Pediatric Neuro-Ophthalmology, Second Edition

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Pediatric Neuro-Ophthalmology Second Edition

Michael C. Brodsky

Pediatric Neuro-Ophthalmology Second Edition

Michael C. Brodsky, M.D. Professor of Ophthalmology and Neurology Mayo Clinic Rochester, Minnesota USA

ISBN 978-0-387-69066-7 e-ISBN 978-0-387-69069-8 DOI 10.1007/978-0-387-69069-8 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2010922363 © Springer Science+Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connec-tion with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with re-spect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

To the good angels in my life, past and present, who lifted me on their wings and carried me through the storms.

Foreword

The first edition of Pediatric Neuro-Ophthalmology, published in 1995, filled an important gap in the disciplines of pediatric ophthalmology, neuro-ophthalmology, and pediatric neurology. It was written in a clear and concise style, which made the volume valuable to the general ophthalmologist seeing children and the pediatric specialists. The book’s large audience, combined with its readability and inclusive contents, combined to make Pediatric NeuroOphthalmology such a success in its genre. Almost 15 years have elapsed since the initial publication, and the growth of the body of knowledge of the developing visual system, sensory and motor, as well as the diseases associated with that sweeping cascade of events, is little short of astonishing. Hence, the need at this juncture for a revised second edition. This new edition is by no means a cursory glance backward at the published literature, as so many second editions of large, multi-authored books can be, but, rather, an in depth, concentrated and critical look at publications since. The author has fitted in the new pieces to update the text, photographs, and references where indicated. This new edition broadens our understanding not only on a phenomenological level but also by adding molecular and genetic mechanisms, insights from population genetics, epidemiology, and advances in other fields far from its domain it burnishes the insight and understanding of the reader. Pediatric Neuro-Ophthalmology very much bear the unique touch of its author. A glance at chapter one, “The Apparently Blind Infant,” will clarify what I mean. The chapter is nearly twice as long, with greatly expanded references. Most importantly, this growth is packed with important new insights without slighting the older but still valid and important observations from the past. For example, the discovery of melanopsin, a bistable visual protein found not in rods or cones but in ganglion cells of the retina, is now known to contribute to our normal pupillary reaction to light. Its probable role in the peculiar paradoxical constriction to darkness is both noted and the connection made to congenital stationary night blindness and achromatopsia, along with other visual system conditions where pupil anomalies are found. These are the types of insights that make this book a delight for the novice as well as for the clinician experienced in the field. In closing, I can but reprise my words from the first edition. “I see it as my responsibility to put this work in perspective for the reader- to-be”—be he novice or specialist, he or she will be rewarded with a truly unique text. “It is both a joy and privilege to write the Foreword again. I have learned immensely from the task.” John T. Flynn, MD Bolton Landing, Lake George, NY

vii

Preface

Due to the generous representation of the afferent visual system within the brain, neurological disease may disrupt vision as a presenting symptom or as a secondary effect of the disease. Conversely, early developmental disturbances of vision often disrupt ocular motor control systems, giving rise to complex disorders such as nystagmus, strabismus, and torticollis. The signs and symptoms of neurological disease are elusive by their very nature, presenting a confounding diagnostic challenge. Neurological medications and neurosurgical treatments can produce neuro-ophthalmological dysfunction that can be difficult to distinguish from disease progression. Affected patients may experience substantial delays in diagnosis and are often subjected to extensive (and expensive) diagnostic testing. Scientific articles pertaining to specific disorders are scattered throughout medical subspecialty journals. These children continue to “fall through the cracks” of our medical education system. The increasing recognition that pediatric neuro-ophthalmology comprises a distinct set of diseases from those seen in adults has led to its emergence as a dedicated field of study. Since the original publication of Pediatric Neuro-Ophthalmology nearly 14 years ago, interest in the field has burgeoned. Pediatric ophthalmology and pediatric neurology subspecialty conferences often include symposia dedicated to recent advances in pediatric neuroophthalmology. Technical advances in neuroimaging have given rise to a more integrated mechanistic classification of neuro-ophthalmological disease in children. Our understanding of neurodevelopmental disorders of the visual system has expanded, longstanding monoliths have been dissembled into component parts, basic molecular mechanisms have taken center stage, and genetic underpinnings have become definitional. Evolutionary alterations can now be observed at the level of the gene, adding a new dimension to our understanding of disease pathogenesis. New classifications now encompass clinically disparate conditions. Descriptive definitions have been supplanted by mechanistic ones, and clinical definitions superseded by genetic ones. Our concept of disease pathogenesis has been revised and in some cases overturned. Bearing witness to these remarkable advancements has impelled me to enhance and expand the first edition of Pediatric Neuro-Ophthalmology into this new and revised one. In the first edition of this book, our goal was to present the clinical characteristics, diagnostic evaluation, and therapeutic options for the common neuro-ophthalmologic disorders of childhood. In so doing, we designed the book to provide a narrative journey through the thought processes involved in the clinical management of these disorders. In this edition, I have retained the basic narrative format of the original book, while expanding the exploration of these complex visual disorders in the context of the many new scientific advancements and discoveries that have come to light. These conditions are fun to diagnose, fascinating to understand, and gratifying to manage. Although my two excellent coauthors have graciously bowed out of rewriting this edition, their formidable contributions to the first edition provide the bedrock of this book, and my gratitude to them is inestimable. Without them, this book would not exist. My hope is that the second edition will serve as a useful resource to ophthalmologists, neurologists, neurosurgeons, and pediatricians; and that it will spur more research into the basic mechanisms of these disorders. Michael C. Brodsky, MD Rochester, MN ix

Contents

1 The Apparently Blind Infant..................................................................................... Introduction.................................................................................................................. Hereditary Retinal Disorders....................................................................................... Leber Congenital Amaurosis.................................................................................. Joubert Syndrome................................................................................................... Congenital Stationary Night Blindness................................................................... Achromatopsia........................................................................................................ Congenital Optic Nerve Disorders............................................................................... Cortical Visual Insufficiency........................................................................................ Causes of Cortical Visual Loss............................................................................... Associated Neurologic and Systemic Disorders..................................................... Characteristics of Visual Function.......................................................................... Neuro-Ophthalmologic Findings............................................................................ Diagnostic and Prognostic Considerations............................................................. Role of Visual Attention......................................................................................... Subcortical Visual Loss (or Periventricular Leukomalacia)........................................ Neuroimaging Abnormalities and their Implications............................................. Neuro-Ophthalmologic Findings............................................................................ Perceptual Difficulties............................................................................................. Dorsal and Ventral Stream Dysfunction................................................................. Pathophysiology...................................................................................................... Intraventricular Hemorrhage........................................................................................ Periventricular and Intraventricular Hemorrhage................................................... Hemianopic Visual Field Defects in Children............................................................. Delayed Visual Maturation.......................................................................................... Blindsight..................................................................................................................... The Effect of Total Blindness on Circadian Regulation.............................................. Horizons....................................................................................................................... References....................................................................................................................

1 1 6 6 9 10 10 10 11 12 19 21 22 25 27 27 27 28 30 31 33 34 34 35 38 41 43 45 46

2 Congenital Optic Disc Anomalies.............................................................................. Introduction.................................................................................................................. Optic Nerve Hypoplasia............................................................................................... Excavated Optic Disc Anomalies................................................................................ Morning Glory Disc Anomaly................................................................................ Optic Disc Coloboma.............................................................................................. Peripapillary Staphyloma........................................................................................ Megalopapilla......................................................................................................... Optic Pit.................................................................................................................. Papillorenal Syndrome (The Vacant Optic Disc)....................................................

59 59 59 67 67 71 75 75 76 78 xi

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Congenital Tilted Disc Syndrome................................................................................ Optic Disc Dysplasia.................................................................................................... Congenital Optic Disc Pigmentation........................................................................... Aicardi Syndrome........................................................................................................ Doubling of the Optic Disc.......................................................................................... Optic Nerve Aplasia..................................................................................................... Myelinated (Medullated) Nerve Fibers........................................................................ The Albinotic Optic Disc............................................................................................. References....................................................................................................................

79 81 81 83 85 86 87 88 89

3 The Swollen Optic Disc in Childhood....................................................................... Introduction.................................................................................................................. Papilledema.................................................................................................................. Idiopathic Intracranial Hypertension (IIH) in Children......................................... Optic Disc Swelling Secondary to Neurological Disease....................................... Optic Disc Swelling Secondary to Systemic Disease............................................. Uveitis..................................................................................................................... Posttraumatic Optic Disc Swelling.............................................................................. Intrinsic Optic Disc Tumors......................................................................................... Optic Disc Hemangioma......................................................................................... Tuberous Sclerosis.................................................................................................. Optic Disc Glioma.................................................................................................. Combined Hamartoma of the Retina and RPE....................................................... Retrobulbar Tumors..................................................................................................... Optic Neuritis in Children............................................................................................ History and Physical Examination.......................................................................... Postinfectious Optic Neuritis.................................................................................. Acute Disseminated Encephalomyelitis................................................................. MS and Pediatric Optic Neuritis............................................................................. Devic Disease (Neuromyelitis Optica)................................................................... Prognosis and Treatment......................................................................................... Course of Visual Loss and Visual Recovery........................................................... Systemic Prognosis................................................................................................. Systemic Evaluation of Pediatric Optic Neuritis.................................................... Treatment................................................................................................................ Leber Idiopathic Stellate Neuroretinitis.................................................................. Ischemic Optic Neuropathy......................................................................................... Autoimmune Optic Neuropathy................................................................................... Pseudopapilledema...................................................................................................... Optic Disc Drusen................................................................................................... Ocular Disorders Associated with Pseudopapilledema.......................................... Systemic Disorders Associated with Pseudopapilledema....................................... References.....................................................................................................................

97 97 98 101 110 111 120 121 122 122 122 123 123 123 124 124 124 124 125 126 127 127 128 128 129 129 132 133 133 133 140 140 142

4 Optic Atrophy in Children......................................................................................... Introduction.................................................................................................................. Epidemiology............................................................................................................... Optic Atrophy Associated with Retinal Disease.......................................................... Congenital Optic Atrophy Vs. Hypoplasia.................................................................. Causes of Optic Atrophy in Children........................................................................... Compressive/Infiltrative Intracranial Lesions......................................................... Noncompressive Causes of Optic Atrophy in Children with Brain Tumors........... Hereditary Optic Atrophy.......................................................................................

155 155 156 159 160 161 161 168 169

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Contents

Dominant Optic Atrophy (Kjer Type)..................................................................... Leber Hereditary Optic Neuropathy....................................................................... Recessive Optic Atrophhy...................................................................................... Behr Syndrome....................................................................................................... Wolfram Syndrome (DIDMOAD).......................................................................... Toxic/Nutritional Optic Neuropathy............................................................................ Neurodegenerative Disorders with Optic Atrophy...................................................... Organic Acidurias.................................................................................................. Optic Atrophy due to Hypoxia-Ischemia..................................................................... Traumatic Optic Atrophy............................................................................................. Miscellaneous Causes ................................................................................................. Summary of the General Approach to the Child with Optic Atrophy......................... References....................................................................................................................

172 175 177 177 178 179 180 185 187 188 188 189 190

5 Transient, Unexplained, and Psychogenic Visual Loss in Children....................... Introduction.................................................................................................................. Transient Visual Loss................................................................................................... Migraine.................................................................................................................. Epilepsy................................................................................................................... Posttraumatic Transient Cerebral Blindness........................................................... Cardiogenic Embolism............................................................................................ Nonmigrainous Cerebrovascular Disease............................................................... Miscellaneous Transient Visual Disturbances in Children..................................... Toxic and Nontoxic Drug Effects........................................................................... Summary of Clinical Approach to the Child with Transient Visual Disturbances..... Laboratory Evaluation of Transient Visual Disturbances in Children.................... Unexplained Visual Loss in Children.......................................................................... Causes of Unexplained Visual Loss in Childhood.................................................. Psychogenic Visual Loss in Children.......................................................................... Clinical Profile........................................................................................................ Neuro-Ophthalmologic Findings............................................................................ Categories of Psychogenic Visual Loss in Children............................................... Management of Psychogenic Visual Loss in Children........................................... Horizons....................................................................................................................... References....................................................................................................................

213 213 214 214 223 227 227 228 228 233 234 235 235 235 239 239 240 241 242 244 244

6 Ocular Motor Nerve Palsies in Children.................................................................. Introduction.................................................................................................................. Oculomotor Nerve Palsy.............................................................................................. Clinical Anatomy.................................................................................................... Clinical Features..................................................................................................... Partial Forms of Oculomotor Palsy......................................................................... Oculomotor Synkinesis........................................................................................... Etiology................................................................................................................... Vascular Third Nerve Palsy in Children................................................................. Differential Diagnosis............................................................................................. Management............................................................................................................ Trochlear Nerve Palsy.................................................................................................. Clinical Anatomy.................................................................................................... Clinical Features..................................................................................................... Bilateral Trochlear Nerve Palsy.............................................................................. Etiology................................................................................................................... Differential Diagnosis.............................................................................................

253 253 256 256 257 257 260 261 266 267 268 270 270 271 273 274 278

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Contents

Treatment................................................................................................................ Abducens Nerve Palsy................................................................................................. Clinical Anatomy.................................................................................................... Clinical Features..................................................................................................... Causes of Sixth Nerve Palsy................................................................................... Differential Diagnosis............................................................................................. Duane Retraction Syndrome................................................................................... Management of Sixth Nerve Palsy.......................................................................... Multiple Cranial Nerve Palsies in Children................................................................. Horizons....................................................................................................................... References....................................................................................................................

279 281 281 281 282 285 285 293 294 295 295

7 Complex Ocular Motor Disorders in Children........................................................ Introduction.................................................................................................................. Strabismus in Children with Neurological Dysfunction.............................................. Visuovestibular Disorders....................................................................................... Neurologic Esotropia.............................................................................................. Neurologic Exotropia.............................................................................................. Skew Deviation....................................................................................................... Gaze Palsies, Gaze Deviations, and Ophthalmoplegia................................................ Horizontal Gaze Palsy in Children......................................................................... Congenital Ocular Motor Apraxia.......................................................................... Vertical Gaze Palsies in Children............................................................................ Diffuse Ophthalmoplegia in Children.......................................................................... Chronic Progressive External Ophthalmoplegia..................................................... Myasthenia Gravis.................................................................................................. Olivopontocerebellar Atrophy..................................................................................... Botulism.................................................................................................................. Fisher Syndrome: A Variant of Guillain–Barré Syndrome..................................... Bickerstaff Brainstem Encephalitis......................................................................... Tick Paralysis.......................................................................................................... Wernicke Encephalopathy....................................................................................... Miscellaneous Causes of Ophthalmoplegia............................................................ Transient Ocular Motor Disturbances of Infancy........................................................ Transient Neonatal Strabismus............................................................................... Transient Idiopathic Nystagmus............................................................................. Tonic Downgaze...................................................................................................... Tonic Upgaze.......................................................................................................... Neonatal Opsoclonus.............................................................................................. Transient Vertical Strabismus in Infancy................................................................ Congenital Cranial Dysinnervation Syndromes........................................................... Congenital Ptosis.................................................................................................... Marcus Gunn Jaw Winking (Trigemino-Oculomotor Synkinesis)......................... Congenital Fibrosis Syndrome................................................................................ Congenital Horizontal Gaze Palsy with Scoliosis.................................................. Möbius Sequence.................................................................................................... Monocular Elevation Deficiency, or “Double Elevator Palsy”............................... Brown Syndrome.................................................................................................... Other Pathologic Synkineses....................................................................................... Internuclear Ophthalmoplegia..................................................................................... Cyclic, Periodic, or Aperiodic Disorders Affecting Ocular Structures........................ Ocular Neuromyotonia.................................................................................................

