transplant rescue, as well as local therapy to the eye tumors. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Figure 8.55 Retinoblastoma Secondary Tumor This computed tomography scan shows glioblastoma multiforme (2nd tumor) in a patient with bilateral retinoblastoma after radiation therapy. Radiation can induce second nonocular malignancies in the radiated field. Second tumors outside the field may also develop in patients with retinoblastoma later in life. (The authors are grateful for the contributions to this legend by Drs. Vikas Khetan and Zhao Jun Yang.)

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 9 Optic Nerve

9 Optic Nerve Alex V. Levin Thomas W. Wilson J. Raymond Buncic Agnes Wong Wai-Ching Lam The optic nerve arises as an outpouching of the anterior neural tube. The optic stalk, formed at the fourth week of gestation, is continuous with the forebrain at one end and the optic vesicle at the other. The optic vesicle, derived from neuroectoderm, forms the neurosensory retina and retinal pigmented epithelium. As early as the sixth week of gestation, ganglion cells in the optic vesicle become the first retinal cells to differentiate and their axons begin to reach the formative occipital cortex by the eighth week. Neural crest cells form the optic nerve sheath. Abnormalities of this process cause congenital anomalies of the optic nerve and optic disc. Optic nerve function is often affected by underlying systemic illness or by local processes, including compression, inflammation, or the effects of other intracranial disease. The optic nerve may respond to the many pathologic processes by becoming

edematous, hyperemic, or, with time, atrophic. Loss of optic nerve fiber is more readily appreciated in children because of visible changes in the normally thick nerve fiber layer in children. Congenital anomalies of the optic nerve may also be associated with underdevelopment of the macula. Although sophisticated evaluation such as optical coherence tomography, Doppler ultrasound, and neuroimaging are helpful, any physician can assess the optic nerve using the ophthalmoscope.

Figure 9.1 Normal Nerve Fiber Layer This photograph demonstrates a normal optic nerve and macula. The nerve fiber layer is thickest in the perifoveal area. The thickness is demonstrated by the relationship of the retinal blood vessels usually buried within the retina and overlying light reflexes. The central reflexes form a doughnut-shaped mound, with a perifoveal inner circular reflex and an outer reflex where the curvature of the macula

evens out. Within the fovea, the nerve fiber layer is absent, thus highlighting the healthy surrounding circular macular mound (mound of Buncic) of the thick nerve fiber layer. Flattening of this mound indicates loss of thickness of the retinal nerve fiber layer and decrease in the number of axons into the optic nerve (Figs. 9.15 and 9.21).

Figure 9.2 Optic Nerve Aplasia Optic nerve aplasia is characterized by a complete absence of the optic nerve and retinal blood vessels. Eyes with aplastic optic nerves do not have any visual potential. This computed tomography scan illustrates the complete absence of the optic nerve structures bilaterally. As the globe is present and represents the end of the optic stalk, optic nerve aplasia is due to either failure of retinal ganglion cell development or abnormal invagination of the ventral fissure. Histopathologically, a vestigial nerve and optic nerve sheath

may be found. This very rare disorder has only been observed sporadically.

Figure 9.3 Optic Nerve Hypoplasia Optic nerve hypoplasia is characterized by a small optic disc (thick arrow). It is often surrounded by a yellowish mottled peripapillary halo, bordered by a ring of increased or decreased pigmentation (the “double-ring” sign, thin arrow). The outer ring represents the normal junction between the sclera and lamina cribrosa, whereas the inner ring represents the termination of an abnormal extension of retina and pigmented epithelium over the lamina cribrosa. The hypoplasia may be unilateral or bilateral. The retinal vessels are often anomalous, as shown here. Visual acuity does not always correlate with the size of the optic disc, whereas the thickness of the macular mound may be helpful. Optic nerve hypoplasia is frequently associated with the de

Morsier syndrome (septo-optic dysplasia), which refers to the constellation of hypoplastic anterior visual pathways, absence of the septum pellucidum, and thinning or agenesis of the corpus callosum. Ectopia of the posterior pituitary gland on magnetic resonance imaging may indicate pituitary deficiency. Other brain abnormalities may coexist.

Figure 9.4 Optic Nerve Coloboma Optic disc coloboma represents incomplete fusion of the embryonic fissure. The superior portion of the nerve appears normal, whereas the inferior portion is often yellowish white, excavated, and surrounded inferiorly by colobomatous choroid and retina. Systemic associations include CHARGE (coloboma, heart defects, atresia choanae, retarded growth and development, genitourinary abnormalities, and ear defects). Optic nerve coloboma can be part of a wide spectrum of coloboma ranging from involvement of the iris

anteriorly to the macula posteriorly, with or without microphthalmia. The optic disc may appear enlarged, and if located within a larger chorioretinal coloboma, it may look quite dysplastic or even be unrecognizable.

Figure 9.5 Morning Glory Disc The morning glory disc anomaly is a congenital, funnelshaped excavation of the posterior fundus that incorporates the optic disc. It is characterized by a central white glial tuft, retinal vessels that exit radially from the borders of the optic nerves, and peripapillary pigmentation. The optic nerve is larger than normal and also has a funnel shape when visualized by neuroimaging or ultrasound. Morning glory disc is usually unilateral, more common in females, and less common in patients of African descent. Visual acuity can vary from normal to hand motion. Morning glory disc can be

associated with basal encephalocele, and a midline notch in the upper lip is a signature sign. Vision loss can also occur from serous retinal detachment. Rarely, a morning glory disc can be contractile.

Figure 9.6 Optic Pit An optic pit (arrow) is an oval depression within the optic nerve. It is usually grayish in color and typically located centrally or temporally. An optic pit is usually unilateral and the affected disc is often slightly larger. Complications include serous detachment of the retina if associated with a temporally located pit. A macular hole can occur as a result of the serous retinal detachment. Without retinal detachment, optic pits rarely affect vision.

Figure 9.7 Megalopapilla Megalopapilla is a larger than normal optic disc. The cup-todisc ratio is often increased, although there is no increased risk for pediatric glaucoma. Visual acuity and visual field are usually normal except for an enlarged blind spot. The cause of this disorder is unknown, although familial megalopapilla has been rarely described. It is not associated with coloboma (Fig. 9.4).

Figure 9.8 Bifid Disc Bifid disc, or doubling of the optic disc, is due to abnormal division of the optic nerve during ocular development. Both optic nerves typically have their own blood supply. As shown here, there is usually a white band between the two discs as well as some contiguous tissue. Visual acuity is subnormal. Only sporadic cases have been described.

Figure 9.9 Congenital Tilted Disc The tilted disc syndrome is a nonhereditary, usually bilateral disorder of the optic nerve. The optic disc is elevated superotemporally and depressed inferonasally, with an inferior scleral crescent. The disc is oval in shape and its long axis tends to be oriented obliquely. There is usually associated situs inversus (Fig. 9.10) of the retinal vessels. A pseudobitemporal hemianopia may be observed. This is considered to be a refractive scotoma related to regional myopia localized to the inferonasal retina. The hemianopia does not respect the vertical meridian and is reduced or eliminated with the use of minus lenses.

Figure 9.10 Situs Inversus Situs inversus is a variation of the course of the temporal

retinal blood vessels. Normally, the temporal retinal blood vessels are directed temporally. In situs inversus, however, the temporal blood vessels course nasally first before turning temporally. Situs inversus is associated with tilted disc syndrome (Fig. 9.9) but can occur in entirely normal eyes. Retinal traction can cause a secondary acquired situs inversus. Primary congenital situs inversus has no visual significance.

Figure 9.11 Prepapillary Vascular Loops Prepapillary vascular loops are extensions of the normal retinal blood vessels into the vitreous. They often have a spiral configuration but do not extend to the posterior capsule and are therefore differentiated from persistent hyperplastic primary vitreous (Chapter 7: Lens, Figs. 7.14 and 7.15). These loops are remnants of the primitive hyaloid vascular system. The majority of the loops are arterial and

can be associated with retinal artery occlusion. Otherwise the loops are entirely benign.

Figure 9.12 Anomalous Vessels The number of variations in optic nerve and retinal vasculature are almost infinite. This photograph illustrates an increased number and enlarged caliber of retinal vessels. This pattern can be seen in Down syndrome, congenital retinal macrovessels, and racemose angioma. In congenital retinal macrovessels, a single vessel is typically involved, whereas in racemose angiomatosis, the retinal vessels are more dilated and tortuous. This photograph was taken from a child with normal vision.

Figure 9.13 Bergmeister Papilla Bergmeister papilla is caused by incomplete regression of the posterior hyaloid artery during ocular development. It may vary from a small glial tuft on the surface of the disc to a large stalk extending into the vitreous cavity. A blood vessel can be seen on occasion within the fibrous stalk. It is a sporadic, nonhereditary abnormality with no visual significance.

Figure 9.14 Hyaloid Glial Veil A glial veil is a sheetlike membrane overlying the optic disc. Glial veils are formed by incomplete regression of hyaloid vascular structures and represent a variant of Bergmeister papilla (Fig. 9.13). They are visually insignificant, although the physiologic blind spot may be enlarged. Usually, as pictured here, the veil is translucent. It is a sporadic, nonhereditary abnormality.

Figure 9.15 Gray Optic Nerve The optic nerve in this photo is from a patient with oculocutaneous albinism (Chapter 15: Dermatology, Fig. 15.17). The gray appearance of the optic nerve is typical of albinism and can also be seen in premature infants, chromosomal aberrations, or other genetic syndromes. In the premature infants, the gray appearance of the optic disc typically resolves with maturation of the visual system. Gray optic nerve may also be smaller than normal.

Figure 9.16 Optic Nerve Nevus This photograph shows an optic disc nevus, which contains nevus cells. Note the dark pigmentation at the center of the optic cup. The differential diagnoses include melanocytoma (Fig. 9.38), malignant melanoma, or combined hamartoma of the retinal pigment epithelium. It is a benign, nonprogressive, and nonhereditary condition. The pathophysiology is unknown and no treatment is indicated.

Figure 9.17 Pseudopapilledema The optic nerves pictured here illustrate pseudopapilledema with absence of the cup and an appearance of disc elevation with blurring of the disc margins. However, the retinal vessels are not obscured (as would be seen in disc swelling) and the retinal blood vessel pattern is anomalous. These eyes are often hyperopic and may be occasionally microphthalmic. They are not more prone to swelling or pediatric glaucoma. There may or may not be visual consequence. Familial pseudopapilledema may occur.

Figure 9.18 Physiologic Cupping This photograph demonstrates an enlarged optic cup in the absence of glaucoma. Physiologic cupping is characterized by very clear, often sharp, edges of the cup. The cup is elongated horizontally as opposed to vertically, the latter being often seen in glaucoma. Although this type of optic nerve is commonly seen in myopes, other refractive errors or emmetropia may be observed. This anomaly is inherited in an autosomal dominant fashion. Examination of the parents may obviate the need for neuroimaging, visual field testing, or glaucoma evaluation.

Figure 9.19 Peripapillary Crescent Peripapillary crescent is caused by a gap between the optic disc edge and the retinal pigment epithelium. The neurosensory retina is still continuous to the edge of the optic disc. The area surrounding the disc temporally in this photograph shows a direct view to the underlying choroid and scleral tissue. The vision is typically normal. Myopia is more common. There may be an increased risk for glaucoma in adulthood. This is a nonhereditary anomaly, which may be unilateral or bilateral.

Figure 9.20 Peripapillary Staphyloma Posterior staphylomas are deep excavations of the globe surrounding a normal or anomalous nerve head. Visual acuity is typically reduced to counting fingers. It may be seen in high myopia, in optic nerve coloboma, or in isolation. The optic nerve may appear tilted or enlarged and, as shown here, the vessels may have a radiating pattern similar to the morning glory disc (Fig. 9.5).

Figure 9.21 Peripapillary Atrophy The optic nerves in these photographs are pale and lack the normal orange-pink color. There is significant nerve fiber layer dropout causing the peripapillary atrophy. Note how the light reflexes line up along the vessels due to the thinning of the nerve fiber layer. Differential diagnoses include previous episodes of optic neuritis, an orbital compressive lesion, ischemia, nutritional deficiencies, hereditary optic neuropathy, trauma, and toxic optic neuropathies.

Figure 9.22 Dominant Optic Atrophy (Kjer Optic Atrophy) Dominant optic atrophy typically presents with decreased vision in the first decade of life. Children often do not have any visual symptoms and the diagnosis may be made on routine examination. Visual acuity is typically between 20/40 and 20/80. A blue-yellow color vision defect is most common. The optic nerve shows sectoral pallor temporally, referred to as “pie in the sky” atrophy. There are no associated systemic findings.

Figure 9.23 Mild Optic Nerve Swelling Causes of optic nerve swelling in children include papilledema from increased intracranial pressure, optic

neuritis, malignant hypertension, and diabetic papillopathy. The optic disc pictured here is elevated and the disc margins are blurred with obscuration of the retinal vessels as they course through the edematous optic disc. Venous pulsations are usually absent. The optic cup is absent and early engorgement of the retinal veins is apparent.

Figure 9.24 Moderate Optic Disc Swelling Moderate optic nerve swelling is demonstrated in this photograph with significantly more nerve fiber layer swelling and obscuration of the disc margin and retinal arterioles, as well as peripapillary flame-shaped hemorrhages. A small cotton wool spot is present inferonasally, as a result of nerve fiber layer ischemia (incorrectly named a “soft exudate” in past nomenclature).

Figure 9.25 Severe Optic Disc Swelling In severe optic nerve swelling, peripapillary hemorrhage (left image) or lipid exudates (right image) can be seen within the nerve fiber layer radiating toward the macula, forming a partial macular star. Spreading of peripapillary edema may cause circumferential wrinkling of the retina (Paton lines). Differential diagnosis includes neuroretinitis, often due to infection such as cat scratch disease. There is extensive nerve fiber layer edema with almost complete obscuration of the retinal vessels on the disc and in the immediate peripapillary area. There is no visible disc margin or optic cup. The retinal veins, particularly in the left image, are markedly engorged and tortuous. With the exception of an enlarged blind spot, visual function may be remarkably preserved in optic nerve swelling.

Figure 9.26 Chronic Optic Disc Swelling Chronic optic nerve swelling leads to irreversible damage of the optic nerve with a resultant optic neuropathy. Visual acuity, visual field, and color vision may be severely affected. The optic nerve is pale and is still elevated. The color and configuration have led to the name “champaign cork” disc, illustrated best in the left image. The disc margins are blurred and there is significant dropout of the nerve fiber layer. This occurs after weeks to months of increased intracranial pressure without treatment. Vascular tortuosity, as seen in the left image, may or may not persist.

Figure 9.27 Papillitis/Optic Neuritis Pediatric optic neuritis represents an acute swelling of the optic nerve due to local factors. It is usually bilateral, and visible optic disc swelling is typically present. Clinical findings include optic nerve dysfunction (decrease in visual acuity, decreased color vision, and visual field loss and relative afferent pupillary defect). Unlike optic neuritis in adults, pediatric patients typically do not have pain with eye movement. The most common causes of pediatric optic neuritis are postinfection (chickenpox, measles, mumps, rubella, mononucleosis, and cat scratch disease), postvaccination, and rarely multiple sclerosis or other neurologic disorders. Workup should include magnetic resonance imaging of the brain and lumbar puncture.

Figure 9.28 Late Optic Neuritis This optic nerve shows significant pallor following an episode of optic neuritis. Visual acuity often returns to normal but other visual functions such as color vision and contrast sensitivity may remain subnormal. Optic nerve pallor may be the only residual sign of previous optic neuritis. Note the peripapillary atrophy (Fig. 9.21). A relative afferent pupillary defect can be seen in acute or late optic neuritis if the optic nerves are affected unilaterally or asymmetrically.

Figure 9.29 Neuroretinitis Neuroretinitis is characterized by a combination of optic disc swelling and associated macular star. The optic nerve swelling (mild in this photograph) is typically unilateral and clinically there is decreased vision and pain with eye movement. The optic nerve swelling resolves over several months and the exudate resolves over months to years. It is not associated with other demyelinating processes such as multiple sclerosis. Common infections preceding neuroretinitis include cat scratch disease, Lyme disease, and mumps. Workup should be targeted to identify the infectious agent.

Figure 9.30 Anterior Ischemic Optic Neuropathy Anterior ischemic optic neuropathy is very rare in children. This optic nerve shows significant pallor with peripapillary hemorrhage and engorgement of the veins. However, edema is not a prominent feature. Visual recovery is less than that seen in optic neuritis and recurrences are common. Patients with anterior ischemic optic neuropathy are generally systemically well, although diabetes mellitus and blood dyscrasias that cause increased serum viscosity must be excluded.

Figure 9.31 Buried Optic Disc Drusen Optic nerve drusen are small lobular collections of a hyalinelike material within the optic nerve. They are a common cause of pseudopapilledema and can be inherited as an autosomal dominant trait. They are often bilateral, although they may be asymmetrical. The visual acuity is typically normal. Loss of visual acuity can be secondary to hemorrhage, or less commonly, subretinal neovascular membrane. Visual field abnormalities include arcuate defects and enlarged blind spot. In cases where clinical confirmation is difficult, ultrasound or computed tomography scan, as shown here, may reveal calcified bodies within the optic disc.

Figure 9.32 Optic Disc Drusen Optic nerve drusen are characterized by yellowish-white elevations. The disc surface is often irregular and there is usually no optic cup. Although the border of the optic disc is obscured or irregular, no true disc edema is present and the vasculature is usually normal. Autofluorescence can be demonstrated and there is no leakage on fluorescen angiography. An important caveat is that all forms of pseudopapilledema may have coexisting true edema (i.e., optic nerve edema).

Figure 9.33 Myelinated Nerve Fibers Optic nerve myelination normally begins at the lateral geniculate body and progresses as far as the lamina cribrosa. Myelinated nerve fibers represent abnormal intraocular myelination of the retinal nerve fiber layer. The areas of nerve fiber myelination are opaque and white and have a characteristic feathery edge. These areas are usually, but not always, adjacent to the optic disc. A visual field defect may correspond to the area of myelination, and occasionally, amblyopia may be present, especially in association with high myopia. Myelination of the nerve fiber layer is more common in Down syndrome and Gorlin-Goltz syndrome (multiple basal cell nevi).

Figure 9.34 Retrograde Trans-Synaptic Degeneration These photographs demonstrate retrograde synaptic degeneration following a lobectomy in the first decade of life involving the optic radiation. Retrograde degeneration affects the synoptic fibers in the right lateral geniculate nucleus. Anteriorly it involves the temporal retinal fibers from the right eye and the nasal retinal fibers from the left eye (i.e., the left optic disc resides in the blind hemiretina). Degeneration of the fibers results in the characteristic pattern seen here. The temporal part of the right optic disc is pale and the left optic nerve shows bow-tie atrophy as a reflection of the retinal nerve fiber pattern feeding into the optic disc.

Figure 9.35 Leber Hereditary Optic Neuropathy Leber hereditary optic neuropathy is a mitochondrial disorder that is maternally inherited. Unlike other mitochondrial disorders, it affects men more frequently than women. Although the disorder can present at almost any age, it is typically observed in the second and third decades of life, with unilateral or bilateral decrease in optic nerve function. The vision typically is less than 20/100 and recovery is limited. Funduscopic examination shows pseudoedema of the optic nerve and nerve fiber layer, with peripapillary telangiectatic vessels in the acute phase (not shown here). There is characteristically no leakage on fluorescein angiography. Differential diagnoses include optic neuritis, anterior ischemic optic neuropathy, nutritional and alcohol amblyopia, and toxic exposure.

Figure 9.36 Optic Nerve Glioma Optic nerve glioma is the most common optic nerve tumor of children. It is commonly associated with neurofibromatosis 1. Patients may present with progressive proptosis, loss of vision, or strabismus. Clinical examination shows reduction of visual acuity and color vision. The optic nerve is typically pale but may have disc swelling, as shown here in the left image, when the glioma abuts on the globe. Optociliary shunt vessels may be observed (right image).

Figure 9.37 Optic Nerve Glioma MRI scan of the left orbit shows an enlarged optic nerve due to glioma. The nerve may be symmetrically enlarged or have a fusiform or tortuous appearance. On coronal views, there may be an effusion within the nerve sheath. The glioma is hyperintense on CT scan and can extend backward to involve the intracranial visual pathway including the optic chiasm and/or radiations as well as the hypothalamus. Magnetic resonance imaging with gadolinium is the preferred neuroimaging technique.

Figure 9.38 Melanocytoma Melanocytoma is a lesion of the optic disc that is composed of magnocellular nevus cells. The tumor has a dramatic jetblack appearance, which is characteristic. Visual acuity is typically normal and malignant transformation is rare. However, the tumor may increase in size slightly over time. Differential diagnoses include optic nerve nevus (Fig. 9.16) and malignant melanoma.

Figure 9.39 Optic Atrophy The end stage to many optic nerve diseases is complete optic atrophy. Note the diffuse white color of this disc, making the cup almost indistinguishable. Also note the changes in the light reflexes as they line up along the blood vessels, indicating severe loss of the nerve fiber layer.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 10 Glaucoma

10 Glaucoma Alex V. Levin J. Raymond Buncic Elise Héon Glaucoma may manifest at any time during childhood. Congenital and infantile glaucoma usually involves a primary dysgenesis of the trabecular meshwork system, whereas later onset often implies a secondary malfunction of aqueous outflow. The primary childhood glaucomas, congenital/infantile and juvenile, have a genetic basis, which is currently being elucidated. Other forms of glaucoma associated with congenital malformation of the anterior segment such as the Axenfeld-Rieger spectrum and aniridia, also have a genetic basis. Virtually every anterior segment dysgenesis leaves the patient with a lifelong risk of developing glaucoma. Some children acquire glaucoma as a result of other events. Aphakic glaucoma is one of the most common causes of pediatric glaucoma. Any child who has cataract surgery is at lifelong risk and must be screened for glaucoma periodically. Some aphakic children may also have a goniodysgenesis, perhaps indicating that there is more to the malformation complex than just the cataract. Other theories for the development of aphakic glaucoma include

barotrauma at the time of surgery, communication of the anterior chamber with the vitreous, and genetic predisposition. The average onset time for developing glaucoma is approximately 8 years after cataract surgery. The effect of intraocular lens implantation is not yet clear, but early indicators suggest that this procedure will not reduce the incidence of glaucoma significantly, particularly in the first 2 years of life. Trauma can also result in glaucoma through direct damage to the aqueous outflow system, inflammation, hyphema, or secondary ghost cell glaucoma. Other causes of secondary glaucoma include infection such as congenital rubella syndrome, uveitis, and the use of steroids. Glaucoma may be an isolated ocular disorder or associated with a wide variety of systemic diseases and syndromes. This chapter focuses on isolated glaucoma. The reader is referred elsewhere in this atlas for discussion of those ocular and systemic disorders that are associated with glaucoma, such as Sturge-Weber syndrome and neurofibromatosis type 1 (Chapter 23: Phakomatoses) and aniridia and Axenfeld-Rieger syndrome (Chapter 6: Iris and Pupils). The most common cause of visual loss in patients with glaucoma is amblyopia. However, left untreated, the glaucoma itself will result in optic neuropathy with visual field and acuity loss. Early identification, aggressive treatment, and careful periodic follow-up are the cornerstones of a successful outcome.

Figure 10.1 Primary Congenital Glaucoma—Buphthalmos Elevated intraocular pressure in the eye of a child less than 2 to 3 years old results in stretching of the pliant sclera and cornea such that the corneal size and axial length increase. Rarely, this can also occur later, in the first 5 to 7 years of life. Buphthalmos will also be reflected in an increasingly myopic refraction. In microphthalmic eyes, the corneal diameter and axial length may be increasing pathologically, even though the absolute values are below the age-matched normative data. Likewise, excessive loss of hyperopia (e.g., in an aphakic eye) can also be a sign of excessive ocular growth due to glaucoma. In the left image, the child's left eye was enucleated (photograph provided by John Ainsworth, Hospital for Sick Children fellow, 1994). In the right image, the child has left microphthalmia with a buphthalmic right eye that was also previously microphthalmic.

Figure 10.2 Primary Congenital Glaucoma—Corneal Edema Corneal edema can occur in both primary and secondary forms of early childhood glaucoma. Epithelial edema is usually reversible with prompt control of the glaucoma. As shown here (left image, left eye), the edema results in a mild haze that obscures the view of the anterior segment. Subtle epithelial edema can be revealed by touching a blunt instrument to the cornea and observing a bluish “pitting” response. Stromal edema (right image) reflects a more chronic edema and is usually more opaque. Corneal transplant may be necessary but over time, the cornea may clear without intervention other than glaucoma control. Unfortunately, the clearance is almost always from peripheral to central, thus leaving the visual axis impaired and the child at risk for irreversible amblyopia if the transplant is deferred too long.

Figure 10.3 Haab Stria Haab stria is one of the cardinal manifestations of early pediatric glaucoma. It represents a break in the Descemet membrane due to stretching secondary to elevated intraocular pressure. The visible lines represent the scrolled back edges from the break. There may or may not be overlying corneal changes: Three variations can be seen. Shown here are Haab stria with no stromal scarring at edges (left image) and with white stromal scarring at edges (right image). In Figure 10.2, right image, the stromal scarring is occurring throughout the width of a Haab stria, the edges of which can be seen at the upper and lower border of the scar. Note the usual scalloped edges and multidirectional patterns, much unlike the straightedged vertically oblique breaks due to forceps injury (Chapter 5: Cornea, Fig. 5.21). The cornea of early primary pediatric glaucoma may have reduced pachymetry or, in the presence of edema or glaucoma associated with aphakia, aniridia, or other anterior segment dysgeneses, elevated pachymetry. The intraocular pressure reading must be interpreted accordingly.

Figure 10.4 Primary Congenital Glaucoma—Iris Changes These two images demonstrate some nonsyndromic unusual anterior segment dysgenesis patterns, that may be associated with primary congenital/infantile glaucoma. The current genetic nomenclature for glaucoma refers to the congenital primary glaucomas as GLC3 with a letter added thereafter referring to the gene identified in chronological order. GLC3A refers to congenital/infantile glaucoma due to mutations in the CYP1B1 gene at 2p21. Any genetic form of congenital glaucoma may still present with variations in anterior segment morphology. An abnormal iris should serve as a marker for possible glaucoma risk, particularly when the pattern differs from other family members and there is a concern that the child may be affected.

Figure 10.5 Primary Congenital Glaucoma—Gonioscopy Historically, primary congenital glaucoma was included in the “anterior segment cleavage disorders,” recognizing that its pathophysiology in part lies in the failure of proper angle differentiation. Clinically, histologically, and particularly during goniotomy surgery, one can often see a gray-white membrane covering the iris insertion and trabecular meshwork, which has been referred to as the Barkan membrane, although there has been some controversy over the nature of this structure. As shown here in these gonioscopy photos, the iris insertion is abnormally high either uniformly (left image) or in patches (right image). There may be increased vascularity or peripheral iris atrophy (Fig. 10.4). Other forms of goniodysgenesis include iridogoniodysgenesis (6p25 and 4q25) and iridogoniodysplasia (6p25) syndromes.

Figure 10.6 Early Childhood Glaucoma—Optic Neuropathy Unlike adults, optic nerve cupping in young children is initially a reflection of bowing backward of the lamina cribrosa rather than nerve fiber loss. As a result, control of intraocular pressure may be associated with dramatic reversal of cupping. When nerve fiber layer loss does occur, there is still more concentric enlargement of the cup rather than the temporal sloping of adult glaucoma, although temporal pallor may occur. Visual field loss in children is harder to assess, but when possible, it usually reflects the pattern of optic nerve change with fairly symmetrical constriction early in the disease. The role of optical coherence tomography (OCT) and Heidelberg retinal tomography (HRT) in following children with glaucoma is currently being explored, and normal age-related values for nerve fiber thickness, much thicker in children, are being developed. Optic nerve notching and hemorrhage are very rare in children.