309 309 309 311 313 315 316 318 318 319 323 326 326 328 335 336 337 338 338 338 338 339 339 339 339 341 342 342 342 343 343 344 346 347 348 350 351 352 353 356

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Contents

Ocular Motor Adaptations and Disorders in Patients with Hemispheric Abnormalities............................................................................... Eye Movement Tics..................................................................................................... Eyelid Abnormalities in Children................................................................................ Congenital Ptosis.................................................................................................... Excessive Blinking in Children............................................................................... Hemifacial Spasm................................................................................................... Eyelid Retraction.................................................................................................... Apraxia of Eyelid Opening..................................................................................... Pupillary Abnormalities .............................................................................................. Congenital Bilateral Mydriasis............................................................................... Accommodative Paresis.......................................................................................... Adie Syndrome....................................................................................................... Horner Syndrome.................................................................................................... References.................................................................................................................... 8 Nystagmus in Children............................................................................................... Introduction.................................................................................................................. Infantile Nystagmus..................................................................................................... Clinical Features..................................................................................................... Onset of Infantile Nystagmus................................................................................. Terminology............................................................................................................ History and Physical Examination.......................................................................... ERG......................................................................................................................... Hemispheric Visual Evoked Potentials................................................................... Overlap of Infantile Nystagmus and Strabismus.................................................... Eye Movement Recordings in Infantile Nystagmus............................................... Contrast Sensitivity and Pattern Detection Thresholds in Infantile Nystagmus....................................................................................... Theories of Causation............................................................................................. Visual Disorders Precipitating Infantile Nystagmus............................................... When to Obtain Neuroimaging Studies in Children with Nystagmus.................... Treatment................................................................................................................ Spasmus Nutans........................................................................................................... Russell Diencephalic Syndrome of Infancy............................................................ Monocular Nystagmus............................................................................................ Nystagmus Associated with Infantile Esotropia.......................................................... Torsional Nystagmus.............................................................................................. Horizontal Nystagmus............................................................................................ Latent Nystagmus................................................................................................... Nystagmus Blockage Syndrome.................................................................................. Treatment of Nystagmus Blockage Syndrome...................................................... Vertical Nystagmus...................................................................................................... Upbeating Nystagmus in Infancy............................................................................ Congenital Downbeat Nystagmus........................................................................... Hereditary Vertical Nystagmus............................................................................... Periodic Alternating Nystagmus.................................................................................. Seesaw Nystagmus....................................................................................................... Congenital versus Acquired Seesaw Nystagmus.................................................... Saccadic Oscillations that Simulate Nystagmus.......................................................... Convergence-Retraction Nystagmus....................................................................... Opsoclonus and Ocular Flutter............................................................................... Voluntary Nystagmus.............................................................................................. Ocular Bobbing............................................................................................................

356 357 357 357 358 360 360 362 362 362 362 362 364 366 383 383 384 384 385 385 386 388 388 389 389 393 393 394 404 405 410 412 413 413 413 414 414 417 417 417 417 418 419 419 420 420 421 421 421 423 424

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Contents

Neurological Nystagmus............................................................................................ Leigh Subacute Necrotizing Encephalomyelopathy............................................. Pelizaeus-Merzbacher Disease.................................................................................... Joubert Syndrome................................................................................................. Santavuori-Haltia Disease . .................................................................................. Infantile Neuroaxonal Dystrophy......................................................................... Carbohydrate-Deficient Glycoprotein Syndromes................................................ Down Syndrome........................................................................................................ Hypothyroidism.................................................................................................... Maple Syrup Urine Disease.................................................................................. Nutritional Nystagmus.......................................................................................... Epileptic Nystagmus............................................................................................. Cobalamin C Methylmalonic Aciduria and Homocystinuria............................... Familial Vestibulocerebellar Disorder.................................................................. Summary.................................................................................................................... References..................................................................................................................

424 425 425 425 426 426 426 426 426 426 427 427 427 427 427 429

9 Torticollis and Head Oscillations............................................................................. Introduction................................................................................................................ Torticollis................................................................................................................... Ocular Torticollis.................................................................................................. Head Tilts.............................................................................................................. Head Turns............................................................................................................ Vertical Head Positions......................................................................................... Refractive Causes of Torticollis............................................................................ Neuromuscular Causes of Torticollis.................................................................... Systemic Causes of Torticollis.............................................................................. Head Oscillations....................................................................................................... Head Nodding with Nystagmus............................................................................ Head Nodding without Nystagmus....................................................................... Visual Disorders.................................................................................................... Otological Abnormalities...................................................................................... Systemic Disorders............................................................................................... References..................................................................................................................

443 443 443 444 445 450 452 453 453 455 455 455 457 459 459 459 460

10 Neuro-Ophthalmologic Manifestations of Neurodegenerative Disease in Childhood................................................................................................ Introduction................................................................................................................ Neuronal Disease....................................................................................................... Neuronal Ceroid Lipofuscinosis........................................................................... Lysosomal Diseases................................................................................................... Gangliosidoses...................................................................................................... Mucopolysaccharidoses........................................................................................ Subacute Sclerosing Panencephalitis......................................................................... White Matter Disorders.............................................................................................. Metachromatic Leukodystrophy........................................................................... Canavan Disease (Spongy Degeneration of Cerebral White Matter)................... Krabbe Disease..................................................................................................... Pelizaeus–Merzbacher Disease............................................................................. Cockayne Syndrome............................................................................................. Alexander Disease................................................................................................ Sjögren–Larsson Syndrome.................................................................................. Cerebrotendinous Xanthomatosis......................................................................... Peroxisomal Disorders...............................................................................................

465 465 467 467 470 470 474 476 477 478 478 479 479 480 481 481 482 482

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Contents

Zellweger Syndrome............................................................................................. Adrenoleukodystrophy.......................................................................................... Basal Ganglia Disease................................................................................................ Pantothenate Kinase-Associated Neurodegeneration........................................... Wilson Disease...................................................................................................... Aminoacidopathies and Other Biochemical Defects................................................. Maple Syrup Urine Disease.................................................................................. Homocystinuria..................................................................................................... Abetalipoproteinemia............................................................................................ Mitochondrial Encephalomyelopathies..................................................................... Chronic Progressive External Ophthalmoplegia (CPEO)..................................... Leigh Subacute Necrotizing Encephalomyelopathy............................................. Mitochondrial Encephalomyelopathy and Stroke-Like Episodes (MELAS).............................................................................................. Myoclonic Epilepsy and Ragged Red Fibers (MERRF)....................................... Mitochondrial Depletion Syndrome..................................................................... Congenital Disorders of Glycosylation...................................................................... Horizons..................................................................................................................... References..................................................................................................................

483 483 485 485 486 486 486 487 487 488 489 490 492 492 492 493 493 494

11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease ......................................................................................... Introduction................................................................................................................ The Phakomatoses..................................................................................................... Neurofibromatosis (NF1)...................................................................................... Neurofibromatosis 2 (NF2)................................................................................... Tuberous Sclerosis................................................................................................ Sturge–Weber Syndrome...................................................................................... von Hippel–Lindau Disease.................................................................................. Ataxia Telangiectasia............................................................................................ Linear Nevus Sebaceous Syndrome...................................................................... Klippel–Trenauney–Weber Syndrome.................................................................. Brain Tumors............................................................................................................. Suprasellar Tumors............................................................................................... Arachnoid Cysts.................................................................................................... Cavernous Sinus Lesions...................................................................................... Hemispheric Tumors............................................................................................. Posterior Fossa Tumors......................................................................................... Brainstem Tumors................................................................................................. Tumors of the Pineal Region................................................................................. Meningiomas......................................................................................................... Epidermoids and Dermoids................................................................................... Gliomatosis Cerebri.............................................................................................. Metastasis.............................................................................................................. Complications of Treatment of Intracranial Tumors in Children......................... Hydrocephalus........................................................................................................... Hydrocephalus due to CSF Overproduction......................................................... Noncommunicating Hydrocephalus...................................................................... Communicating Hydrocephalus............................................................................ Common Causes of Hydrocephalus in Children................................................... Clinical Features of Hydrocephalus...................................................................... Effects and Complications of Treatment............................................................... Vascular Lesions........................................................................................................ AVMs....................................................................................................................

503 503 503 503 510 513 517 519 521 523 523 525 527 528 528 529 530 533 536 537 537 538 538 538 539 540 540 540 541 548 551 553 553

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Contents

Cavernous Angiomas............................................................................................ Intracranial Aneurysms......................................................................................... Isolated Venous Ectasia......................................................................................... Craniocervical Arterial Dissection........................................................................ Strokes in Children.................................................................................................... Cerebral Venous Thrombosis................................................................................ Cerebral Dysgenesis and Intracranial Malformations................................................ Destructive Brain Lesions..................................................................................... Malformations Due to Abnormal Stem Cell Proliferation or Apoptosis.............. Malformations Due to Abnormal Neuronal Migration......................................... Malformations Secondary to Abnormal Cortical Organization and Late Migration........................................................................................... Anomalies of the Hypothalamic–Pituitary Axis................................................... Encephaloceles...................................................................................................... Cerebellar Malformations..................................................................................... Miscellaneous............................................................................................................ Congenital Corneal Anesthesia............................................................................. Reversible Posterior Leukoencephalopathy.......................................................... Cerebroretinal Vasculopathies.............................................................................. Syndromes with Neuro-Ophthalmologic Overlap..................................................... Proteus Syndrome................................................................................................. PHACE Syndrome................................................................................................ Goldenhar Syndrome (Oculoauriculovertebral Dysplasia)................................... Delleman (Oculocerebrocutaneous) Syndrome.................................................... Encephalocraniocutaneous Lipomatosis............................................................... Incontinentia Pigmenti (Bloch–Sulzberger Syndrome)........................................ References..................................................................................................................

556 556 557 557 557 558 559 560 562 564 565 568 568 569 572 572 572 573 573 573 573 573 574 574 574 576

Index.................................................................................................................................. 597

Chapter 1

The Apparently Blind Infant

Introduction Visual unresponsiveness, in an otherwise healthy infant, is an alarming finding. Parents are staring down the cannon at a lifetime of potential blindness in their baby and are understandably anxious and inquisitive about the cause, severity, and prognosis of the condition. Depending on the underlying cause, the visual outcome may range from normal vision to complete blindness. The importance of establishing an accurate diagnosis in this setting is obvious. This chapter emphasizes the congenital visual disorders in infancy but includes some discussion of other visual system disorders that may manifest later in childhood. Decreased vision in infancy is generally due to developmental malformations or acquired lesions of the eyes, anterior visual pathways, or posterior visual pathways. Some causes involving ocular structures are readily identifiable on careful eye examination (e.g., cataracts, corneal opacities, refractive errors). Most congenital retinal dystrophies (e.g., Leber congenital amaurosis [LCA], congenital stationary night blindness [CSNB], achromatopsia) lack conspicuous ophthalmoscopic signs in early infancy (although arteriolar constriction is usually detectable on direct ophthalmoscopy)231 and therefore necessitate electroretinography (ERG) to establish the diagnosis.252 Because rod and cone waveforms mature slowly over the first year of life,183,232,610 we generally wait until 1 year of age to perform ERG. However, some specialized electrophysiology laboratories can derive meaningful information from studies performed earlier in infancy. Neurological visual impairment (e.g., cortical visual impairment [CVI]) can also be suspected clinically but requires neuroimaging to confirm. Mentally retarded or autistic children may appear visually unresponsive despite intact visual pathways. However, physically or mentally disabled children may also have occult ophthalmologic disorders that are difficult to diagnose because of their disability.173 Compared with children who are only blind, blind children who have additional neurologic handicaps show a more marked motor delay in postural and locomotor development and developmental skills such as

reach on sound.148 The diagnosis of disorders causing visual disability in infants and children depends first and foremost on a pertinent clinical history and a thorough examination. The information thus obtained should enable a clinician with a thorough grasp of the various clinical entities that may cause an infant to act blind to formulate a list of differential diagnoses. The correct diagnosis may then be reached using a thoughtful diagnostic paradigm to work up such patients (Fig. 1.1). Important clues to the cause of blindness in an infant may be derived from various aspects of the ophthalmologic evaluation. Infantile nystagmus is generally absent in children with cortical visual loss but is a common feature in those with congenital ocular or anterior visual pathway disorders. However, it also manifests infrequently in premature children with subcortical injury to the optic radiations (periventricular leukomalacia).286 As discussed in Chap. 8, many children with infantile nystagmus have underlying visual sensory disorders,187,211 even when the eyes appear structurally normal.608 It should be emphasized that the clinical appearance and the electro-oculographic waveforms of infantile nystagmus are identical whether or not a sensory deficit is detectable. If damage to ocular or anterior visual pathway structures occurs postnatally, the nystagmus is said to appear about 1 month after visual loss and develop only when the visual loss occurs prior to 2 years of age.93 The term “congenital nystagmus” is a misnomer because the nystagmus usually develops between 8 and 12 weeks of age.290 Thus, during the first 2 months of life, the absence of nystagmus (in infants who will subsequently acquire it) eliminates an important diagnostic clue in differentiating an anterior visual pathway disorder from lesions of the posterior pathway. This distinction becomes especially important when dealing with ocular conditions that show minimal ophthalmoscopic signs in early infancy (e.g., LCA) or at any age (e.g., achromatopsia, CSNB). Infants with nystagmus due to anterior visual pathway abnormalities typically have certain directions of gaze in which the nystagmus is less intense and the vision is better (null points or null zones). Such children may hold their heads at eccentric angles when fixating an object. The presence

M.C. Brodsky, Pediatric Neuro-Ophthalmology, DOI 10.1007/978-0-387-69069-8_1, © Springer Science+Business Media, LLC 2010

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1 The Apparently Blind Infant

Fig. 1.1 Flow chart depicts simplified diagnostic algorithm to be used in evaluation of the apparently blind infant

of such a preferential head posture usually implies the presence of fixation and functional vision. Unlike head nodding observed in patients with spasmus nutans, the head shaking seen in some patients with infantile nystagmus and poor vision presumably does not prolong foveation time and would not, therefore, be expected to improve vision. However, this is a controversial issue, with some authorities maintaining that the head shaking is a learned, voluntary neurovisual adaptation to improve vision.294 This is supported by the observation that the head shaking is noted during intense visual fixation.294 Infantile nystagmus due to sensory visual dysfunction should be distinguished from “roving” or “drifting” eye movements, the latter implying worse visual function. Roving eye movements are often seen in affixational patients with ocular or anterior visual pathway lesions whose vision is worse than 20/400. They consist of slow, aimless drifting of the eyes back and forth, usually horizontally.290 Jan et al290 likened fixation to an “anchor” without which the eyes “rove” back and forth. Nystagmus may be seen in some patients with roving eye movements when an object is held close enough to allow some fixation, or it may replace roving altogether in those whose vision improves.290 Jan et al290 observed that some characteristics of infantile nystagmus due to anterior visual pathway abnormalities correspond with the age of the onset of visual loss and level

of vision. Thus, nystagmus associated with extremely poor vision and/or vision loss before 6 months of age showed slow velocity and large amplitudes. Roving eye movements may represent one extreme in this continuum. In such infants, it is important to ask about disruption of normal sleep patterns as the absence of light entrainment of circadian rhythms may respond to oral melatonin. To summarize, nystagmus in an apparently blind infant is a valuable clinical marker for anterior visual pathway disease. Patients with bilateral disorders of the eye or anterior visual pathways may display roving eye movements if the vision is extremely poor with absent fixation; horizontal nystagmus, if the vision is less than 20/70 in the better eye, but fixation is present; or neither, if the vision is better than 20/70. The 20/70 cutoff is somewhat arbitrary, and variations on this are common. It is not unusual to see patients with CSNB, albinism, or blue-cone monochromatism, with visual acuity as good as 20/40, who display nystagmus. It is therefore probably an oversimplification to suggest that the nystagmus is a result of the visual deficit in such patients. The finding of ocular movement abnormalities, including nystagmus, in obligate carriers of blue-cone monochromatism who had visual acuity of 20/20 or better suggests that the nystagmus is intrinsic to the disease and can appear independent of the visual impairment.214 Theoretically, the two traits (the cone disorder and the associated nystagmus)

Introduction

may be inherited through linked genes rather than a single gene. The pupillary examination may provide valuable clues to the diagnosis in this setting to the extent that it can be reliably performed in small, uncooperative infants. Infants with blindness due to congenital retinal disorders show sluggishly reactive pupils, whereas the pupillary light reaction is usually spared in patients with pure CVI. A “paradoxical” pupillary response (initial constriction of the pupil to darkness) is classically present in CSNB (an isolated rod dystrophy) and congenital achromatopsia (an isolated cone dystrophy).39,175,470 It is not entirely specific to these disorders, however, and has been occasionally in a variety of developmental optic nerve disorders and even normal eyes.181 Paradoxical pupillary responses are often difficult to detect in infants but become more apparent during the first few years of life. As discussed in Chap. 8, the existence of melanopsin-containing retinal ganglion cells probably explains the paradoxical pupillary phenomenon. Certain congenital retinal disorders are characteristically associated with high refractive errors: high hyperopia in some types of LCA24,631 and high myopia in patients with CSNB and other congenital retinal dystrophies.346 Children with albinism may have high hyperopia or high myopia. These associations are not constant but are sufficiently frequent to warrant consideration of retinal disorders in a blind infant with nystagmus. The funduscopic appearance of the infant eye differs sufficiently from that of the adult eye in ways that may cause a diagnostic problem for the clinician. The optic discs of young infants often appear pale even when undue pressure on the globe is avoided while opening the eyelids. In equivocal cases, the presence of asymmetric disc appearance or peripapillary nerve fiber layer dropout may serve to corroborate the impression of genuine disc pallor. The fundus of young infants often has a pale, speckled appearance that may be difficult to distinguish from an abnormal fundus with ophthalmoscopy. Foveal hypoplasia is one of the more difficult causes of decreased vision to diagnose. Although a common feature of ocular albinism and aniridia, it occasionally occurs as an isolated familial disorder.446 Some congenital retinal disorders are associated with various degrees of photophobia (intolerance to light). Most notably, children with congenital achromatopsia display an extreme aversion to light. Marked photophobia may also be seen in achromatopsia, cone–rod dystrophy, and LCA. For reasons that are poorly understood, the extreme photophobia that characterizes achromatopsia may not be apparent early in infancy. Children with optic nerve hypoplasia and dominant optic atrophy are often mildly photophobic. Photophobia and glare arising from corneal or lenticular opacities can be readily classified as such on ocular examination. Even when other ocular disorders (e.g., media opacities, iritis, albinism, aniridia) are excluded, photophobia is not invariably of retinal origin. Photophobia has been reported in a patient with no

3

light perception.14 It seems plausible that, in patients with deficient photoreceptors, the newly discovered melanopsincontaining retinal ganglion cells may play a role in producing photophobia.57,237 A variety of neurological disorders are associated with photophobia, including meningitis, subarachnoid hemorrhage, migraine, trigeminal neuralgia, thalamic infarct, head injuries, and tumors compressing the anterior visual pathways.126,352,567 CVI can also be associated with photophobia (approximately one-third of patients in the study by Jan et al)293, presumably a result of associated thalamic damage or the cortical lesion itself. The photophobia in most patients is mild, with a tendency to resolve or diminish along with visual and other symptomatic improvement. Jan et al293 did not find a close relationship between the photophobia and the severity of the visual loss or the peripheral field defects. It should be noted that some patients with CVI show a compulsive tendency to gaze at room lights, especially fluorescent lights, or other bright objects, including the sun (light gazing).295 Photophobia and light gazing in patients with CVI are not mutually exclusive, with many children, paradoxically, exhibiting both.293 Jan et al293 feel that “light-gazing is such a compulsive behavior that even the presence of photophobia is not a deterrent.” The presence of mild photophobia cannot, therefore, be used to distinguish a primary retinal disease from cortical visual loss. However, more severe photophobia is highly suggestive of congenital retinal dystrophy. Some children with very poor vision habitually press their eyes with a finger or a fist. This “oculodigital sign” appears to be specific for bilateral congenital or very early-onset blindness due to retinal disease (most often in LCA but, rarely, in severe cases of retinopathy of prematurity [ROP]).291 It does not occur in children with only one blind eye, irrespective of cause, and is not seen in children with cortical blindness, media opacities, or optic nerve disease. Children who engage in frequent eye poking often exhibit sunken eyes because of orbital fat atrophy. This probably explains the observation that children with CVI do not show deep-set orbits.296 Jan et al291 speculated that eye pressing stimulates the visual cortex by mechanically triggering ganglion cell action potentials (phosphenes). However, we believe that this compulsion will ultimately prove to be a phantom limb syndrome. Eye pressing should be distinguished from eye rubbing and eye poking.292 For example, children who are sleepy tend to rub their eyes, and those with blinding ocular disorders tend to press their eyes, whereas severely mentally disabled children with self-injurious behavior may poke their eyes or even rub their corneas, sometimes with disastrous results.292 We have seen vigorous eye poking in children with Down syndrome leading to dislocation of the crystalline lens. In addition to eye pressing, children with retinal blindness may wave their fingers between their eyes and a bright light (finger waving). Finger waving may also be seen in photoconvulsive epilepsy and autism.

4

1 The Apparently Blind Infant

In children with congenital retinal blindness, functional magnetic resonance imaging (MRI) has shown the functioning visual cortex to be capable of supporting novel nonvisual functions through mechanisms of crossmodal plasticity.443 In these children, the occipital cortex participates in semantic processing of spoken language, with greater activation in the left occipital lobe, possibly relating to its spatial proximity to other left hemispheric language areas.469 The visual cortex can be activated by Braille reading in blind people.504 Patients say that they can localize hearing in space, so that their ears become like eyes. Because of cortical plasticity, these patients effectively acquire the ability to “see with their ears.”480 Some children with bilaterally poor vision display a phenomenon termed “overlooking” (Fig. 1.2). Instead of looking at the object of regard directly, affected children look above the object. Initially attributed to relative preservation of the inferior visual field in patients with certain retinal disorders,559 it was later reported to be not disease-specific but rather to represent a sign of bilateral central scotomas (and vision of 20/200 or worse) in children from a variety of causes.203

Nevertheless, most patients who display this sign are found to have congenital retinal disorders. Overlooking may initially be mistaken for lack of either cooperation or comprehension on the part of the patient. Indeed, some children and adults with central scotomata can be trained to “overlook” in order to establish a preferred retinal locus for reading by eccentric fixation.442 Cruysberg et al100 have found that children with overlooking frequently display dystonic posturing, in which the eyes and head are maintained in an upward position. These authors have attributed the overlooking in some of the children with neuronal ceroid lipofuscinosis to tonic upgaze (probably associated with brain stem pathology) rather than greater sensitivity of the lower retina. We believe that bilateral congenital visual loss directly inhibits the cerebellar flocculi which normally exert downward innervation via the vestibulo-ocular pathways. In the absence of macular function, the resulting tonic upgaze is not corrected by fixation. Blind patients at various ages may experience formed and/or unformed hallucinations.348 In the absence of epilepsy, these have been considered to represent a release

Fig. 1.2 Overlooking. Eight-year-old boy habitually views objects by looking above them. (a) Patient attempting to view target attached to camera’s lens. (b and c) Fundus pictures depict arteriolar narrowing and

mottling of retinal pigment epithelium. He was diagnosed as having rod–cone dystrophy

Introduction

phenomenon akin to the Charles Bonnet syndrome.519 Release phenomena refer to neurological disorders resulting from maladaptive activity of disinhibited neurons following damage to their source of inhibition. The fixation pattern of children with congenital visual defects follows a general pattern based on the extent of the vision loss: Children with vision better than 20/200 follow mostly with their eyes, those with 20/200 follow with both their eyes and head, and those with severe vision loss follow mostly with their head.290 Those with severe, congenital loss of vision have difficulty producing willful saccades into any suggested direction, with upward gaze being most markedly limited.290 The suggestion that this limitation in upgaze results because the superior fields are relatively unimportant (and thus infrequently utilized)290 may be valid although this dictum would appear to be more applicable to adults than to children, in whom (because of short stature) much of the world resides in the superior fields. A preference to view objects of regard at very close range is seen occasionally in normal children, reflecting a transient behavioral pattern. Children with poor vision often do so consistently to produce linear magnification (by shortening the focal length), to damp an existing nystagmus with convergence to improve vision or, in the case of uncorrected aphakic children, to induce a miotic response to increase depth of focus and create a pinhole effect.208 In the hyperopic aphakic child, the effects of linear magnification are more offset than those of increased image blur. Assessment of vision in children with severe visual deficits requires the utilization of specialized techniques or specific adaptations of techniques commonly used in children.201 The usual qualitative subjective methods of assessing the ability of the child to fix and follow, the steadiness of fixation, and the ability to maintain fixation are not helpful because most such children are affixational. It is practically more relevant to obtain a measure of overall visual function than to simply attempt measurement of distance visual acuity, which is difficult or impossible with severe visual impairment. Snellen acuity charts and similar tests are often useless. Parental accounts of the child’s visual behavior are usually good starting points. Patiently playing with affected children using a variety of toys of different colors and sizes provides useful information. Can the child recognize various objects in the environment, navigate effectively, and interact visually with other people? How does the child respond to the examiner’s face, larger objects, or movement of the parent nearby? How does the child react to penlight or to flickering of room lights on and off? A widening of the palpebral fissures when room lights are extinguished indicates the presence of at least light perception. A measure of vision can be achieved with the dynamic vestibulo-ocular reflex. This is evoked by holding the infant face-to-face with the examiner at about arm’s length and

5

spinning the infant around. The infant develops nystagmus as the eyes move counter to the direction of rotation and, at the limit of their excursion, make a quick movement in the opposite direction before the cycle is repeated. When the spinning stops, the inertia of the endolymph in the semicircular canal evokes nystagmus in the opposite direction that is dampened within 5 s in a child with good vision; the nystagmus lasts longer in a blind infant because of poor fixation. Visual function may also be qualitatively evaluated with the optokinetic reflex. When the visual field moves with respect to the eyes, as with a rotating optokinetic drum, the eyes track the moving field to the limit of their excursion and then make a recovery saccade in the opposite direction and so on, producing optokinetic nystagmus. Totally blind infants cannot generate optokinetic nystagmus. It has been estimated that visually impaired patients with horizontal nystagmus who are able to generate an optokinetic nystagmus to a vertically rotating drum should be able to achieve a significant measure of visual independence (i.e., they probably will not be required to be in a school for the blind). Generally, the vision of infants and children with various neurological diseases (e.g., cerebral palsy, mental retardation) is more difficult to evaluate irrespective of its level.188 Numerous studies have demonstrated a higher prevalence of subnormal acuity in children with cerebral palsy than in agematched controls.188,390 Hertz and Rosenberg247 found that the more severe the physical and neurological disability in children with cerebral palsy, the worse the visual performance on the acuity cards. They reasoned that poorer visual performance may reflect a combination of genuine poor visual function and difficulty in test administration and interpretation in this group of patients. The poorer vision in more severely affected children with cerebral palsy is not surprising, given the diffuse nature of the encephalopathic process. The vision of infants and children with cerebral palsy and mental retardation, with or without severe visual impairment, may be quantitatively evaluated with preferential looking techniques (e.g., Teller acuity cards).130,166,247 These techniques are also useful to document the visual improvement that occurs in some of these patients, especially those with CVI or delayed visual maturation (DVM).218 However, the results of Teller acuity card testing and similar tests of grating acuity should be interpreted with caution.334 Hoyt261 suggested that Teller acuity card methods have low sensitivity in detecting significant visual dysfunction during infancy. Infants who score entirely within the normal range with Teller acuity cards may later be found to have significantly reduced acuity with recognition visual acuity testing (e.g., Snellen acuity). Visual function in visually impaired children is more accurately evaluated with a combination of Teller acuity cards and a battery of other visual function behavioral tests than by Teller cards alone.132 Citing these and other potential pitfalls, Kushner337 cautioned against using the results of

6

grating acuity to classify children as legally blind for social service purposes as doing so may overestimate their visual function and unjustifiably deny financial benefits to qualified children. While conventional visual evoked potential (VEP) testing has not proved to be a reliable method of quantitative visual evaluation in patients with cerebral palsy, mental retardation, or severe neurological disease,19,61,176,182,395,396,557 modified techniques using sweep and step VEP may provide more accurate information.200,375,376 In children with poor vision and nystagmus due to anterior visual pathway disorders, Jan et al298 proposed the performance of the “unequal nystagmus test” to determine which eye, if either, has better vision. The test is performed by noting the degree of nystagmus while the child views an attractive toy at a distance with both eyes open and then with alternate eyes covered. The nystagmus is similar in patients with similar acuity in both eyes. When the acuities are different, wider and slower excursions of nystagmus are noted in the worse eye, and faster and smaller-amplitude nystagmus is noted in the better eye. Other batteries of tests with the stated purpose of evaluating vision in children with severe visual deficits have been recently described.132 Much valuable clinical information about visual impairment in children has been gleaned from the collaborative efforts of various subspecialists working as multidisciplinary diagnostic teams. The collaborative efforts of pediatric ophthalmologists, pediatric neurologists, electrophysiologists, behavioral psychologists, and developmental specialists, among others, will be needed to further enhance our understanding of the various disorders discussed within. Besides rendering accurate diagnoses and treating the remediable causes of blindness, the clinician should be acquainted with the mental, psychological, neuroendocrinologic, developmental, and educational needs of visually impaired children. Knowledge of the various available programs that may act as resources for affected children and their families is essential, especially because, unfortunately, definitive treatment of many of the underlying conditions remains elusive. This chapter addresses causes of blindness that are neurological in origin or that have features that warrant including them in the differential diagnoses of neurologic causes of blindness. Emphasis will be placed on CVI and related disorders. Causes of blindness due to congenital ocular disorders associated with obvious structural ocular abnormalities (e.g., albinism, congenital cataracts, chorioretinal colobomas, ROP) are discussed elsewhere.

Hereditary Retinal Disorders Causes of blindness in infancy due to opacities of the optical media or to refractive errors are usually discovered during a

1 The Apparently Blind Infant

thorough ophthalmologic evaluation. Optic nerve hypoplasia may be potentially overlooked if the examiner mistakes the border of the outside ring in the classic double-ring sign with the border of the disc.342 Generally, hereditary diseases of the retina should be suspected in children who present with a bilateral decrease in vision, light sensitivity, color deficiency, visual impairment confined to either daytime or nighttime, and a tendency to bump into objects and to hold objects very close to the face. A family history of similarly affected members may be elicited, and a history of consanguinity is highly suggestive, because many of these disorders are recessively inherited. Many patients with congenital retinal dystrophies have characteristic features that are highly suggestive, if not virtually diagnostic, of a specific underlying disorder. For instance, profound photophobia and high-frequency nystagmus in a blind child with otherwise normal-appearing eyes suggest rod monochromatism, whereas blindness and nystagmus in the presence of diffuse pigmentary retinal changes suggest LCA. Unfortunately, not all patients can be pigeonholed into these classic presentations; some require further investigation, for instance, the blind infant with an ostensibly normal fundus appearance who has LCA. Many congenital retinal dystrophies are distinguishable on the electrophysiological level but remain otherwise poorly defined as simply cone dystrophies, cone–rod dystrophies or rod–cone dystrophies, although diagnosis at the molecular level is rapidly becoming available.

Leber Congenital Amaurosis LCA is a congenital retinal dystrophy involving both rods and cones.244 It is usually autosomally recessive, but occasionally autosomal dominant.565 It is characterized by the onset of blindness at birth, a variable fundus picture, and an absent or extremely attenuated ERG. Photophobia is seldom present and is never of the degree found in congenital achromatopsia. Patients show roving eye movements, poorly reactive or unreactive pupils, and a positive oculodigital sign of Franceschetti (pushing on the eyes or rubbing them with a finger or fist) to create phosphenes. The fundus picture may appear normal at birth or shortly thereafter. However, a variety of pigmentary changes may develop over months or years (Fig. 1.3). These include salt-and-pepper pigmentation, yellowish flecks, a mosaic pattern, periarteriolar distribution of yellow lesions, a retinitis pigmentosa–like fundus, macular colobomas that may gradually enlarge, and pseudopapilledema.549 The abnormal retinal appearance may be progressive, leading to a variable picture of chorioretinal degenerative changes, vascular narrowing, and optic disc pallor. The vascular narrowing is probably present at birth but is easily overlooked.