Figure 10.7 Early Aphakic Glaucoma—Anterior Segment Changes Less commonly, glaucoma can develop in the early postoperative period following cataract surgery. This may be due to an abnormal anterior rotation of the iris–ciliary body complex or may simply be an unusual manifestation of uncomplicated aphakic glaucoma; however, more often it is the result of the aggressive inflammation that characterizes the response of the pediatric eye to surgery. The angle may be closed by peripheral anterior synechia or there may be midperipheral iridocorneal adhesions. Medical treatment rarely succeeds and surgical reduction of intraocular pressure (IOP) becomes necessary. However, if iritis is controlled and IOP lowered surgically, the prognosis can be quite favorable and long-term treatment may not be needed.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section I - Isolated Pediatric Eye Disorders > 11 Orbit

11 Orbit Alex V. Levin Thomas W. Wilson Dan DeAngelis Robert Pashby Jeffrey Hurwitz The orbit contains multiple tissues, each of which is subject to disease. A disease process in any tissue may have contiguous effects on neighboring tissues within this closed and compact compartment, in particular the optic nerve. Compression, stretching, or ischemia of the optic nerve will lead to rapid visual field and/or vision loss, which may or may not be irreversible. Tumor of virtually any orbital tissue can cause optic nerve compression. Likewise, hemorrhage, infiltration, infection, or vascular malformation may cause optic nerve compression. In the latter, if there is a lymphangiomatous component, compression may only occur when infection, for example, an upper respiratory viral systemic infection, results in temporary swelling of the orbital lesion. Tumors of the optic nerve itself are covered in Chapter 9: Optic Nerve. Proptosis occurs when there is an increase in retrobulbar orbital

volume. This can be acute or chronic. It may result from a variety of benign and malignant lesions. Benign tumors include vascular malformations and cysts. Orbital malignancy may be local (e.g., rhabdomyosarcoma, optic nerve glioma) or systemic (e.g., leukemia, neuroblastoma). Infectious causes of proptosis may also be acute (e.g., bacterial orbital cellulitis) or chronic (e.g., parasitic cyst). Acute inflammatory disease includes pseudotumor. As the globe translates forward for any reason, the optic nerve is stretched, resulting in serious vision loss. Surgical decompression of the orbit may be needed.

Figure 11.1 Orbital Dermoid Orbital dermoids are common lesions noted of the anterior orbit in children. They arise in the locations of the frontozygomatic suture and, less commonly, the frontonasal sutures. During embryogenesis, dermal elements may get “pinched off” and reside in the suture lines. Superficial dermoids are easily palpable and generally grow with facial

growth. Deeper dermoids may not be noted until later in childhood and may have intracranial extension through the suture with a mass on either side of the cranial vault, sometimes called “dumbbell dermoids.” The cysts' walls have dermal elements and the contents can contain keratin hair follicles. Rupture by trauma, including surgery, can elicit a severe granulomatous response.

Figure 11.2 Lymphangioma Lymphangiomas are benign lesions that have been more recently categorized as part of a spectrum of combined venous–lymphatic abnormalities. Recurrent proptosis and visual loss can occur through recurrent hemorrhages. The left image shows a child at baseline with an inferior orbital mass. With upper respiratory tract infection, dramatic swelling can occur (right image). Proptosis and visual loss may occur. Surgical extirpation or transcutaneous draining of affected areas may be needed.

Figure 11.3 Capillary Hemangioma Capillary hemangiomas commonly occur on the lids and anterior orbit. Clinically, they range from small isolated lesions to larger tumors that can cause ptosis (as seen in this child's left medial upper lid) and visual loss. There may or may not be an overlying “strawberry” lesion (Chapter 2: Lids and Adnexa, Figs. 2.17 and 2.18). Systemic considerations include the Kasabach-Merritt syndrome, a consumption coagulopathy associated with large hemangiomas. The natural history involves a proliferative phase in the first year of life followed by regression. Indications for treatment include amblyopia, proptosis, and optic neuropathy. Intralesional steroids are not recommended for deep lesions like the one shown here. Other treatment options include surgical excision, systemic steroids, or interferon.

Figure 11.4 Rhabdomyosarcoma Rhabdomyosarcoma is the most common malignant orbital tumor of childhood and the third most common soft tissue tumor of childhood. It typically presents with an acute onset of proptosis, globe dystopia, visual loss, and an orbital mass. The tumor may extend beyond the confines of the orbit into the sinuses and intracranial cavity. Diagnosis is made by incisional biopsy. Although previous treatment modalities included exenteration, the current preferred treatment is with combination orbital radiation and systemic chemotherapy. Rhabdomyosarcoma should be considered in the differential diagnosis of almost all rapid and slowgrowing orbital masses.

Figure 11.5 Teratoma Teratomas are rare orbital tumors that characteristically have components of all three germ layers: Ectoderm, endoderm, and mesoderm. They present with massive congenital proptosis, facial distortion, and reduced visual acuity. Histologically, these tumors can contain cartilage, bone, hair follicles, and neural tissue. Treatment may range from excision of the localized tumor to orbital exenteration. Visual prognosis is poor due to the massive compression and stretching of the optic nerve.

Figure 11.6 Ewing Sarcoma Ewing sarcoma is an uncommon, primarily bony tumor of the extremities that can involve the orbit through metastases. It presents as a lytic lesion of the bony orbit or a soft tissue mass, as shown here. Treatment consists of combined aggressive surgical resection and chemotherapy. Note the proptosis demonstrated in both the clinical and radiologic images. The lesion is usually slow growing. The primary bone lesion may or may not be identified at the time of orbital presentation.

Figure 11.7 Preseptal Cellulitis Infection of the tissues anterior to the orbital septum is called preseptal or periorbital cellulitis. The infection is usually bacterial. If there is a primary break in the skin that served as an access for bacteria, the organism is usually Staphylococcus or Streptococcus. In a well child, oral antibiotics may be effective. In a child who has not been vaccinated for Haemophilus influenzae, this organism must be ruled out. Neonates, unwell children, immunocompromised children, and those with sickle cell anemia should probably be treated with parenteral antibiotics to avoid sepsis.

Figure 11.8 Orbital Cellulitis This child has orbital cellulitis with infection extending posterior to the orbital septum. Characteristic signs include proptosis, restricted eye movements, and signs of optic nerve compromise. These children tend to be unwell. Orbital cellulitis is commonly secondary to infectious sinusitis, which breaks through the medial orbital wall, introducing pathogens into the orbit. If a localized subperiosteal abscess forms, symptoms may be limited to proptosis and some motility restriction. Treatment consists of intravenous antibiotics and usually surgical drainage with sinus drainage where indicated.

Figure 11.9 Cavernous Sinus Thrombosis Cavernous sinus thrombosis is a rare complication of orbital cellulitis. When the intraorbital infection courses posteriorly to the orbital apex, it can enter the cavernous sinus unilaterally or even spread to the contralateral side. These patients are systemically very ill with unilateral or bilateral ophthalmoplegia of varying degrees, proptosis, and reduced vision. Treatment is with intravenous anticoagulation and antibiotics.

Figure 11.10 Idiopathic Orbital Inflammation (Inflammatory Pseudotumor) The cause of orbital pseudotumor is unknown. Patients present with a subacute onset of pain with eye movements, proptosis, diplopia, headache, and systemic signs. This patient is attempting left gaze with a restriction of right adduction and an erythematous right medial rectus insertion. Peripheral blood eosinophilia is not uncommon in these cases. Imaging reveals a diffusely enlarged extraocular muscle that involves the tendinous insertion, unlike thyroid eye disease, which spares the tendon (Chapter 16: Endocrine, Fig. 16.5). More diffuse orbital involvement may also be seen. Biopsy may be helpful and the response to treatment with systemic corticosteroids particularly useful, as most of these patients will gain significant improvement over 24 to 48 hours.

Figure 11.11 Microphthalmia with Cyst Microphthalmia is a congenital ocular malformation that results in a globe that is smaller than normal. It may be associated with a cystic component due to failure of fusion of the choroidal fissure and outpouching of the neurosensory retinal tissues. A normal-sized globe is a required stimulus for growth of the normal orbit and adnexal structures. Patients with microphthalmia may need surgery to increase orbital volume using orbital expanders, whereas patients with cysts may get volume expansion by the presence of the cyst alone.

Figure 11.12 Anophthalmia Anophthalmia is a very rare condition characterized by the absence of any visible or rudimentary ocular tissue. If these patients have any rudimentary ocular tissue in their orbits that can be visualized on ultrasonography or neuroimaging, then the diagnosis is microphthalmia. True anophthalmia is due to a failed or incomplete formation of the optic stalk and vesicle. Some reports link anophthalmia to pesticide use and/or mutations in a number of developmental genes. Orbital reconstruction with volume expansion may be necessary in some cases. (Photograph provided by Ayesha Khan, Pakistan, fellow, 2004–05.)

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 12 - Child Abuse

12 Child Abuse Alex V. Levin Child abuse is often categorized into four subgroups: physical abuse, sexual abuse, child neglect, and emotional abuse. All types of child abuse may have ocular manifestations. It is estimated that 4% to 6% of all child abuse cases will first present to an ophthalmologist. In most developed countries, ophthalmologists would be considered mandated reporters of suspected child abuse. The suspicion need not be proven by the physician. Child protective agencies, the judicial system, and the police are entities responsible for determining whether the suspicion is validated and, if so, determining who the perpetrator is. The ophthalmologist's responsibility is to report the ocular manifestations and the degree of certainty to which these findings support a diagnosis of abuse. Inflicted eye injuries may be isolated, part of the battered child syndrome, or secondary to shaken baby syndrome. Long-term outcomes in abused children include visual loss due to amblyopia, injury, and the sequelae of brain injury (e.g., cortical visual impairment, visual field loss). Children who are victims of sexual abuse may experience the ocular effects of sexually transmitted disease (e.g., cytomegalovirus due to HIV infection [Chapter 19:

Infectious Diseases, Figs. 19.9, 19.10 and 19.11]). Noncompliance and neglect are frequent problems in the ophthalmic care of children. Ophthalmologists will often see parents missing appointments made for their child and failing to comply with prescribed therapy such as patching without any apparent reason for doing so, such as financial or child care obstacles. Nonorganic failure to thrive, also known as psychosocial dwarfism, is a more dramatic and systemic manifestation of child neglect. Lastly, emotional abuse may have its ocular manifestation in what children are allowed to see. In today's society, children are increasingly and inappropriately exposed to graphic if not real images of sexual activity, drug abuse, and violence. Emotional abuse also entails severe verbal belittlement and harsh discipline. It may be difficult to draw distinct lines along the continuums that describe the many behaviors referred to as child abuse. In some cultures, actions such as spanking, coining, and even shaking may be acceptable practices. Marriage and sexual intercourse with young adolescents are accepted in some cultures as well. Child care practices and means of discipline vary widely around the world. However, as ophthalmologists, we must uphold a standard that protects children from harm and rely on public systems and personal advocacy aimed at following through on our suspicions in any individual case that a child may indeed be at risk for, if not already a victim of, child abuse.

Figure 12.1 Shaken Baby Syndrome—Brain Injury Shaken baby syndrome is a form of physical abuse in which the perpetrator submits a child to violent acceleration–deceleration forces with or without impact of the head. Characteristic brain injuries include subdural hemorrhage (arrows). This child's imaging suggests blood of two separate ages. The hemorrhage size is compressing the brain, causing a shift of the midline and obliteration of the ventricles. There is also diffuse severe cerebral edema with loss of gray-white differentiation. Other brain injuries in shaken baby syndrome include subarachnoid hemorrhage and, less commonly, parenchymal hemorrhage or contusion and brain laceration.

Figure 12.2 Shaken Baby Syndrome—Brain Injury Approximately 25% to 35% of the victims of shaken baby syndrome die and another third survive with long-term neurologic sequelae including visual loss or blindness, cerebral palsy, and mental retardation. This image demonstrates the cerebral atrophy that may occur. The most common cause of visual loss following inflicted childhood neurotrauma is cortical visual impairment due to coup or contrecoup contusion of the occipital lobes or infarction of the posterior cerebral circulation as a result of severe cerebral edema.

Figure 12.3 Shaken Baby Syndrome—Rib Fractures This child has numerous rib fractures, some of which are circled. In the “classic” form of shaken baby syndrome, the perpetrator grasps the child by the thorax and shakes him or her violently. There are usually no external signs of injury. Crying of an infant is the most common inciting event, and victims are usually less than 1 year old (although child victims as old as 5 years have been reported). Posterior and posterior–lateral rib fractures are the most common thorax injury. Other fractures occur when the child is grasped by a limb and shaken. This may result in stripping of the periosteum with subperiosteal hemorrhage and typical metaphyseal fractures, termed chip, corner, or bucket handle fractures of the long bones.

Figure 12.4 Shaken Baby Syndrome—Mild Retinal Hemorrhages Retinal hemorrhages are the characteristic ocular manifestation of shaken baby syndrome and perhaps the most common manifestation of physical abuse that an ophthalmologist will encounter. One must carefully describe the number, type, pattern, laterality, and distribution of the hemorrhages to best document and interpret the finding. Use of the generic term “retinal hemorrhages” is discouraged. This child shows a nonspecific hemorrhagic retinopathy characterized by a small number of intraretinal (nerve fiber layer [flame hemorrhage, f] more than deeper [dot/blot] hemorrhage, d) and preretinal, p hemorrhages confined to the peripapillary region. Although shaken baby syndrome may be the most common cause of this picture in an otherwise previously well infant, there are numerous other causes that should be considered.

Figure 12.5 Shaken Baby Syndrome—Moderate Retinal Hemorrhages As compared to Fig. 12.4, this child has a larger number of intraretinal and preretinal hemorrhages, which extend beyond the view of this photograph throughout the macula and almost to the midperiphery. Although this is more likely a victim of shaken baby syndrome, such patterns can also be seen after severe life-threatening accidental injury (e.g., motor vehicle accident), normal birth, and leukemia, and perhaps in rare cases as a result of other systemic diseases which are usually readily apparent. Note that this victim of shaken baby syndrome does not have papilledema. Papilledema occurs in less than 10% of cases.

Figure 12.6 Shaken Baby Syndrome—Severe Retinal Hemorrhages This victim of shaken baby syndrome has a severe hemorrhagic retinopathy, with too numerous to count preretinal, intraretinal, and subretinal hemorrhages. Other than birth, there is virtually no other reported explanation for these findings, with the exception perhaps of severe fatal head crush injury. Birth flame hemorrhages resolve by 1 week (usually 2 to 3 days) and dot/blot hemorrhages by 4 to 6 weeks. Retinal hemorrhages of shaken baby syndrome can't be dated. Many of the hemorrhages pictured here have white centers. This is a very nonspecific finding that can be seen with retinal hemorrhage from any cause. Note also the venous engorgement. Venous obstruction due to increased intracranial pressure plays a role in only a minority of cases of shaken baby syndrome. Vitreoretinal interface shearing and perhaps shaking injury to orbital tissue appear to play the prominent pathogenic role.

Figure 12.7 Shaken Baby Syndrome—Peripheral Retinal Hemorrhages Hemorrhage to the ora serrata is a sign seen in approximately two thirds of shaken baby syndrome cases. The presence or absence of signs of head impact does not influence the type or severity of hemorrhagic retinopathy. The attachment of the vitreous to this peripheral region of the retina (P) is likely the key element as the severe repetitive acceleration–deceleration forces would result in more damage to this area via vitreoretinal traction. Note also the relative sparing of the midperipheral retina (*), an area where there is less vitreoretinal adhesion. Hemorrhage in the peripheral retina is statistically more likely to indicate inflicted versus accidental injury.

Figure 12.8 Shaken Baby Syndrome—Asymmetric Retinal Hemorrhages The retinal hemorrhages of shaken baby syndrome may be unilateral or asymmetric, as shown here. The cause for this well-recognized phenomenon is not known but may be due to the differential forces experienced by the two orbits and globes. In studies large enough to do proper statistical analysis, there does not appear to be a relationship between the sideness of the intracranial hemorrhage and the sideness of the hemorrhagic retinopathy. Likewise, Terson syndrome (intracranial plus intraocular hemorrhage usually due to trauma or subarachnoid hemorrhage in adults) is very uncommon in children.

Figure 12.9 Shaken Baby Syndrome—Purtscher Retinopathy Note the intraretinal white patches in the macula of this child. Purtscher retinopathy is due to severe compression of the chest. Given the presence of rib fractures in some victims (Fig. 12.3), it is not surprising that Purtscher retinopathy would occasionally be seen. However, increased intrathoracic pressure is not a major component to the pathophysiology of retinal hemorrhage in child abuse. Cardiopulmonary resuscitation (CPR) rarely causes retinal hemorrhage, and if it does, only a few intra- or preretinal hemorrhages in the peripapillary area would be expected. Purtscher retinopathy has never been seen as a result of the chest compressions of CPR in animal models or humans.

Figure 12.10 Shaken Baby Syndrome—Traumatic Retinoschisis Due to the tight adherence of the pediatric vitreous to the macula, the severe acceleration–deceleration forces of shaken baby syndrome, with or without head impact, can result in shearing of the retina such that a space is created between any layers, usually the internal limiting membrane, within which blood can accumulate. There is characteristically a curvilinear line at the edge of the elevated schisis cavity that is hemorrhagic or hypopigmented due to traumatic disruption of the retinal pigmented epithelium. Macular retinoschisis has not been reported in a child from any other condition, except perhaps severe fatal head crush injury. Hemorrhage can leave the cavity to create vitreous hemorrhage.

Figure 12.11 Shaken Baby Syndrome—Paramacular Folds Seen best when the dome of the central schisis (Fig. 12.10) cavity collapses, ante- or postmortem, a curvilinear hemorrhagic or more often hypopigmented/white (arrows) raised fold of retina demarcates the outer edge of the traumatic retinoschisis. Blood vessels can be seen coursing up and over the fold. Hemorrhage is still present within the retina and under the internal limiting membrane within the base of the cavity. Histologic preparations may show vitreous still attached to the apex of the folds.

Figure 12.12 Shaken Baby Syndrome—Retinoschisis When hemorrhage occurs over a blood vessel, it can become trapped under the internal limiting membrane, which is tightly adherent to the vessels. This creates a lesion that resembles the traumatic retinoschisis of shaken baby syndrome but is far less specific. Virtually any cause of hemorrhage due to a ruptured vessel can result in this finding. Note the absence of retinal folds or demarcation lines at the edge of the cavity. This child is a victim of shaken baby syndrome who also had sickle cell retinopathy (Chapter 18: Hematology, Figs. 18.1, 18.2, 18.3 and 18.4).

Figure 12.13 Shaken Baby Syndrome—Optic Atrophy The second most common cause of visual loss following shaken baby syndrome is optic atrophy. Recent research suggests that this atrophy is due to direct optic nerve injury

as a result of the severe acceleration–deceleration forces on orbital tissues. Even optic nerve sheath laceration has been observed. Retinal hemorrhage and traumatic retinoschisis (Figs. 12.10 and 12.11) rarely result in visual loss. However, as shown here, retinal scarring and pigmentary changes may occasionally occur. The optic nerve atrophy may take weeks to develop. Ophthalmic follow-up is recommended in all cases of shaken baby syndrome.

Figure 12.14 Physical Abuse This child was the victim of a belt beating by his father. The child squirmed and the belt buckle “accidentally” struck the eye, resulting in hyphema (left image) and commotio retina (right image). The use of implements to discipline a child is considered abuse. Such behaviors set up a situation in which the caretaker is more likely to lose control of the situation. It is this loss of control, especially in periods of stress, that characterizes child abuse. Virtually any ocular injury can be the result of abuse. Some ocular findings, such as

sclerocorneal laceration or avulsion of the vitreous base, are always an indicator of trauma. Findings such as unilateral cataract, optic atrophy, and cornea scarring with no other explanation might also raise the possibility of prior covert inflicted injury.

Figure 12.15 Physical Abuse Periocular and facial injury is a not uncommon manifestation of child physical abuse. This child demonstrates both acute and chronic injuries. The head and neck are the most often injured body areas as a result of abuse. However, accidental facial injury is far more common than abuse. Forehead injury can cause bilateral periocular ecchymosis, which can mimic child abuse. Therefore, a diagnosis of abuse must also take into consideration a full ocular examination pattern of

injuries and a good history. In child abuse, the history typically is inconsistent with the ocular findings or changes repeatedly with different inquiries.

Figure 12.16 Physical Abuse—Pattern Injury The ophthalmologist should examine the child when suspicions of abuse are raised by the ocular findings if there is not another pediatric professional involved. This child demonstrates characteristic loop-shaped bruises on his back due to a beating with a belt. One can also see circular areas

representing the belt buckle. An endless assortment of implements have been used on children ranging from cigarettes and cigarette lighters to straps and chords, all of which may leave a pattern of bruising that clearly could not be accidental in nature. Hand prints from a spanking or slap may also be seen.

Figure 12.17 Physical Abuse—Burns Burning, either by forced submersion, the use of hot implements, or, as in this case, the throwing of hot water on the child, is another form of physical abuse. The sparing of the eyelid skin in this photograph indicates that the child had time to forcibly close his eyes. It is important, however, to also rule out the presence of injury to the ocular surface. Other signs of physical abuse may also be present. Burns may leave significant scarring, thus simultaneously representing both physical and emotional abuse.

Figure 12.18 Munchausen Syndrome by Proxy (Factitious Disorder by Proxy) This child is a victim of covert suffocation by his mother, the most common form of Munchausen syndrome by proxy, a form of child abuse in which a parent, almost always the mother, engages in behaviors that result in the appearance of an illness in her otherwise well child. The perpetrator may falsify historical information, manipulate laboratory test results (e.g., spitting in a blood culture tube), or covertly cause direct physical injury. Other reported ocular signs include pupillary abnormalities due to covert poisoning or topical medication instillation, corneal scarring due to instillation of noxious chemicals, or orbital cellulitis due to the periocular injection of foreign materials. The child is usually preverbal. The perpetrator often has a history of working within a health care setting or some other familiarity with medical issues and may appear to be a very

loving and cooperative caretaker. Early suspicion and recognition of this disorder can prevent physicians from engaging in unnecessary diagnostic investigations.

Figure 12.19 Sexual Abuse—Pubic Lice Sexual abuse is a chronic secretive act in which the perpetrator is usually known to the child and can manipulate the child through coercion or threat to engage in a wide variety of acts ranging from inappropriate fondling to vaginal or anal penetration. It may be years before the child discloses the abuse. The diagnosis is made by trained child abuse professionals skilled in proper examination and interviewing techniques. The suspicion of sexual abuse may be raised when an ophthalmologist sees ocular manifestations of sexually transmitted disease in a nonneonatal prepubertal child. However, some of these

infections may be transmitted nonsexually, such as the pubic lice seen here, herpes simplex, and molluscum. There is evidence that chlamydia and gonorrhea may be nonsexually transmitted to the eye, unlike the genitals or throat. It is advised that the ophthalmologist to obtain professional consultation for a full diagnostic evaluation before reporting prematurely.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 13 - Chromosomes

13 Chromosomes Nasrin Najm-Tehrani Alex V. Levin The genetic information in each cell is in the form of DNA, the majority of which is in the nucleus as chromosomes. A much smaller proportion of DNA is located in the mitochondria in the cytoplasm of the cell. Mitochondrial disorders are covered elsewhere in this book (Chapter 21: Neurologic). Humans have 23 pairs of nuclear chromosomes, including the X and Y chromosomes that determine gender. Reported aberrations in the human genome are extremely numerous. This chapter deals with some of the more common and recognizable abnormalities, which include: 1. Trisomy: A duplication (i.e., three copies rather than two) of part or all of a chromosome 2. Monosomy: A deletion (i.e., one copy rather than two) of part or all of a chromosome 3. Translocation: A rearrangement of chromosomal material such that part of one chromosome is found attached to another chromosome. If the translocation is balanced, then there may be no resulting clinical abnormalities. However,

translocations may result in damage or deletion of genes, particularly at the points where one chromosome is broken or where a part of another chromosome is attached. 4. Other rearrangements: A wide variety of rearrangements of a chromosome (e.g., inversions, rings) can result in gene disruption and disease. To test the integrity of nuclear chromosomes, a karyotype is performed. At a specific stage of cellular replication, chromosomes are harvested from lymphocytes (the test can also be performed on tissues such as skin fibroblasts) and stained to create banding patterns. These bands do not correspond to specific genes. Rather, each band contains many of the approximately 35,000 human genes. Therefore, a cytogenetically visible chromosomal aberration almost always means that more than one gene has been disrupted. As a result, the patient will usually have more than one abnormality, one of which often is developmental delay. A normal karyotype does not rule out disease, as there can still be a submicroscopic aberration (e.g., microdeletion) or a molecular change within a single gene. This chapter focuses on the systemic manifestations of chromosomal aberrations, as many of the individual ocular manifestations (e.g., coloboma, cataract) are otherwise generic and featured elsewhere in this atlas.

Figure 13.1 Deletion 4p (Wolf-Hirschhorn Syndrome) The classical findings in partial deletion of the short arm of chromosome 4 are microcephaly, developmental delay, growth retardation, cleft lip/palate, congenital heart disease, seizures, genital abnormalities, and a characteristic head shape with a prominent glabella and long nasal root (beaked nose) that have led to comparison to a Greek helmet in profile. Most children die before reaching 2 years old. The critical deleted region appears to be 4p16.3. Oculofacial manifestations include hypertelorism, arched eyebrows with medial thinning, epicanthus, colobomatous microphthalmia, ptosis, and strabismus. Anterior segment abnormalities include Axenfeld-Rieger spectrum, corneal opacities such as the Peter anomaly, and cataracts.

Figure 13.2 Deletion 5p (Cri du Chat Syndrome) Partial deletion of the short arm of chromosome 5 presents in the neonate with low birth weight, hypotonia, and slow growth rate. The striking catlike cry of the infant is due to structural anomalies in the larynx. Typical facies show microcephaly, micrognathia, and low-set ears. Cardiac abnormalities may be present. Ophthalmic involvement includes epicanthus, ptosis, myopia, decreased tear production, strabismus, cataracts, glaucoma, retinal vessel tortuosity, foveal hypoplasia, optic atrophy, and colobomatous microphthalmia

Figure 13.3 Deletion 11q (Jacobsen Syndrome) The critical deleted region for the development of Jacobsen syndrome is 11q23.3-24.1. Ocular abnormalities most commonly associated include telecanthus and/or hypertelorism, ptosis, epicanthal folds, and strabismus. Less common ocular abnormalities are coloboma with or without microphthalmia, nuclear cataract, abnormal eyelashes/eyebrows, iris discoloration, microcornea, nasolacrimal duct obstruction, amblyopia, and exotropia with anomalous extraocular muscles. Patients often have growth and mental retardation, craniosynostosis, abnormal facies, thrombocytopenia/pancytopenia, and, less commonly,

congenital heart malformations and hand/foot anomalies.

Figure 13.4 Trisomy 13 (Patau Syndrome) Trisomy 13 is characterized by microphthalmia, scalp defects, cleft lip/palate, polydactyly, congenital heart defects, and severe developmental delay. It is associated with a markedly shortened life span, although approximately 10% of children can survive into later childhood. Eye abnormalities include hypertelorism, epicanthal folds, colobomatous microphthalmia, cataracts, corneal opacities, glaucoma, persistent hyperplastic primary vitreous (Chapter 7: Fig. 7.14), intraocular cartilage, and retinal dysplasia with possible retinal nonattachment (Chapter 8: Fig. 8.24).

Figure 13.5 Deletion 15q (Prader-Willi and Angelman Syndromes) Although each syndrome is potentially caused by a mutation in a different gene, the manifestations are more often caused by deletion of a region involving both genes. However, this region is imprinted such that the gene associated with Prader-Willi is only expressed from the paternal copy of the region and the gene associated with Angelman is only expressed on the maternal allele. PraderWilli, pictured here, is characterized by hypotonia, hypogonadism, small hands and feet, and obesity. It is caused by the deletion of the paternally derived copy of 15q11.3. Angelman syndrome, characterized by seizures often associated with laughter, absent speech, severe developmental delay, and puppetlike jerky gait, results from deletion of the maternally derived copy. As the p gene lies within the same region, many patients with deletions show iris transillumination and other signs of hypopigmentation. The p gene is expressed from both alleles. In approximately

1%, if the remaining p gene allele is also hypopigmentary, then the patient may show type 2 oculocutaneous albinism (Chapter 15: Dermatology, Figure 15.20). In both syndromes ophthalmic manifestation includes ocular hypopigmentation.

Figure 13.6 Deletion 18q (de Grouchy Syndrome) The de Grouchy syndrome phenotype is associated with

deletion distal to and including 18q21. Systemic findings are usually severe developmental delay, failure to thrive, palmar creases, and hearing loss with or without abnormal external ears. Other reported features include cleft lip/palate, microcephaly, absent labia minora, cutaneous hemangiomas, congenital heart disease, and minor distal skeletal anomalies, in particular cutaneous dimples in the fossae overlying the extensor surfaces of joints. Poor vision due to pigmentary retinal dystrophy, optic atrophy, and nystagmus is the cardinal ophthalmic feature. Strabismus (shown here), high myopia, microcornea/microphthalmia, corneal opacity, iris defects, corectopia, and straightening of the retinal vessels and ptosis have also been observed.

Figure 13.7 Trisomy 21 (Down Syndrome) Down syndrome is caused by trisomy 21, the most common chromosomal aberration in liveborn children. Features can also be seen as a result of partial trisomy, mosaicism, or translocation. There is an associated risk with rising maternal age. Children have a typical facies and variable developmental delay, often in combination with congenital

heart disease, gastrointestinal malformations such as duodenal atresia, single palmar crease, immune system abnormalities, and a higher risk of developing leukemia. The patients may have prominent or even floppy eyelids (right image), nasolacrimal obstruction, high refractive error, hypoaccommodation, strabismus, nystagmus, keratoconus, and blepharitis. The optic nerve may show an increased number of retinal vessel branching or a spoke-wheel configuration of the vessels (as shown here).

Figure 13.8 Trisomy 21 (Down Syndrome)—Anterior Segment Patients with trisomy 21 may show many cataract phenotypes (Chapter 7: Lens), including total white cataract, nuclear, posterior subcapsular, and the more common “snowflake” opacities (left image), which may be variable in size and color. Brushfield spots of iris (right image) are areas of hyperplasia of the iris always white and symmetrically distributed circumferentially on the peripheral iris. Similar iris lesions can also be seen in normal children,

but the eponym is not used. Congenital glaucoma is a very rare association. Ophthalmic follow-up throughout the developmental years is therefore essential to discover emerging and treatable ocular pathology such as cataracts.

Figure 13.9 Supernumerary 22q (Cat Eye Syndrome) The critical region for cat eye syndrome is 22q11. The supernumerary chromosome results in trisomy or tetrasomy of the involved area. Systemic associations with this condition include mental retardation, preauricular skin tags or pits, micrognathia, hearing impairment, growth retardation, hemivertebra, and cleft palate. Cardiac defects are present in approximately one third of patients. Iris coloboma is common but not obligatory and gives the syndrome its name. Less frequent ophthalmic findings may include hypertelorism, epicanthus, and downslanting palpebral fissures. Microphthalmia and Duane syndrome (Chapter 1: Strabismus) have also been reported.

Figure 13.10 Fragile X Syndrome (Martin-Bell Syndrome) This syndrome is usually caused by the expansion of a repeat nucleotide sequence on the X chromosome. Fragile X has variable expression in the hemizygote and the female heterozygote. One of the most common chromosomal causes of mental retardation, fragile X is estimated to occur in 1 in 2,000 male births. Systemic findings also include macrocephaly, prognathism, thickening of the nasal bridge extending down to the nasal tip, large ears, and macroorchidism. Ophthalmic findings are epicanthus, pale blue irides, and, less commonly, strabismus, nystagmus, myopia, and, as shown here, ptosis (see also Chapter 2: Lids and Adnexa, Figure 2.9). Visual avoidance behavior is common. (Anisocoria shown here is a pharmacologic artifact.)

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 14 - Craniofacial

14 Craniofacial Alex V. Levin Thomas W. Wilson J. Raymond Buncic The craniofacial disorders are characterized by malformation of the cranial vault and/or facial bones. Premature fusion of one or more sutures, known as craniosynostosis, results in myriad congenital syndromes that are distinguished not only by the involved sutures and appearance of the head and face, but also by the presence and absence of other systemic findings. The genes involved in craniofacial development may also be involved in the formation of other body parts. Clefting abnormalities are a group of disorders that are the result of incomplete closure of the face and branchial clefts as defined by the Tessier clefting system. One must also distinguish between primary craniofacial malformations and the secondary deformations such as positional plagiocephaly. Craniofacial disorders often have ophthalmic manifestations. A multispecialty team approach is required for the care and treatment of these patients. Significant vision loss can be observed due to primary coexisting malformations such as optic nerve hypoplasia, secondary effects of the disorder such as

corneal exposure due to exorbitism or strabismic amblyopia, and complications of treatment such as hemorrhagic conjunctival prolapse following a bicoronal flap for surgical intervention.

Figure 14.1 Metopic Synostosis Metopic craniosynostosis (trigonocephaly) is due to premature closure of the metopic suture of the skull. This causes a wedge-shaped malformation of the frontal bone, which leads to hypotelorism and pseudoesotropia. Increased intracranial pressure is rare. This is usually an isolated anomaly that does not affect cognition but may result in significant departure from a normal appearance.

Figure 14.2 Coronal Synostosis Coronal craniosynostosis (anterior plagiocephaly) is due to premature closure of the coronal suture. This threedimensional reconstruction of the skull shows premature closure of the right coronal suture. Note the posterior displacement of the superior and superolateral orbital rim, sometimes referred to as the “owl eye” or “harlequin orbit.” Bilateral coronal synostosis may also. Although often associated with other abnormalities of the skull or body, unilateral or bilateral coronal synostosis may also occur as an autosomal dominant condition due to mutations in the fibroblast growth factor receptor gene FGFR2 at 10q26. Elevated intracranial pressure may be present, particularly in bilateral cases.

Figure 14.3 Coronal Synostosis Due to the superior and superolateral orbital rim recession, patients with coronal synostosis (anterior plagiocephaly) appear to have a recessed forehead on the affected side and pseudoproptosis. Misdiagnosis as buphthalmos (Chapter 10: Glaucoma, Fig. 10.1), contralateral hemifacial atrophy, or contralateral ptosis is not uncommon. The view from above (bottom image) is very useful in evaluating patients with craniofacial disorders and in this case immediately reveals the diagnosis.

Figure 14.4 Coronal Synostosis Approximately 50% of patients with anterior plagiocephaly will have a vertical and/or horizontal strabismus with limited eye movements. This child has limited supraduction in abduction and eye movements consistent with bilateral inferior oblique overaction. This abnormal pattern may be associated with absent or malpositioned eye muscles, particularly in bilateral cases. Astigmatism is more common on the involved side(s).

Figure 14.5 Sagittal Synostosis Sagittal synostosis (scaphocephaly) is due to premature closure of the sagittal suture. The skull is elongated in an anterior posterior direction. Often, there will be a palpable ridge along the fused suture and the anterior and posterior fontanelles will be completely or partially closed. Increased intracranial pressure is not uncommon and papilledema is the major ocular sign. Until cranial vault reshaping is performed, periodic ocular examination is suggested.

Figure 14.6 Exorbitism In the multiple craniosynostosis syndromes the orbit is relatively shallow, leading to prominence of the globe. This is different than proptosis in which there is something (e.g., tumor) pushing the globe forward. Exorbitism can result in spontaneous and recurrent subluxation of the globe. Severe exorbitism can result in the lids being positioned behind the equator. Exposure keratopathy is a particular concern. Although subluxation may be treated by firm gentle pressure to reposit the globe in the orbit, craniofacial surgery is required for a more definitive result.

Figure 14.7 Complicated Exorbitism Severe exorbitism can lead to conjunctival edema and corneal exposure, particularly if the eye becomes trapped anterior to the orbital rim, as seen here. Compromise to the optic nerve may occur. If the eye cannot be manually reposited within the orbit, treatment of this patient acutely would involve aggressive lubrication of the conjunctiva and cornea. Tarsorrhaphy is very difficult unless the eye can be placed back in the orbit. This patient required urgent advancement of the orbital bones.

Figure 14.8 Multiple Craniosynostosis Strabismus The most common strabismus is a V-pattern exotropia with hypertropian adduction. Extraocular muscle anomalies are common and lead to strabismus. Anomalies include absent or malpositioned muscles with atypical insertion sites. Satisfactory surgical management of this strabismus is difficult. The elevation in adduction and V pattern might suggest an overaction of the inferior oblique muscles (Chapter 1: Strabismus, Figs. 1.28, 1.31, and 1.38), but the mechanism is most likely more complex. This pattern has been observed even in children with multiple craniosynostosis, exorbitism, and absent inferior oblique muscles.

Figure 14.9 Apert Syndrome—Strabismus This child with the multiple craniosynostosis syndrome, Apert syndrome, shows significant exorbitism (Fig. 14.6) and strabismus. Syndactyly of the fingers and toes is a characteristic of Apert syndrome. The child has a large-angle right exotropia and hypotropia. This picture was taken in upgaze. Note the deficient elevation in both eyes, more so on the right. This may be due to anomalous or absent extraocular muscles. The patient is at risk for developing exposure keratopathy and amblyopia. Patching therapy is difficult due to the risk of corneal abrasion from the patch. This patient most likely will need advancement of the orbital bones. Following this surgery, strabismus surgery can be considered.

Figure 14.10 Apert Syndrome—Anomalous Muscles Coronal computed tomography scan (left image) of the orbit shows malposition of the extraocular muscles. The superior rectus muscles are displaced temporally and the inferior rectus muscles are displaced medially. The long white lines bisect both muscles. It is difficult to predict the effects of such muscle aberrations and the appropriate strabismus surgery to correct strabismus if present. Exorbitism itself is also associated with excyclotorsion (Fig. 14.12), making it important to distinguish true anomalous location of the muscles versus rotation of the entire globe. The right image shows, intraoperatively, the absence of the inferior rectus muscle, which should have been located at the left (posterior) arm of the caliper.

Figure 14.11 Apert Syndrome— Syndactyly Apert syndrome is the combination of multiple craniosynostosis and severe bony and cutaneous syndactyly. It is an inherited autosomal dominant disorder due to a mutation in the fibroblast growth factor receptor gene (FGFR2) at 10q26. The head is brachycephalic and may be turricephalic. There is marked hypoplasia of the midface with a prominent nose and hypertelorism. The ears are typically low set. Palate and dental abnormalities are common. This patient has already had several operations on his hands to attempt to convert what was complete five-digit syndactyly to a more functional hand. Crouzon syndrome, also due to mutation in FGFR2, is very similar to Apert but with normal hands.

Figure 14.12 Apert Syndrome— Excyclotorsion This fundus photograph shows significant excyclotorsion of the right eye. The fovea is well below the horizontal meridian of the optic nerve. Patients with multiple craniosynostosis and exorbitism frequently have this sign. Excyclotorsion can be the result of mal- position of the recti muscles (Fig. 14.10) or the anomalous orbital structure. The excyclotorsion is usually bilateral and rarely results in symptoms. Stereopsis can still be maintained in many of these children and surgical correction for asymptomatic excyclotorsion is not advised.

Figure 14.13 Clover Leaf Skull Kleeblattschädel (“clover leaf skull”) is a head shape that is due to synostosis of all sutures except the squamosal. The resulting head shape is characterized by a towering vertex of the head and temporal bulging (“trilobate skull”), as demonstrated in this image. The head shape is not a syndrome alone but is seen in a variety of multiple

craniosynostosis syndromes including Apert and Crouzon. It is associated with hydrocephalus, which is the major cause of morbidity. Exorbitism can be quite profound (Figs. 14.6 and 14.7). Globe subluxation and corneal exposure are common.

Figure 14.14 Treacher-Collins Syndrome Treacher-Collins syndrome (mandibulofacial dysostosis) is an autosomal dominant craniofacial abnormality of structures derived from the first branchial arch. Facial features include malar hypoplasia, triangular-shaped face, mandibular hypoplasia, and ear anomalies including deafness. There is a characteristic downslanting of the palpebral fissures with a sharply angular lower lid coloboma (Fig. 14.16). The disorder is bilateral. Exposure of the cornea becomes an increasing problem with age.

Figure 14.15 Treacher-Collins Syndrome This profile view demonstrates the severe mandibular hypoplasia with microretrognathia. The ear has been partially reconstructed but the child has severe hearing loss and requires a bone conducting hearing aid. Oblique astigmatism is common but the wearing of spectacles can be a challenge if severe microtia or other ear anomalies are present. Until reconstruction is completed, glasses can be affixed to a head band worn over the cranial vault. This disorder is due to mutations in the treacle gene (TCOF1) at 5q32-33.1.

Figure 14.16 Treacher-Collins Syndrome—Lower Lid Coloboma Patients with Treacher-Collins syndrome have a characteristic sharply downslanting lower lid coloboma with absent lashes and often an absent or otherwise anomalous lower lid puncta. The lateral edge of the coloboma rises acutely back to the normal lateral aspect of the lid margin. The lid aperture takes on a trapezoidal configuration. The lacrimal drainage system may be anomalous and dysfunctional or completely absent, but the superior puncta are often present and functional. Chronic tearing and discharge usually do not appear until later in childhood. The palpebral fissure shortens horizontally with forced lid closure. This is secondary to absence or laxity of the lateral canthal tendon.

Figure 14.17 Binder Syndrome Binder syndrome (maxillofacial dysplasia) is a developmental abnormality of the anterior maxilla and nose. Clinical features include a flat vertical nose and hypoplasia of the upper jaw and midfacial structures. Perhaps the most characteristic feature is the absence of the anterior nasal spine on radiographs. Hearing abnormalities may necessitate the use of a hearing aid, as seen here. Ocular manifestations may include strabismus, refractive error, exorbitism, and ptosis. Anomalous eye muscles have not been reported, unlike other multiple craniosynostosis syndromes.

Figure 14.18 Goldenhar Syndrome Goldenhar syndrome is a subset of the oculo-auriculovertebral spectrum, disorders caused by abnormal development of tissues derived from the first branchial arch. Goldenhar syndrome is characterized by mandibular hypoplasia and hemifacial microsomia. Preauricular tags and an abnormal external ear are common (right image). The findings may be unilateral or bilateral. One ophthalmic abnormality, shown in the left image, is upper lid coloboma, usually involving the medial upper lid, with or without adhesion to the surface of the eye. This child's coloboma, particularly of the left upper lid, demonstrated the characteristic rectangular defect.

Figure 14.19 Goldenhar Syndrome—Limbal Dermoid Limbal dermoids are round or oval opaque white masses attached to the cornea and sclera. They consist of surface ectoderm–derived tissue and may contain hair and sweat glands. These lesions are classified as choristomas. They are most commonly located at the inferotemporal limbus but may also occur on the conjunctiva or central cornea. Astigmatic or occlusion amblyopia is a concern. Surgical intervention usually involves peripheral lamellar or fullthickness keratopathy. Limbal dermoids are most frequently seen as part of Goldenhar syndrome.

Figure 14.20 Goldenhar Syndrome—Lipodermoid Subconjunctival lipodermoids are most commonly found in the temporal orbit presenting as a smooth, pink, congenital, nonprogressive mass hugging the globe most often over the lateral rectus muscle. A few cilia are rarely present. The lipodermoid may encase recti muscles and intercalate themselves between the muscle fibers with or without an effect on eye movement. Surgical intervention is largely designed to address abnormal appearance. Deep dissection is therefore not recommended because inadvertent injury to the muscle with incomitant strabismus may occur.

Figure 14.21 Goldenhar Syndrome—Caruncle Some patients with Goldenhar syndrome will have an absent or an abnormal caruncle. The caruncle may be enlarged, hypoplastic, or bilobed. In this child, the caruncle appears as an ectopic mass in the medial palpebral conjunctiva of the lower lid (arrow). Ectopic caruncle is often associated with lateral displacement of the lower lid puncta with or without nasolacrimal duct dysfunction. Although an abnormal caruncle has no effect on vision, it is a marker for an increased frequency of abnormalities of the ipsilateral nose and nasal cavity in Goldenhar syndrome.

Figure 14.22 Oculo-auriculo-vertebral Spectrum— Duane Syndrome All forms of oculo-auriculo-vertebral spectrum, including Goldenhar, Wildervanck, and Klippel-Feil syndromes, may be associated with Duane syndrome (Chapter 1: Strabismus, Figs. 1.59, 1.60, 1.61, 1.62 and 1.63), usually type I Duane. There may be ipsilateral ear abnormality and hearing loss. This patient is attempting to look to his left. Notice the narrowing of the palpebral fissure on adduction of the right eye and absence of left eye abduction. The child has bilateral type III Duane syndrome in association with bilateral Goldenhar syndrome.

Figure 14.23 Fibrous Dysplasia Fibrous dysplasia of the orbit is a disorder where excess osteoblastic activity results in fibrous replacement of bone. Virtually any bone in the body can be affected including the cranial vault, often involving the orbital bones. There are four forms: Monostotic, polyostotic, craniofacial, and cherubism. The craniofacial form is nonhereditary and typically unilateral, and most commonly affects the orbital roof and frontal and sphenoid bones, leading to downward displacement of the eye, proptosis, and extraocular muscle movement restriction, as shown here. Fibrous dysplasia usually is self-limiting, although orbital reconstruction is reserved for severe cases. Optic nerve compression may occur and requires urgent decompression of the optic canal.

Figure 14.24 Fibrous Dysplasia Fibrous dysplasia is diagnosed by radiologic imaging, which demonstrates the excess fibrous stromal replacement of bone. The left image shows dramatic involvement of the clivus (arrow) with impending compression of both optic nerves. The three-dimensional reconstruction of the orbital roof, in the right image, shows infiltration of the bone with mass lesion on the left extending over to the right side as well. This patient had limited elevation of the left eye and proptosis.

Figure 14.25 Anterior Encephalocele Encephaloceles are caused by defects in the cranial bones with herniation of dura with or without brain tissue. The brain tissue within the encephalocele may be dysplastic. Encephaloceles can occur in different locations, including the other two common locations: Occipital and basal. In the latter circumstance, the patient may demonstrate a notch in the upper lip and morning glory disc (Chapter 9: Optic Nerve, Fig. 9.5). Hypertelorism results from displacement of the orbits laterally as the orbital angle cannot be reduced due to the intervening brain during embryogenesis. Craniofacial and neurosurgical correction are necessary.

Figure 14.26 Anterior Encephalocele This child has no brain tissue within the encephalocele, as demonstrated by the marked transillumination. The ocular effects of anterior encephalocele, in addition to the hypertelorism (Fig. 14.25), include amblyopia due to obstruction of the visual axis, and strabismus. Ocular malformations may also occur, including bilateral optic nerve hypoplasia or coloboma and bilateral microphthalmia.

Figure 14.27 Frontonasal Dysplasia When there are more extensive midline defects, often including the nose, which may have a midline furrow indicating incomplete midline formation (left image), the term frontonasal dysplasia is used. Brain anomalies such as callosal agenesis may be associated. The right image illustrates a large encephalocele herniating through the ethmoid and sphenoid sinuses into the nasal cavity and the resulting severe hypertelorism. Should craniofacial surgery require intubation of the nasolacrimal system, the ophthalmologist must be cautious about intranasal manipulation. Other associated ocular findings may include strabismus (left image), optic nerve hypoplasia or coloboma, and microphthalmia.

Figure 14.28 Hypotelorism

Hypertelorism and hypotelorism refer to abnormalities in the distance between the anterior medial orbital rims as opposed to telecanthus, which refers to the soft tissues. Patients with hypotelorism may have associated abnormalities of the brain including holoprosencephaly and the absence of a separation and distinction between the two cerebral hemispheres. Holoprosencephaly is due to a mutation in the Sonic Hedgehog gene. Phenotypic variation ranges from fatal holoprosencephaly with a proboscis below a cyclopean eye to a normal craniofacial structure with the only abnormality being a single upper incisor.

Figure 14.29 Lateral Facial Dysplasia The lateral facial dysplasias are a group of nonprogressive craniofacial malformations characterized by abnormal asymmetry of the facial structures, often including hemifacial atrophy. Associated ophthalmic anomalies include ipsilateral optic nerve hypoplasia and microphthalmia. The eye on the affected side may also appear enophthalmic and may have restrictions of eye movement (right image,

patient looking to her left) and anterior segment abnormalities. In the left image, note also the deviation of the nose and the abnormal ear.

Figure 14.30 Amniotic Bands Facial clefting can also occur in nonanatomic planes due to amniotic bands. These bands are felt to be due to rupture of the amniotic sac during development. The bands inhibit normal growth and lead to cleftlike syndromes. Significant facial and other developmental abnormalities can occur. Digits or limbs may be amputated or show significant constriction from the intrauterine effect of these bands.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 15 - Dermatology

15 Dermatology Alex V. Levin Thomas W. Wilson David Rootman Elise Héon Dermatologic diseases will often have an associated ophthalmic manifestation because of the common embryologic origin of the ocular structures and the skin. The skin and ocular surface are both of ectodermal origin. The skin covering the eyelids, the lashes, all eyelid glands, the lacrimal gland, the conjunctival epithelium, and the corneal epithelium are all derived from surface ectoderm. The lens of the eye is also a surface ectoderm derivative. Dermatologic disease involving the periorbital skin area can cause secondary abnormalities of the ocular surface. Skin diseases affecting the mucous membranes such as StevensJohnson syndrome will often have ocular manifestations as conjunctiva is a mucous membrane. The ectodermal dysplasias are a group of rare genetic diseases with a wide clinical spectrum involving skin, eyes, teeth, hair, nails, and sweat glands. Ocular manifestations may include corneal surface disease, conjunctival disorders, lid abnormalities, or cataract.

Skin pigment is derived from melanosomes, which originate as neural crest cells. Likewise, the melanocytes of the uveal tract are also neural crest descendants. Melanosomes are also found in the retinal pigment epithelium, a neuroectodermal derivative, where pigmentation is required for normal development of the overlying retina. Oculocutaneous albinism refers to those disorders in which deficiency of melanin or melanosomes manifests in both skin and eye. Ocular albinism refers to an isolated ocular hypopigmentation disorder. Dermatologic treatments can also cause ocular side effects. Steroid creams can cause an increase in intraocular pressure and lead to glaucoma cataracts. Systemic tetracycline used to treat acne can cause pseudotumor cerebri. The retinoids are natural and synthetic compounds that produce similar effects to vitamin A and can also cause pseudotumor cerebri. There are numerous other examples of combined dermatologic and cutaneous manifestations, many of which are covered elsewhere, such as the phakomatoses (Chapter 23), rheumatologic disorders such as lupus (Chapter 27), and skeletal disorders such as pseudoxanthoma elasticum (Chapter 28). This chapter will focus on disorders that are primarily dermatologic and that have associated involvement of the oculofacial regions.

Figure 15.1 Ectrodactyly–Ectodermal Dysplasia (EEC Syndrome) The predominant features of this autosomal dominant syndrome are ectrodactyly (shown here), ectodermal dysplasia, and cleft lip/palate. When associated with urinary tract abnormalities, the syndrome is named EEC-UT. Other manifestations include oral and facial abnormalities, dry eye, and hypohidrosis. Patients have absence of eyelashes, thin hair and eyebrows, and decreased skin pigmentation. Meibomian glands are decreased or absent, leading to corneal vascularization and scarring. The lacrimal punctum may be small or absent. Aggressive tear replacement therapy is necessary to maintain normal ocular surface and reduce photophobia. Retinal detachment may also occur. One variant is the rare autosomal recessive association of ectodermal dysplasia and macular dystrophy: Ectrodactyly– ectodermal dysplasia–macular dystrophy (EEM) syndrome.

Figure 15.2 Incontinentia Pigmenti (Bloch-Sulzberger Disease) Incontinentia pigmenti is an X-linked dominant disorder that is almost always lethal in males. It is caused by mutations in the NEMO gene at Xq28 with another locus postulated for the disorder at Xp11. The cutaneous lesions, which are distributed along the lines of Blaschko, evolve from an early bullous phase with erythematous papulosquamous lesions (left image) to a hyperkeratotic verrucous stage, followed by swirling and patchy hyperpigmentation (right image) with or without hypopigmentation, atrophy, and scarring in its later stages. Neurologic features include seizures and mental retardation. (The authors are grateful for the contributions of Dr. Christopher Cessna to this legend.)

Figure 15.3 Incontinentia Pigmenti (Bloch-Sulzberger Disease) Ocular manifestations are often asymmetric and include peripheral retinal avascularity similar to that seen in retinopathy of prematurity (Chapter 8: Retina and Vitreous, Figs. 8.6, 8.7, 8.8, 8.9, 8.10, 8.11, 8.12, 8.13, 8.14, 8.15, 8.16, 8.17, 8.18, 8.19, 8.20, 8.21, 8.22 and 8.23) with retinal ischemia inducing neovascularization and bleeding/exudation. The findings are usually worse temporally. Milder cases may only show straightening of the far temporal peripheral retinal vessels. Temporal dragging of the macular vessels is an ominous sign. If a child is fully vascularized without leakage or traction on first examination, then he or she will not develop retinopathy.

Figure 15.4 Incontinentia Pigmenti (Bloch-Sulzberger Disease) In cases of retinopathy, progression to traction retinal detachment can be rapid. Careful periodic follow-up is essential. Other reported signs include optic atrophy, foveal hypoplasia, microphthalmos, cataracts, conjunctival pigmentation, iris hypoplasia, uveitis, nystagmus, strabismus, and whorllike epithelial keratitis. Dental abnormalities are seen in greater than 80% of cases and include absent teeth and conical teeth with supplemental cups.

Figure 15.5 Hypomelanosis of Ito Patients with hypomelanosis of Ito present with cutaneous abnormalities consisting of hypopigmented patches and streaks. (right image) Brain migration disorders are common and result in brachycephaly and micropolygyria. Ophthalmic manifestations include coloboma, iris heterochromia, microphthalmia, and choroidal atrophy. (left image) Biopsy of affected skin may show mosaicism for one of the many reported associated chromosomal aberrations. This girl had congenital glaucoma, developmental delay, and a mosaic isochromosome 8.

Figure 15.6 Xeroderma Pigmentosa Xeroderma pigmentosum is a rare disorder that is characterized by skin atrophy, telangiectasia, mottled hypopigmentation and hyperpigmentation, and scarring in the early years of life, and has a high rate of malignant transformation as a result of abnormal repair of DNA damaged by ultraviolet light. Multiple genes have been identified, which are usually inherited in an autosomal recessive pattern. Ophthalmic manifestations are very common, with photophobia and conjunctivitis being the earliest findings, with the later development of blepharitis, symblepharon, madarosis, entropion, ectropion, trichiasis,

symblepharon, ankyloblepharon, xerosis, pinguecula, and malignancy. Corneal neovascularization, ulceration, and opacification, along with iris inflammation and atrophy and synechia formation, can also occur. Patients have a higher risk of developing internal tumors. (The authors are grateful for the contributions of Dr. Rupan Trikha to this legend.)