Hereditary Retinal Disorders

7

Fig. 1.3 (a) Fundus appearance of infant with LCA shows attenuated retinal arterioles but little, if any, pigmentary changes. (b) Fundus appearance in 5-year-old boy with LCA shows pallor of optic disc, retinal arteriolar attenuation, and diffuse mottling of retinal pigment epithelium

Patients have a higher-than-normal risk of developing keratoconus and cataracts later in life. The pattern VEP is absent, as is the flash VEP in most cases. This disorder is now known to comprise a number of genetically heterogeneous conditions.241,549 The visual acuity ranges from 20/200 (rare) to no light perception.346,347 Parents can be reassured that the visual impairment is usually nonprogressive, despite the visible progression of the fundus findings.241 Exceptional cases showing further visual deterioration with time belong either to the subgroup of LCA with macular colobomas or to harbor cataracts or keratoconus.241 Conversely, some patients with Leber amaurosis may show some visual improvement in the first several years of life, enough to have visually guided behavior and measurable grating acuity. A similar phenomenon occurs in some patients with albinism and some children with optic nerve hypoplasia. It is attributed to a secondary delay in maturation of the posterior visual pathways.166,168 As many as half of the patients with LCA examined before 1 year of age may show a normal retinal appearance,241 although careful examination using direct ophthalmoscopy shows marked arteriolar narrowing. Because nystagmus may not be present during the first few months of life, the normal retinal appearance in many infants with LCA may pose a diagnostic dilemma, raising the specter of CVI or DVM, among other conditions. The ERG is the definitive test in establishing the diagnosis of LCA. The range of refractive errors associated with LCA is wide, ranging from high hyperopia to high myopia, with high hyperopia being far more common. Some studies have suggested that associated high hyperopia differentiates a distinct subset of the disorder, uncomplicated by neurologic or systemic disease.180a Subsequent studies disproved this distinction, showing that high hyperopia (which is associated with the CRB1 mutation)3 cannot be

used to differentiate complicated cases from uncomplicated ones.565 One to three percent have nephronophthiasis, osteoporosis, ataxia, cardiomyopathy, or cerebellar disease. The purported association with mental retardation is mainly attributable to the inadvertent inclusion of children with peroxisomal disorders. Although some mutations (RPGRIPI and CRB1) are expressed in the brain, there are no reported LCA patients with these genotypes who have brain abnormalities.565 A careful consideration of neurologic, systemic, and biochemical disorders should be offered to patients with LCA, regardless of refractive error.346 The optic discs appear normal early but may later develop pallor (Fig. 1.3). Sullivan et al549 retrospectively reviewed the optic disc findings in 77 patients with LCA. Sixty-nine percent showed normal discs, 23% showed varying degrees of optic atrophy, 3% showed pseudopapilledema, and 1% showed gray discs. They concluded that the optic discs are frequently normal, even in older patients with LCA, and suggested that the finding of significant optic atrophy in an infant suspected of having LCA should suggest one of the systemic, metabolic disorders associated with infantile retinal dystrophies (e.g., peroxisomal disorders). In our experience, careful examination using direct ophthalmoscopy shows a striking diffuse arteriolar narrowing in otherwise normal optic discs. A number of systemic disorders manifesting a congenital retinal dystrophy in association with other neurologic or systemic disorders have been previously grouped with LCA. These include medullary cystic kidney disease or nephronophtisis (Senior–Löken syndrome), cone-shaped epiphyses of the hand and cerebellar ataxia (Saldino–Mainzer syndrome), vermis hypoplasia, ocular motor disturbances and neonatal respiratory problems (Joubert syndrome), psychomotor retardation, mental retardation, autistic behavior, hydrocephalus, deafness, epilepsy, or cardiomyopathy.

8

The admixture of neurologic or systemic disease in patients who have been diagnosed with LCA is well-recognized.565 Patients with systemic diseases that do not manifest early in infancy continue to be misdiagnosed as having LCA because vision loss occurs early and dominates the clinical phenotype early in the course of the disease. One of the common and challenging diagnostic situations involves the blind infant with a provisional diagnosis of LCA who shows behavioral and developmental abnormalities that are interpreted by some as being caused by the visual impairment and by others by the associated neurological abnormalities. The association of an LCA ocular phenotype with autism or other neurodevelopmental diseases has been well documented by a number of authors.12,56,88,155,441,518 Autistic behavior consequent to early interactive visual experiences can be prevented through specific strategies of intervention.155 The ever-increasing identification of distinct disorders once grouped with LCA and the heterogeneity of the findings associated with LCA reflect the fact that LCA is not a single nosologic entity but rather a group of genetically heterogeneous disorders, many of which have now been characterized.9 Furthermore, many children with peroxisomal disorders and blindness get classified as having LCA until their underlying metabolic disturbance becomes evident.226 It should be noted that the various disorders of congenital retinal dystrophy described earlier do not have identical clinical presentations. For instance, most children with neurometabolic disorders who are misdiagnosed as having LCA early in life show better visual acuity than the typical child with LCA. Thus, the finding of an extinguished ERG in a young child with good vision should arouse clinical suspicion of an underlying neurometabolic syndrome. A number of oculocerebral disorders associated with peroxisomal dysfunction and a high blood level of very longchain fatty acids177,465 may simulate LCA. The peroxisome is a single-membrane subcellular organelle that mediates the catabolism of very long-chain fatty acids, phytanic acid, and pipecolic acid, as well as the biosynthesis of some types of membrane lipids.539 Cerebro-hepato-renal syndrome (Zellweger syndrome), neonatal adrenoleukodystrophy, and infantile Refsum disease are associated with peroxisomal dysfunction and progressive deterioration of rod and cone function.625 All three conditions show rapidly progressive neurological deterioration, but the initial manifestation before this deterioration occurs may resemble LCA both clinically and electrophysiologically. In fact, it is felt that some patients described in the older literature (before the advent of advanced metabolic testing) with LCA and neurological disease might have had one of these disorders. In an infant with poor vision and nystagmus, the findings of seizures, failure to thrive, developmental delay, neurosensory deafness, neurological deterioration, or dysmyelination of the brain on MRI should suggest a peroxisomal disorder and

1 The Apparently Blind Infant

prompt a metabolic workup. Therefore, infants or young children suspected of harboring LCA, especially if other neurodevelopmental abnormalities exist, should not only have a thorough ophthalmologic examination but should also be seen by a pediatrician or pediatric neurologist experienced in metabolic disorders.112 A minority of patients with LCA may show associated neuroimaging abnormalities, such as ventriculomegaly, dysmyelination, or cerebellar vermis hypoplasia.540 The finding of vermis hypoplasia should suggest a diagnosis of Joubert syndrome (discussed below). Recently, CPE290 mutations, which were first identified in Joubert syndrome, were discovered in patients with seemingly pure LCA (without structural or functional brain and without renal disease). 118 A dosage model has been proposed that is similar to the dosage model that attempts to explain that retinitis pigmentosa, cone-rod dystrophy, and Stargardt macular dystrophy are all caused by ABCA4 mutations.118 According to this model, when the CEP290 protein is completely abolished, Joubert syndrome ensues, while if there is remaining CEP290 protein, albeit low and abnormal, neurological and renal disease is prevented, and only photoreceptor death occurs, causing isolated LCA. Does early-onset blindness due to ocular disorders such as Leber amaurosis affect myelination and maturation of the posterior visual pathway? The optic radiations normally appear hyperintense on T2-weighted images and hypointense on T1-weighted images.320 Although the issue remains controversial,102,541 quantitative MR imaging has shown that early-onset blindness produces reduced white matter volumes in the optic tract, optic radiations, and significant gray matter losses in the visual cortex.451 In one child with bilateral anophthalmia, MR imaging showed complete agenesis of the anterior and posterior optic pathways.10 LCA should be differentiated from nonocular causes of blindness like cortical blindness or DVM. Infants with LCA may be thought to have CVI in the first few weeks of life, before the nystagmus appears. Conditions that are commonly mistaken for LCA include CSNB, achromatopsia, infantileonset retinitis pigmentosa, peroxisomal disorders, Joubert syndrome, and neuronal ceroid lipofuscinosis.346 ERG is particularly helpful in distinguishing between the various disorders in infants with poor vision, nystagmus, and a seemingly normal ocular examination.252 The three most common such disorders are LCA, CSNB, and congenital achromatopsia. LCA is characterized by extinguished or markedly attenuated ERG. Achromatopsia shows markedly attenuated or nonremarkable cone-mediated ERG; the rodmediated ERG is usually spared. CSNB shows a normal a wave but an attenuated b wave on rod-mediated ERG; the cone-mediated ERG may also be abnormal. It is important to realize that ERG is not a prognostic test. It simply indicates which retinal components are affected and to what extent,

Hereditary Retinal Disorders

but the test needs to be repeated if one is to determine whether or not a disorder is progressive (and at what rate) in a given individual. Eleven different genes are responsible for 70% of cases of LCA.544 They involve six functional categories: phototransduction, cell polarity, intracellular transport, protein chaperoning, transcription regulation, and cell cycle progression.544 The identification of distinctive clinical characteristics in patients lumped together under the syndrome of LCA is becoming increasingly important diagnostically as well as therapeutically.565 For example, some patients with the CRX genotype show spontaneous marked improvement in vision in the first decade of life.324 Other mutations may give rise to gene-specific pharmacologic intervention, retinal transplantation, stem-cell based approaches, and gene therapy.13,56,118,323 The best known example of therapy for retinal diseases in general, and for LCA in particular, involves the Briard dog model, in which the defective RPE65 gene was replaced by a normal copy via transfer by an adeno-associated viral vector. Gene therapy in humans with this mutation has recently been shown to produce visual improvement and has so far been found to be safe and effective.28,379,396a Subsequent analysis of treated eyes by ERG revealed a substantial restoration of both rod and cone function confirmed by behavioral tests.6,431 Genetic testing also yields valuable prognostic information by identifying autosomal dominant (CRX) mutations or cases resulting from uniparental isodisomy.

Joubert Syndrome Joubert syndrome was first described in 1969.302 It is characterized by a variable combination of the following features: episodic neonatal tachypnea and apnea, rhythmic protrusion of the tongue, ataxia, hypotonia, and variable degree of psychomotor retardation.343 The episodic tachypnea presents in the neonatal period and alternates with periods of apnea, resembles the panting of a dog, and usually resolves or improves. Notable associated eye findings may include congenital retinal dystrophy, nystagmus, abnormal supranuclear eye movements, colobomas, or congenital ocular fibrosis and other forms of strabismus. A congenital retinal dystrophy is seen in approximately 50% of patients with Joubert syndrome.277,319 This retinal dystrophy was at first labeled a variant of LCA. It was subsequently considered different from LCA in that the visual loss is usually not as profound (20/60– 20/200, compared with counting fingers or worse), and the VEPs are relatively spared (mild to moderate reduction in amplitudes, compared with absent or highly attenuated signals). Both conditions show flat or highly attenuated ERGs. Ocular motor disorders described in Joubert syndrome include slow, hypometric saccades, ocular motor apraxia, periodic

9

alternating gaze deviation, pendular torsional nystagmus, see-saw nystagmus, skew deviation, and defective smooth pursuit as well as optokinetic and vestibular responses.343 Dysgenesis or hypoplasia of the cerebellar vermis is a typical and a highly characteristic morphological feature of Joubert syndrome and Related Disorders (JSRD)316 (Fig. 1.4). MR imaging shows a “molar tooth” sign in the axial plane, which consists of an abnormally deep cleft in the isthmus of the brainstem, thickened and reoriented superior cerebellar peduncles, and vermian hypoplasia.332 The pathological findings include vermian hypoplasia or dysplasia, elongation of the caudal midbrain tegmentum, and marked dysplasia of the caudal medulla. These findings reflect a lack of decussation of the superior cerebellar peduncles, central pontine tegmental tracts, and corticospinal tracts.456 Genetically, Joubert syndrome is a heterogenous group of disorders with mapping to more than one chromosome site (9q34, 11p12-q13, 2q13, and 6q23). Two genes have been linked to Joubert syndrome. Mutations of AHI1 or Jouberin on chromosome on chromosome 6p23 usually presents with the classic form of Joubert syndrome.128,159 Patients with mutations of CEP290 on chromosome 12q usually present with additional ocular and kidney involvement.580 Classic Joubert syndrome has also been mapped to chromosome 9q34.3,497 while Joubert syndrome with additional eye and kidney involvement has been mapped to chromosome 11p12-q13.3.580 Complete agenesis of the cerebellar vermis may also occur, which is usually distinguishable from the vermian agenesis that occurs with the Dandy–Walker variant by the associated findings. For instance, hydrocephalus and cystic dilatation of the fourth ventricle do not occur with Joubert syndrome. However, 10% of patients with a Dandy–Walker cyst have the molar tooth sign and are clinically similar to classic Joubert syndrome patients. Such patients are referred to as Dandy–Walker Plus.383 Additional sporadic structural defects reported in association with the Joubert syndrome include other cerebellar midline defects, a dilated fourth ventricle, short neck, occipital meningoencephalocele, microcephaly, unsegmented midbrain tectum, absence of the corpus callosum and brainstem, multicystic kidneys, congenital ocular fibrosis, and bilateral retinal colobomas. The condition may be sporadic, but familial cases are inherited in an autosomal recessive pattern. The Joubert syndrome has some overlapping features with the Arima syndrome (cerebro-oculohepato-renal syndrome), COACH syndrome, and Senior-Löken syndrome.516 The Arima syndrome exhibits pigmentary degeneration suggestive of LCA, severe psychomotor retardation, hypotonia, characteristic facies, polycystic kidneys, and absent cerebellar vermis. Joubert and Arima syndromes may be distinguished by such clinical features as neonatal tachypnea, which is one of the cardinal features of Joubert syndrome. The ocular motor features of this condition are discussed in Chap. 7.

10

1 The Apparently Blind Infant

Fig. 1.4 Joubert syndrome. (a) Sagittal MR image shows severe vermis hypoplasia with large fourth ventricle. (b) Axial MR image shows the classic “molar tooth” sign

Congenital Stationary Night Blindness This condition is clinically classified into two subtypes: one with a normal fundus appearance and another with an abnormal fundus.414 Subtypes of CSNB with abnormal fundi include Oguchi disease and fundus albipunctatus. Vision of affected children ranges from 20/20 to 20/200 and does not deteriorate with time. Those with X-linked recessive CSNB have reduced vision with a myopic refractive error and typically show nystagmus. The autosomal recessive or dominant cases generally do not show nystagmus. Typically, the ERG shows a normal a wave and an attenuated b wave under scotopic conditions. The dark adaptation curve is usually 2–3 log units higher than normal. The recognized genetic subtypes of CSNB are detailed in Chap. 8.

Achromatopsia This is a congenital, nonprogressive defect of the cone photoreceptors. Affected children present with nystagmus, decreased vision, defective or absent color discrimination, photophobia, and paradoxical pupils (initial constriction upon dimming ambient light). The fundus appears normal. Achromatopsia has been subdivided into two categories: complete (autosomal recessive), in which cone function is absent and vision ranges from 20/200 to 20/400, and incomplete

(X-linked), in which residual cone function is present and vision may range from 20/40 to 20/400. The incomplete variety may be further subdivided on the basis of residual sensitivity to one or a combination of red, green, or blue light stimuli. The associated nystagmus in some incomplete cases may improve with time or may disappear altogether. The ERG is characterized by diminished or absent cone response and a normal rod response.