Figure 15.7 Ichthyosis Ichthyosis comprises a large variety of genetic disorders with abnormal differentiation and desquamation of the epidermis leading to thickening (hyperkeratosis), fissuring, and scaling of the skin. Severity and extent can vary tremendously, ranging from dry skin (left image, note mild ectropions) to more severe desquamation (right image, lamellar ichthyosis) or even a life-threatening multisystem disorder. Ocular manifestations include corneal opacities, conjunctivitis, and keratitis. The nails and hair may also be involved. Keratitis, ichthyosis, and deafness (KID) syndrome is one rare variant. (The authors are grateful for the contributions of Dr. Nick Ulrich to this legend.)

Figure 15.8 Ichthyosis One severe form of ichthyosis presenting in the neonatal period is the collodion baby syndrome, in which the child may have severe desquamation and a cicatricial, almost glistening tight membrane covering the entire body. Congenital ectropion, as shown here (left image), may occur. With resolution, the child can be left with hypertrophic, atrophic, and scarred skin with variable pigmentation (right image). Hyperkeratosis of the palms, soles, and feet as well as abnormal nails and hair also may occur. Possible treatment options include systemic retinoids (vitamin A preparations) for cutaneous symptoms and topical cyclosporine for vascularizing keratitis.

Figure 15.9 Epidermolysis Bullosa Epidermolysis bullosa (EB) describes a group of conditions associated with abnormalities of the epidermal basement membrane and mucous membranes. It is typically genetically determined. The characteristic features are skin and mucosal fragility. A tendency to blister occurs after even minor trauma. The involvement of the eye with conjunctival and corneal blistering can lead to progressive scarring with reduced vision and even blindness. There are several genetic subtypes: Dystrophic, junctional, and simplex. Within subtypes clinical variability has been observed. The more severe variants, as shown here, can be associated with scarring, fusion of neighboring areas of skin, and even loss of tissue. This girl suffers from repeated episodes of large corneal abrasion after minimal or no trauma. (The authors are grateful for the contributions of Dr. Wells Reinheimer to this legend.)

Figure 15.10 Erythema Multiforme (EM)/StevensJohnson/Toxic Epidermal Necrolysis EM refers to a self-limited, mucocutaneous hypersensitivity reaction that classically presents with a sudden onset of a papular, erythematous rash, with symmetrical distribution and centripetal spread. These cutaneous lesions evolve into target lesions. More severe immunologic responses result in Stevens-Johnson syndrome or toxic epidermal necrolysis. The mucous membranes are particularly involved, including the oropharynx and conjunctiva. Skin desquamation is seen in response to minimal trauma (Nikolsky sign). No genetic predisposition or specific cause has been identified, but many potential triggers have been associated, including herpes viruses, adenovirus, Coxsackie virus, mycoplasma, and many prescribed drugs. (The authors are grateful for the contributions of Dr. Rupan Trikha to this legend.)

Figure 15.11 Stevens-Johnson Syndrome Destruction of conjunctival goblet cells leads to severe keratitis sicca (dry eye, right image) with the characteristic formation of adhesions between the inside surface of the eyelids (palpebral conjunctiva) and the bulbar conjunctiva or cornea. These symblepharons (left image) portend a poor prognosis, and patients may go on to severe vascularized and keratinized corneal scarring, for which even heroic surgery is often not successful in restoring vision. Daily examination during the acute phase of the illness, possibly with the lysing of early symblepharon, copious lubrication, and in some cases topical steroid use, may reduce the incidence of poor outcomes.

Figure 15.12 Atopic Dermatitis/ Eczema Atopic dermatitis/eczema describes a chronic, relapsing, pruritic skin condition with clinical features of xerosis, inflammation, scaling, and lichenification. Flexor surfaces of extremities are most commonly involved. Involvement of the lids and adnexa may lead to chronic eye rubbing and surface irritation. The pathogenesis is unknown, but elevated immunoglobulin E levels and eosinophilia are found in most patients. Patients may have other atopic signs including asthma and seasonal allergy and may present within the first 3 to 6 months of life. In more severe cases, punctual stenosis, weeping fissures at the lateral canthi, conjunctival papillae, symblepharon, entropion, trichiasis, punctuate keratitis, and even corneal ulceration, vascularization, and opacification may occur. Atopic dermatitis is also associated with anterior subcapsular cataract and keratoconus. (The authors are grateful for the contributions of Dr. Nick Ulrich to this legend.)

Figure 15.13 Contact Dermatitis Contact dermatitis is an acute, sometimes patterned response to a local topical irritant. Often the offending substance is never discovered. The response can be very pruritic and may be characterized by edema, erythema, and vesicle formation. Although the appearance may be similar to herpes, the absence of pain helps to differentiate contact dermatitis. This child was evaluated and treated for zoster infection (Chapter 19: Infectious Diseases, Fig. 19.7) before it was recognized that this was a response to a new hair gel.

Figure 15.14 Albinism—Iris Transillumination Albinism is a group of disorders characterized by abnormalities in pigmentation. The involvement of the eye and the skin can be variable. Patients often present with nystagmus in the first several months of life and decreased vision. The cardinal ocular finding is iris transillumination, which may range from a few punctate dots to a severity that is grossly apparent, as seen here, with the lens edge visible through the iris (arrow). Iris transillumination can also be seen following trauma or infection (e.g., herpes) and in some congenital malformations of the anterior segment, but its presence otherwise indicates that the patient either has or carries a gene mutation for albinism.

Figure 15.15 Albinism—Retina Almost all patients with albinism have some degree of macular hypoplasia and fundus hypopigmentation. Both are due to a deficiency of melanin in the retinal pigmented epithelium. The abnormal macular development results in a poorly differentiated vascular pattern such that the typical normal arc of the temporal superior and inferior arcades may not be recognizable and vessels encroach upon or even cross what would be the foveal avascular zone. In the right image, it is almost impossible to tell if this is a right or left eye due to the undifferentiated vascular pattern.

Figure 15.16 Albinism—Retina The pigmentary deficiency becomes more apparent peripherally where the deficiency of choroidal melanocyte pigmentation and absence of other macular pigments (e.g., lipofuscin) results in a direct view of the sclera with the exception of retinal and choroidal vessels. The optic nerve may be gray and small. Multichannel visual-evoked potential usually shows abnormal decussation of the visual pathways such that there is an overabundance of fibers crossing to the contralateral side of the brain.

Figure 15.17 Oculocutaneous Albinism Type 1A (OCA1A) Oculocutaneous albinism is characterized by the presence of variable skin hypopigmentation, the degree of which depends on the molecular genetic defect involved. The ratelimiting step in melanin synthesis is dependent upon tyrosinase, the first step in tyrosine metabolism. Autosomal recessive mutations in the tyrosinase gene result in OCA type 1. The term “tyrosinase negative” is no longer used. Complete absence or severe deficiency of tyrosinase results in a markedly hypopigmented phenotype (OCA1A), with no visible pigmentation and severe ocular involvement. Vision is usually in the range of 6/60 or worse. Patients have snow white hair and extremely fair skin throughout their lifetime without any increased pigmentation. These patients are susceptible to sun damage and skin cancer.

Figure 15.18 Oculocutaneous Albinism Type 1B (OCA1B)— Yellow Variant Oculocutaneous albinism type IB is due to specific mutations in the tyrosinase gene that reduce its function but do not create null alleles. Reduced production of the products of tyrosinase leads to a shunting of the metabolic pathway away from the production of the darker pigments (eumelanins) toward the production of the more yellow pigments (pheomelanins). Patients are typically born with white hair and skin, but develop some moderate amounts of pigmentation with age. While doing so the hair goes through a typical “white tipped” phase. In the yellow variant (OCA1B) the hair may develop a yellow or light brown color with fair skin and moderate reductions in visual acuity. Nystagmus and iris transillumination are present but the macular hypoplasia and nystagmus are not as severe as seen in OCA1A.

Figure 15.19 Oculocutaneous Albinism Type TS (OCA TS)— Temperature Sensitive Temperature-sensitive OCA results from a specific temperature-sensitive tyrosinase mutation that renders the enzyme nonfunctional only in the areas where the temperature is elevated: The groin, scalp, and axillae. On the cooler chest and extremities, the enzyme is fully functional and the hair color is dark. As the eyes are placed within the head, they are subjected to warmer temperatures, resulting in ocular findings similar to OCA1A. Notice white axillary hair (left image) in contrast to darker forearm hair (right image).

Figure 15.20 Oculocutaneous Albinism Type 2 (OCA 2) Oculocutaneous albinism type 2 is secondary to an abnormality in the p gene located on chromosome 15q11. This gene appears to play a role in transport across the melanosome membrane. Previously these patients were labeled as “tyrosinase positive” because of the normal levels of tyrosine on incubated hair bulbs. But some tyrosinaserelated forms of OCA are phenotypically indistinguishable from OCA2. Infants with OCA2 may present in infancy with a similar appearance to OCA1A (Figure 15.17). However, they acquire greater amounts of pigment in early childhood, largely pheomelanins. Vision is less severely affected than with OCA1. There are a wide variety of OCA2 phenotypes, including “brown albinism” and albinism with ephelides.

Figure 15.21 Hermansky-Pudlak Syndrome Hermansky-Pudlak syndrome is a combination of oculocutaneous albinism of variable severity, bleeding diathesis, and, in some patients, accumulation of ceroidlike material. This disorder is an autosomal recessive trait and most prevalent in Puerto Rico and Switzerland. Multiple causative genes are known, all of which share in common a role in the formation and trafficking of intracellular vessels, which include melanosomes, lysosomes, and platelet-dense bodies. The pigmentary and ocular phenotype is very variable. The bleeding diatheses are secondary to decreased aggregation of platelets. The platelet aggregation defect manifests as easy bruising (seen here), epistaxis, and gingival bleeding. Accumulation of ceroid lipofuscin material in the lungs and gastrointestinal tract can be life threatening. In this family portrait, the two brothers in the

first row, center and right, are affected.

Figure 15.22 Chediak-Higashi Syndrome Like Hermansky-Pudlak syndrome (Fig. 15.21), ChediakHigashi is an autosomal recessive form of oculocutaneous albinism caused by mutations in one of several genes involved with intracellular vesicular manufacture and function, including melanosomes. In this disorder, it is the intracellular vesicles of white blood cells rather than

platelets that are affected and result in impaired neutrophil chemotaxis with a predisposition to infection. The hair has a characteristic metallic gray sheen and other features of mild oculocutaneous albinism are present. Other systemic manifestations include progressive peripheral neuropathy and a lymphohistiocytic proliferative phase. The clinical findings include white skin with a metallic sheen to the hair. The disorder may be fatal.

Figure 15.23 Ocular Albinism Ocular albinism is most often an X-linked recessive disorder linked to Xp22 (OA1, Nettleship-Falls type). Less commonly, an autosomal recessive form of ocular albinism may be caused by mutations in the tyrosinase or p genes (Fig. 15.20). Patients with OA1 may have darkly pigmented hair and skin or be well pigmented less so than their average family member. Skin biopsy may show macromelanosomes (right image, arrow, electron microscopy), reflecting the role the OA1 gene is felt to play in melanosome biology. The ocular manifestations tend to

be more variable.

Figure 15.24 Ocular Albinism Type 1 (OA1)—Carriers As OA1 is an X-linked recessive disorder, females are carriers. As a result of lyonization, they will have clones of cells in their eye and skin that will be expressing the OA1 gene copy that is mutated while others use the normal allele. This can be seen clinically either via iris transillumination, the presence of hypopigmented skin macules (left image, lesion surrounded by arrows), or the “mud splattered” fundus (right image) reflecting interspersed cell populations of different pigmentation. However, it is very rare that a manifesting heterozygote has a clinical reduction in vision, nystagmus, or macular hypoplasia.

Figure 15.25 Albinoidism Albinoidism describes a hypopigmented phenotype that is enough to cause a gross alteration in hair and skin color along with iris transillumination, but yet not enough to result in macular hypoplasia or significantly reduced vision. This patient has a well-developed fovea. Mild nystagmus may be present and sometimes the line of distinction between frank albinism and albinoidism may be difficult to discern. However, albinoidism is an autosomal dominant condition. Multichannel visual-evoked potential does not show an abnormal decussation of optic nerve fibers.

Figure 15.26 Piebaldism Piebaldism presents with ventral amelanotic patches and, in some patients, a white forelock. The forehead, eyebrows, chin, chest, abdomen, and extremities may be affected. Iris heterochromia has been associated with this condition. Piebaldism is an autosomal dominant disorder. Causative mutations in the cKIT proto-oncogene (4q11-q12) results in a failure of neural crest melanocyte precursors to properly migrate into the affected areas. (Photograph courtesy of Dr. Bernice Krafchik.)

Figure 15.27 Molluscum Contagiosum Molluscum contagiosum is a common DNA pox viral infection contracted by direct contact or via fomites. Characteristic discrete nodular lesions are approximately 2 to 4 mm and with a central umbilication and an underlying pearly white material that can be expressed but contains active virus. Giemsa stain reveals molluscum bodies (eosinophilic inclusion bodies on a basophilic cytoplasm). Lesions are common on the face, eyelids, neck, axillae, and thighs, often in linear streaks as a result of local spread through scratching. Lid margin involvement can lead to chronic ocular irritation due to virus shedding into the conjunctival sac. Patients can present with chronic follicular blepharoconjunctivitis and superficial punctate keratopathy. The virus can rarely directly involve the conjunctiva, causing molluscum lesions.

Figure 15.28 Granuloma Annulare Granuloma annulare is a benign annular lesion commonly seen in children. Initially the lesions consist of a small erythematous nodule on the surface of the skin. These lesions spread circumferentially to form an erythematous ring with a discolored center. They most commonly occur on the dorsal surface of the hands and feet but can involve the periorbita. Pathologic examination shows a classic granuloma with areas of central necrosis, deposition of mucin, and peripheral foreign body giant cells and histiocytes. Granuloma annulare can easily be differentiated from tinea corporis by its absence of scales. Spontaneous involution may occur after several months to years. Topical or subcutaneous corticosteroids may shorten the duration.

Figure 29 Juvenile Xanthogranulomatosis Juvenile xanthogranulomatosis is characterized by firm, domeshaped, orange lesions (A) that evolve from small macules and papules. Benign histiocytic infiltration characterized by lipidladen histiocytes, inflammatory cells, and Touton giant cells is seen microscopically. Lesions typically resolve over several years. Involvement of the heart, kidneys, skeletal system, gonads, and salivary glands is uncommon. Ocular manifestations include iris (B), ciliary body, or choroid (C) lesions. Patients may present with spontaneous hyphema under which is a small iris xanthogranuloma. Differential diagnosis must include retinoblastoma. Steroids can be used to reduce the inflammatory component and help reduce visionthreatening complications.

Figure 15.30 Linear Nevus Sebaceum (Nevus of Jadassohn) Linear nevus sebaceum usually occurs on the face and is associated with ocular malformations in approximately one half of cases including microphthalmia, choristomas, and coloboma of the lids and/or iris/choroid/optic nerve. The most common ocular abnormality is conjunctival choristoma. This skin lesion is also associated with seizures and mental retardation. It is perhaps a type subset of epidermal nevus syndrome. Patients may also have cardiac, renal, and skeletal abnormalities. The skin lesions are enlarged and very yellow at birth, as the infant's sebaceous glands are activated by maternal hormones. They then regress but often reactivate during puberty. Patients are at risk for benign and malignant tumors developing in the lesions. Treatment may involve observation or surgery.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 16 - Endocrine

16 Endocrine Alex V. Levin Thomas W. Wilson Robert Pashby The pituitary gland is responsible for regulating hormonal activity within the body. Abnormalities of the pituitary gland may lead to hormonal disruption with secondary effects in the eye. The close proximity of the pituitary to other midline brain structures and the optic chiasm may lead to combined endocrine and ophthalmic findings. An example is septo-optic dysplasia (De Morsier syndrome). Hormone-secreting tumors can also lead to ophthalmic pathology. Other organs in the endocrine system include the pancreas, adrenal glands, parathyroid glands, and thyroid gland. Disease in any of these structures may have a remote secondary effect on the eye by a variety of mechanisms. Knowledge of these complications will assist the primary care physician and endocrinologists in making appropriate referrals to the ophthalmologist both for screening and in response to ocular signs and symptoms.

Figure 16.1 Diabetes Mellitus— Cataract Although retinopathy is common in adults, diabetes rarely has ocular complications in the prepubertal years. This photograph shows multiple cortical opacities, similar to the pulverulent cataract (Chapter 7: Lens, Fig. 7.10). Cataract onset may range from infancy to adolescence, and a wide variety of morphology may be seen also, including posterior subcapsular, lamellar, and total cataract (Chapter 7: Lens). Cataract may present before, at, or after the diagnosis of diabetes. Although visual prognosis following surgery is generally good, there is some evidence to suggest that surgery may hasten the onset or progression of diabetic retinopathy.

Figure 16.2 Diabetes Mellitus— Papillopathy Diabetic papillopathy is an uncommon association with diabetes mellitus in children. Patients typically present with bilateral optic nerve edema and hyperemia with or without significant vision loss. The disc margins can be blurred with engorgement of the retinal arteries and veins. There is typically no optic cup. The cause of the disc changes may be ischemic and similar to anterior ischemic optic neuropathy (AION). Because of the collateral flow in children, permanent damage is not as severe as with AION in adults.

Figure 16.3 Thyroid Eye Disease—Lid Retraction Thyroid orbitopathy is uncommon in the pediatric population. Patients may present with restricted eye movements, proptosis, lagophthalmos, and, as shown here, lid retraction. This patient shows retraction of the upper and lower lids. The lid abnormalities may in part be due to infiltration of lid muscles as well as proptosis due to enlargement of the extraocular muscles (Fig. 16.5). The abnormal lid position with scleral show may contribute to corneal exposure and desiccation.

Figure 16.4 Thyroid Eye Disease—Strabismus Extraocular movements can be significantly limited in thyroid orbitopathy. Our youngest patient with active eye muscle disease was 2 years old. The most common muscle involved is the inferior rectus and, therefore, upgaze is often restricted. Children may present with strabismus in the primary position as shown here along with proptosis. This child also has no upgaze. Treatment of the hyperthyroidism may result in improvement of the eye movements. However, if strabismus persists following a period of observation of at least 6 months, strabismus surgery, using adjustable suture technique, may be indicated for large-angle and amblyogenic strabismus. Smaller deviations may be managed with prism glasses.

Figure 16.5 Thyroid Eye Disease This computed tomography scan illustrates proptosis secondary to extraocular muscle enlargement. The medial and lateral rectus muscles are infiltrated but the muscle tendons are spared, which differentiates this disorder from orbital myositis (Chapter 11: Orbit, Fig. 11.11). This gives the muscles a fusiform appearance. Compression of the optic nerve can cause a compressive optic neuropathy and permanent vision loss. Patients need to be followed routinely with color vision testing and computerized visual fields. Systemic steroids, external radiation, and orbital wall decompression may be necessary.

Figure 16.6 Multiple Endocrine Neoplasia (MEN) Increased visibility of corneal nerves in children may be due to MEN type 2b. This finding is not visually significant. The syndrome is characterized by medullary thyroid carcinoma, pheochromocytoma, benign tumors of the adrenal medulla, and parathyroid hyperplasia. This autosomal dominant cancer syndrome is caused by mutations in the RET protooncogene at 10q11.2. The benign mucosal neuromas are characteristic of MEN 2b but are not seen in MEN type 2a.

Figure 16.7 Pseudohypoparathyroidism Pseudohypoparathyroidism or Albright hereditary osteodystrophy is caused by an abnormal protein that binds parathyroid hormone to tissues. This results in high levels of circulating parathyroid hormone to which the body is insensitive, resulting in hyperphosphatemia and hypocalcemia. This autosomal dominant disorder has been linked to chromosome 20q13.2. Systemic findings include tetany, seizures, mental retardation, and short stature. Ocular abnormalities include a corneal keratopathy with subsequent vascularization and abnormalities of the lid margin due to meibomian gland dysfunction.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 17 - Gastrointestinal

17 Gastrointestinal Alex V. Levin Thomas W. Wilson Stephen P During development, neural crest migration to form the gastrointestinal tract and many of the ocular tissues occurs at similar times of gestation. As a result, some abnormalities of both systems may coexist. Yet, other coexisting abnormalities seem to have their basis in manifestations of a mutated gene that has a role in both locations that may be quite different and not embryologically based. Some gastrointestinal disorders also involve the eye as a complication of the primary problem, as seen with iron deposition in Wilson disease. Gastrointestinal disorders, such as Alagille syndrome, may be indications for eye examination both for diagnosis and for possible later complications. Some ocular findings, such as uveitis, should prompt the ophthalmologist to consider gastrointestinal manifestations that have yet to be recognized or diagnosed, such as inflammatory bowel disease.

Figure 17.1 Inflammatory Bowel Disease—Episcleritis Inflammatory bowel disease is a term encompassing ulcerative colitis, Crohn disease, and overlap patients. It is a chronic gastrointestinal disorder with potential ophthalmic manifestations both related to the disease and secondary to its treatment. Patients can develop diffuse (seen in this image) or nodular episcleritis, and there may be a correlation with gastrointestinal disease activity. There may be associated mild nongranulomatous iritis. The episcleritis often responds to systemic treatment of the gastrointestinal disease, but topical treatment is useful, particularly when patients have pain and uveitis.

Figure 17.2 Inflammatory Bowel Disease—Scleritis Nodular and posterior scleritis are uncommon findings of inflammatory bowel disease. Nodular scleritis is more common in Crohn disease than ulcerative colitis and more severe when there is also arthritis involving large peripheral joints. Posterior scleritis causes severe pain and potential vision loss from optic nerve or retinal edema. The retinal folds and peripapillary elevation seen in this photograph are secondary to the severe scleral inflammation and thickening, mimicking a posterior retrobulbar mass. The sclera is thickened on B-scan ultrasound.

Figure 17.3 Inflammatory Bowel Disease—Chorioretinitis The white patches and areas of pigmentation seen in this image are the result of chorioretinitis and subsequent retinal pigment epithelium hypertrophy, respectively. Macular involvement can reduce the visual acuity. Papillitis (Chapter 9: Optic Nerve, Fig. 9.27) and retinal vasculitis are other uncommon manifestations of inflammatory bowel disease. Retinal vasculitis and chorioretinitis can coexist. Systemic treatment of the gastrointestinal disease with consideration of sub-Tenon deposteroids is recommended for the fundus manifestations of inflammatory bowel disease.

Figure 17.4 Hirschsprung Disease Hirschsprung disease, or congenital megacolon, is a common cause of neonatal bowel obstruction in infants. The underlying cause is failure of embryonic neural crest migration into the muscular layers of the colon. Likewise, failure for the neural crest derived melanocytes of the iris to reach their target destination results in sector iris

heterochromia (Chapter 6, Iris and Pupils, Fig. 6.21). Patients present with failure to thrive and chronic constipation. This photograph shows a barium enema revealing the characteristic finding of severe dilation of the colon with areas of constriction. The areas of glomal innervation are dilated and the areas of constriction are aganglionic. The diagnosis can be confirmed with anorectal manometry, which shows an increased pressure in patients with congenital megacolon. Rectal biopsy reveals a lack of ganglion cells in the submucosal and intramuscular layers. Treatment is surgical and includes resection of the aganglionic colon with colostomy of the distal portion of the normally innervated colon.

Figure 17.5 Icterus Icterus is the result of high serum bilirubin levels and coincides with jaundice. Bilirubin, especially when

unconjugated, has a high affinity for elastin, which is concentrated in the episclera and conjunctiva. The common term scleral icterus is therefore a misnomer. High levels of bilirubin are the result of excessive production or decreased secretion and can cause brain damage. Elevated bilirubin is often seen in neonates, especially premature infants and newborns with hemolysis secondary to Rh incompatibility. Hepatitis or other bile duct abnormalities can also elevate serum bilirubin levels.

Figure 17.6 Wilson Disease—Kayser-Fleischer Ring Wilson disease, also known as hepatolenticular degeneration, is an autosomal recessive disorder of copper metabolism resulting in tissue deposition of copper. Levels of ceruloplasmin, the copper-transporting protein, are low. Unbound freely circulating copper is then deposited into numerous tissues including the liver, brain, kidneys, and cornea. Deposition of copper in the peripheral Descemet membrane forms a ring of golden brown or aqua-colored deposits called a Kayser-Fleischer ring. The deposits usually start superior-temporally and are most concentrated at the

12 and 6 o'clock positions. Recognition can be difficult in the presence of icterus (Fig. 17.5), and some recommend gonioscopy for diagnosis.

Figure 17.7 Wilson Disease— Sunflower Cataract Copper deposition may also occur in the lens capsule, leading to a “sunflower” pattern. This finding is usually visually insignificant and does not require surgery, but without treatment of the systemic disorder visual loss can occur. Treatment in Wilson disease is based on the need to remove excess copper through chelation and limit dietary intake and absorption of copper. (Note: The multiple white dots around the light reflex in this image are artifact.)

Figure 17.8 Alagille Syndrome— Retinopathy Alagille syndrome is an autosomal dominant disorder characterized by biliary atresia (intrahepatic cholestasis), cardiovascular abnormalities including moyamoya abnormality in the brain, mental retardation in approximately 15%, and butterfly-shaped vertebra. The characteristic facial features include a pointed chin, deep-set eyes, telecanthus, and a bulbous nose. Typical retinal pigmentary changes are seen in one third of patients, as demonstrated here in a child who is also myopic. They may even be present in infancy. Chorioretinal atrophy is seen later in the disease course.

Figure 17.9 Alagille Syndrome— Posterior Embryotoxon An anterior displaced Schwalbe line (white line at arrows), also known as posterior embryotoxon, is seen in over two thirds of patients with Alagille syndrome. However, it is also present in 10% of the normal population and in other disorders such as Axenfeld-Rieger syndrome (Chapter 6: Iris and Pupils, Fig. 6.15). Unlike Axenfeld-Rieger, posterior embryotoxon in Alagille syndrome is not associated with glaucoma. Gonioscopy may be helpful in identifying this malformation.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 18 - Hematology

18 Hematology Alex V. Levin Thomas W. Wilson David Smith Abnormalities in the hematologic system will often have associated ocular diseases or findings. All four major components of the blood (serum, red blood cells, white blood cells, and coagulation factors) have been implicated as the underlying cause of vision loss and eye disease. The maintenance of ocular health depends upon the hematologic system. Anemia and abnormalities of red blood cell function and morphology will lead to mild to severe ischemia within the eye. Mild ischemia will be manifested as cotton wool spots (ischemia of the nerve fiber layer), microaneurysms, and scattered hemorrhages throughout the retina. Severe ischemia will lead to neovascular proliferation and the potential for significant vision loss from extensive hemorrhage or tractional retinal detachment. Proliferation of the white blood cells in lymphoma and leukemia will have direct (invasion in ocular tissues) and indirect (increased risk of infection due to immunosuppression) effects on the visual system. White blood cell abnormalities have been reported in the

ataxia telangiectasia (telangiectatic conjunctival vessels, progressive ataxia, decreased IgA, and decreased T-cell–mediated immunity) and Chediak-Higashi (albinism and defective chemotaxis and degranulation of neutrophils) syndromes. Abnormalities of coagulation will often have associated conjunctival and retinal hemorrhages. The retinal hemorrhages of coagulopathies are typically few in number and located in the posterior pole. Disorders of blood serum including hyperviscosity can cause retinal venous disease.

Figure 18.1 Sickle Cell Anemia— Peripheral Retinal Vasculopathy Sickle cell anemia is a disease characterized by chronic hemolysis secondary to abnormal red blood cells. During deoxygenation, the sickle hemoglobin changes its configuration to form a filamentous structure that leaves the red blood cell rigid. There is an abnormal valine substitution in the sixth position of the β chain. Clinical manifestations

include acute painful crises secondary to vaso-occlusion. More severe crises can cause significant ischemic damage to the heart, liver, and kidneys. This photograph illustrates peripheral abnormal vasculature.

Figure 18.2 Sickle Cell Anemia— Neovascularization Sickle cell disease can lead to neovascularization of the disc, macula, and peripheral retina. Proliferation of new blood vessels in the peripheral retina is the most common location. Proliferative sickle retinopathy is classified into five stages: (a) peripheral arterial occlusion; (b) peripheral arteriolar– venular anastomoses; (c) neovascular proliferation; (d) vitreous hemorrhage; and (e) retinal detachment. In the third stage, the proliferation of new blood vessels in the periphery typically forms a C-fan configuration as seen here. Treatment of proliferative disease includes cryotherapy and laser photocoagulation.

Figure 18.3 Sickle Cell Anemia— Salmon Patch A salmon patch is a retinal hemorrhage located in the subhyaloid space or superficial retina. It is typically located in the midperiphery and becomes an orange-red color over several days. After the hemorrhage is absorbed, there may be a schisis cavity containing refractile bodies known as iridescent spots. These iridescent spots are actually macrophages filled with iron from the degrading hemoglobin.

Figure 18.4 Sickle Cell Anemia— Sunburst This photograph demonstrates the classic black sunburst seen in sickle cell retinopathy. The lesions are round or oval and can be as large as two disc diameters. They are dark, black, and located in the peripheral retina. They represent retinal pigment epithelium that has migrated through the Bruch membrane during a vaso-occlusive episode within the retina. Following the migration, the retinal pigment epithelium undergoes hyperplasia.

Figure 18.5 Sickle Cell Disease— Orbital Bone Infarction One of the cardinal clinical manifestations of sickle cell disease are the recurrent bony vaso-occlusive crises characterized chiefly by pain, often with overlying edema. Rarely, the orbital bones may be involved, resulting in painful periorbital and/or orbital swelling that may mimic periorbital or orbital cellulitis (Chapter 11: Orbit, Figs. 11.8 and 11.9). Proptosis may also be observed. However, in sickle cell disease the optic nerve is almost always spared and patients are rarely febrile.

Figure 18.6 Thalassemia Thalassemia is a group of hypochromic anemias secondary to abnormal production of globin chains. The two types of globin chains—α chain and β chain—are deficient in αthalassemia and β-thalassemia. One of the two globin chains is deficient in thalassemia minor, and both chains are absent in thalassemia major. Both α- and β-thalassemia lead to microcytic anemias, and the level of ocular disease is proportional to the severity of the anemia. Ischemia of the retina and optic nerve can lead to chronic optic neuropathy and retinal cotton wool spots. Subretinal, intraretinal, and preretinal hemorrhages are also associated with chronic anemia.

Figure 18.7 Leukemia—Retinal Hemorrhage Ocular manifestations can occur in both myelogenous and lymphocytic leukemia and are more common in the acute leukemias. Leukemia can cause abnormalities of the retina, choroid, optic nerve, and anterior segment. Retinal manifestations include cotton wool spots, retinal hemorrhages, venous stasis disease, and leukemic retinal infiltrates. Retinal hemorrhages can occur preretinally (boatshaped hemorrhages or well-circumscribed round hemorrhages), intraretinally (dot-blot hemorrhages), or subretinally (dark, well-circumscribed hemorrhages). Hemorrhages may have a white center due to leukemic infiltrates, fibrin, or ischemia.

Figure 18.8 Leukemia—Retinopathy Hyperviscosity due to the increased number of white blood cells in the serum causes microinfarcts within the nerve fiber layer and presents clinically as cotton wool spots. Other white lesions represent leukemic retinal infiltrates. These infiltrates cluster at smaller vessels, in particular in the far periphery where larger infiltrative masses may be found. Infiltrates are almost always accompanied by retinal hemorrhage.

Figure 18.9 Leukemia—Choroidal Invasion Choroidal involvement is a common ocular manifestation of leukemia. Histopathologic examination of the choroid will often reveal choroidal involvement that was not detected on fundus examination. Thickening of the choroid on B-scan ultrasound may be the only indicator. Leukemic infiltrates of the choroid can change the permeability of the retinal pigment epithelium and cause serous retinal detachment, as shown here.

Figure 18.10 Leukemia—Optic Nerve Infiltration In central nervous system leukemia, the optic nerve may become involved and when involved indicates a poor prognosis. Optic nerve infiltration leads to compression of the optic nerve and significant permanent visual loss. Optic nerve pallor and edema are clinical signs of optic nerve involvement. Serial examinations should be performed to assess the optic nerve function. Visual acuity, color vision, visual field, and pupillary examination are required with each visit. Progressive vision loss is an indication for aggressive treatment, including intrathecal chemotherapy and optic nerve radiation. Despite these therapies, progressive visual loss is common.

Figure 18.11 Leukemia—Anterior Chamber Involvement of the anterior segment is an uncommon manifestation of systemic leukemia; however, patients can present with diffuse infiltration of the iris. This can lead to iritis and hypopyon. Patients may also develop glaucoma secondary to direct infiltration of the trabecular meshwork or to debris obstructing the trabecular meshwork. Patients may present with heterochromia or hypopyon. A paracentesis should be considered in cases where the cause of the pseudohypopyon is not clear. Any patient with known leukemia and iritis should have a paracentesis and iris biopsy before steroid treatment.

Figure 18.12 Leukemia— Spontaneous Ecchymosis This photograph illustrates the coagulopathy often associated with leukemia due to infiltration of the bone marrow. This child may have been diagnosed incorrectly to have cellulitis or to have been abused. Orbital hemorrhage or leukemic infiltrate may also occur and present as acute proptosis.

Figure 18.13 Anemia Chronic anemia can be caused by increased red blood cell loss or decreased red cell production. Causes of decreased production include iron deficiency, folic acid deficiency, lead poisoning, bone marrow abnormalities, and thalassemia. Increased red blood cell loss can be secondary to autoimmune diseases and hemoglobinopathies. Ocular manifestations of anemia include ischemia of the nerve fiber layer causing cotton wool spots, shown here. Retinal hemorrhages occur only in severe anemia, especially when thrombocytopenia is also present. Usually they are few in number, intraretinal or preretinal, and confined to the posterior pole. Chronic anemia and deficiencies of vitamin B 12 and folic acid, which cause anemia, can lead to irreversible optic neuropathy.

Figure 18.14 Histiocytosis Histiocytosis is a group of disorders that include HandSchüller-Christian disease, eosinophilic granuloma, and Letterer-Siwe syndrome. These disorders have in common an antigen-processing disorder of Langerhans cells. Patients with histiocytosis will often have skeletal involvement, with the skull and face being most commonly affected. Patients may present with localized edema and pain. Lymphadenopathy and hepatosplenomegaly are common.

Figure 18.15 Histiocytosis Histiocytosis may involve the orbit, as demonstrated in this computed tomography scan. It is typically bilateral and leads to exophthalmia. Other involved organs include the lungs, the pituitary gland, and the liver. Biopsy shows Langerhans cells with Birbeck granules. Immunosuppressive therapy including prednisone, methotrexate, and cyclophosphamide has been shown to slow the progression of the disease.

Figure 18.16 Thrombocytopenia Clinically evident bleeding from thrombocytopenia is uncommon with levels above 30,000 platelets. When bleeding does occur, common manifestations include petechia, subconjunctival hemorrhage, epistaxis, or gum bleeding. Less commonly, and with more severe depression of the platelet levels, retinal hemorrhages, shown here, may occur. These tend to be intraretinal or preretinal, small in size and number, and confined to the posterior pole.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 19 - Infectious Diseases

19 Infectious Diseases Alex V. Levin Thomas W. Wilson Nasrin Najm-Tehrani Virtually every infectious disease may affect the eye either through direct infection, hematogenous spread, contiguous spread, or complications related to a primary infection at another site. This chapter focuses on ocular complications of systemic and remote infection. Diagnosis of the ocular manifestation might require culture from a site remote from the eye or, less commonly, sampling of intraocular fluids or tissues. Given the difficulty in obtaining intraocular tissues for culture, careful attention to remote sites for diagnostic culture or titers becomes essential. Suspicion of an infectious cause for an ocular abnormality might stem from the presence of systemic signs such as fever, shock, or other more localized indicators. The presence of infection in the cerebrospinal fluid or blood is particularly worrisome with regard to potential ocular involvement. Transplacental spread of infection to a fetus may present with multiorgan system involvement or even malformations. Taking a careful history is another powerful

diagnostic tool and should include queries regarding contacts and exposures, course of the illness, other systemic indicators of infection, treatment with antibiotics or other agents, contact with pets and other animals, travel, and, in the case of suspected fetal infection, pregnancy history. Diagnostic studies on family members (e.g., the mother in a case of suspected fetal infection) may be appropriate in some circumstances. Some ocular complications of systemic and remote infectious disease are treated by topical or intraocular agents, whereas others require systemic treatment. When diagnostic tissue culture is not obtainable, broad-spectrum antibiotic coverage may be appropriate. The American Academy of Pediatrics Red Book is a particularly useful reference for diagnosis and treatment guidelines.

Figure 19.1 Gradenigo Syndrome Aggressive bacterial otitis media can lead to involvement of the petrous bone and mastoid. Cranial nerve VI runs over the intracranial petrous bone on its way to the ipsilateral lateral rectus muscle. Inflammation in the intracranial space

can result in an abduction deficit, as shown in this child's right eye (Chapter 1: Strabismus, Fig. 1.51). Other diagnostic findings include otitis media, papilledema from increased intracranial pressure, signs of systemic illness (in particular pain, fever, and headache), and diagnostic inflammatory signs in the region of the petrous bone with or without mastoiditis on computed tomography scan or magnetic resonance imaging.

Figure 19.2 Necrotizing Fasciitis/ Flesh-eating Disease Necrotizing fasciitis is a cutaneous disease with aggressive destruction of the skin and underlying tissues. Skin injury almost always precedes the infection. Death can result within days. The infection is caused by anaerobic bacteria with or without aerobic bacteria or group A streptococcus (as shown in the photograph). Pain and fever are key signs, along with a characteristic feathery appearance to the

infected area with air on computed tomography or magnetic resonance imaging. Debridement and a variety of antibiotics have been the cornerstone of treatment. Hyperbaric oxygen therapy has also been used. Survivors usually require extensive reconstructive plastic surgery.

Figure 19.3 Toxoplasmosis Toxoplasmosis is an infectious disease caused by the protozoan Toxoplasma gondii. Humans acquire the infection from ingestion of oocysts contained within cat feces or undercooked meat. Congenital toxoplasmosis occurs following transplacental transmission of the protozoan and presents with the classic triad of chorioretinitis, hydrocephalus, and intracranial calcification. This photograph shows optic atrophy and a typical dense chorioretinal scar, typically located in the macula. Diagnosis of toxoplasmosis can be confirmed by serology tests.

Treatment modalities include pyrimethamine and sulfadiazine.

Figure 19.4 Congenital Rubella Clinical findings of congenital rubella include posterior cervical and retroauricular adenopathy, a rash on the soft palate and pharyngeal mucosa, growth and mental retardation, congenital heart defects (especially peripheral pulmonic stenosis), hearing loss, hepatosplenomegaly, intracranial calcification, and thrombocytopenic purpura. Ocular manifestations include cataracts, glaucoma, microphthalmia, and corneal endotheliitis. Active virus can be isolated from the lens for diagnosis. Retinal pigmentary disturbances include a “salt and pepper” mottling due to internal limiting membrane gliosis and retinal pigment epithelium hyperplasia. The vision tends to be normal with a normal electroretinogram, which differentiates this condition from other retinal dystrophies. Retinal blood vessels and the optic nerve may appear surprisingly healthy.

Figure 19.5 Herpes Simplex Herpes simplex virus type I (and less commonly type II) primary infection typically occurs within the first decade following contact with an adult with oral herpes and presents with aphthous stomatitis, dermatitis, or conjunctivitis. The herpes simplex virus becomes latent within the trigeminal ganglion. Factors that may cause recurrence include stress, ultraviolet radiation, menses, fever, and trauma. The skin lesions typically clear within 1 to 2 weeks without significant scarring, although they may become secondarily infected with bacteria and cause a preseptal cellulitis. Approximately 25% of patients with primary herpetic conjunctivitis will develop keratitis including superficial punctate keratitis, subepithelial infiltrates, and possibly dendrites. Patients with primary herpetic conjunctivitis should be treated with topical antiviral ointment or drops.

Figure 19.6 Corneal Herpes Recurrent herpes simplex is caused by latency of the herpes virus within the trigeminal ganglion. Clinical manifestations include vesicular lesions on the lids, conjunctivitis, epithelial keratitis (classically in the form of dendrites with terminal bulbs), stromal keratitis, sclerokeratitis, and endotheliitis. Blepharoconjunctivitis rarely occurs without corneal involvement. The dendrites will spontaneously heal over 1 to 2 weeks and may be associated with loss of corneal sensation. Severe infections can cause stromal scarring (shown here) and vascularization. Patients should be treated with antiviral medications, including trifluorothymidine drops nine times a day. Patients may also benefit from debridement of the corneal epithelium.

Figure 19.7 Varicella Zoster Herpes zoster ophthalmicus involves the ophthalmic branch of the trigeminal nerve and is secondary to reactivation of the varicella virus within the trigeminal ganglion. The reactivation is more common in the elderly population and in the immunocompromised host. Postherpetic neuralgia (severe pain and pruritus) can cause patients to excoriate themselves (right image). Other ocular complications of herpes zoster include uveitis, retinal vasculitis, acute retinal necrosis, cranial nerve palsies, and neuroretinitis. Treatment of zoster includes steroids to control the ocular inflammation as well as systemic antiviral medications, including acyclovir, which may also decrease the incidence of postherpetic neuralgia.

Figure 19.8 Varicella (Chickenpox) Varicella, or chickenpox, presents with a low-grade fever and fatigue, followed by a scarlatina-form rash and subsequently clear teardrop vesicles on an erythematous base. The contents of the vesicles become cloudy over several days and then break open and form crusting. The lesions typically start on the trunk and spread to the face, and can involve the eyelids and conjunctiva, usually at the limbus. Varicella keratitis presents as superficial punctate keratopathy with possible dendrites, which is similar to herpes simplex virus type I. Other ocular manifestations of varicella include interstitial keratitis, neurotrophic corneal ulcers, external ophthalmoplegia, cataract chorioretinitis, and optic neuritis. Intrauterine varicella infection can lead to retinochoroidal lesions (right image), cutaneous scars, and other malformations.

Figure 19.9 Cytomegalovirus (CMV)—Congenital Maculitis CMV retinitis will occur in a small percentage of patients with congenital CMV. The necrotic retinitis has a predilection for the macula. Patients may develop low-grade fever, headache, myalgia, and sore throat. In rare circumstances, especially in immunocompromised children, acquired CMV can cause meningitis and encephalitis, esophagitis, myocarditis, or interstitial pneumonia; CMV retinitis and potential vision loss may also develop. Patients with CMV retinitis should be treated with intravitreal ganciclovir or foscarnet. Both agents have been demonstrated to decrease the progression and complications of CMV retinitis.

Figure 19.10 Congenital Cytomegalovirus (CMV) Infants who are infected during gestation can have severe congenital abnormalities and possibly die. Patients who are immunocompromised, such as those with AIDS, can have significant retinitis. Congenital CMV is the most common intrauterine infection and affects approximately 1% of all newborns. Patients can present with mental retardation, seizures, hearing loss, and intracranial calcifications.

Figure 19.11 Acquired Cytomegalovirus (CMV) Retinitis Retinal CMV infection is largely confined to children with AIDS and other forms of immunodeficiency with significantly depressed T-cell counts. The frequency of CMV in pediatric AIDS is much lower than seen in adults. Routine serial screening is not required. Unlike congenital CMV (Fig. 19.10), this necrotic retinitis has a predilection for the periphery of the retina and progresses to involve the macula and optic nerve. The infection does respond well to systemic parenteral treatment, but maintenance is required to prevent recurrence unless immunocompetency is restored, for example, with bone marrow transplantation for severe combined immune deficiency syndrome.

Figure 19.12 Candida Candida albicans is a dimorphic yeast that is commonly found in the environment. Candida is not considered to be normal skin flora. However, it can colonize in the gastrointestinal tract or vagina in situations of increased temperature and humidity. Candidal infections may also involve the nails (left image), bloodstream, and ocular structures. The most common digit to be involved is the thumb, especially in children who suck their thumb. Candida albicans may also form a plaque-like material on the tongue and gums (oral thrush; right image). Ocular infection is rare in immunocompetent children.

Figure 19.13 Candida Lens Abscess A rare complication of Candida endophthalmitis is involvement of the lens or anterior chamber structures. This is most often seen in septic premature infants with a persistent tunica vasculosa lentis (Chapter 7: Lens, Fig. 7.2). Systemic treatment for Candida is the first line of treatment: Intravenous amphotericin B with or without flucytosine. Lens extraction can then be performed. In patients with large amounts of vitreous inflammation, a vitrectomy can be performed to confirm the diagnosis, followed by intravitreal amphotericin B.

Figure 19.14 Retinal Candida Endogenous candidal endophthalmitis is almost always associated with disseminated candidiasis with extensive tissue invasion in other organs, particularly the heart and kidney. Immunocompromised patients and patients with a contaminated indwelling catheter or endotracheal tube have the greatest risk of developing endophthalmitis. In coherent individuals, the symptoms include floaters and loss of vision. Clinical examination shows multiple discrete white fundi with an overlying vitreous reaction. These lesions usually respond well to intravenous agents.

Figure 19.15 Tuberculosis Tuberculosis is a disease caused by infection with Mycobacterium tuberculosis. Tuberculosis typically affects the lungs and is more common in immunocompromised patients. Clinical manifestations of tuberculosis primarily affect the respiratory system. Most patients with primary pulmonary tuberculosis are asymptomatic and are detected on tuberculin skin test or abnormal chest radiograph. Definitive diagnosis may require morning gastric lavage for acid fast stain and culture. Extrapulmonary tuberculosis can involve any organ system via hematogenous spread.

Figure 19.16 Tuberculosis Retinitis and Optic Nerve Infiltration The ocular manifestations of tuberculosis include uveitis and retinitis. This patient has retinal lesions. Patients may also present with vision loss secondary to infiltration of the optic nerve and optic nerve inflammation as shown here. Typically there is a focal lesion that does not have an overlying vitreitis or associated uveitis. Ocular manifestations of tuberculosis respond well to systemic treatment.

Figure 19.17 Tuberculosis Phlyctenule Worldwide, tuberculosis is the most common cause of phlyctenule. Usually presenting as a solitary white peripheral corneal lesion that may be raised and/or vascularized, (arrow) tuberculosis phlyctenule is an immunologic response to Mycobacterium. Histologically, the lesion is a collection of white blood cells. Treatment requires systemic antituberculosis therapy with topical measures for comfort and reduction of the often-present uveitis. This patient has a stromal scar at the site of her phlyctenule.

Figure 19.18 Pertussis Pertussis, or whooping cough, is caused by a Gram-negative coccobacillus Bordetella pertussis. Clinical manifestations include repetitive forceful coughing with a subsequent large inspiratory effort, which creates the whooping sound as the inhaled air travels through the narrowed pharynx. This photograph shows a patient with subconjunctival hemorrhage secondary to Valsalva. Increased venous pressure during the coughing episodes can cause rupture of subconjunctival capillaries and result in significant subconjunctival hemorrhage. Treatment is not indicated unless there is significant conjunctival exposure and dryness and would include artificial tears and lubrication.

Figure 19.19 Leprosy Leprosy is caused by infection with Mycobacterium leprae. The most commonly involved areas include the peripheral nervous system and skin. Ocular involvement is uncommon. This photograph shows a lesion of the right brow. This represents erythema nodosum leprosum, and consists of a tender nodule. This lesion will typically grow if not treated with appropriate systemic therapy. Treatment options include dapsone, rifampin, and clofazimine. Other ocular manifestations of leprosy include prominent corneal nerves, superficial punctate keratopathy, conjunctivitis, and uveitis.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 20 - Metabolic

20 Metabolic Alex V. Levin Thomas W. Wilson J. Raymond Buncic Diseases of metabolism are classified according to the type of substance accumulated or absent due to an error in enzyme production or function, including amino acids (cystinosis, homocystinuria, phenylketonuria, and tyrosinemia), organic acids (glutaric aciduria and alkaptonuria), cholesterol (Smith-LemliOpitz), sugars (diabetes mellitus, galactosemia, and carbohydratedeficient glycoprotein syndrome), lipids (abetalipoproteinemia, hyperlipoproteinemia, and lecithin acyltransferase deficiency), neural components (Fabry, galactosialidosis, mucopolysaccharidosis, mucolipidosis, and sphingolipidosis), peroxisomal (Zellweger, neonatal adrenoleukodystrophy, Refsum, and hyperoxaluria), and metals (Menkes and Wilson disease). Ocular abnormalities in the sphingolipidosis are caused by accumulation of products of metabolic degradation of cerebral tissue. A cherry red spot is seen in Tay-Sachs, Niemann-Pick, Sandhoff, Farber, metachromatic leukodystrophy, and GM1 gangliosidosis. Optic atrophy is a manifestation of metachromatic

leukodystrophy, Krabbe, Zellweger, and all mucopolysaccharidoses. Corneal abnormalities are common in Fabry (corneal verticillata) and corneal cloudiness in Lowe, metachromatic leukodystrophy, Zellweger, mucolipidoses, and mucopolysaccharidoses. Kayser-Fleischer rings can be located in the peripheral cornea of patients with the copper metabolism abnormality Wilson disease. Cataracts are common in diabetes mellitus, mannosidosis (spokewheel cataract), Lowe, Fabry (spoke-wheel cataract), and Niemann-Pick (brown anterior lens changes).

Figure 20.1 Cystinosis—Cornea Cystinosis is a group of metabolic disorders that results in excess cystine in the tissues throughout the body. Patients present with photophobia due to deposition of corneal crystals (left image). The crystals are deposited in the peripheral cornea and then progress centrally. Their highest concentration is in the anterior stroma. Patients can also have deposition of cysteine in other ocular tissues, and crystals have been observed in the anterior lens capsule, iris (right image), and retina. Oral cysteamine can decrease

extracellular levels of cysteine. Clinical trials are currently in progress to determine the effect of cysteamine applied topically to decrease the corneal crystals. Renal failure is the major cause of nonocular morbidity.

Figure 20.2 Cystinosis—Retina Pigment retinopathy is concentrated in the periphery and is characterized by pigment clumps and areas of atrophy. The macula may also be involved. Retinal crystals of cystinosis can be deposited with the layers of the retina. Cystinosis can lead to retinal dysfunction as demonstrated on electroretinogram and dark adaptation. Progressive vision loss is common. Systemic manifestations include renal failure from a deposition of cystine. Patients will often present with dehydration because of the decreased reabsorption of water. The deposition of cystine within body tissue confirms the diagnosis of cystinosis. Treatment of

renal failure requires transplantation.

Figure 20.3 Homocystinuria Homocystinuria involves the abnormal metabolism of sulfurcontaining amino acids. The most common enzyme deficiency is cystathionine β-synthase. Homocystinuria is inherited as an autosomal recessive trait and has been linked to chromosome 21. Patients will have increased levels of homocysteine and methionine. Ocular features include ectopia lentis and retinal detachment. Patients with homocystinuria are at increased risk of developing thromboembolic events and vascular occlusions. Patients often have skeletal changes similar to Marfan syndrome (arachnodactyly, scoliosis, and increased limb length [Marfanoid habitus]) but also often have mental retardation of learning delays not seen in Marfan syndrome. Treatment includes supplemental pyridoxine and cystine and a methionine-free diet.

Figure 20.4 Galactosemia Galactosemia is a group of metabolic disorders with defects in galactose metabolism. Different enzyme deficiencies will lead to specific clinical features. Newborns with galactose-1phosphate uridylyl transferase deficiency will commonly present as a newborn with jaundice, difficulty feeding, irritability, and hepatomegaly. Permanent damage to the brain and liver are inevitable without an early diagnosis. Classic cataract of galactosemia is an oil droplet located in the nucleus. Other causes of galactosemia include galactokinase deficiency. Diagnosis of galactosemia is demonstrated by increased levels of reducing substance in the urine. Treatment includes avoiding milk products and foods containing galactose.

Figure 20.5 Mucopolysaccharidosis Mucopolysaccharidosis type 1H, or Hurler syndrome, is a disorder of abnormal degradation and storage of glycosaminoglycans. The enzyme deficiency of Hurler syndrome is α-L-iduronidase with accumulation of dermatan and heparin sulfate within body tissues. Clinical features include the characteristic of facies (left image). The head is enlarged with frontal bossing. The nasal bridge is depressed and the nose is wide and flat. There is also deposition in the subcutaneous tissues resulting in thickening and decreased flexibility (right image).

Figure 20.6 Mucopolysaccharidosis—Cornea Ocular manifestations include cloudy corneas, retinal pigment degeneration, and optic atrophy. Adverse systemic features include hepatosplenomegaly, mental retardation, and cardiac abnormalities. Umbilical and inguinal hernias are more common than in the normal population. Mucopolysaccharidosis type 1S, or Scheie syndrome, is secondary to accumulation of dermatan sulfate within the body tissues. The clinical manifestations are milder than in Hurler syndrome and include a normal level of intelligence with similar facial appearance.

Figure 20.7 Mucopolysaccharidosis— Hunter Syndrome Mucopolysaccharidosis type 2, or Hunter syndrome, is secondary to a deficiency of iduronate sulfatase. Clinical manifestations include coarse facial features, joint stiffness, and dwarfism. Patients develop severe mental retardation and a progressive decline of their mentation. Ophthalmic features include retinal and optic nerve degeneration. The corneas are typically clear. Hunter syndrome is inherited as an X-linked recessive disorder with the gene location at Xq28.

Figure 20.8 Mucopolysaccharidosis—Maroteaux-Lamy Disease Maroteaux-Lamy disease, or type 6 mucopolysaccharidosis, is a systemic disease with similar features to Hurler disease. Patients have coarse facies and short stature. Contractures of the hands (as shown here) and knees are common. Patients have an increased risk of umbilical and inguinal hernias. There is an increased risk of cardiac valve abnormalities, including mitral insufficiency and aortic regurgitation. Ocular manifestations include mild cloudy cornea and optic atrophy. Patients typically have a normal level of intelligence. Patients have increased levels of tissue dermatan sulphate. The enzyme deficiency is Nacetylgalactosamine-4-sulphatase.

Figure 20.9 Niemann-Pick Disease Niemann-Pick disease is a deficiency of sphingomyelinase and has increased accumulations of sphingomyelin. It is inherited as an autosomal recessive trait and is more common in Ashkenazi Jews. Patients present with hepatosplenomegaly and infiltration of the lungs with sphingomyelin. Bone marrow biopsy demonstrates foam cells. Several subtypes have been described with different times of onset and severity of disease. Type A Niemann-Pick disease has a continued deterioration of mental status and physical development, with death by age 3. Ophthalmic features include corneal opacities and a brownish hue to the anterior lens capsule. A cherry red spot in the macula secondary to accumulation of sphingomyelin within the nerve fiber layer is common. There can be a cystoid halo around the fovea.