Congenital Optic Nerve Disorders Some congenital disorders of the optic nerves should be mentioned in the context of infant blindness, although these disorders are discussed at length in other chapters. The most relevant for this discussion is bilateral optic nerve hypoplasia (Chap. 2) and congenital, or early-onset, optic atrophy (Chap. 4). Neuroimaging studies are generally required in patients with optic nerve hypoplasia as a part of both a neuroendocrinologic workup (i.e., the presence of posterior pituitary ectopia on MRI is a useful marker for associated pituitary gland dysfunction) and a neurodevelopmental evaluation (i.e., the presence of hemispheric abnormalities on computed tomography [CT] or MRI scanning is a clinical marker for associated developmental abnormalities).77,78,529 Congenital or early-onset bilateral optic atrophy always warrants neuroimaging to look for supra-sellar tumors (craniopharyngioma, glioma) or hydrocephalus.475

11

Cortical Visual Insufficiency

Cortical Visual Insufficiency Cortical visual insufficiency (CVI) is now the single greatest cause of visual impairment in young children in developed countries.138,178,197,262,264,481,485 The proportion of blindness in children attributable to this disorder has increased as a result of two major factors: (1) Advancement in neonatal medicine has saved the lives of an increasing number of premature infants and children with severe brain damage. (2) Advancement of ophthalmologic techniques to treat other causes of blindness in children, such as cataracts, has reduced the proportion of such children in schools for the blind. Medical advances to prevent and treat CVI have lagged behind.262 At the outset, clarification of certain aspects of related terminology may be useful.158 Cortical blindness refers to complete loss of vision resulting from disorders of the geniculostriate pathway. Some investigators prefer to more accurately refer to the visual deficit as cerebral rather than cortical because injury to the optic radiations, occipital cortex, or higher cortical centers can selectively diminish vision. The term cortical continues to be the one in common use and will be used in this discussion. Furthermore, because the degree of vision loss resulting from a cortical insult is highly variable, rarely complete, and often shows a degree of recovery, many investigators prefer the term CVI to cortical blindness to avoid the dismal prognostic implications suggested by the term blindness.296,613 We have advocated the term subcortical visual loss for the focal white matter lesions confined to the optic radiations in premature infants (periventricular leukomalacia).76 Despite the apparent selective white matter involvement on neuroimaging, however, these patients often have a more global brain injury, with many symptoms referable to higher cortical dysfunction.253,254,262,264,265,463 As a corollary, children whose injury appears to be confined to the subcortical visual system on neuroimaging can still have significant cognitive visual disturbance. The general term cerebral visual loss gently but nonspecifically encompasses both entities, along with the temporary dysfunction of higher cortical centers that may define DVM (discussed below). Perinatal injury to the developing visual system is a common cause of visual impairment and neurologic morbidity in children.35,174,210,265,271,341,599 Although multiple etiologies are recognized, hypoxic-ischemic events are most frequently implicated.35,174,210,265,271,341,599 Injuries to the retrogeniculate visual pathways are heterogenous with respect to cause, mechanism, timing, degree, location, and duration. They fall into two general groups comprising term injury predominantly to the visual cortex and adjacent white matter, and preterm injury to the subcortical white matter (periventricular leukomalacia). As discussed below, these two patterns of injury give rise to distinct constellations of neuro-ophthalmologic signs.76 The territorial distributions and neurologic consequences of perinatal retrogeniculate injury reflect the developing

brain’s level of maturity at the time of injury (Table 1.1).34,37, 38,91,144,174,265,280,281,349,599 In the full-term infant, the brain receives its vascular supply primarily from the major cerebral arteries, and its watershed areas lie at the interfaces between the major cerebral arterial distributions.35,174,599 Mild degrees of term hypoxic-ischemic injury produce watershed infarctions in the arterial border zones (i.e., the parieto-occipital and parasagittal cortex), injuring both gray and white matter, usually resulting in encephalomalacia. Severe hypoxic-ischemic insult in the term newborn may also involve the deep central gray matter (thalami and basal ganglia) and may be associated with spastic quadriplegia, microcephaly, and seizures.599 Perinatal cortical visual loss at term is usually attributed to hypoxic-ischemic injury, but less common etiologies include meningitis, encephalitis, nonaccidental head trauma, hydrocephalus, and metabolic derangements.35,174,265,599 Inciting events include ruptured or occluded umbilical cord, ruptured uterus, profound bradycardia, or cardiocirculatory arrest, polyhydramnios, maternal eclampsia, placental abruption, and fetal-maternal transfusion with resultant hypovolemia.38 The ability of MR imaging to readily differentiate gray matter from white matter makes it particularly useful for distinguishing cortical from subcortical retrogeniculate injury.38,86 In hypoxic-ischemic term injury to the brain, MR imaging shows variable, high- or low-signal changes on both T1- and T2-weighted images in the cerebral cortex, basal ganglia, or thalamus, depending on the severity of injury and the timing of the injury in relation to the study (Fig. 1.5). High-signal changes on T1-weighted images, especially in the parasagittal cortex and deep gray matter, are often present in term hypoxicischemic injury. Diffusion-weighted imaging shows areas of hyperintensity (restricted diffusion) in injured tissue earlier than findings on conventional imaging.35,174,599 Proton spectroscopy shows elevated lactate in injured areas of the brain.35 The original definition of CVI is derived almost entirely from experience with adult patients who have acquired cortical lesions.253,254 In this context, the diagnosis of CVI requires very poor vision, normal pupillary light reflexes, no nystagmus, and an otherwise normal eye examination. However, Table 1.1 Morphology of lesion relative to timing of central nervous system injury Central nervous system lesion

Timing

Pathophysiology

First trimester

Liquifaction necrosis Congenital malformation Tissue resorption No gliosis Hypoxia-ischemia to Periventricular leukomalacia subcortical white matter with gliosis Hypoxia-ischemia to Encephalomalacia (cortical + subcortiparasigittal cal) watershed zones with gliosis

Late second to third trimester Term

12

1 The Apparently Blind Infant

which do not synapse at the lateral geniculate nucleus but at the pretectal area, may also be susceptible to transsynaptic degeneration.572 Fourth, affected patients may display intermittent, unsustained bursts of nystagmus. Characteristic wandering eye movements seen in severe CVI should not be mistaken for nystagmus. Finally, the eye examination may reveal coexistent optic atrophy due to associated anterior pathway disease or transsynaptic degeneration of the retinogeniculate pathway.

Causes of Cortical Visual Loss A wide range of etiologies for CVI have been documented.76,262,264,318 These include trauma (accidental and nonaccidental),217,229 neurodegenerativedisorders,hypoglycemia,425 hemodialysis,415 infectious disorders,63 encephalitis/meningitis,4,5,146,439,531,562 hydrocephalus,17,96,371 and seizures.328 The major causes of cortical visual loss are discussed below.

Perinatal Hypoxia-Ischemia Fig. 1.5 Bilateral occipital encephalomalacia. Axial T1-weighted MR image shows bilateral occipital injury with loss of the posterior periventricular white matter and ventricular dilatation. With permission from Brodsky et al76

congenital or early-acquired cortical visual loss in children may be quite different from the acquired variety in adult life. The immature, extremely adaptable infantile brain may react differently to injury than the adult brain. As the entity of CVI in infants and children is explored further in this chapter, the reader should keep in mind that some qualifying remarks are necessary for each of the classic features included in the above definition. First, the visual loss need not be severe; CVI represents a spectrum of disability. Second, although most children with cortical visual loss have obvious neurologic deficits,281,318 the diagnosis of CVI should be suspected in all children with unexplained bilaterally decreased vision, even when there are no overt neurological problems.372 In this setting, a history of prematurity is highly suggestive of periventricular leukomalacia (discussed below). Third, the pupillary reaction to light may not be completely normal. This finding may be due to coexisting disorders of the anterior visual pathway, the sympathetic and parasympathetic pathways, transsynaptic degeneration of the pupillomotor fibers if the cortical lesion is prenatal, or direct geniculate injury in some cases.572 On the basis of clinical evidence derived from patients with congenital homonymous hemianopia due to congenital occipital lesions, it appears that the pupillomotor fibers,

The most common cause of CVI in children has long been considered to be hypoxic brain insult (asphyxia).262,264–266 In full-term infants who sustain hypoxic-ischemic injury, neurons that are primarily in the deep gray nuclei and perirolandic cortex are most likely to be injured.160,597,598,601 Hypoxia and the accompanying hypercarbia causes a loss of vascular autoregulation in the brain, resulting in a pressure-passive blood flow.116 The resulting pattern of injury has been described to be within the “watershed zones” of the cerebral cortex (the areas between the anterior and middle cerebral artery circulation and the middle and posterior cerebral artery circulation).160,262,264–266 In full-term infants, the watershed zones lie in the regions between the anterior and middle cerebral arteries and between the middle and posterior cerebral arteries. The resulting watershed area is termed the parasagittal region. Ischemic lesions most commonly involve either the frontal region or the parieto-occipital region at the posterior parasagittal area (so that the visual cortex is particularly susceptible to injury). Many watershed zones between two arteries exist in the brain, but the only triple watershed areas are the parietooccipital areas and the area of the body of the caudate nucleus. It is in these watershed zones that tissues are most vulnerable to hypoxia and hypotension. It should be noted that damage to the radiations carries a worse prognosis than damage to the cortical areas.341 Ischemic brain damage may occur perinatally or any time after birth, as it may occur following respiratory or cardiac arrest.

13

Cortical Visual Insufficiency

However, the longstanding view that neonatal brain injury is uniform and due primarily to acquired insults such as birth asphyxia has also undergone some revision.27 Most neonatal brain injury is now viewed as metabolic, whether from transient ischemia-reperfusion events or from defects in inherited metabolic pathways expressed soon after birth.160 In addition to hypoxia, it is known that oxidative stress, excitotoxicity, inflammation, and apoptosis play important roles.160 The cellular and molecular mechanisms involved in the pathogenesis of cortical visual loss are becoming clear. Oxidative stress and excitotoxicity, through downstream intracellular signaling, produce both inflammation and repair. Cell death begins immediately and continues over days to weeks. The cell-death phenotype changes from an early necrotic morphology to a pathology resembling apoptosis.160

Postnatal Hypoxia-Ischemia Perinatal strokes, defined as occurring between 28 weeks of gestation and 7 days of age, have an estimated incidence of up to 1 in 4,000 live births.374 They are often arterial in origin and ischemic in nature160 although at least 30% are due to sinovenous thrombosis.123 Prepartum factors such as preeclampsia and intrauterine growth restriction have been implicated.617 Most strokes occur at or near the time of birth, resulting in hemiplegic cerebral palsy. Coagulation abnormalities (decreased levels of protein C, protein S, and antithrombin III and elevated plasma levels of Lp[a] lipoprotein and homocysteine), as well as certain genetic mutations and polymorphisms (including factor V Leiden G 1691A, factor II G20210A, and methylenetetrahydrofolate reductase C677T) have been identified as risk factors,222,402 especially in neonates with stroke due to cerebral venous thrombosis.160,616 Newborns with stroke usually have more than one risk factor, and perinatal complications such as hypoxic-ischemic events are frequently present.160,242,616 Postnatal hemodynamic changes associated with generalized hypotension, cerebral angiography, cardiac surgery, cardiac arrest, and air embolism may result in CVI by diminishing the blood supply to the posterior visual pathway. Hypertensive crisis may result in occlusion of the posterior cerebral arteries, causing a similar problem. Transtentorial herniation may cause compression of the posterior cerebral arteries. Infarcts may also result from vascular malformations or from congenital central nervous system (CNS) tumors directly compressing cranial vessels. The most common cause of embolic phenomena in the neonatal brain is congenital cyanotic heart disease. Thrombotic disorders may result from polycythemia, trauma, meningitis, and obliterative arteritis associated with neurofibromatosis and sickle cell disease. Anoxia may have been the etiology of cortical blindness in a patient with acute intermittent porphyria.339

Cerebral Malformations A variety of cerebral malformations may be associated with CVI or congenital homonymous hemianopia. These include occipital or parietal encephaloceles, Chiari malformations, Dandy–Walker complex, hydranencephaly, porencephalic cysts (from either vascular compromise, infective processes, or hemorrhagic dissection),546 or neuronal migrational abnormalities.32 During the seventh week of gestation, a neural layer known as the germinal matrix is formed through proliferation of neurons in the subependymal layer of the walls of the lateral ventricle. In the eighth gestational week, these neurons begin to migrate centrifugally from the germinal matrix to form the cerebral cortex. The route of neuronal migration is guided by radial glial fibers extending from the germinal matrix to the cortex. Events that interfere with this migration (e.g., infections, ischemia, metabolic derangements) can cause a migrational abnormality. A migrational anomaly shows normal neurons in an abnormal location, somewhere between the walls of the lateral ventricles and the cortex. The clinical manifestations of migrational abnormalities depend on the severity, nature (diffuse versus focal), and location of the abnormalities. Differences in the timing and severity of the migrational arrest result in different categories of abnormalities. The most severe of the migrational anomalies is lissencephaly, which includes agyria (absence of gyra on the surface of the brain) or pachygyria (a few broad, flat gyri), or both (Fig. 1.6). In polymicrogyria, the neurons reach the cortex but distribute abnormally,

Fig. 1.6 Proton density axial MR imaging scan from child with cortical blindness and Walker–Warburg syndrome demonstrating lissencephaly (agyria) and hydrocephalus

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1 The Apparently Blind Infant

Fig. 1.7 Axial MR imaging showing large, bilateral porencephalic cysts in 6-year-old boy with cerebral palsy and cortical blindness

forming multiple small gyri. Neuronal heterotopias are focal collections of neurons in abnormal locations. Schizencephaly denotes gray matter–lined clefts extending from the lateral ventricles to the surface of the brain.33 Unilateral megalencephaly consists of a hamartomatous overgrowth of all or part of one cerebral hemisphere, with migrational anomalies (pachygyria, polymicrogyria, and neuronal heterotopia) and gliosis of the affected hemisphere. Strictly speaking, porencephaly refers to a focal cavity devoid of surrounding glial reaction resulting from the localized brain destruction that occurs during the first 20 weeks of gestation (Figs. 1.7–1.9). It differs from schizencephaly, a migrational anomaly resulting from destruction of a portion of the germinal matrix and consisting of a gray matter–lined cavity. Porencephaly also differs from encephalomalacia, which occurs later in pregnancy or anytime thereafter. These forms of cerebral dysgenesis are detailed in Chap. 11.

Head Trauma Nonaccidental trauma (shaken baby syndrome) has been identified as a common cause of CVI in infancy. The diagnosis is established by the characteristic retinal hemorrhages and associated CNS abnormalities (subdural or epidural

Fig. 1.8 MRI scan of 7-year-old boy with spastic diplegia, mental retardation, betaketothiolase deficiency, and severe CVI. Note posterior, porencephalic-like dilatation of occipital horns of lateral ventricles. Only thin margin of overlying cortex remains

hematoma), the appropriate social picture, and the fastidious exclusion of other mechanisms of intracranial injury. In this setting, the retinal hemorrhages resolve but the child remains blind or severely visually impaired. The spectrum of traumatic head injury may range from mild concussion to a severe contusion, laceration, or diffuse axonal damage. The injury may also cause or be followed by epidural, subdural, subarachnoid, intracerebral, or optic nerve sheath hemorrhage.619 Permanent visual loss in shaken baby syndrome is usually caused by CVI.391 Diffusion-weighted MR imaging is the study of choice to identify the posterior cerebral ischemia that causes permanent visual loss, and the subdural hematomas that characterize this condition.60 In some children, however, the resulting visual morbidity may be attributable to retinal detachment, retinal folds, macular hole, or epiretinal membrane, alone or in combination with CNS injury.149,450 It is useful to separate cases occurring after minor or trivial trauma, which have a benign course, from those occurring after severe head trauma that often lead to permanent neurological and visual sequelae. Patients in the latter category usually show external or radiological signs of trauma (e.g.,

Cortical Visual Insufficiency

15

Fig. 1.9 (a) Axial and (b) coronal MR imaging of 3-year-old girl with left homonymous hemianopia and questionable history of viral infection at about 8 weeks gestation. Note large, right cerebral poren-

cephalic cyst, compensatory hemihypertrophy of left cerebral hemisphere and macrogyria with limited sulcal formation

skull fracture, frank cerebral injury, intracranial hemorrhages, hemotympanum). For example, a 13-year-old boy was hit with a baseball bat on his occiput, and he lost consciousness for 4 min. On recovering consciousness, he was noted to be agitated, disoriented, and blind. Neuroimaging displayed comminuted skull fractures and contusions of both occipital lobes and the right parietal lobe. Various neurological complications, including papilledema, developed. Vision recovered in 10 days, but visual field defects persisted. Follow-up CT showed atrophy of the previously injured lobes.313 In patients with severe trauma, neuroimaging of the brain may demonstrate cerebral edema, massive brain swelling, hemorrhage, or resulting hydrocephalus. The visual loss may be permanent, or it may resolve partially or totally over several weeks. Children with nonreactive pupils and those who are ventilator-dependent carry a worse prognosis.318 Older children with transient CVI after minor or apparently trivial trauma may have total or partial blindness, homonymous hemianopia, palinopsia, a patchy visual loss, or a “whiteout” of the visual fields, or they may describe fine flickering of vision resembling a snow storm.147,236 Affected children usually have an otherwise normal examination, but they may occasionally show soft tissue swelling and tenderness corresponding to the area of cranial trauma. Neuroimaging studies are typically nonrevealing. In all reported cases, blindness occurred within several hours of head injury and lasted less than 24 h. Patients characteristically do not experience loss of consciousness. They

typically show visual recovery, which may occur from minutes to days after injury (on average, a few hours).217,236 Such patients may have electroencephalographic (EEG) findings that initially show either generalized or posterior, bioccipital slowing that subsequently normalizes. The younger child may not report visual loss and may not recognize blindness but may display any combination of the following signs and symptoms: agitation, restlessness, uncooperativeness, confusion, irritability, disorientation, headaches, vomiting, drowsiness, and unsteady gait. To avoid underdiagnosis, it has therefore been recommended that traumatic CVI should be suspected in trauma patients who exhibit such findings.621 Whether the associated agitation and restlessness are a psychological reaction to the blindness or a result of traumatic brain dysfunction is uncertain. The nature of traumatic cerebral dysfunction may include a concussive cerebral injury, localized edema, ischemia, or epilepsy. Damage to the posterior visual pathway may occur via a coup or contracoup mechanism. Patients with transient blindness after minor trauma often have a family history of migraine, implicating a possible vascular role (a migraine equivalent), possibly local cerebral vasospasm.147 The visual snow storms described in some patients are also described with migraine, and many of the abovementioned associated symptoms and signs are common in migraines. The patient who loses vision after voluntarily striking a soccer ball with his head236 shows close clinical