Figure 20.10 Gaucher Disease Gaucher disease is a type of sphingolipidosis secondary to a deficiency of the enzyme glucocerebroside with accumulations of glucosyl ceramide. It is most commonly found in the Eastern European Jewish population and is inherited as an autosomal recessive trait. Clinical features include hepatosplenomegaly and pancytopenia secondary to Gaucher cells in the bone marrow. The skin has a yellowishbrown tint. Ophthalmic manifestations include accumulations of Gaucher cells, which are seen as white patches in the retina and choroid. Macular changes may lead to a lesion similar to a cherry red spot (Fig. 20.15) but often less striking and more grey. There is a web-shaped area of thickening of the limbal conjunctiva, which probably represents a pinguecula.

Figure 20.11 Infantile Refsum Disease Infantile Refsum disease is secondary to abnormal peroxisomes. Clinical features include increased phytanic acid levels. Patients have dysmorphic features, mental retardation, and associated hearing loss. Patients with infantile Refsum have a retinal pigmentary degeneration.

Figure 20.12 Lowe Syndrome Lowe oculocerebrorenal syndrome is a metabolic defect inherited as an X-linked recessive trait. Patients present with hypotonia, decreased tendon reflexes, and mental retardation. Patients progress to renal tubular acidosis and secondary renal failure with rickets and proteinuria. Carriers of Lowe syndrome can have punctate lenticular opacities within the cortex.

Figure 20.13 Lowe Syndrome—Cataract Lowe oculocerebrorenal syndrome has several associated ocular manifestations. This is one of a few disorders that have the combination of congenital cataract and congenital glaucoma. This rare combination is also caused by rubella syndrome. The anterior lens capsule is thicker than normal and the posterior capsule is thinner than normal. Opacities of different sizes and morphology have been reported. Other findings of Lowe oculocerebrorenal syndrome include corneal keloids and pupillary abnormalities. The female carriers of this X-linked recessive disorder may demonstrate a characteristic pattern of radiating lens opacities (right image).

Figure 20.14 Tyrosinemia Type 2 (Richner-Hanhart syndrome) There are several disorders of tyrosine metabolism, of which Richner-Hanhart syndrome is of ophthalmic significance. In this autosomal recessive disorder, deficiency of hepatic tyrosine aminotransferase leads to elevated blood tyrosine. The classic clinical triad consists of pseudodendritic keratitis, shown here, sometimes painful hyperkeratosis of the palms and soles, and developmental delay. Ocular symptoms may be seen as early as 3 months old. Unlike herpes, the corneal findings are bilateral. Cataract has been observed infrequently. Conjunctival biopsy with staining for tyrosine crystals can be diagnostic.

Figure 20.15 Tay-Sachs Disease (GM2 Gangliosidosis Type 1)—Cherry Red Spot Tay-Sachs disease is due to a deficiency of the enzyme hexosaminidase A. This autosomal recessive neurodegenerative disorder usually results in death before 4 years of age. The classic cherry red spot shown here is due to GM2 ganglioside lipid-laden ganglion cells. As there are no ganglion cell bodies in the fovea, no opacity results and the underlying retinal pigmented epithelium and reddish choroid are visible. Other metabolic causes of a cherry red spot include GM1 gangliosidosis, Niemann-Pick disease, metachromatic leukodystrophy, Farber disease, Sandhoff disease (GM2 gangliosidosis type 2), Gaucher disease, and others.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 21 - Neurologic

21 Neurologic Alex V. Levin Thomas W. Wilson J. Raymond Buncic During embryogenesis, the brain and many ocular structures are derived from neuroectoderm. Therefore, many structural abnormalities of the brain will be associated with ocular anomalies. Optic nerve hypoplasia is associated with anterior pituitary abnormalities, agenesis of the corpus callosum, absence of the septum pellucidum, and schizencephaly. Morning glory disc can be associated with basal encephalocele, and tilted disc syndrome can be associated with suprasellar tumors. Nystagmus and abnormalities of extraocular eye movements are commonly external signs of neurologic abnormalities. Infants with constant exotropia will often have developmental delay. Specific nystagmus patterns can help localize structural pathology (downbeat nystagmus—Arnold Chiari malformation). Myasthenia gravis, multiple sclerosis, mitochondrial diseases, and storage disease will often present with ocular/visual abnormalities prior to systemic symptoms.

Increased intracranial pressure from brain tumors or pseudotumor cerebri can present as vision loss and examination of the optic disc reveals papilledema. Headaches are a common reason for referral to an ophthalmologist. The cause of headache is rarely secondary to strabismus or refractive error. However, careful neuro-ophthalmic examination, including evaluation of the visual acuity, visual fields, color vision, pupils, and extraocular movement as well as visualization of the optic disc, is required to exclude any underlying pathology.

Figure 21.1 Schizencephaly Schizencephaly is an abnormality of brain cell migration during embryogenesis. Normal cell migration is dependent upon a radial glial fiber system that orients the neuronal tissue into its proper anatomic location. Schizencephaly represents abnormal clefting within the cerebral hemispheres. These defect(s) may be unilateral or bilateral, fused or unfused, large or small. Porencephaly refers to

enclosed cysts within the cerebral tissue. Associated clinical findings with schizencephaly include severe mental retardation and associated seizures, which are often unresponsive to conventional treatment.

Figure 21.2 Holoprosencephaly Holoprosencephaly is an abnormality of development of the midline structures of the brain and face. Clinical features of holoprosencephaly include agenesis of the premaxilla, cleft upper lip (left image), hypotelorism, mental retardation, microcephaly, and oligodontia. A mild form of the disease will present as hypotelorism and mild changes of the midface. A severe form of holoprosencephaly with cyclopia is incompatible with life (right image). Multiple genetic and chromosomal abnormalities have been identified in holoprosencephaly. Surgical reconstruction of the face, including cleft palate repair, are indicated for severe defects.

Figure 21.3 Arnold-Chiari Malformation Arnold-Chiari malformation is characterized by extension of the brainstem and cerebellar tissue into the cervical canal (right image). The inferior part of the fourth ventricle may also be displaced downward. It is commonly associated with spina bifida and myelomeningocele (Arnold-Chiari type II). Patients typically present with signs of increased intracranial pressure, including headache and visual loss. Patients may also demonstrate downbeat or seesaw nystagmus, ataxia, multiple cranial neuropathies, and quadriparesis. Stretching of the trigeminal nerve can cause corneal anesthesia with painless scarring of the cornea (left image). Posterior fossa decompression and/or shunting may be required.

Figure 21.4 Aicardi Syndrome Aicardi syndrome is an X-linked dominantly inherited disorder that is lethal in males and involves the brain and eye. Infant girls present with infantile spasms and seizures and have significant developmental delay and mental retardation. This computed tomography scan of the brain shows a sagittal midline view, demonstrating absence of the corpus callosum. The brain shows a variety of anatomic abnormalities including schizencephaly, cysts, hemispheric asymmetry, and migration abnormalities (pachygyria and microgyria). The corpus callosum is formed from the commissural plate, and insults to this embryologic tissue cause agenesis.

Figure 21.5 Aicardi Syndrome—Ocular Findings Characteristic ocular findings of Aicardi syndrome include well-circumscribed lacunae in the retina. Histopathologically, these lesions represent defects in the chorioretina, including the retinal pigment epithelium, to variable depths. Patients may also have optic disc colobomas or other less specific optic disc anomalies. The retinal lacunae are multiple and are concentrated about the optic disc. These lesions are classic for Aicardi syndrome. Patients may also have abnormalities of the vertebrae. The disease is lethal in males. A careful family history, including a history of multiple miscarriages during pregnancy, should be obtained in cases where Aicardi syndrome is suspected.

Figure 21.6 Acquired Myasthenia Gravis Myasthenia gravis is an autoimmune disorder characterized by abnormal transmission at the neuromuscular junction. Infants born to myasthenic mothers will often have a transient abnormality of neuromuscular transmission. Patients with ocular manifestations of myasthenia gravis may have associated systemic findings, including difficulty swallowing, facial weakness, and difficulty breathing. Ocular manifestations include a variable strabismus that is worse in the evening and ptosis with fatigue. Other associated systemic diseases include thyroiditis and thymoma. The diagnosis is confirmed by serologic demonstration of antiacetylcholine receptor antibodies, single muscle fiber electromyography, Tensilon testing, and the ice test. Treatment includes the anticholinesterase agent pyridostigmine bromide (Mestinon), systemic steroids, and thymectomy. Patients with ocular myasthenia will often respond better to systemic steroids than neostigmine.

Figure 21.7 Mitochondrial Abnormalities—Stroke Findings in a Nonvascular Pattern Mitochondrial abnormalities with ocular involvement include chronic progressive external ophthalmoplegia (Fig. 21.8 and Chapter 1: Strabismus, Fig. 1.72), MELAS syndrome (myopathy, encephalopathy, lactic acidosis, and stroke), MERRF syndrome (myoclonus, epilepsy, and ragged red fibers), and Leber hereditary optic neuropathy (Chapter 9: Optic Nerve, Fig. 9.35). Patients with MELAS syndrome present with seizures, significant development delay, hemiparesis, short stature, and elevated serum lactate levels. Ragged red fibers are demonstrated on muscle biopsy, which are indicative of abnormalities in electron transport within the mitochondria. Patients have a progressive decline and no treatment is yet effective for this disease. MERRF is another progressive mitochondrial disorder presenting after several years with myoclonic seizures, ataxia, and nystagmus.

Figure 21.8 Mitochondrial Abnormalities—Retinopathy Chronic progressive ophthalmoplegia may be associated with atypical retinitis pigmentosa and complete heart block in Kearns-Sayre syndrome and is caused by deletions in mitochondrial DNA. Fundus examination shows mottling of the retinal pigment epithelium with or without peripheral bone spicules. This patient has no eye movements and almost complete ptosis. Electroretinogram findings are typically normal or minimally reduced early and then later decline. The complete heart block associated with KearnsSayre can lead to sudden death and often requires a pacemaker. Patients with significant strabismus may improve their binocular function with eye muscle surgery. Coenzyme Q10 may improve the cardiac dysfunction but has minimal effect on chronic progressive ophthalmoplegia, retinopathy, ptosis, and orbicularis weakness.

Figure 21.9 Craniopharyngioma Craniopharyngioma is the most common supratentorial brain tumor in children. Craniopharyngiomas arise from remnants of the Rathke pouch and are located with the sella turcica. The mass may extend outside the sella to compress on the chiasm, third ventricle, and pons, causing hydrocephalus, growth abnormalities, and bilateral temporal hemianopia. Craniopharyngiomas contain multiple cystic areas and may contain typical calcifications, which can be visualized on computed tomography scan imaging. Treatment includes resection, radiation, and endocrine management.

Figure 21.10 Neuroblastoma Neuroblastoma is the most common solid tumor in children, is derived from neural crest cells within the sympathetic chain, and can be found in the adrenal glands (most common), mediastinum (paravertebral ganglia), cervical sympathetic chain, and pelvis. The oncogene N-myc will normally suppress tumor growth. Visceral neuroblastoma will often present with opsoclonus (rapid uncontrollable saccadic movements). Neuroblastoma is the most common cause of acquired Horner syndrome (ptosis, miosis, and anhydrosis) in children. Patients may also have heterochromia (lighter color) if the neuroblastoma presents in the first year of life. Localized tumor of the orbit and periorbital region can be secondary to metastasis of neuroblastoma from a distal site, usually to the bones of the lateral orbital wall (right image). Patients have a characteristic periorbital ecchymosis (“raccoon eyes”). Urine should be tested for catecholamines, vanillylmandelic acid, and homovanillylmandelic acid. Treatment for neuroblastoma includes complete surgical resection and chemotherapy. Radiation therapy has also been used to reduce the size of tumors.

Figure 21.11 Multiple Sclerosis Multiple sclerosis is an inflammatory condition with demyelination of white matter. The neurologic abnormalities are separated in time and location and vision loss is commonly the presenting symptom. Clinical evaluation may reveal profound decrease in color perception, visual field defects, afferent pupillary defect, and decrease in visual acuity as well as ocular motor problems. The optic nerve may appear swollen (papillitis, Chapter 9: Optic Nerve, Fig. 9.27) or normal. The vision loss is typically sudden and slightly progressive with improvement over weeks to months. Pain with eye movement is a common feature of optic neuritis secondary to multiple sclerosis. Multiple sclerosis may also cause internuclear ophthalmoplegia (INO), skew deviation, and, less commonly, retinitis, retinal vasculitis, anterior uveitis, and pars planitis. Magnetic resonance imaging reveals characteristic bright spots of demyelination in periventricular distribution typically. Treatment should be according to the optic neuritis treatment trial (IV steroids followed by an oral taper).

Figure 21.12 Batten Disease Batten disease is a group of disorders with abnormal neuronal storage of lipofuscin. Patients may present with delayed development, seizures, ataxia, or visual loss. The diagnosis can be confirmed in suspected cases with increased levels of urine dolichol and curvilinear bodies (inclusions within the cytoplasm of neurons) located within lymphocytes or conjunctival biopsy. Batten disease is inherited as an autosomal recessive trait and a deletion in the CLN3 gene has been mapped to chromosome 16p in cases with juvenile onset. Patients can often present with deteriorating night vision and clinical signs of retinitis pigmentosa (retinal arterial narrowing, optic atrophy, and pigment disturbances within the fundus). The electroretinogram is significantly reduced in most patients and no specific treatment is available at this time.

Figure 21.13 Facial Nerve Palsy Isolated facial nerve palsy in children is rare. Patients will present with inability to completely close the eyelids. Differential diagnoses includes myasthenia gravis, Bell palsy, trauma, brainstem tumors, demyelination, ischemia, mastoiditis, postviral, and Moebius syndrome. In managing patients with facial nerve palsy, it is important to assess their Bell phenomenon (reflexive supraduction with stimulation of the corneal nerves) and corneal sensation. Patients with decreased Bell phenomenon and corneal anesthesia are at increased risk of exposure keratopathy. Lubrication and sometimes tarsorrhaphy are the mainstays of treatment.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 22 - Vitamins

22 Vitamins Alex V. Levin Thomas W. Wilson Elise Héon Vitamins, minerals, and metals are critical for the maintenance of ocular health and are required for the visual process. Many imbalances of these substances can lead to significant vision loss from ocular surface disease, cataract, retinal dysfunction, and optic neuropathies. Vitamin deficiencies can be the result of a decreased intake (starvation, alcoholism, and poor diet) or decreased absorption (cystic fibrosis and inflammatory bowel diseases). Decreased vitamins can also be secondary to abetalipoprotein- emia. Hypervitaminosis can be secondary to consumption of foods high in vitamins (increased vitamin A from ingestion of polar bear liver) or supplemental oral intake. Increased levels of vitamin A have been associated with pseudotumor cerebri and loss of vision secondary to increased intracranial pressure. Decreased levels of vitamin D have been shown to cause corneal band keratopathy. Poor nutrition is a common cause of vision loss in the third-world countries. Low levels of vitamin B12 and folate can cause

significant dysfunction of the optic nerve with irreversible loss of color vision, central vision, and visual field. Vision loss can also occur from low levels of vitamin A. Vitamin A is critical for the functioning of rods and cone photoreceptors. Supplemental vitamin intake has been recommended for several ocular diseases. For example, supplemental vitamin E, an antioxidant, is commonly administered to premature infants to theoretically decrease free radical oxygen. The effects of vitamin E on retinopathy of prematurity (ROP) have been studied, and the results do not significantly show a harmful or beneficial effect of vitamin E on the severity or progression of ROP.

Figure 22.1 Vitamin A Deficiency—Xerophthalmia Vitamin A is necessary for growth and proper functioning of epithelium and mucous membranes throughout the body. Deficiency leads to squamous metaplasia, keratinization of mucous-secreting epithelium, thinning of hair, and dry, scaling skin. Ocular changes resulting from vitamin A deficiency are termed xerophthalmia and reflect a conjunctival goblet cell deficiency with potential secondary inflammatory response. Devitalized epithelium will stain with

rose Bengal (right image). The World Health Organization's recommendation for the prevention of xerophthalmia in children less than 12 months of age is 100,000 IU vitamin A every 4 to 6 months and for children more than 12 months of age is 200,000 IU vitamin A every 4 to 6 months. In the developed world this is usually achieved through daily dietary intake without supplementation. (The authors are grateful for the contributions of Dr. Christopher Cessna to this legend.)

Figure 22.2 Vitamin A Deficiency Other signs of hypovitaminosis A include retinal disease, night blindness, decreased rod function mimicking retinitis pigmentosa, and Bitot spots. The latter are keratinized plaques (left image) on the conjunctiva that have a white foamy appearance and tend to be temporal and bilateral. Keratomalacia or melting of the cornea is the most severe form of vitamin A deficiency and is associated with high morbidity/mortality. Fundus specks may be seen in patients with severe vitamin A deficiency. However, the pathophysiology of these lesions is not well understood.

Retinal wrinkling of the paramacular area is shown in the right image. Vitamin A deficiency can also exacerbate the ocular and systemic side effects of measles.

Figure 22.3 Vitamin K Deficiency There are three forms of vitamin K deficiency in children: Early onset, occurring in the first 24 hours of life; classic onset, occurring 1 to 7 days after birth; and late onset, occurring at 2 to 6 weeks old. Patients exhibit coagulopathy due to deficiency of vitamin K–dependent factors II, VII, IX, and X. Early onset is usually due to maternal ingestion of phenobarbital, phenytoin, antituberculosis medications, or anticoagulants. The common classic form is more common in breastfed babies, particularly if they did not receive neonatal supplementation orally or by injection. The late form is more often seen in babies with gastrointestinal malabsorption and/or liver disease, as in this child, who presented in coma due to intracranial bleeding (right image). The classic form of vitamin K deficiency usually presents with gastrointestinal bleeding, intracranial bleeding, large areas of ecchymosis, and umbilical stump

hemorrhaging. Retinal hemorrhages are mild and concentrated in the posterior pole (left image). Differential diagnoses would include normal birth and shaken baby syndrome (Chapter 12: Child Abuse). Administration of vitamin K will treat the underlying coagulopathy and confirm the diagnosis.

Figure 22.4 Vitamin B2 Deficiency Vitamin B2 , also known as riboflavin, is present in milk and many vegetables and meats. It is involved with the structure and function of many enzymes, particularly those involved with oxidation reduction. Manifestations of riboflavin deficiency include angular stomatitis and inflammation of the nasal and oral mucosal membranes (left image). Ocular surface disease can be quite symptomatic if not visually threatening (right image, corneal ulcer).

Figure 22.5 Vitamin C Deficiency Vitamin C, or ascorbic acid, is required in the production of collagen. Deficiency of vitamin C leads to the clinical manifestation known as scurvy. Patients present with irritability, poor appetite, hair loss, petechia due to capillary fragility, gum bleeding, limb tenderness, and pain with movement. Radiographs of the long bones are often diagnostic. Hemorrhaging can occur in the conjunctiva, eyelids, and, less commonly, the orbit and retina. The retinal hemorrhages are few in number and typically confined to the posterior pole. Serum vitamin C levels are an inaccurate reflection of true stores. Lymphocyte assays are

required.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 23 - Phakomatoses

23 Phakomatoses Alex V. Levin Thomas W. Wilson Agnes Wong The phakomatoses are a group of diseases that have cutaneous, central nervous system, and ocular manifestations. They often present with dermatologic and ocular manifestations, which subsequently lead to diagnosis of the underlying brain involvement. Significant vision loss can occur due to involvement of either the central nervous system or the eyes, or both. At least three of the major phakomatoses—neurofibromatosis, tuberous sclerosis, and von Hippel-Lindau—share a common genetic basis: Mutation of a tumor suppressor gene leads to local cellular proliferations in the forms of tumor or skin changes. These three disorders are autosomal dominant in inheritance and demonstrate variable expression, though penetrance approaches 100%. As a result, the detection of affected family members may require extensive investigations, including neuroimaging and abdominal ultrasound. When counseling for autosomal dominant disorders, one must remember that even though each child of an affected parent carries a 50% risk of being affected, the severity

of the disease may be very different between the parent and the child. Ataxia telangiectasia is the only autosomal recessive phakomatosis. Some of the phakomatoses, such as Sturge-Weber syndrome, appear to be sporadic with only very rare reports of familial occurrence. This suggests a somatic (postzygotic) mutation resulting in localized affectation of the field of tissues that are the descendants of the mutated cell. Such disorders would only be heritable if the somatic change also affects the patient's sperm or eggs. As the manifestations of these disorders are largely confined to the head and neck, gonadal involvement is uncommon.

Figure 23.1 Tuberous Sclerosis—Shagreen Patch Tuberous sclerosis is an autosomal dominant phakomatosis caused by mutations in one of two genes: TSC1 at 9q34 or TSC2 at 16p13. The former produces the protein hamartin and the latter tuberin, both of which appear to have a role in

cellular vesicular trafficking. Type 1 tuberous sclerosis has a lower incidence of mental retardation. There are no differences, however, in the ocular or dermatologic manifestations. Shagreen patches, shown here, are rough, raised lesions most commonly found in the lumbosacral region. They sometimes have an orange hue, but they may be more easily detectable by palpation than by inspection.

Figure 23.2 Tuberous Sclerosis—Adenomatous Sebaceum Adenoma sebacea are not true adenomas and are not of sebaceous origin. They are actually angiofibromas. The reddish lesions are distributed in a butterfly distribution on the face extending from the malar region across the bridge of the nose. They may be confused with the common cystic acne, particularly since the lesions can become more prominent during adolescence. This skin manifestation is rarely seen in the first decade of life.

Figure 23.3 Tuberous Sclerosis—Subungual/ Periungual Fibroma Subungual/periungual fibromas are fibromatous growths under or around the nails, usually in the region of the cuticle. Despite their size, they are often asymptomatic but may require surgical intervention. They are rarely observed in the first decade of life and enlarge with age.

Figure 23.4 Tuberous Sclerosis—Ash Leaf Spot Ash leaf spots are hypopigmented lesions of the skin that often have edges and a shape reminiscent of an ash tree leaf. They are sometimes difficult to detect, especially in children with fair skin. However, they can be easily visualized with a Wood ultraviolet light. One must be careful to ensure that a false-positive Wood lamp test is not being caused by debris and other substances, which will also illuminate. The melanosomes in the region of the lesion are abnormally small and contain less melanin than the surrounding skin. The number of melanocytes is normal.

Figure 23.5 Tuberous Sclerosis—Cortical Lesions Central nervous system manifestations of tuberous sclerosis include seizures, mental retardation, astrocytic hamartomas of the brain (cortical tubers, shown here), and subependymal calcifications. Seizures are typically myoclonic spasms that present in infancy and occur in many patients with tuberous sclerosis. As shown in these images, the benign astrocytic hamartomas often appear as calcified lesions and are most commonly located in the periventricular area. Neurosurgical intervention is rarely needed and visual field defects from the tubers are also uncommon.

Figure 23.6 Tuberous Sclerosis— Retinal Astrocytic Hamartoma Retinal astrocytic hamartomas are one of the cardinal signs of the disorder. The sessile lesions are located in the nerve fiber layer and, as shown here in an infant, typically begin as noncalcified lesions. Note that the lesion is almost translucent, and in some cases, it may be difficult to recognize as it may only start as a faint gray superficial patch. The lesions have a predilection for the posterior pole but can occur anywhere in the retina. They are benign and usually of no visual consequence.

Figure 23.7 Tuberous Sclerosis— Retinal Astrocytic Hamartoma As the lesion matures, it becomes more opaque and eventually calcifies. In all phases, the differential diagnosis must include retinoblastoma (Chapter 8: Retina and Vitreous, Figs. 8.42, 8.43, 8.44, 8.45, 8.46, 8.47, 8.48, 8.49, 8.50, 8.51, 8.52 and 8.53). It can be differentiated from retinoblastoma based on its smooth surface, the absence of associated vascular abnormalities, exophytic growth, or vitreous seeding; and the presence of other systemic manifestations. Eyes have unfortunately been enucleated due to an incorrect suspicion of retinoblastoma.

Figure 23.8 Tuberous Sclerosis—Optic Nerve Hamartoma Astrocytic hamartomas of tuberous sclerosis also have a predilection to involve the optic nerve head. The risk of leakage resulting in an exudative retinal detachment or hemorrhage, but still quite low. This photograph shows the remaining calcified mass following retinal laser to eliminate the exudative tumor. The lesions initially appear to have a multilobulated surface with intralesional calcium that may also be confused with retinoblastoma. The nickname “mulberry lesion” is sometimes applied.

Figure 23.9 Tuberous Sclerosis—Retinal Pigmentary Lesion Areas of depigmentation may occur in the retinal periphery or midperiphery. The discrete lesion represents an area of decreased melanosome size and decreased melanin concentration similar to ash leaf spots (Fig. 23.4) of the skin. The lesion involves the retinal pigmented epithelium. It is benign, may be multiple, usually does not have an ash leaf mulberry appearance, and does not involve the overlying sensory retina. These lesions are visually insignificant. They are not diagnostic of tuberous sclerosis, as small hypopigmented lesions can be due to a variety of causes and may even be seen in normal children.

Figure 23.10 Tuberous Sclerosis—Renal Cyst

Other systemic findings of tuberous sclerosis include renal cysts or renal angiomyolipoma, cardiac rhabdomyoma, and other cysts or tumors of bone, liver, pancreas, and lung. Dental findings include pitting of the teeth and gum fibromas. Additional central nervous system manifestations include behavioral disorders, mental retardation, and even psychiatric manifestations. Complete screening of parents to search for low expression in a carrier who may not be aware that he or she is affected should include abdominal ultrasound, dilated retinal examination, dental examination, neuroimaging and dermatologic assessment, including Wood lamp.

Figure 23.11 Ataxia Telangiectasia Ataxia telangiectasia is an autosomal recessive phakomatosis. The ocular findings include conjunctival telangiectasias, concentrated in the canthal region, as shown

here. Ocular motor apraxia is the cardinal eye movement feature but there is also an increased incidence of strabismus and nystagmus. The fundus is normal. Telangiectatic vessels also occur on the face, antecubital fossa, and popliteal fossa. The ataxia is secondary to a progressive cerebellar degeneration and dysarthria is common. The causative gene, ATM at 11q22-23, is involved in DNA repair. Patients often have immune dysfunction and suffer from recurrent infections and lymphoproliferative disorders.

Figure 23.12 Von Hippel-Lindau Disease Von Hippel-Lindau is an autosomal dominant disorder caused by mutation in the VHL gene at 3p25-26. Retinal angioma, shown here, and cerebellar hemangioblastomas are the two major components. The retinal angioma is classically a small

ovoid lesion with a single feeder vessel and a single draining vessel. Leakage from the retinal lesions can result in significant vision loss. Laser photocoagulation, cryotherapy, and surgical removal are treatment options depending on the size and location. The disorder is subcategorized as VHL1 (no pheochromocytoma), VHL2A (low risk for renal and pancreatic cancer), VHL2B (multitissue involvement), and 2C (pheochromocytoma only), all of which are allelic.

Figure 23.13 Sturge-Weber Syndrome—Port Wine Mark This characteristic vascular abnormality of the subcutaneous tissues usually involves the trigeminal distribution and is seen in almost all cases of Sturge-Weber syndrome. The lesion typically presents at birth as a flat red mark (left image) but with age (right image) becomes thickened and purple in color. Early laser treatment helps to prevent this outcome. Evidence suggests that lack of vascular tone from the trigeminal nerve leads to the disease. The incidence of glaucoma is greatly increased if the upper lid is involved, although glaucoma can develop in the absence of upper lid involvement.

Figure 23.14 Sturge-Weber Syndrome—Leptomeningeal Angiomatosis Central nervous system findings of Sturge-Weber syndrome include prominent vessels of the meninges, shown here in this contrast-enhanced computed tomography scan. These lesions are typically present in the temporal and, as shown here, occipital lobes. Intracranial calcifications involving the cerebral blood vessels and gray matter can form a doubleline, termed “railroad track,” sign. Vascular abnormalities can be associated with focal deficits, including visual field

deficits or seizures. The increased vascularization of the blood–brain barrier also makes these children more susceptible to the sedating effects of topical brimonidine use in the treatment of glaucoma.

Figure 23.15 Sturge-Weber Syndrome—Cerebral Atrophy Significant brain atrophy may occur in the region of the leptomeningeal angiomatosis. Patients with this manifestation commonly have associated mental retardation and seizures. Visual field defects may be associated as well as significant contralateral motor abnormalities. SturgeWeber syndrome is usually a unilateral disorder, with involvement of the brain, skin, and eye on the same side. The disorder is bilateral in 10% of cases. Patients with bilateral disease are usually more severely affected with severe retardation, extensive port wine mark, and bilateral

glaucoma.

Figure 23.16 Sturge-Weber Syndrome—Choroidal Hemangioma This patient has a diffuse choroidal hemangioma of the right eye (left image), the most common ocular finding in Sturge-Weber syndrome, which is present in 40% of patients. The hemangioma is always ipsilateral to the port wine mark. The involved fundus has a more reddish color with loss of visible choroidal vasculature markings when compared to the noninvolved eye (right image) and has been described as having a “tomato ketchup appearance.” More localized hemangioma may also occur. Occasionally, overlying retinal vascular tortuosity may occur. Leakage or serous retinal detachment is very uncommon. Therefore, prophylactic treatment is usually not necessary.

Figure 23.17 Sturge-Weber Syndrome—Congenital Glaucoma Glaucoma is present in more than half of patients with Sturge-Weber syndrome and is ipsilateral to the port wine mark. Congenital or infantile glaucoma, indistinguishable from primary infantile glaucoma with typical angle appearance (Chapter 10: Glaucoma, Fig. 10.1), is the earliest form of glaucoma seen in Sturge-Weber. This child has glaucoma in his right eye and presents with corneal haze due to edema, increased corneal diameter, and enlargement of the optic cup. Goniotomy and trabeculotomy are first-line treatments. The contralateral eye is only at risk if a port wine mark is also present on that side, as seen here.

Figure 23.18 Sturge-Weber Syndrome—Prominent Episcleral Vessels Patches of dilated episcleral vessels (left image) are frequently observed on the side of the cutaneous lesion. They represent telangiectatic vessels similar to the dilated subcutaneous vessels. The extensive honeycomblike network is often not apparent until the Tenon fascia is retracted at surgery. Between the ages of approximately 4 and 13 years, hypertrophy of these vessels, although not apparent to the observer, results in an increased episcleral venous pressure and impaired outflow from the anterior chamber with secondary glaucoma. On gonioscopy, blood may be seen in the Schlemm canal (right image, arrows).

Figure 23.19 Sturge-Weber Syndrome—Optic Nerve Cupping Glaucomatous changes of the optic cup secondary to SturgeWeber–related glaucoma are demonstrated in the left image. However, this patient also has a diffuse choroidal hemangioma (Figure 23.16). The presence of diffuse choroidal hemangioma, even in the absence of glaucoma, will also enlarge the optic cup, perhaps by posterior displacement of the lamina cribrosa due to heaping of the hemangioma in the peripapillary region, as demonstrated by this three-dimensional ultrasound (right image). One must therefore be careful about overdiagnosis of glaucoma on the basis of optic nerve cupping in a child with choroidal hemangioma.

Figure 23.20 Neurofibromatosis I Neurofibromatosis type I is an autosomal dominant phakomatosis caused by mutations in the NF1 gene at 17q11.2, the product of which is the protein neurofibromin. The disease is diagnosed when a patient meets at least two of seven criteria: (a) six or more café au lait spots (>0.5 cm in greatest diameter if prepubertal, >1.5 cm if postpubertal); (b) axillary/inguinal freckling (shown here); (c) two or more neurofibromas of any type, or one plexiform neurofibroma; (d) sphenoid bone dysplasia or thinning of long-bone cortex, with or without pseudoarthrosis; (e) optic nerve glioma; (f) two or more Lisch nodules; and (g) a firstdegree relative with neurofibromatosis I. This patient met the first two criteria. Subcutaneous neuromas are often more prominent in adulthood, as shown here.

Figure 23.21 Neurofibromatosis I—Subconjunctival Neuroma Although much more commonly subcutaneous, neurofibromas can also occur within the subconjunctival space in association with neurofibromatosis. The lesions are typically elevated and represent a collection of peripheral nerve structures including axons, Schwann cells, and fibroblasts. Patients with neurofibromatosis have an increased incidence of other neural tumors and malignancies, including schwannoma. Nonneural tumors, including Wilms tumor, pheochromocytoma, rhabdomyosarcoma, melanoma, and leukemia, also occur with a higher incidence than in a normal population.

Figure 23.22 Neurofibromatosis I—Pseudoarthrosis Pseudoarthrosis in this child's right leg represents pathologic fracture with poor healing and subsequent deformity. This is the most common peripheral skeletal abnormality, which is one of the diagnostic criteria. Other skeletal abnormalities include sphenoid wing dysplasia (Fig. 23.23), scoliosis, and hemivertebra.

Figure 23.23 Neurofibromatosis I—Sphenoid Wing Dysplasia One of the bony manifestations of neurofibromatosis I is dysplasia or absence of the sphenoid wing in the orbit. Note the downward displacement of this patient's left eye and what appears to be ptosis. These findings are due to contact between the intracranial space and the superior orbit. The patient may also demonstrate pulsating proptosis. Computed tomography scan with three-dimensional reconstruction illustrates the defect in the sphenoid bone. The dissolution of the sphenoid is progressive and begins with bony dysplasia. These patients tend to have an orbital form of neurofibromatosis with severe ocular involvement including glaucoma, ipsilateral plexiform neurofibroma, and poor visual prognosis.

Figure 23.24 Neurofibromatosis—Plexiform Neurofibroma Plexiform neurofibromas of the upper eyelid are often described as “a bag of worms” on palpation. Involvement of the eyelid causes ptosis with an S-shaped contour to the eyelid margin. The image on the left shows the earliest phases of this lesion in the patients left upper lid before lid margin changes. On the right, a larger lesion is shown. Severe distortion of the face due to cutaneous hypertrophy and progressive growth of the lesion can occur. Surgical repair is difficult and may result in accelerated growth of the tumor. There is a high risk for amblyopia, restrictive strabismus, and glaucoma.

Figure 23.25 Neurofibromatosis I—Lisch Nodules Small, avascular, yellow-brown hamartomas can be present on the iris. These Lisch nodules are diagnostic of neurofibromatosis and rarely occur in any other condition. In patients with known neurofibromatosis type I, approximately 40% of patients will have Lisch nodules by 4 years of age, 60% by 6 years, and 90% by 9 years. The absence of Lisch nodules after puberty indicates a less than 2% chance of the patient being affected.

Figure 23.26 Neurofibromatosis I—Lisch Nodules On a brown iris, Lisch nodules usually appear tan. Lisch nodules can be distinguished from other lesions of the iris (Chapter 6: Iris and Pupils) in that they are raised, usually have discreet borders, are scattered in distribution, are asymmetric between the two eyes, and have a different pigment from the background iris. Iris nevi usually have a chocolate brown pigmentation, no elevation, and indistinct borders. Lisch nodules are benign and have no visual consequence.

Figure 23.27 Neurofibromatosis I—Amelanotic Lisch Nodules Rarely, in light-colored eyes, the Lisch nodules can have little or no pigment and have a gray appearance. A group of barely pigmented Lisch nodules can be seen in front of the arrow. Other variants of Lisch nodules (not shown here) include stellate, buried, and clumped patterns. Instead of the typical round domelike appearance, there may be fingerlike extensions into or onto surrounding iris tissues. Regardless of the appearance, vision is unaffected by Lisch nodules.

Figure 23.28 Neurofibromatosis I—Optic Nerve Glioma Optic nerve gliomas are seen in 12% to 15% of patients with neurofibromatosis I. Although frequently asymptomatic and undetectable on clinical examination, they may also present with ipsilateral decreased vision, monocular nystagmus, afferent pupillary defect, visual field changes, color vision defects, proptosis, strabismus, or an abnormal appearance to the optic nerve (Chapter 9: Optic Nerve, Fig. 9.36). These benign tumors grow slowly, but malignant transformation can rarely occur.

Figure 23.29 Neurofibromatosis I— Visual Pathway Glioma Optic nerve glioma may also occur in the absence of the systemic disorder. It is usually asymptomatic even when the optic nerve is grossly enlarged, as seen in the left image. The glioma can extend posterior to involve the chiasm, as shown in the right image where the hyperintense glioma has a “butterfly configuration,” resulting in bilateral visual loss and even hydrocephalus. Rarely, acute growth can occur. Patients with normal neuroimaging by the age of 6 to 7 years old rarely develop a new glioma. Treatment includes chemotherapy and surgical removal. Tumor resection can cause significant visual loss.

Figure 23.30 Neurofibromatosis I—Brain Central nervous system manifestations of neurofibromatosis I include benign brain tumors and developmental delay. The left photograph demonstrates hamartomas of the brain, particularly in the frontal region. Malignant transformation can occur. Other associated tumors include glioma, meningiomas, astrocytomas, and neurofibromas. Small tumors may involve isolated nerves such as cranial nerve IV, resulting in superior oblique palsy (left eye, right image). There is some evidence that developmental delay in neurofibromatosis I results from contiguous gene deletion involving the neighboring JJAZ1 gene in some patients. There remains controversy regarding the need for routine neuroimaging in asymptomatic patients with neurofibromatosis I.

Figure 23.31 Neurofibromatosis I—Retinal Hamartoma This patient has an extensive peripapillary retinal hamartoma. As the macula is spared, the visual prognosis is good. Other retinal tumors in neurofibromatosis I include combined hamartomas of the retinal pigment epithelium, retinal pigment epithelial abnormalities (hyper- or hypopigmentation), and, less commonly, hemangioma or melanoma. With the exception of optic nerve glioma (Chapter 9: Optic Nerve, Fig. 9.36), most patients with neurofibromatosis I have a normal fundus.

Figure 23.32 Neurofibromatosis I—Choroidal Nevi Although not common and not a diagnostic criterion, multiple choroidal nevi are seen in neurofibromatosis I and a few other conditions. The lesions are benign, and malignant transformation has not been reported. The nevi have a predilection for the posterior pole. Nevi are more common in adulthood. This patient also has a coincidental peripapillary crescent temporally (Chapter 9: Optic Nerve, Fig. 9.19), which is unrelated to neurofibromatosis.

Figure 23.33 Neurofibromatosis I—Corneal Nerves Prominent corneal nerves occur in approximately 25% of patients with neurofibromatosis I. The differential diagnosis is discussed elsewhere (Chapter 5: Cornea, Fig. 5.7), but multiple endocrine neoplasia (MEN) type IIB must be considered in patients with café au lait spots and prominent corneal nerves because of the association with medullary carcinoma of the thyroid. The prominent corneal nerves are not visually significant and are not correlated with other ocular manifestations of neurofibromatosis.

Figure 23.34 Segmental Neurofibromatosis Segmental neurofibromatosis is an uncommon variation with findings limited to one dermatome. The lesions do not cross the midline and associated findings elsewhere in the body are less common. Lisch nodules of the iris have been rarely reported. Brain involvement is also less common.

Figure 23.35 Neurofibromatosis Type II Neurofibromatosis type II is due to mutations in the NF2 gene at 22q12.2, which manufactures the protein merlin/schwannomin. It is also an autosomal dominant phakomatosis. Its major manifestation is acoustic neuroma. Lisch nodules have rarely been reported. Posterior subcapsular cataracts (left image) are common in neurofibromatosis II and may occur as early as the first or second decade. Surgery may be required. Other ocular manifestations include epiretinal membrane formation, as seen in the peripapillary region here (right image).

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 24 - Psychiatric

24 Psychiatric Alex V. Levin Thomas W. Wilson Psychiatric illnesses and ophthalmic disorders can be associated in three different patterns: (a) psychiatric diseases causing ophthalmic disease; (b) ophthalmic diseases causing emotional stress and related mental health issues; and (c) ophthalmic conditions with strong associations with psychiatric diseases. Trichotillomania (compulsive eyebrow and eyelash pulling), ocular manifestations of Münchhausen syndrome (self-inflected injuries) or Münchhausen syndrome by proxy (factitious disorder by proxy), and functional visual disorders are examples of ocular manifestations of mental health disorders. Functional visual disorders include blinking, vision loss, eyelid pulling, and photophobia. Functional disorders may be signs of significant stress in the home including covert physical, emotional, or sexual abuse. Malingering and functional hysteria may also present with ophthalmic symptoms. Patients with visual loss and a completely normal examination can also have other organic ophthalmic diseases including Stargardt disease, autosomal dominant optic atrophy, optic neuritis, and retinal degenerative disorders. In

addition, patients with psychiatric illnesses tend to be less compliant with treatment. Significant emotional stress can occur with patching therapy, visual impairment, and cosmetically significant strabismus, ptosis, or globe disfigurement. These emotional factors can lead to the potential for mental health symptoms, and it is important for the pediatric ophthalmologist to recognize and minimize these risk factors. Several ophthalmic disorders have an associated psychiatric illness. Alagille syndrome (Chapter 17: Gastrointestinal) and Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) are examples.

Figure 24.1 Trichotillomania Trichotillomania is a condition characterized by compulsive eyebrow and/or eyelash pulling, which is secondary to

emotional stress. As shown here, slit-lamp examination reveals that the bases of the lashes are still present. The lid margin may also be swollen and erythematous. Often, the lash pulling goes completely unobserved by family members or friends. Other causes of absence of the eyelashes and eyebrows include alopecia universalis, progeria, ichthyosis, and ectodermal dysplasia. Patients with trichotillomania should be referred for a psychologic evaluation. Treatment includes glasses to block the eyelash pulling, gloves, or ophthalmic lubrication ointment to make eyelash and eyebrow pulling more difficult. Identifying potential triggers along with behavior modification is the cornerstone of treatment.

Figure 24.2 Münchhausen Syndrome Münchhausen syndrome is a psychiatric disorder when patients have self-inflicted bodily injury in order to receive

the attention of medical care. Examples of self-inflicted injuries include repeated abscesses secondary to autoinoculation, digit amputation, scars from self-inflicted lacerations or burns, chronic diarrhea, and bleeding abnormalities. These patients will often have a history of emotional and/or physical abuse. The goal of the treatment is to address their underlying emotional and psychiatric disorders. This patient colored her lids red, presumably with cosmetics, to create the appearance of inflammation.

Figure 24.3 Factitious Esotropia Factitious esotropia is an uncommon presentation for children seeking attention or expressing a physical manifestation of underlying stress. Most children seeking glasses will complain of blurred vision, headaches, double vision, and colored lines/spots. By stimulating the near triad of accommodation, convergence, and miosis, children can maintain the esotropia for short periods of time. The pupils are relatively constricted and the distance vision blurred secondary to activation of accommodation and induced myopia. Both eyes converge symmetrically. Children with

factitious esotropia cannot maintain this position long enough to induce amblyopia or medial rectus contracture. Patients should be referred for evaluation and counseling if the behavior persists.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 25 - Pulmonary

25 Pulmonary Alex V. Levin Thomas W. Wilson Stephen Kraft Few pulmonary disorders have ophthalmic manifestations. In addition to sarcoidosis, the focus of this chapter, patients with asthma may have signs of atopy, including allergic or vernal conjunctivitis (Chapter 4: Conjunctiva, Figs. 4.10 and 4.11) or cataract. As the sympathetic chain travels over the apex of the lung before innervating the intraocular and periocular structures, tumors or inflammatory processes at the lung apex can result in ipsilateral Horner syndrome (Chapter 6: Iris and Pupils, Fig. 6.22). Cystic fibrosis is associated with ocular surface abnormalities and, without enzyme replacement, vitamin A deficiency (Chapter 22: Vitamins, Figs. 22.1 and 22.2). Other systemic diseases may have pulmonary and ocular manifestations (e.g., Marfan syndrome, tuberculosis). Pulmonary disease may result in systemic abnormalities that have ocular signs. Severe hypoxia from any pulmonary disorder can rarely result in retinal vascular change and, occasionally, a small number of intraretinal hemorrhages in the posterior pole. Lastly,

although outside the scope of this book, the treatment of pulmonary disorders may have ocular complications such as those seen after lung transplantation with immunomodulators.

Figure 25.1 Sarcoidosis—Rash Sarcoidosis is a systemic granulomatous disease affecting the skin, lung, thoracic lymph nodes, and eye. Unlike adults, children more often present with peripheral extensor surface rash (shown here), fatigue, and respiratory symptoms. Laboratory data supporting the clinical diagnosis include an elevated serum angiotensin-converting enzyme level, elevated serum calcium level, positive skin biopsy demonstrating a noncaseating granuloma, or chest radiograph with hilar adenopathy. This nonpruritic, nonerythematous rash may easily escape detection by physical examination and history as caretakers may incorrectly attribute the area to “dry skin.” The small papules are initially a yellowish-orange color and subsequently turn a reddish-brown color.

Figure 25.2 Sarcoidosis—Granulomatous Uveitis Ocular findings of sarcoidosis include anterior uveitis and posterior inflammation, including retinal phlebitis, vitreitis, retinitis, and optic nerve disease. The left photograph illustrates typical granulomatous or “mutton-fat” keratoprecipitates. The large white iris nodule located in the angle in the right image (arrow) represents a Busacca nodule: A local granuloma. Similar but smaller lesions can be found at the pupil border and are named Koeppe nodules. Glaucoma, cataract, and posterior synechia are often associated with sarcoidosis uveitis. As systemic steroids are often used to treat sarcoidosis, even in the absence of uveitis, periodic ophthalmic follow-up is required to detect complications of treatment, which also include glaucoma and cataract.

Figure 25.3 Sarcoidosis The vitreitis associated with sarcoidosis in children can be aggressive and visually threatening. Vitrectomy may be useful but peripheral traction is difficult to relieve. This patient also suffered a macular hole (not pictured). Epiretinal membranes are also seen (left image). Traction and rhegmatogenous retinal detachment may occur. The right image shows involvement of the optic nerve, which can also lead to visual loss. If the optic nerve involvement is asymmetric, there may be an afferent pupillary defect in the eye that is more affected. Notice the vitreitis overlying the optic nerve.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 26 - Renal

26 Renal Alex V. Levin Thomas W. Wilson Andrew Budning Many diseases have both ocular and renal abnormalities. Metabolic disorders including cystinosis (Chapter 20: Metabolic, Figs. 20.1 and 20.2) and Fabry disease %(Chapter XX:, Figure XX.X) result in accumulation of intracellular materials within the eye and kidney tissue. Diabetes mellitus (Chapter 16: Endocrine, Figs. 16. 1 and 16.2) commonly causes damage to the peripheral blood vessels and results in retinopathy, nephropathy, and neuropathy. Hypertension also targets the eyes and kidneys. Renal and perirenal tumors are associated with specific eye diseases. The phakomatoses (Chapter 23: Phakomatoses) have an association with ocular abnormalities and renal tumors, including renal cysts (tuberous sclerosis), pheochromocytoma (neurofibromatosis type I), and renal cell carcinoma (von HippelLindau). There is also a strong association between sporadic aniridia and Wilms tumor. Pigmentary retinopathy has been associated with other systemic syndromes including Senior-Loken syndrome (nephronophthisis

and retinitis pigmentosa [Chapter 8: Retina and Vitreous]), Bardet-Biedl syndrome, and Cockayne syndrome (Chapter 29: Syndromes). The oculocerebrorenal syndrome of Lowe has the combination of ocular and renal tubular abnormalities (Chapter 20: Metabolic, Fig. 20.12). Cryptophthalmus in Fraser syndrome will often have an associated renal hypoplasia (Chapter 2: Lids and Adnexa, Fig. 2.1).

Figure 26.1 Alport Syndrome— Anterior Lenticonus Alport syndrome is due to abnormal collagen type 4. It may be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive disorder depending on which of the three collagen strands in the collagen fibril triple helix is affected. Renal manifestations include hemorrhagic nephritis leading to hematuria, which is the most common presenting sign. Anterior lenticonus, as shown here, is a forward bowing out of the lens centrally with or without lens opacity. This is caused by abnormal type 4 collagen within the lens capsule. The collagen weakness within the anterior

lens capsule allows the cortical material to become displaced anteriorly, which forms the characteristic anterior lenticonus with or without subcapsular opacification.

Figure 26.2 Alport Syndrome—Retina The fundus will often contain white flecks or larger white coalescent opacities at the level of the retinal pigment epithelium. They are concentrated within the macula and midperiphery, but typically spare the central fovea. The retinal function remains normal and the vision and electroretinogram are typically normal. Retinal blood vessels are not attenuated and there is no disc pallor, as seen in the retinal degenerations.

Figure 26.3 Renal-Coloboma Syndrome Renal-coloboma syndrome (also known as papillorenal syndrome) is due to mutation in the pax2 gene. This developmental homeobox gene is responsible for ensuring development of an optic stalk on each side of the anterior neuropore (neural tube). The optic nerve malformation is not a classic optic nerve coloboma, but rather often appears as an enlarged optic nerve head with surrounding peripapillary atrophy and possibly an enlarged cup. A wide variety of renal abnormalities may be seen.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 27 - Rheumatology

27 Rheumatology Alex V. Levin Thomas W. Wilson David Rootman Rheumatologic diseases include the collagen vascular disorder, systemic vasculitides, and other related disorders. These diseases often have an immunologic pathophysiology. Arthritis may or may not be a key feature. The most commonly involved ocular tissue in rheumatologic diseases is the uvea: the iris, ciliary body, and choroid. Manifestations include any combination of anterior uveitis, posterior uveitis, vitreitis, paras planitis (intermediate uveitis), papillitis, or panuveitis. Complications from chronic uveitis include glaucoma, cataract, band keratopathy, and cystoid macular edema. Significant visual loss and amblyopia are common in undertreated patients and those with chronic ocular involvement. Treatments of systemic rheumatoid diseases will often have toxic effects on the ocular tissues. Systemic steroids may cause posterior subcapsular cataracts and steroid-induced glaucoma. Hydroxychloroquine may cause retinal toxicity with long-term use. The ophthalmologist plays several roles in the care of children

with rheumatologic disease. Some disorders, such as juvenile idiopathic arthritis, require periodic screening to detect the first signs of ocular involvement. Other patients with chronic rheumatologic disease will present to their rheumatologist or pediatrician with an ocular complaint that prompts referral to the ophthalmologist. Lastly, the ophthalmologist may make a diagnosis of an ocular manifestation of an underlying rheumatologic disorder that has not yet been diagnosed. The classic example is the onset of iritis prior to the development of the joint manifestations of juvenile idiopathic arthritis, a sequence that occurs in approximately 10% of affected patients. Collaboration between the pediatrician or rheumatologist and the ophthalmologist is essential for the management of ocular manifestations of rheumatologic disease. In addition to the diagnostic collaboration, the nonophthalmologist is often the key physician in the management of systemic medications such as prednisone, methotrexate, antitumor necrosis factor agents, or other immunosuppressants. Likewise, the ophthalmologist often provides the screening that is required to ensure that patients do not develop systemic side effects of these medications.

Figure 27.1 Juvenile Idiopathic Arthritis—Papillitis Juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis or juvenile chronic arthritis) is the most common rheumatologic disease of childhood and the most common identifiable cause of iritis. The iritis is usually granulomatous and the response to steroids may be variable. The iritis may be a single acute event, recurrent, or chronic. Pauciarticular and polyarticular forms occur with some patients starting as the former and evolving into the latter. At younger ages, antinuclear antibody–positive, rheumatoid factor–negative, pauciarticular girls are more commonly affected. There is no correlation between severity or activity of the joint and eye disease. Although an uncommon manifestation, this photograph shows papillitis with hyperemia and swelling of the optic nerve, which portends a poor visual outcome.

Figure 27.2 Juvenile Idiopathic Arthritis—Granulomatous Uveitis Approximately 20% of patients with juvenile rheumatoid arthritis will develop anterior uveitis. The severity of uveitis can range from mild anterior chamber reaction to severe chronic uveitis. Granulomatous uveitis with “mutton fat” keratoprecipitates is an uncommon presentation. Even hypopyon may rarely be seen as well as vitritis, pars planitis (Fig. 27.17), or panuveitis. Initial treatment would include high-dose topical prednisolone and a mydriatic agent. Following the resolution of the uveitis, the steroids should be tapered slowly over several weeks or months as tolerated. Adjunct interventions may be required including sub-Tenon depot steroid injections, methotrexate, antitissue necrosis factor agents, or, less commonly, immunosuppressive agents such as

cyclosporine or azathioprine.

Figure 27.3 Juvenile Idiopathic Arthritis—Serous Retinal Detachment The serious retinal detachment in this photograph is an uncommon manifestation of juvenile rheumatoid arthritis. It is usually confined to those cases with severe chronic uveitis and often optic nerve involvement as well. There is often an overlying vitritis. With aggressive treatment of the uveitis and vitritis, the detachment may settle although the visual prognosis is very guarded, particularly if cystoid macular edema has occurred.

Figure 27.4 Juvenile Idiopathic Arthritis—Vitritis Decreased vision in juvenile rheumatoid arthritis can be secondary to amblyopia, cataract, vitreitis, band keratopathy, cystoid macular edema, and glaucoma. This photograph shows significant vitreous involvement (arrow), an uncommon but significant ocular complication indicating the need for medical interventions beyond topical therapy. Cystoid macular edema and posterior subcapsular cataract are likely to form in this setting. Note also the posterior synechiae and early cataract, which characterize this disorder.

Figure 27.5 Juvenile Idiopathic Arthritis—Cataract This image is the most common appearance of chronic complicated anterior uveitis due to juvenile idiopathic uveitis. Note the severe posterior synechia and total white cataract. Significant synechia formation can lead to iris bombe (Fig. 27.6) with secondary glaucoma. The cataract may have started as the typical posterior subcapsular cataract, which then progresses to a total white cataract, often acutely, and sometimes with intumescence of the lens and shallowing of the anterior chamber. Phacomorphic and phacolytic glaucoma can occasionally occur. When possible, cataract surgery should be deferred until there is iritis control and a decline in visual function.

Figure 27.6 Juvenile Idiopathic Arthritis—Iris Bombe Multiple 360-degree posterior synechia can lead to iris bombe. In addition to the synechia seen at the pupil edge, there are often broad-based synechia involving the posterior surface of the mid-iris. Aggressive mydriasis is rarely successful in breaking the synechia and laser iridotomy may also be difficult as well as proinflammatory with a high incidence of hyphema. Therefore, surgical intervention may be required and would include breaking of the synechia, cataract surgery if needed, and a surgical iridectomy.

Figure 27.7 Dermatomyositis—Heliotrope Dermatomyositis is an idiopathic inflammatory myopathy characterized by proximal muscle weakness. This child demonstrates two of the oculofacial manifestations: A malar erythematous rash and a %variant of a heliotrope rash involving the upper eyelids. The clinical features of dermatomyositis include proximal muscle weakness and cutaneous abnormalities. Intraocular involvement is very rare. The external involvement requires no intervention, although it may be associated with increased systemic disease activity.