16

resemblance to the phenomenon of “footballer’s migraine.”170 One reported case of a child who might have had as many as four separate episodes of transient posttraumatic blindness suggests a possible predisposition to this syndrome in some patients.258 Some cases of transient posttraumatic blindness reported in the literature are inconsistent with a pure cortical etiology. For example, several cases have been described with either unilateral visual loss or bilaterally dilated and fixed pupils.621

Twin Pregnancy Twin pregnancy increases the risk of neurologic injury to the visual cortex and optic radiations.204 Because twins tend to be born prematurely, their risk for periventricular leukomalacia is inherently higher. Twin-to-twin transfusion syndrome occurs when deep anastomosis in monochorionic twins allow shunting of blood from one fetus to the other.204 The fetal circulation is such that the umbilical artery carries deoxygenated blood to the placenta, where reoxygenation occurs. The blood returns to the fetus through the umbilical vein, which connects not only to the inferior vena cava but also to the portal circulation. In twin-to-twin transfusion syndrome, anastomoses may occur between artery and vein, and between vein and vein.204 Arteryto-vein and vein-to-vein anastomoses are most problematic.53 The shunting of blood from one fetus to the other results in diminished size of the donor fetus. An increasing difference in size of the fetuses eventually becomes apparent. The rate of in-utero fetal demise is quoted at 5%.367 Several mechanisms of neurologic injury may coexist in the twin-totwin transfusion syndrome.204 First, acute twin-to-twin transfusion syndrome after fetal demise may result in a rapid transfusion of blood from the surviving to the deceased fetus, producing transient hypovolemia. Rapid transfusion stresses the integrity of the survivor’s vascular system. Second, the release of thromboplastin by the dead fetus can induce disseminated intravascular coagulation in the survivor. Third, emboli may also enter the survivor’s circulatory system and cause neurologic damage.204 Survivors of twin-to-twin transfusion syndrome may show dermal and scalp erosions, intestinal atresia, and neurologic damage.524,547 When transfusions occur early in gestation, the neurologic outcome is usually less problematic than when transfusions occur later.367 Late transfusions may result in multiple cortical infarcts, porencephalic cysts, hydranencephaly, and hydrocephalus.202

Metabolic and Neurodegenerative Conditions Metabolic and neurodegenerative causes of cortical visual loss usually present later in childhood, but the major ones are

1 The Apparently Blind Infant

mentioned here for the sake of completeness. Metabolic disturbances (e.g., profound hypoglycemia, carbon monoxide poisoning, nitrous oxide poisoning, cocaine, lead poisoning, uremia, hemodialysis, dialysis disequilibrium syndrome) are occasionally associated with CVI.415,425 CVI may be one of the clinical features of various neurodegenerative conditions, including metabolic encephalopathy, lactic acidosis, and strokelike episodes (MELAS), ornithine transcarbamylase deficiency, Fabry’s disease, Leigh’s disease, and X-linked adrenoleukodystrophy.520 In metachromatic leukodystrophy, one-third of cases are associated with optic atrophy, but a component of CVI is not infrequent. Byrd et al82 described three children who experienced transient cortical blindness while receiving vincristine therapy for various malignancies. The cortical blindness in these patients, attributed to vincristine neurotoxicity, recovered completely after 1, 3, and 14 days.

Meningitis, Encephalitis, and Sepsis Bacterial meningitis in infancy is an uncommon cause of CVI, accounting for only 5% of severe cases.613 The most common organisms include Haemophilus influenzae, pneumococci, and streptococci. The CVI occurs within a week of the onset of meningitis in about half the cases, and within 1 month of the onset in almost all cases. Haemophilus influenzae meningitis shows a predilection toward damaging the occipital cortex,122,382 with some cases showing CVI after recovery. A variety of neurologic or visual defects have been associated with meningitis, including mental retardation, seizures, hemiplegia, quadriplegia, homonymous hemianopia, double hemianopia with macular sparing, visual hallucinations, and CVI.466 The postmeningitic CVI may be permanent or show partial or complete recovery. The pathogenesis of postmeningitic CVI may be mediated by venous sinus thrombosis, thrombophlebitis, hydrocephalus, or hypoxic-ischemic insult in the watershed areas.563 Neonatal herpes simplex infection is frequently associated with severe CVI (Fig. 1.10).146 Eighty percent of these infections are caused by type 2 herpes simplex virus. Most affected children have severe brain damage due to necrotizing encephalopathy and demyelination, with diffuse neurological disease, including quadriplegia. CT findings in patients with neonatal herpetic encephalitis typically show extensive destruction of hemispherical white matter.548 El Azazi et al146 found 12 of 30 children with neonatal herpes simplex virus infection to have severe visual impairment, presumably due to cortical damage, although many of these also showed optic atrophy. Granulomas, hydatid cyst infestation, syphilis, cerebral malaria, AIDS-related encephalopathy, and sepsis may also result in cortical blindness (Fig. 1.11).

Cortical Visual Insufficiency

17

Fig. 1.10 Axial MR images showing signs of early gestational diffuse cortical injury with reabsorption of cortex in a patient with congenital herpes simplex virus infection (left) and congenital toxoplasmosis and (right)

Fig. 1.11 (a) Axial and (b) coronal MR imaging of 3-year-old girl who suffered episode of Gram-negative sepsis at 1 year of age that resulted in complete blindness for 2 weeks. Subsequent gradual recovery of vision occurred to 20/20 in each eye, despite persistence of occipital lesions on MR imaging

Hydrocephalus, Ventricular Shunt Failure Patients with hydrocephalus may show a spectrum of visual impairment with a variety of visual field defects, including homonymous hemianopia. Mixed anterior and posterior visual damage is frequently encountered in patients with

hydrocephalus,17 either primarily or following shunt malfunction. Damage to the anterior visual pathway may result from postpapilledema optic atrophy, chiasmal traction, a markedly dilated third ventricle that compresses the chiasm, compression of the optic tracts by the tentorial edge during herniation of the hippocampus, associated developmental

18

1 The Apparently Blind Infant

Preictal, Ictal, or Postictal Phenomena

Fig. 1.12 Axial CT scan of 11-year-old boy, born 3 months prematurely, who had hydrocephalus and 20/30 vision bilaterally. Deterioration of vision to 20/200 bilaterally over several weeks was associated with shunt dysfunction and enlarging occipital horns of lateral ventricles. Vision improved after shunt revision

anomalies, or from other vascular effects on the visual pathways. Damage to the posterior visual pathway due to hydrocephalus or shunt malfunction presumably results from compression of the posterior cerebral arteries against the tentorium.17 This vascular compression is thought to produce laminar necrosis of the visual cortex,97 which may also be related to the coexisting congenital abnormalities or other structural alterations of the brain. In infants and young children, the visual impairment may resolve either partially or completely with time after shunt revision (Fig. 1.12). Rare instances of dramatic visual improvement occurring within a few hours to days of shunt revision have also been described.95 CVI due to hydrocephalus may be transient or episodic,571 presumably due to a vascular dysfunction mediated by intracranial hypertension. Some patients with compensated hydrocephalus can retain vision and cognitive function despite massive degrees of ventricular enlargement with little residual cortical mantle.307 Rabinowicz471 examined visual perception in 100 hydrocephalic patients and found constructional apraxia, dyscalculia, and homonymous field defects in some of the patients, suggesting disorders of the posterior visual pathway and the parietal lobe. Hydrocephalus should not be confused with hydranencephaly. The latter denotes a severe process in which there is nearly complete destruction and reabsorption of the cerebral hemispheres, with replacement by cerebrospinal fluid. Affected infants are uniformly blind.

Neuro-ophthalmologic signs and symptoms of seizures include excessive eyelid blinking, fluttering, or spasms, nystagmus, contraversive gaze deviations or head deviations, spasms of the near reflex, unilateral pupillary dilatation, dyschromatopsia, altered stereopsis, unformed (elementary) hallucinations, hemianopsia and other transient or permanent visual field defects, and transient or permanent cortical blindness.12,42,511 A history of seizures is commonly found in children presenting with visual impairment, especially on the basis of cortical disease. The loss of vision may occur as an aura,42 a direct manifestation of the seizure itself,287 or a postictal phenomenon,42 or it may be attributed to altered alertness due to the side effects of seizure medications. In children with infantile spasms, the apparent blindness can precede the seizure activity and EEG abnormalities by several weeks, leading the clinician to diagnose DVM.288 Conversely, infantile spasms can produce a treatable form of acquired visual loss.80 Children with West syndrome (the triad of infantile spasms, psychomotor retardation, and hypsarrhythmia) who are visually inattentive at the time of diagnosis have a poorer prognosis for future visual and psychomotor development than those who are normally visually attentive when first seen.85 Cases of blindness due to seizure activity directly may present a diagnostic quandary and are probably underrepresented in the literature, although some authors have speculated that unexplained cortical blindness may represent unrecognized seizure activity more often than may be inferred from reported cases.42 Blindness due to seizure activity may be complete or may manifest as scotomata, homonymous hemianopia, or unformed positive visual symptoms such as phosphenes.42,444 Some patients concurrently describe the sensation of eyelid pulling, and are seen to have rapid eyelid fluttering and eye blinking or epileptic nystagmus.444,614 Strauss545 described an 11-year-old boy who had complete blindness associated with bilateral occipital spike-wave activity without affecting consciousness. This so-called status epilepticus amauroticus has been documented in a handful of cases.40 Barry et al40 described a 13-year-old girl who experienced episodic blindness, usually while walking to school, and was found to have light-stimulated bioccipital spike-wave activity. Jaffe and Roach287 described three youths with intermittent blindness due to occipital seizures that improved with anticonvulsant medication. The symptoms included headaches and vomiting, rendering differentiation from migrainous vertigo difficult. Zung and Margalith629 described a 7-year-old boy who experienced episodic blindness accompanied by gastrointestinal symptoms and a sensation of fright but no alteration of consciousness. CT of the brain was normal; interictal EEG showed bioccipital epilepsy.

Cortical Visual Insufficiency

It is recommended that EEG evaluation be included in the ancillary diagnostic testing of patients who present with cryptogenic acute blindness, even in the absence of obvious clinical symptoms of epilepsy. Infants with infantile spasms or constant seizures may seem blind because the seizure activity precludes visual attentiveness. The EEG in infants with infantile spasms shows hypsarrhythmia; affected infants sometimes show hundreds of small seizures daily. If visual pathway abnormalities are excluded with neuroimaging studies, the visual function may be expected to improve, sometimes dramatically, once the seizures are controlled. Postictal blindness in infants was described as early as 1884 by Nettleship.436 Kosnik et al328 found an occipital focus in about 50% of children with seizures. They explained the predilection of occipital involvement in children with seizures by the presence of unstable electrical activity due to a putative relative immaturity of the occipital cortex in children. This high incidence of occipital lobe seizure activity in children explains why postictal blindness is more common in children. The precise pathophysiologic basis of postictal blindness is unknown, but a mechanism similar to Todd’s paralysis has been suggested (Fig. 1.13). Todd’s paralysis denotes the postictal occurrence of focal neurologic deficits,

19

which are mostly motor, but sensory deficits may also be associated. The mechanism of Todd’s paralysis itself also remains speculative, with Jasper301 suggesting, and Miller409 supporting as the best available explanation, the occurrence of “neuronal exhaustion” due to hypoxia or high metabolic demands postictally. This notion is supported by the observation of one patient with postictal blindness who demonstrated marked hyperperfusion in both occipital regions on an ictal (single photon emission computed tomography) SPECT, carried out at the onset of the seizure.42 Occasionally, the seizure activity itself may be associated with drug toxicity. For example, a young patient with a blood cyclosporine level almost six times the therapeutic value suffered transient cortical blindness associated with continuous focal occipital EEG discharge.492 Cortical blindness and seizures have also been reported following cisplatin treatment.250,586 Visual disturbances are recognized as common side effects of anticonvulsant therapy.474 Side effects of common antiseizure medications usually include sedation, with a decreased level of alertness that may adversely affect visual performance during the examination. Other visual disturbances associated with anticonvulsant therapy include vertical or horizontal diplopia and oscillopsia, as well as pursuit and gaze-holding disorders, nystagmus, convergence spasm, and gaze palsy.354 These symptoms may be ascribed to ophthalmoplegia, vertical nystagmus, or abnormalities of the vestibulo-ocular reflex.474 Despite the best efforts to uncover the cause of cortical damage in patients with CVI, some cases elude classification into any of the etiologies previously detailed (Figs. 1.14 and 1.15).

Associated Neurologic and Systemic Disorders

Fig. 1.13 MR imaging in 21-month-old girl with cerebral palsy and seizure disorder secondary to perinatal asphyxia who developed status epilepticus. The MR imaging obtained after control of status shows edema of nearly entire cerebral hemisphere, especially posteriorly, presumably as result of status epilepticus and sustained metabolic demands placed on left hemisphere as a result

Cortical visual loss is often accompanied by cerebral palsy, seizures, and microcephaly. Because cerebral palsy is so prevalent in children with CVI, a short discussion of its clinical spectrum is in order. Cerebral palsy represents a heterogenous group of disorders caused by nonprogressive disturbances of the developing brain, leading to dysfunction of movement and postural development.18,45,198,496 Other impairments (vision, sensation, cognition, communication, perception, behavioral, seizure disorder) often accompany the motor dysfunction.18,188 The motor disturbances associated with cerebral palsy can range from mild to severe and may dramatically impair a child’s functional abilities. Children with cerebral palsy frequently have mixed motor disorders (e.g., spasticity, athetosis, ataxia, weakness), and each likely impairs their functional movement in a different way. Despite the coexisting motor disorders, children with

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1 The Apparently Blind Infant

Fig. 1.15 Axial CT scan from infant with cerebral palsy, CVI, seizures, and deafness, demonstrating early gestational injury with diffuse tissue resorption of posterior hemispheres. Etiology was unknown Fig. 1.14 T2-weighted MRI of 1-year-old girl with congenital profound CVI and developmental delay reveals marked atrophy of occipital regions of uncertain etiology

cerebral palsy often fall into one of two classifications: “spastic” or “extrapyramidal.” Although children with cerebral palsy and strabismus tend toward esotropia more than exotropia, both occur commonly. Gaze apraxia may cause them to use horizontal or vertical head thrusts to facilitate gaze shifts.188 Saccades, smooth pursuits, and fixation are also impaired.188 Some may have the coexistent ocular motor nerve dysfunction.151 Hypertonia and athetosis are primary neurologic findings of extrapyramidal cerebral palsy, presumably as a result of abnormalities in basal ganglia-cortical circuits. Hypertonia can be divided into spasticity, dystonia, and rigidity. Spasticity is defined as increasing resistance to increasing speed of stretch relative to the direction of joint movement or a rapid rise in resistance above a speed or joint position threshold.513 Studies of spasticity in the lower extremities have not correlated well with aspects of gait function.1 Children with “spastic” cerebral palsy characteristically present with a combination of spasticity, weakness, and loss of manual dexterity due to abnormalities in descending motor pathways and motor cortex. In spasticity, resistance to passive stretch is dependent on speed. When the examiner moves the patient’s arms passively and slowly, there is initially no resistance in spasticity, but with increased velocity of movement, resistance increases.