Figure 27.8 Dermatomyositis—Heliotrope Note the purplish supraciliary discoloration that on high power may be associated with small vessel telangiectasia. This is an often-missed sign of the disease. Other ocular involvement may be from the ocular side effects of steroids, in particular subcapsular cataracts, and these are more common than the intraocular effects of the disease. The heliotrope is not painful or pruritic and is rarely associated with edema or fever, thus differentiating it from periorbital cellulitis (Chapter 11: Orbit, Fig. 11.8) or allergy.

Figure 27.9 Dermatomyositis—Gottron Sign Gottron papules and Gottron sign are pathognomonic cutaneous manifestations of dermatomyositis. Gottron papules are erythematous papules on the dorsal surface of the metacarpophalangeal and proximal interphalangeal joints. Gottron sign is demonstrated in this photograph, which consists of scaly, erythematous plaques on the dorsal metacarpophalangeal and interphalangeal joints. Similar patches may occur on the elbows, knees, or medial malleoli. Although there is no correlation between these signs and the absence or presence of ocular involvement, they do denote that the child likely has dermatomyositis.

Figure 27.10 Dermatomyositis—Lid Lesion This excavated “pox” lesion (arrow) is characteristic of dermatomyositis and is noted after a period of disease activity with or without heliotrope. It is similar to the excavated scar of primary varicella infection (Chapter 19: Infectious Diseases, Fig. 19.7) but is distinguished by its solitary nature and location. Similar lesions may occur elsewhere but the lid is a common site. This child has a typical excavated lesion on the medial aspect of his left upper lid.

Figure 27.11 Systemic Lupus Erythematosus Systemic lupus erythematosus is a chronic inflammatory disease that affects the skin and may have associated synovitis, pericarditis, pleuritis, nephritis, vasculitis, and cerebral involvement. The most common cutaneous manifestation is a malar butterfly rash, shown here. The skin is erythematous, edematous, and often indurated. Typically, the rash extends from the malar region across the bridge of the nose. The facial rash is not necessarily correlated with particular systemic manifestations or ocular involvement.

Figure 27.12 Lupus Retinitis Ocular manifestations of lupus include dry eye, eyelid lesions, and retinal vascular lesions. The most common retinal manifestation of systemic lupus erythematosus includes characteristic large amorphous cotton-wool spots, which represent infarctions of the nerve fiber layer. The presence of cotton-wool spots often correlates well with the activity of the systemic illness. Severe ischemia and vascular congestion can also occur, often with exudates and retinal hemorrhage. The visual acuity in both patients was significantly reduced. The retinopathy will often respond to systemic treatment for the lupus. Visual recovery can occur.

Figure 27.13 Kawasaki Disease— Conjunctivitis Kawasaki disease (mucocutaneous lymphadenopathy syndrome) is an autoimmune vasculitis that presents with high fever, cervical lymphadenopathy, desquamation of the extremities, mucous membrane inflammation, and an erythematous exanthem. Ocular manifestations are one of the cardinal features, in particular a bilateral nonpurulent bulbar conjunctivitis. Anterior uveitis can also be associated with this disease, but the course is usually mild and selflimited, and may not require pharmacologic treatment. Retinal involvement is very rare.

Figure 27.14 Kawasaki Disease— Rash Although the desquamating skin disorder in Kawasaki disease more typically involves the hands and feet, involvement of the groin, as seen in this older child, may also occur. Treatment of Kawasaki disease initially involves immunoglobulins and aspirin. The role of corticosteroids is unclear and there is some concern that they may increase the risk for coronary aneurysm, the major cause of outcome morbidity and mortality. There is no known correlation between ocular and cardiac involvement.

Figure 27.15 Behçet Disease Behçet disease is an autoimmune disorder that has a higher incidence in patients of Far Eastern or Mediterranean descent. The major features are aphthous ulcers of the gastrointestinal tract, genital ulcers, and erythema nodosum. Ocular manifestations include severe bilateral anterior uveitis with hypopyon. The uveitis is nongranulomatous and is typically associated with posterior synechiae and cataract. Posterior uveitis presents as a vasoocclusive retinitis with vitreous inflammation. Aphthous ulcers occur in most patients with Behçet disease. The ulcers shown here are typically located on the gums and the soft palate. The lesions are painful and recurring, and can last weeks.

Figure 27.16 Scleroderma Scleroderma is a systemic disease of connective tissue that is characterized by inflammation and subsequent degeneration and fibrosis. The skin and skeletal muscle are most commonly affected, but the gastrointestinal tract, respiratory system, heart, and kidneys can be affected. Ocular manifestations include keratoconjunctivitis sicca and conjunctival fibrosis with shortening of the inferior fornix. Linear scleroderma, also known as morphea, is a localized form of scleroderma that can involve the forehead or one side of the face, as shown here. It may begin as a localized yellow or hypopigmented patch of hard taught skin. A depression in the affected area leads to progressive deformation that has also been given the name “coup de sabre.” Ipsilateral or, rarely, bilateral uveitis may occur.

Figure 27.17 Pars Planitis Pars planitis or intermediate uveitis is an ocular inflammatory disorder of the uveal tissues in the ciliary body and anterior choroid that affect young adults and children. Patients present with significant anterior vitreous involvement (Fig. 27.4), which can be complicated by cataract and macular edema. Although pars planitis may be an isolated idiopathic disorder, associated systemic diseases include Lyme, sarcoidosis (Chapter 25: Pulmonary, Figs. 25.1 and 25.2), and multiple sclerosis (Chapter 21: Neurologic, Fig. 21.11). Patients will often complain of decreased vision with floaters due to vitritis aggregates of inflammatory debris, as shown here. Some patients will have the classic snow banking on the pars plana. Differential diagnosis would include other infectious causes of uveitis and vitritis. Treatment is periocular and/or systemic.

Figure 27.18 Sjögren Syndrome— Raynaud Phenomena Sjögren syndrome is an autoimmune disorder characterized by chronic inflammation of the salivary glands, lacrimal glands, and connective tissues. Patients typically present with xerostomia (dry mouth), xerophthalmia (dry eye), and arthritis. This patient demonstrates severe Raynaud phenomenon: Vascular occlusion secondary to cold environment, which initially appears as blanching followed by reflex erythema, but in this case ultimately led to necrosis. Diagnosis is made on clinical findings and by the presence of Ro/SSA and La/SSB antibodies. Artificial tears and immunosuppressive therapy are the mainstays of treatment.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 28 - Skeletal

28 Skeletal Alex V. Levin Thomas W. Wilson Skeletal and connective tissue disorders will often have significant ocular manifestations. The connective tissue disorders are often the result of defects within tissue collagen. The abnormal collagen leads to structural weaknesses of the cornea, sclera, lens zonules, and Bruch membrane. These defects also cause systemic disorders of the skin, musculoskeletal system, heart, and vascular system. Collagen abnormalities of the cornea result in keratoconus and keratoglobus (Chapter 5: Cornea, Figures 5.18 through 5.20). Structural defects within the sclera lead to globe elongation resulting in high myopia, retinal detachment, and susceptibility to ruptured globe following minor trauma. Weakness of the Bruch membrane (the basement membrane of the retinal pigment epithelium) results in angioid streaks and subsequent visionthreatening subretinal neovascular membrane. Ectopia lentis is secondary to abnormal lens zonules. Vitreous collagen abnormality may lead to retinal detachment. Similar defects in collagen may affect the heart valves and vascular tissues. Patients may present with an ocular problem and

have a life-threatening systemic abnormality. One example would include a patient with Marfan syndrome presenting with symptoms of ectopia lentis and aortic root dilation detected before aneurysmal rupturing. A patient presenting with acute changes in vision secondary to angioid streaks and subretinal neovascular membrane may have the potential for severe uterine or gastrointestinal bleeding. Ocular abnormalities may be the key factor in the identification of a skeletal system disorder that also has other associated serious systemic abnormalities.

Figure 28.1 Stickler Syndrome Stickler syndrome is an autosomal dominant–inherited disorder with ocular and systemic features. The underlying abnormality is in the production of type 2A1 (12q13.11), 11A1 (1p21), or 11A2 (6p21.3) collagen. The latter form does not have ocular signs. Clinical features include high myopia, wedge-shaped cortical cataract, optically empty vitreous, perivascular lattice, and retinal detachment.

Systemic findings include midfacial hypoplasia with Pierre Robin sequence, deafness, heart valve abnormalities, and progressive arthropathy. This photograph demonstrates pseudoproptosis from the axial myopia as well as the characteristic facies with midface hypoplasia and flat nasal bridge.

Figure 28.2 Pierre Robin Sequence The Pierre Robin sequence is also associated with Stickler syndrome. This complex includes micrognathia, high arched or cleft palate, and relative glossoptosis. The primary defect is the failure of the fetal mandible to grow. This leaves the tongue in an elevated position, which prevents closure of the palatal shelves. Approximately one-third of patients with Pierre Robin sequence have no systemic manifestations, one third have a recognizable syndrome, and one third have other manifestations but no recognizable syndrome. The ophthalmologist must be careful when examining children with Pierre Robin sequence in the supine position, as the tongue may obstruct the airway. In this child, recurrent tongue obstruction led to the need for tracheostomy.

Figure 28.3 Stickler Syndrome— Cortical Wedge Cataract Cataracts are common in patients with Stickler syndrome, but due to the peripheral location, they may not require surgery. However, more visually significant cataracts may occur including presenile nuclear sclerosis and even total white cataract. The cataract in this photograph is the classic wedge-shaped cataract and is not causing any visual loss. Due to the vitreous abnormalities in this syndrome and the high risk for retinal detachment, it is advisable not to invade the posterior capsule during surgery. Fortunately, cataract surgery is rarely needed in infancy.

Figure 28.4 Stickler Syndrome— Vitreous Abnormalities The vitreous of patients with Stickler syndrome becomes optically empty. The vitreous is liquefied but may contain freely mobile avascular bands or veils. These bands do not cause significant retinal traction or visual compromise. In Stickler syndrome due to mutations in the COL11A1 gene, the vitreous may be visible but synergetic with beaded fibrils. In this photograph, the vitreous can be seen in the retrolenticular space and fleck-shaped opacities are located with the lens.

Figure 28.5 Stickler Syndrome— Perivascular Lattice The retina of Stickler syndrome is atrophic and is typical of high myopia. The refractive error is typically 8 to 12 diopters and nonprogressive. Ametropic amblyopia can occur if not detected at an early age. Perivascular lattice degeneration, shown here, in the peripheral retina and breaks within the retina are common. Children should be monitored on a regular basis with a peripheral retinal examination because of the high risk of retinal detachment. Stickler syndrome is the most common systemic disorder associated with giant retinal tears in children.

Figure 28.6 Marfan Syndrome—Arachnodactyly Marfan syndrome is a systemic abnormality secondary to mutations in the fibrillin-1 gene at 15q21. Systemic findings are predominantly cardiovascular and musculoskeletal, although other organ systems such as the pleura, skin, and dura may also be involved. Skeletal abnormalities include long arms when compared to the overall height (Marfanoid habitus), arachnodactyly (long, thin fingers and toes, left image), dolichostenomelia (long, thin arms and legs), scoliosis, pectus excavatum (depressed sternum), and pectus carinatum (prominent sternum). The positive thumb sign of Marfan syndrome (Steinberg sign) is when the long thumb can be folded under the fingers and protrudes beyond the ulnar border of the hand (right image). Normal individuals may be able to do this as well.

Figure 28.7 Marfan Syndrome—Wrist Sign The positive wrist sign occurs when the patient is able to overlap the thumb and fifth digit wrapped around the opposite wrist. This nonspecific sign may also be seen in normal individuals. Marfan patients also have increased joint flexibility, high arched palate with crowded teeth, and increased incidence of inguinal and umbilical hernias. Cardiac abnormalities can be life-threatening and include dilation and rupture of the aorta and mitral valve prolapse. Cardiac evaluation is an essential part of the ophthalmologist's preoperative workup for all patients with ectopia lentis of unknown cause.

Figure 28.8 Marfan Syndrome— Ectopia Lentis Ectopia lentis occurs in the majority of patients with Marfan syndrome but may be absent. Classically, the lenses are displaced superiorly and laterally but may move in any direction or even stay central with phacodonesis. Lenticular myopia and astigmatism can lead to significant refractive amblyopia in younger patients. Due to the fibrillin abnormality, the zonules are stretched rather than broken as in homocystinuria (Chapter 20: Metabolic, Figure 20.3). As a result, complete dislocation of the lens into the anterior chamber or vitreous is less common. The most amblyogenic period is when the lens edge is within 3 mm of the central visual axis. Where possible, surgery may be avoided by refracting the patient through his or her aphakic visual axis. The risk of postoperative retinal detachment may be as high as 20%.

Figure 28.9 Weill-Marchesani Syndrome Weill-Marchesani syndrome is a disorder that is inherited as an autosomal dominant (mutations in the fibrillin-1 gene, FBN1, at 15q21.1, which also is responsible for Marfan syndrome [Figs. 28.6, 28.7 and 28.8]) or autosomal recessive (mutations in the ADAMTS10 gene at 19p13.313.2) disease. The clinical features include short stature, short spadelike hands, brachydactyly, and a depressed nasal bridge. In this photograph, the affected mother's fingers (left side) are smaller than those of her 10 year old daughter (right side). Ophthalmic manifestations include microspherophakia (Chapter 7: Lens Chapter, Fig. 7.20). These globular lenses may dislocate into the anterior chamber. This can lead to angle closure or pupillary block glaucoma. The anterior chamber progressively shallows as the anterior–posterior diameter of the lens increases. Early surgery and avoidance of pilocarpine is advised.

Figure 28.10 Pseudoxanthoma Elasticum Pseudoxanthoma elasticum is caused by an abnormal production, calcification, and degeneration of the elastin component of connective tissue. Systemic findings include peripheral vascular, skin, and ocular abnormalities. The disorder may be inherited as autosomal recessive or autosomal dominant, both involving the ABCC6 gene at 16p13.1. This photograph shows weblike folds of the neck and the hypermobility of joints. The skin may have orangeyellowish lesions located in the axillae, popliteal, neck, and groin that form plaques referred to as peau d'orange. Vascular manifestations include a significant risk of gastrointestinal and uterine hemorrhage, cardiovascular disease, peripheral vascular disease, and cerebrovascular disease.

Figure 28.11 Pseudoxanthoma Elasticum—Angioid Streaks Angioid streaks are caused by breaks in the Bruch membrane due to calcification and fragility of elastin fibers. The streaks radiate from the optic nerve. Subsequent formation of subretinal neovascular membranes may lead to hemorrhage and scarring of the macula. The retina may also have a peau d'orange (skin of an orange) appearance secondary to irregular yellowish-orange colored lesions with overlying mottling of the retinal pigmented epithelium. The differential diagnoses of angioid streaks in childhood include pseudoxanthoma elasticum, Ehlers-Danlos syndrome (Fig. 28.12), sickle cell retinopathy, and lacquer cracks of high myopia.

Figure 28.12 Ehlers-Danlos Syndrome Ehlers-Danlos syndrome is an inherited connective tissue disorder with systemic and ocular manifestations. EhlersDanlos has at least 10 different clinical subtypes. All types of Ehlers-Danlos have in common hypermobility of the joints (left image). Systemic manifestations also include hyperelasticity and fragility of the skin leading to easy bruising. Patients may develop blue sclera, keratoconus, ectopia lentis, and myopia. In type VI (ocular type), the genetic defect in the enzyme lysyl hydroxylase has been located on chromosome 1p36. In this subtype, the collagen of the cornea is particularly fragile; even minor trauma can lead to a ruptured globe.

Figure 28.13 Osteogenesis Imperfecta Osteogenesis imperfecta is an autosomal dominant abnormality of bone strength leading to multiple fractures. The patients will commonly have blue sclera, as shown here. The primary disorder in all subtypes of this disorder is an abnormality in type I collagen (COL1A1 or COL1A2). There are at least four subtypes: Type I—mildest form, some fractures, no bone deformity, may have hearing loss; type II —most severe form, multiple fractures and bone deformity, may be lethal; and types II and III—intermediate severity. One must differentiate the milder forms from nonaccidental trauma (Chapter 12: Child Abuse).

Figure 28.14 Kniest Syndrome Kniest syndrome (metatrophic dwarfism) is a rare abnormality in bone production and growth due to mutations in a gene encoding for the α1 component of collagen II (COL2A1). It is inherited as an autosomal dominant disorder. Patients have midfacial hypoplasia and hypertelorism with or without cleft palate. Hearing loss and arthropathy are common. Ocular findings are similar to Stickler syndrome and include vitreoretinal degeneration and retinal detachment. However, patients with Kniest syndrome may also have congenital glaucoma. Epiphyseal ossification is delayed in the hips, hands, and knees, leading to limited mobility and joint deformities.

Figure 28.15 Osteopetrosis Osteopetrosis is an autosomal recessive bone abnormality characterized by a progressive increase in bone density and thickness. The bone marrow rapidly becomes occupied by the production and lack of reabsorption of normal bone tissue. The increasing thickness of bone within the optic foramen leads to slowly progressive visual loss from optic nerve compression. The axial view of the orbital computed tomography scan (right image) demonstrates the narrowing with the optic foramen and overall thickness and density of the cranium. Proptosis may occur when the orbit becomes increasingly occupied by bone. Retinal dystrophy has been reported in a small number of patients. Thrombocytopenia and anemia occur secondary to the limited capacity of the bone marrow to produce blood cells. This patient has a left sensory exotropia due to optic atrophy, which is worse on that side; proptosis; and severe blepharitis, perhaps due to an altered immune response seen in this disorder.

Editors: Levin, Alex V.; Wilson, Thomas W. Title: Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition Copyright ©2007 Lippincott Williams & Wilkins > Table of Contents > Section II - Ocular Manifestations of Systemic Disease > 29 - Syndromes

29 Syndromes Alex V. Levin Thomas W. Wilson Elise Héon The eye is the second most commonly involved organ in systemic syndromes after the central nervous system. Most syndromes are genetic in origin with the expression of abnormal genes in various tissues throughout the body. Multisystem involvement may occur because the same gene plays a vital role in each affected tissue or because more than one gene is involved, as in a contiguous gene deletion syndrome. Patients may present with ocular abnormalities that lead to the diagnosis of an underlying syndrome. Knowing the ocular manifestations of syndromes also allows for appropriate ophthalmic screening. The number of known syndromes is in the thousands and is far beyond the scope of this chapter and the knowledge base of any one ophthalmic practitioner. Perhaps the most comprehensive source of information can be found in the online version of Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim/). Syndromes with a major manifestation in a particular organ system may be found

elsewhere in this atlas. For example, Apert syndrome is discussed in Chapter 14: Craniofacial; WAGR syndrome in Chapter 6: Iris and Pupils; and Alagille syndrome in Chapter 17: Gastrointestinal.

Figure 29.1 Cockayne Syndrome Cockayne syndrome is an autosomal recessive disorder characterized by rapid premature aging, deafness, miosis, cataract, and pigmentary retinopathy similar to retinitis pigmentosa (Chapter 8: Retina and Vitreous). Microphthalmia may also occur. Facial features include microcephaly with loss of facial adipose tissue and dermatitis secondary to sun exposure, which can also be seen in combination with xeroderma pigmentosa (Chapter 15: Dermatology, Fig. 15.6). Patients typically have some degree of developmental delay and growth retardation.

Fibroblast cultures from patients with Cockayne syndrome have an increased sensitivity to ultraviolet light, and the underlying mechanism is most likely secondary to an inability to repair the skin following exposure to the sun. Patients with Cockayne syndrome can have pigmentary degeneration of the retina.

Figure 29.2 Cornelia de Lange Syndrome (Brachmann-de Lange Syndrome) Cornelia de Lange syndrome is a genetic abnormality due to mutations in the NIPBL gene at 5p13.1 in 50% of patients, with a characteristic facies, variable mental and growth retardation, skeletal abnormalities ranging from small hands to severe limb reduction, and gastroesophageal reflux. Other findings may include deafness, cardiac abnormalities, Raynaud phenomena (Chapter 27: Rheumatology Fig. 27.18), and cleft palate. The most common facial features include hypertrichosis of the eyebrows with a “V shaped” synophrys and long arcuate eyelashes. Other ocular manifestations include unilateral or bilateral congenital ptosis, myopia, peripapillary hyperpigmentation, and

blepharitis. Nasolacrimal anomalies and nystagmus may also be seen.

Figure 29.3 Hallermann-Streiff Syndrome (Oculomandibulodyscephaly with Hypotrichosis Syndrome) Hallermann-Streiff syndrome is characterized by a triangular facies with hypoplastic mandible, beaked nose, hypoplastic

nasal alae, proportionate short stature, and hypotrichosis. Ocular manifestations include bilateral microphthalmia (80%) and cataracts (94%). Nystagmus and strabismus are likely secondary manifestations. The cataract may spontaneously resorb, leaving the patient spontaneously aphakic. The involved gene and inheritance pattern are unknown. The majority of patients have normal development; however, mental retardation has been reported.

Figure 29.4 Johanson-Blizzard Syndrome Johanson-Blizzard syndrome is an autosomal recessive disorder that is characterized by pancreatic agenesis,

hypothyroidism, ectodermal dysplasia, deafness, and developmental abnormalities. The pancreatic insufficiency leads to malabsorption and nutritional challenges. Craniofacial findings include midline scalp defects and hypoplastic or absent alae nasi. Dental abnormalities are common and include absence or hypoplasia of the permanent teeth. The major ocular difficulties are due to the disrupted nasolacrimal system. This syndrome is caused by mutations in the E3 ubiquitin ligase gene (UBR1) at 15q14-21.1.

Figure 29.5 Joubert Syndrome Joubert syndrome is characterized by developmental delay, a variable breathing pattern, cerebellar vermal hypoplasia, and a retinal dystrophy. Some children will have renal disease. Patients often have tremor, ataxia, and a variety of unusual, sometimes dysconjugate, abnormal eye movements. Other ocular manifestations include optic atrophy and strabismus. The fundus is often abnormal in infancy. In a patient suspected of having Leber congenital amaurosis (Chapter 8: Retina and Vitreous, Fig. 8.33), a careful history should be obtained regarding irregular

breathing patterns and eye movements to evaluate the possibility of Joubert syndrome.

Figure 29.6 Kabuki Syndrome (Kabuki Make-up Syndrome, Niikawa-Kuroki Syndrome) Kabuki syndrome is a systemic disorder characterized by mild developmental delay, characteristic facies, cardiac abnormalities, large ears with preauricular pits, and skeletal anomalies. The facial features include very unique elongated palpebral fissures in the horizontal direction with euryblepharon (turning out and laxity of the lateral portion of the lower eyelid). This is asymptomatic and requires no intervention unless there is a desire to normalize the appearance. Patients may also have high arching eyebrows, deficient lateral third of the eyebrows, and ptosis. The fingertip pads can be more prominent than normal (fetal pads).

Figure 29.7 Microphthalmia Linear Skin Defect Syndrome (MIDAS) This syndrome is also known as MIDAS for its microphthalmia, dermal aplasia, and sclerocornea (Chapter 5: Cornea, Figure 5.2). There is localized dermal hypoplasia involving the head, face, or neck. These cutaneous lesions are typically linear and irregular with an erythematous appearance. There is an absence of fat herniation in the base of these defects. This genetic defect has been mapped to Xp22.3. The inheritance pattern is X-linked dominant (lethal in males).

Figure 29.8 Nager Syndrome (Acrofacial Dysostosis) Nager syndrome is a combination of malar hyperplasia and auricular abnormalities, similar to Treacher-Collins syndrome (Chapter 14: Craniofacial, Figs. 14.14, 14.15 and 14.16), and radial limb anomalies, in particular short forearms and absent thumbs. Ocular abnormalities include a downwardslanting palpebral fissure and hypoplasia of the lower eyelashes with or without the typical lower lid coloboma seen in Treacher-Collins.

Figure 29.9 Nail-Patella Syndrome In patients with Nail-Patella syndrome one finds absent or dysplastic nails and hypoplasia of the patellae. Other clinical manifestations include iliac horns, renal failure, and limited pronation and supination of the arms secondary to abnormal elbows. This autosomal dominant disorder is secondary to mutations in LIM-homeodomain transcription factor protein (LMX1B) at 9q34.1. There is an increased risk of glaucoma. The central portion of the iris has a flower-shaped area of pigmentation (Lester sign). Lester sign does not correlate with the incidence of glaucoma and can also be observed in the normal population.

Figure 29.10 Parry-Romberg Syndrome Parry-Romberg syndrome is a disorder characterized by slowly progressive atrophy and distortion of one side of the face. The bone, cartilage, muscle, subcutaneous tissue, and skin slowly lose volume and structure over several years. Typical onset is within the first decade of life. Differential diagnosis includes linear scleroderma (Chapter 27: Rheumatology, Fig. 27.16). Ophthalmic findings include atrophy of the periocular tissues including the orbital bones and orbital fat. This loss of orbital volume leads to enophthalmos and possible strabismus. Atrophy of the lids also is common and can lead to corneal exposure and vision loss. Heterochromia and pigmentary retinopathy have also

been observed.

Figure 29.11 Rubinstein-Taybi Syndrome Rubinstein-Taybi syndrome is characterized by broad thumbs (right image) and great toes, mental retardation, and a characteristic facies. This autosomal dominant disorder is due to mutations in the CREB binding protein at 16p13.3. Ocular manifestations include heavy-arched eyebrows with long eyelashes and possible ptosis. Patients with RubinsteinTaybi also have an increased risk of glaucoma and cataracts. Iris coloboma has also been reported.

Figure 29.12 Williams Syndrome Williams syndrome is an autosomal dominant disorder due to mutation or deletion of the elastin gene at 7q11.2 consisting of structural cardiac abnormalities, mild mental retardation, an outgoing gregarious personality, characteristic facies, and dental abnormalities. The two most common cardiac abnormalities include supravalvular aortic and pulmonary artery stenosis. Patients have an elfin face that includes full cheeks, a broad forehead, a short nose with upturned nares, and a prominent upper lip (left image). Patients may have increased levels of serum calcium. The classic ophthalmic finding includes a stellate pattern to the iris (right image), which is present in approximately 50% of patients. Other reported findings include hyperopia, strabismus, and retinal vascular tortuosity.

Figure 29.13 Jeune Syndrome (Asphyxiating Thoracodystrophy) This autosomal recessive, potentially lethal syndrome is characterized by a bell-shaped and constricted thorax, as seen in this radiograph. The gene locus has been mapped to 15q13. Other skeletal changes, particularly of the pelvis and limbs, may be seen. Polydactyly is not uncommon, and the kidneys, liver, and gastrointestinal tract may also be involved. Juvenile retinal dystrophy can be documented by electroretinogram in early infancy, and patients may have a relatively normal-appearing retina or pigmentary stippling at

the level of the retinal pigmented epithelium with or without changes in the overlying internal limiting membrane.

Índice Authors Preface Acknowledgments

Contents 1 - Strabismus 2 - Lids and Adnexa 3 - Lacrimal 4 - Conjunctiva 5 - Cornea 6 - Iris and Pupils 7 - Lens 8 - Retina and Vitreous 9 - Optic Nerve 10 - Glaucoma 11 - Orbit 12 - Child Abuse 13 - Chromosomes 14 - Craniofacial 15 - Dermatology 16 - Endocrine 17 - Gastrointestinal

1 6 8

10 12 89 117 127 151 186 212 234 292 330 339 352 374 386 416 448 456

18 - Hematology 19 - Infectious Diseases 20 - Metabolic 21 - Neurologic 22 - Vitamins 23 - Phakomatoses 24 - Psychiatric 25 - Pulmonary 26 - Renal 27 - Rheumatology 28 - Skeletal 29 - Syndromes

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