Dystonia is defined as sustained or intermittent muscle contractions causing twisting and slow repetitive movements or abnormal postures.513 It can manifest as overflow of activity to muscles that are normally silent during a voluntary movement (e.g., other muscles in that limb or other limbs) or involuntary activation of muscles at rest.384 Children with dystonia cannot voluntarily relax their muscles completely. Rigidity is secondary to cocontraction of agonist and antagonist. With effort, children with rigidity can assume a posture with normal baseline muscle activity.46 Cocontraction can also occur in dystonia, so this is not the distinction between rigidity and dystonia. Cocontraction does not characterize spasticity. The vast majority of children with cerebral palsy display mixed hypertonia with some degree of spasticity and dystonia.513 Newer quantitative testing measures can distinguish between these different motor disorders.213 Hemiplegic cerebral palsy is now one of the most common types, with a prevalence of approximately 3 per 4,000 live births.251 This condition may often be due to vascular events. Athetosis produces slow, writhing movements of the extremities secondary to extrapyramidal lesions. Once considered a monolith, cerebral palsy comprises a group of disorders with different etiologies, which constitutes a useful socio-medical framework for certain children with motor disabilities and special needs.329 Cerebral palsy results from an acquired lesion in most cases. Cerebral malformations are rare, and most cases show clear lesional

21

Cortical Visual Insufficiency

patterns of different timing. Thus, the common assumption that obstetric caregivers can prevent cerebral palsy by actions taken during labor and delivery is based largely on erroneous assumptions.377 Well-designed studies have shown that lack of oxygen causes only a small proportion of cases. Furthermore, cerebral palsy associated with birth injuries has never been shown to be preventable.432 Known risk factors for cerebral palsy include chorioamnionitis, death of a cotwin in utero, arterial ischemic stroke in the fetus or newborn, an umbilical cord wrapped tightly around the neck of the fetus, and premature birth.331 Other possible antenatal risk factors under investigation include viral infection, fetal thrombophilias, and polymorphisms of genes regulating inflammation, coagulation, and endothelial activation.193,433 In 10 developed countries, including the United States, the incidence of cerebral palsy has remained steady, at about 1 in 500 births, despite a fivefold increase in cesarean deliveries over recent decades, driven in part by the use of fetal monitoring. Thus, while some causes of cerebral palsy are known, most are unknown, not foreseeable before birth, and not currently preventable. Patients with cerebral palsy may vary in topography (diplegia, hemiplegia, quadriplegia), physiology (spasticity, dyskinesia, dystonia, and ataxia), and neurologic comorbidities involving vision, hearing, and epilepsy. In the Bax study,44 white matter abnormalities were present in 43% overall and in 71% of children with diplegia, 34% of children with hemiplegia, and 35% of children with quadriplegia. Other important neuroimaging findings included basal ganglia abnormalities in 13%, malformation in 9.1%, cortical and/or subcortical abnormalities in 9.4%, and focal infarcts in 7%. Of children with basal ganglia and thalamic injury, 76% had dystonia. Of children with hemiplegic cerebral palsy, 27% had focal infarcts. Cerebellar vermian atrophy has also been described in a significant proportion of patients who have neonatal hypoxic-ischemic encephalopathy.515 Periventricular leukomalacia is now considered the most common cause of cerebral palsy.46,422 However, about 8% of children with spastic diplegia have normal MR imaging results, and 25% of children with periventricular leukomalacia on MRI do not have any neurological disorder.449 Ocular abnormalities are a common problem in children with cerebral palsy.338 In one prospective study,338 neuro-ophthalmological abnormalities were found in 28.2% of children with cerebral palsy. More than half (61.9%) of those with neuroophthalmological abnormalities were completely blind. Optic atrophy and strabismus were each seen in 50%, and cortical visual loss was found in 47.7%. Spastic quadriplegia was associated with an increased risk of neuro-ophthalmological abnormalities. Although Jan et al297 have suggested that some children with cerebral palsy behave as blind because of a “dyskinetic” eye movement disorder, causing

impaired motor control of saccades, pursuit, or fixation, Roulet-Perez and Deonna490 questioned whether these movements may be secondary to a central visual disorder rather than to a distinct ocular motor abnormality. Whether they are consequent to decreased vision or to superimposed motor disturbances, these children have been found to have a variety of ocular motor disturbances.188,512 Difficulties with accommodation have also been reported.392

Characteristics of Visual Function The degree of CVI in a given child can range from a defect that is barely detectable to complete blindness. The visual acuity may be spared in unilateral cortical lesions or bilateral lesions, with sparing of cortical regions subserving the macula. In patients with profound visual impairment, appropriate methods of visual function assessment must be employed. Generally, it is very difficult to distinguish whether an infant is unable to see or simply unable to interpret visual input (visual agnosia). Snellen acuity measurements and similar methods have little to no utility in visual assessment of children with severe CVI. It is more relevant to obtain a measure of overall visual function than to simply attempt measuringt of visual acuity. Can the child recognize various objects in the environment, navigate effectively, and interact visually with other people? Obtaining a visual history from the parents and spending some time playing with these children provides valuable information about the children’s overall visual function.296 Because the visual impairment in these infants may span a number of neurological functions, it is conceptually useful to separately consider the four As of visual loss: acuity, assimilation, attention, and apraxia. Children with CVI typically see better in a familiar environment. They often use touch to identify objects of interest.296 They prefer to view objects at close range (independent of refractive errors) and appear to have a crowding phenomenon wherein individual objects are seen better against a plain background than against a patterned background or amongst a group of objects. The preference of close viewing may be to produce linear magnification (by shortening the focal length) or to reduce crowding by viewing the object singly at close range. They frequently look away from objects of interest, as if trying to use their peripheral vision. Patients with CVI display on-again, off-again vision with wide fluctuations. Their visual function may be noted to vary widely from day to day and even from hour to hour.296 This variability may correspond to changes in lighting conditions, attentiveness, tiredness, medications, illness, seizures, or environmental changes (e.g., noise, colors) but may also

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p arallel the variable performance in other neurologic spheres that is characteristic of brain-damaged children. In some instances, variability of visual test results may arise from the presence of a “Swiss-cheese” visual field in which an object may or may not be seen, depending on whether it falls within a region of intact field. The extreme variability of visual function found in some patients with CVI may sometimes lead to the impression that the child is “faking.” To be differentiated from true CVI is the visual disregard and intermittent visual inattention often seen in patients with developmental delay and other neurological disorders with intact posterior visual pathways. The phenomenon of decreased visual attention to novel stimuli in infants who later prove to be mentally retarded or autistic should also be borne in mind.153 Children may show a tendency to gaze at room lights, especially fluorescent lights or other bright objects, including the sun (light gazing).295 The precise explanation for this phenomenon is unknown, but it has been considered by some investigators to be a bad sign, indicating severe visual system injury. Paradoxically, instead of light gazing, some degree of photophobia may be present in about one-third of children,293 but this is usually much less than the severe photophobia so characteristic of retinal conditions, such as congenital achromatopsia. The cause of this photophobia is unknown, but damage to retinal, thalamic, or cortical structures may be responsible.208,293 It is possible that, in some cases, it may be of a retinal origin, arising from a hypoxiadamaged retina. Visual acuity of some children with cortical visual loss is better under low-luminance conditions than under normal luminance conditions.206 Nickel and Hoyt440 have shown that hypoxic insults can cause transient but notable ERG changes in children. The photophobia may be a result of associated damage to the thalamus, a phenomenon called “thalamic dazzle.”101 Most cases of photophobia are thought to arise from damage to the striate cortex itself.293 This may be analogous to the photophobia observed in Macaque monkeys when the occipital lobes are amputated.119 The visual performance of some patients is better for moving objects than static objects. This holds true for striate cortex and ventral stream pathology but is often not the case in children who have dorsal stream dysfunction, which may be associated with akinetopsia or at least dyskinetopsia (see below). Some affected children see better when traveling in a car, while the opposite is true in others.296 Some ambulatory children with CVI show better visual function in terms of navigating successfully and avoiding obstacles than in performing near-vision tasks. Jan et al296,300 postulated that the most plausible explanation for this discrepancy is the presence of an extrageniculostriate (collicular) visual system, calling this “travel vision.” However, the role of any

1 The Apparently Blind Infant

accessory system in humans remains controversial (see “blindsight” below). Patients are often able to identify the color of objects better than the form and shape of objects. This discrepancy has been attributed to several factors: (1) Color perception requires fewer neurons than form perception.604 (2) Color perception, unlike form perception, is bilaterally represented in the cerebral hemispheres (but with dominance in one hemisphere), so it is more resilient to injuries that may affect form perception. (3) Color perception is diffusely represented in the striate cortex and the lingual and fusiform gyri. (4) Color perception may be preserved within the extrageniculostriate visual system.542 Some children with CVI turn their head a certain way or look away to either side, usually with a slight downward gaze, when reaching out for an object.296 They display preference for peripheral vision over central vision, viewing objects eccentrically. This may result from bilateral central scotomas associated with sparing of the temporal crescent, which is represented by the most anterior portion of the striate cortex. Alternatively, it could be a manifestation of the complex gaze apraxia that so often accompanies cerebral palsy.188 Accurate evaluation of the visual fields is notoriously difficult in children with CVI. Clinical clues may be obtained by moving colorful toys in their visual fields while observing the child’s reaction. Even children with severe visual impairment often show asymmetric involvement, with preferential relative sparing of either the right or the left visual fields.296 Visual evoked potential recordings with separate hemispheric electrodes may help assess the presence of relative hemianopic defects in some children. When quantitative visual fields can be performed, many children with CVI show severely constricted peripheral visual fields.588

Neuro-Ophthalmologic Findings The neuro-ophthalmologic signs of CVI are summarized in Table 1.1. In a retrospective review of 50 patients,76 Brodsky et al. found the four common neuro-ophthalmologic signs to Table 1.2 Neuro-ophthalmologic findings in cortical visual impairment versus subcortical injury (periventricular leukomalacia) Gaze deviation Nystagmus Strabismus Optic discs

Cortical

Subcortical

Horizontal conjugate gaze deviation None or intermittent Constant exotropia Normal or mildly atrophic

Tonic downgaze Latent or rarely congenital Esotropia > Exotropia Hypoplastic or large cups

Cortical Visual Insufficiency

Fig. 1.16 Congenital horizontal gaze deviation with ipsiversive head turn as a sign of CVI. With permission from Brodsky et al76

be horizontal conjugate gaze deviation, a constant exotropia, absence of nystagmus, and normal optic discs or a mild degree of optic atrophy. The finding of horizontal conjugate gaze deviation (Table 1.2) in infancy is a useful diagnostic sign of CVI. In this condition, both eyes are tonically deviated to one side (Fig. 1.16), and the head is tonically deviated in the ipsiversive direction, so that the child appears to be trying to look behind the head. This oculocephalic dyskinesia reflects a multiplicity of mechanisms by which asymmetric injury to cortical eye movement command centers can modulate horizontal conjugate gaze. These include unilateral epileptic excitation, saccadic or pursuit imbalance between the two hemispheres, optokinetic asymmetries, congenital homonymous hemianopia, unilateral injury to visual attention centers.76 CVI is a recognized cause of congenital exotropia.76 As isolated congenital exotropia is rare, it is important to consider the diagnosis of cortical visual loss in children with congenital exotropia and to look closely for signs of visual and neurologic impairment.1 A regular rhythmical conjugate nystagmus is rare in CVI, but occasional patients display roving eye movements while others display a fine, erratic intermittent nystagmus that is superimposed upon a horizontal conjugate gaze deviation,76 or occasional, unsustained beats of nystagmus. Bilateral occipital lobectomy in monkeys results in latent, but not manifest, nystagmus.623 Fielder and Evans165 have speculated that an intact geniculostriate pathway is a prerequisite for the development of congenital nystagmus. This is corroborated by the observation of Jan et al290 of the disappearance of nystagmus in a patient with anterior visual pathway dysfunction after the onset of cerebral disease. It is also supported by the observation that horizontal nystagmus, due to various

23

disorders of the eye or anterior visual pathway, appears to develop at an age when the geniculostriate system is emerging functionally (around 2–3 months of age). Fielder and Evans165 argued that patients with CVI who, by definition, do not have a normally functioning geniculostriate pathway, would not be expected to develop nystagmus. However, the frequent finding of either latent nystagmus or, less commonly, congenital nystagmus in premature children with periventricular leukomalacia would seem to belie this explanation. Tusa et al570 have suggested that “sensory” nystagmus results from interference with gaze-holding mechanisms, probably via visual deafferentation of the flocculus by the inferior olivary nucleus. Patients with CVI and a few beats of nystagmus are likely to have coexisting anterior visual pathway dysfunction or to have developed the visual loss before the first year of life. Patients with “mixed mechanism” visual loss with both anterior as well as posterior visual pathway dysfunction are not uncommon. The degree and characteristics of nystagmus in these visually impaired children may theoretically be used as a rough assessment of the severity of the anterior visual pathway dysfunction. In light of evidence suggesting that the geniculostriate pathway is a prerequisite for the development of nystagmus,165 one can infer that a patient with mixed mechanism visual loss may not show significant nystagmus even in the presence of severe anterior visual pathway damage if significant posterior pathway damage coexists. Conversely, finding sustained nystagmus in patients with anterior and posterior pathway disease indicates that the posterior component is not severe. The optic discs are commonly said to be normal in patients with CVI, but involvement of the retina, optic nerves, or chiasm is not unusual, arising from the same disease process that caused the cerebral damage. Some children with poor vision that may be readily attributable to other developmental ophthalmologic abnormalities may harbor at least a component of CVI as well. In children with cortical visual loss, Brodsky et al76 found normal discs in 56%, optic atrophy in 24%, optic nerve hypoplasia without atrophy in 8%, and combined hypoplasia with atrophy in 12%. Thus, optic atrophy is seen much more commonly than optic nerve hypoplasia in CVI. The presence of optic atrophy in patients with CVI due to hypoxia-ischemia should not be surprising;209 it may be argued that the reportedly low prevalence of concurrent optic atrophy may itself be surprising. Six out of 30 children with hypoxic CVI described by Lambert et al341 showed mild optic atrophy. In a series of infants with significant hypoxic encephalopathy, Good et al209 found that less than 15% had optic atrophy. The fact that many children with severe ischemic cortical damage do not show optic atrophy signifies that the anterior visual pathways are more resistant to the effects of hypoxia

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than the posterior visual pathways. However, it may be argued that concurrent anterior visual pathway involvement is underreported, in part due to mistakenly considering such defects to be the sole cause of the visual impairment.491 For example, about 20% of children with optic nerve hypoplasia also show hemispheric abnormalities77,78 that may involve the posterior visual pathway. Quantitative studies showing that patients with CVI have smaller optic nerve heads with increased excavation and temporal pallor may have included patients with periventricular leukomalacia.491 Coexisting CVI should be suspected when the degree of visual deficit is not fully explained by the ocular defects.613 Associated optic atrophy may be due to concomitant anterior pathway insult or to retrograde transsynaptic degeneration of the retinogeniculate pathway.498 Patients with “mixed mechanism” visual loss with both anterior and posterior visual pathway dysfunction are not uncommon. This “mixed” category has been largely underemphasized in the literature but represents a diagnostic challenge in terms of determining the weighted contribution to the visual impairment of each insult. Retrograde transsynaptic degeneration of the retinogeniculate pathway is known to occur in nonhuman primates following cerebral lesions even in adult life.127 In contrast, retrograde transsynaptic degeneration in humans is said to occur only if the cortical lesion occurred in utero.113,259,340 However, the presence of even severe postnatal cortical insults or malformations does not appear to be sufficient for the occurrence of transsynaptic degeneration. For instance, the literature contains well-described cases of severe occipital lesions, even tomographic absence of the occipital cortex550 with normal fundus and optic disc appearance. In general, descriptions of normal optic discs in children with CVI may be explained by one of the following: (1) Cortical damage may involve the visual association areas without significant damage to the geniculostriate pathway.19 (2) Subtle mild optic nerve pallor may be overlooked in infants and young children. (3) The nature, location, timing, or extent of the cerebral lesion is not sufficient to cause transsynaptic degeneration. (4) Other heretofore undetermined factors that are necessary for the development of transsynaptic degeneration may be lacking. Generally, optic disc pallor found in association with cortical damage may be due to the same process that caused the cortical damage, subsequent hydrocephalus, transsynaptic degeneration, a direct disruption of synaptogenesis at the geniculate level (especially in PVL), or an entirely unrelated process. A primary insult to the retinogeniculate pathway with optic atrophy may be theoretically distinguishable from transsynaptic degeneration by the following means: (1) Documentation of healthy optic disc appearance shortly after the cortical insult, with subsequent corresponding optic atrophy (typically, years afterward) not explicable by other interceding disorders would argue for transsynaptic degeneration.

1 The Apparently Blind Infant

(2) Because significant primary anterior visual pathway disease in early life may be accompanied or followed by nystagmus, one may be tempted to use this sign to distinguish between primary versus transsynaptic optic atrophy. However, it has been argued that an intact visual cortex is necessary for the development of such nystagmus,165 so that children with combined anterior and posterior pathway insults may not show nystagmus. Hence, we lose the opportunity to use nystagmus as a relatively reliable sign of profound anterior pathway disease in early life. (3) Scrutiny of optic discs in patients with unilateral or asymmetric postgeniculate pathway disease for signs of corresponding band atrophy would provide strong evidence of transsynaptic degeneration, assuming that the original damage did not involve the geniculate nucleus or optic tract on the same side. (4) Patients with pure cortical blindness usually show normal pupillary reactions. However, it appears that the pupillomotor fibers, which do not synapse at the lateral geniculate nucleus but at the pretectal area, may also be susceptible to transsynaptic degeneration.572 On the basis of this evidence, the pupillary examination may not be sufficient in distinguishing anterior visual pathway disease from CVI in all instances. Transsynaptic degeneration has been proposed to occur in humans after lesions during adult life in a variety of other locations in the nervous system. For instance, reduction in the number of lower motor units and electromyographic denervation activity have been found following upper motor neuron lesions caused by injury to the spinal cord or by cerebral hemorrhage; transsynaptic dysfunction has been presumed responsible.55,81,325,393 Crossed cerebellar atrophy has been demonstrated on neuroimaging following cerebral hemorrhage or infarction; transsynaptic degeneration of the corticopontocerebellar tract and the cerebellorubrothalamic tract has been proposed as an explanation.233 Oculopalatal myoclonus is thought to result from hypertrophy of the inferior olive because of transsynaptic degeneration.350 Nerve fiber layer atrophy may also occur in conditions affecting outer retinal elements, presumably due to transsynaptic degeneration.193,285,438 Iris heterochromia has been demonstrated in patients with acquired Horner’s syndrome; transsynaptic degeneration of postganglionic sympathetic fibers has been suggested as an explanation.108 Transsynaptic degeneration of postganglionic parasympathetic fibers has been suggested as an explanation for cholinergic super-sensitivity of the iris sphincter noted after preganglionic oculomotor nerve lesions.279 Transsynaptic degeneration of the visual pathways may also be antegrade. For example, the cells of the lateral geniculate nucleus showed transsynaptic degeneration following injury to the optic nerve in adult patients.507,538 Transsynaptic degeneration was postulated to affect the retinal ganglion cells of humans after postnatal cerebral

Cortical Visual Insufficiency

damage as early as 1880. However, reported cases have had confounding findings, such as papilledema,225,581 intraocular hypertension, and optic disc cupping,152 raising doubt as to the contribution of transsynaptic degeneration. Beatty and associates47 presented compelling histopathologic data that retrograde transsynaptic degeneration of the retinal ganglion cells with optic atrophy may occur after cerebral damage during adulthood. They presented the case of a patient who died 40 years after surgical removal of one occipital hemisphere. The vascular supply of the lateral geniculate nucleus and ipsilateral optic tract were not damaged. Using specialized staining techniques of histopathologic specimens, they demonstrated striking asymmetry of the appearance of the retinogeniculate pathway: only the lateral geniculate nucleus and optic tract on the affected side showed atrophy and axonal degeneration. This is in contradistinction to what is found in cases of optic nerve damage, where both optic tracts demonstrate atrophic axons and both lateral geniculate nuclei show atrophy in the laminae corresponding to the damaged nerve. Band atrophy of the optic disc is most often encountered in patients with compressive lesions of the anterior visual pathway (e.g., pituitary adenomas, craniopharyngiomas).405,577 Concurrent damage to the optic tract or lateral geniculate body should be ruled out in patients who are suspected of having transsynaptic degeneration after acquired cerebral lesions. For example, observation of band atrophy of the contralateral optic disc in three patients with cerebral arteriovenous malformations might have been thought to represent transsynaptic degeneration across the optic tract. However, neuroimaging studies revealed abnormal deep venous drainage involving the optic tract, presumably causing direct axonal damage.333

Diagnostic and Prognostic Considerations Although usually recognized in children with major neurologic deficits, CVI may be isolated, affecting otherwise healthy children.372 Mild variants of CVI in schoolchildren who have no other problems may be fairly common. More commonly, CVI is found in association with other neurological and systemic diseases. Associated disorders may directly arise from the same event that caused the CVI (e.g., trauma, hypoxia) or may represent a constellation of findings characteristic of a syndrome that also exhibits CVI (e.g., MELAS, meningomyelocele with hydrocephalus, X-linked adrenoleukodystrophy). Beside cerebral palsy, other associated disorders include, mental retardation, learning disabilities, seizure disorders, microcephaly, hydrocephalus, and myelomeningocele. It should be noted, however, that some children with mental retardation or autism may be mistakenly diagnosed as

25

having CVI because they display visual inattention, with lack of interest and detachment from their environment. The gaze avoidance that typifies autism can raise similar concerns. Although an intact visual system can often be demonstrated in such patients with the use of forced preferential looking techniques,210 this technique is not useful in children with autism.337 Improvement of vision occurs to varying degrees in most patients with CVI. In several studies of patients with CVI, over half of the children showed a significant improvement of vision on followup.218,341,613 While many patients have some recovery in visual acuity, most never see well.318 In one study, patients with the greatest improvement in visual function were those who had better initial acuity.318 When the etiology of the CVI is taken into consideration, a more accurate prediction of visual prognosis may be made. For instance, ischemic and traumatic cases are more likely to show improvement than those due to neurometabolic disorders (e.g., X-linked adrenoleukodystrophy). Seizures and microcephaly are felt to impart a worse long-term prognosis in children with cortical visual loss260a although medical control of seizures can produce striking improvement in vision. The full scope of visual recovery may, in some cases, take several years to be realized.218 However, improvement of vision that occurs after a year of the initial injury may reflect our better ability to accurately test older children and the increased ability of these children to use their limited vision with time.341 The sequence of visual recovery includes color vision, form vision and, finally, visual acuity. Persistent visual function despite apparently severe cortical damage may be due to a variety of possibilities, such as the following: (1) Children may still have residual cortex, with some sparing of vision because central vision is widely represented in the occipital cortex. (2) Some visual recovery may be attributable to the plasticity of the brain in children, with other parts of the brain taking over via rewiring of neuronal connections, reactive synaptogenesis, rerouting of axons, and neurochemical adaptations.170 This may be interpreted by clinicians, parents, and teachers as simply learning to better “interpret” poor images. (3) Residual vision may be due to the so-called “blindsight” phenomenon. The collicular or pulvinar systems, the putative centers for blindsight, may be the area in the CNS that subserves vision even in patients with little or no cortical tissue. (4) Finally, it is theoretically possible that residual vision stems from heterotopic cortex. Currently, the extent of cortical damage is studied with anatomical neuroimaging modalities such as CT or MRI.152 The neuroimaging abnormalities found in patients with CVI range from essentially normal to highly abnormal imaging studies, demonstrating a virtual absence of the posterior visual pathway (Fig. 1.13). Frequent findings on neuroimaging studies include diffuse cerebral atrophy, bioccipital lobe infarctions, periventricular leukomalacia, cerebral dysgenesis,

26

and parieto-occipital and parasagittal “watershed” infarctions. In children with hypoxic cortical insults, Lambert et al341 demonstrated a significant positive correlation between a poor visual outcome, an early age of hypoxic damage, and the degree of damage to the optic radiation. There was no statistically significant correlation between the visual outcome and the degree of damage to the striate and parastriate cortex. Other studies have found a neuroimaging correlation with neurodevelopmental prognosis, with deep gray matter involvement on MR imaging, encephalomalacia, or periventricular leukomalacia indicating a poor prognosis,53 and normal neuroimaging indicating a favorable neurodevelopmental outcome35 Diffusion-weighted MR imaging (which identifies cytotoxic edema in acute ischemia and several other conditions)426 and diffusion tensor imaging (which depicts the three dimensional structure of the optic radiation)408 may provide valuable adjunctive information regarding mechanism of injury and anatomical integrity of the optic radiations. Difficulties in establishing clinical-neuroimaging correlation may reflect the fact that anatomy and function are not one and the same; areas that may appear relatively spared on anatomic neuroimaging may have considerable dysfunction, and areas that appear damaged may still have persistent function. By correlating occipital lesions demonstrated on MRI with homonymous field defects, Horton and Hoyt256 demonstrated that central macular vision is more widely represented in the occipital cortex than previously thought. Therefore, even an extensive lesion of the occipital cortex is sometimes compatible with some degree of central “macular” sparing. Functional neuroimaging studies such as positron emission tomography (PET)64 and SPECT445,525 have the added advantage of providing information regarding the functional, as opposed to anatomic, integrity of the brain on the basis of the underlying biochemistry. These studies may help delineate the site of dysfunction in cases in which anatomical neuroimaging shows little or no abnormality and vice versa. They also may enhance our understanding of the pathophysiology in cases in which results of clinical, electrophysiologic, and imaging studies appear incongruent. For instance, the clinical utility of SPECT has been documented in patients with CVI in whom MRI was either normal or inconclusive.525 The advent of functional brain imaging such as PET and SPECT scanning has shown that areas of the brain that are remote from the location of the primary insult may show concurrent impaired function, a phenomenon called diaschisis.15 This phenomenon infers that some patients with acute hemispheric injuries affecting the visual pathway may experience bilateral hemispheric symptoms through transhemispheric diaschisis. Functional neuroimaging may be particularly useful in cases with widespread nonocclusive cerebral ischemia and diffuse axonal injury from trauma in which the functional defect may be considerably greater than the anatomical lesion.526

1 The Apparently Blind Infant

ERG is not of clinical value in CVI, except to exclude concomitant retinal disease.183 Routine VEPs may be helpful in monitoring visual recovery, but they have limitations; they are fraught with technical and interpretational pitfalls, and their value remains controversial. Taylor and McCulloch560 have reported that flash VEPs may have a prognostic value in following young children with acute cortical blindness who have no preexisting neurologic disorders, irrespective of etiology. They demonstrated that an intact flash VEP in a previously normal child with cortical visual loss carries a favorable prognostic significance for visual recovery. Conversely, absent VEP signals carry a poor prognosis.560,561 Whiting et al613 reported that VEP mapping might be more helpful than traditional VEP recordings in the investigation of cortical blindness. In their study of 50 children with permanent CVI, the VEP map was always abnormal and showed good correlation with the CT scan results, whereas the conventional VEP recordings were abnormal in only 50% of cases. In addition to their utility as a tool to evaluate visual function, VEPs may have some value in predicting the neurodevelopmental outcome. Muttitt et al428 performed serial VEPs in a series of term infants with birth asphyxia and found good correlation between the VEPs and the neurodevelopmental outcome. Early reports stressed the absence or marked attenuation of VEP responses in patients with acute cortical blindness, with recovery of VEP responses as vision improved over time.483 However, significant VEP signals may be recorded in some infants who are cortically blind.19 For example, Bodis-Wollner et al61 found normal VEPs to flash, pattern, and sinusoidal gratings in a blind child who had CT evidence of loss of the visual association cortex. This emphasizes the point that VEPs may be valuable in testing that the primary visual pathways are intact, but they do not test perception.176 Frank and Torres182 recorded VEPs in 30 cortically blind children as well as 30 sighted children who had a similar CNS disease. They found some degree of abnormality in all recordings but no significant difference between the two groups. In patients with neurologic disorders, flash VEPs are often abnormal even when the patient is well-sighted557 and have little prognostic value.395,396 As a rule, modest increases in visual acuity, preferential looking and VEPs occur over time.365,386 Sweep and step VEP have been shown to be a useful and repeatable way to quantitate vision in children with cortical visual loss.200,201,375,376 Highly specialized orientationreversal visual event related potentials have been found to correlate with severity of perinatal brain damage as assessed by MR imaging in preterm infants.22 However, it is not known to what extent CVI, PVL, and selective injury to higher cortical centers differentially affect the VEP. Increased luminance causes a worsening of acuity thresholds in children with cortical visual loss.206 Vernier acuity is relatively lower than grating acuity in children with CVI.530 Because it more accurately correlates with visual acuity, and because it is cortically-mediated, Vernier acuity may provide

27

Subcortical Visual Loss (Periventricular Leukomalacia)

a more useful quantitative estimate than grating acuity for patients with cortical visual loss.530

Role of Visual Attention Despite the billions of neurons that constitute the CNS, the visual environment is of such complexity and richness that the brain must actively choose which aspects it will process. This selective processing is termed visual attention. The primary role of impaired visual attention in contributing to CVI, PVL, and DVM (discussed below) is now increasingly recognized.110,584 Clinical and electrophysiologic tests of visual function may fall short in predicting visual potential or functional vision when injury to higher cortical centers produces selective deficit in visual attention. The lateral geniculate nucleus, thalamic reticular nucleus, superior colliculus, and pulvinar are among the widely distributed networks of brain areas that subserve visual attention and operate across various processing areas. The lateral geniculate nucleus is the first stage at which visual input is modulated by bottom-up visual attention.264 Its modulation may be under direct control of the thalamic reticular nucleus, which operates as a local integrator of visual information. Intermediate cortical areas V4 and TEO (cytoarchitectonic area located in the inferotemporal and occipital cortex, ventral to area V4) act as filter sites to reduce the amount of unwanted visual information. The posterior parietal cortex contributes significantly to top-down attentional visual function.110,412,537 More specifically, higher-order areas in the lateral intraparietal area and frontal eye fields integrate information from the visual system and provide a top-down attentional control via feedback connections. The pulvinar may act as an additional integrator receiving information from both the visual system and the higher-order areas via the superior colliculus.309 The overall view that emerges is that neural mechanisms of selective attention operate at multiple stages in the visual system, and that visual attention is subserved by a bottom-up stimulus driven process and a top-down feedback attentional network.264,310,419 The extent to which cortical visual loss can be purely attentional in children with cystic periventricular leukomalacia (particularly those with normal VEPs) or DVM remains to be determined.139

Subcortical Visual Loss (Periventricular Leukomalacia) As noted earlier, the umbrella term cortical visual injury comprises two conditions; one having a term injury that predominantly involves the striate and peristriate cortex and the other having preterm injury that predominantly involves the subcortical white matter, including the optic radiations. The lumping together of term cortical and preterm subcortical visual injury

creates terminologic confusion and obscures the fact that these two complex mechanisms of injury produce distinct constellations of neuro-ophthalmologic signs.76 Prematurity is a common cause of neurologic morbidity and visual impairment in c hildren.32,174,210,265,271,341,599About 40% of cases of cerebral palsy occur in children of very low birth weight.449 An increasing number of premature children with PVL are surviving to manifest central visual impairment.36,99,265,281 Neuroimaging abnormalities in these children are frequently confined to subcortical white matter (optic radiations and corticospinal tracts) as opposed to the cortical gray matter injury that predominates in term anoxia.32,35,36,144,174,265,280,281,341,349,599 Preterm injury to the developing brain that primarily injures subcortical white matter produces PVL.76 PVL is usually seen in ventilator-dependent premature infants who survive longer than a few days.32 It arises between the 27th and 34th week of gestation when the premature infant’s cortex and underlying white matter receive their blood supply from ventriculopetal branches of the blood vessels on the surface of the hemispheres.32 While birth injury is an important pathogenetic factor, it is now believed that most PVL originates before birth. The occurrence of white matter injury is likely related to many different factors, including intrauterine infection, premature rupture of membranes, maternal chorioamnionitis, and hypotension with impaired autoregulation.434,591,593,597,599,630 In a study by Olsén et al449 of premature children with birth weights lower than 1,750 g, the incidence of PVL was 32%. PVL was observed in all children with cerebral palsy, in 25% with minor neurological dysfunction, and in 25% of healthy preterm children. PVL is an important cause of cerebral palsy (mainly spastic diplegia), intellectual impairment, and visual impairment.41,42,46,48,82,83,89,280,349,448,449,587 Some children with PVL are neurologically normal and function within the normal range at detailed neuropsychological and cognitive testing.23,494,618 However, even premature infants with normal neurologic outcomes have a high incidence of neurocognitive impairment.61,488,489 In addition to mild cognitive impairment, these children have a high prevalence of low-severity dysfunctions, including learning disabilities, borderline intellectual functioning, attention deficit/hyperactivity disorders, and specific neuropsychological deficits; behavioral problems reportedly occur in 50% to 70%.224,423,558 Abnormal outcome is associated with increasing severity of white-matter injury, as well as ventriculomegaly and intraventricular hemorrhage (IVH).410

Neuroimaging Abnormalities and their Implications PVL is usually first identified on ultrasonographic examination in the newborn nursery, leading to MR investigation. MR imaging in PVL shows a reduction in the amount of periventricular white matter, a compensatory ventricular dilation, an irregular outline of the lateral ventricle, and an

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1 The Apparently Blind Infant

abnormally high signal intensity of the periventricular white matter on T2-weighted images (Fig. 1.17).29,35–37,76 Lesser degrees of injury to the occipital cortex may be seen in severe cases.144,349 Periventricular gliosis may be present when the gestational age is greater than 28 weeks. Premature infants with profound asphyxia show more severe injury, as manifested by signal abnormalities, encephalomalacia, or shrinkage of the thalami, basal ganglia, brain stem, and cerebellum (Fig. 1.17).37,76,366,521 Some patients with PVL show loss of volume within the corpus callosum, and some patients seem to develop new visual processing strategies that allow them to function normally.514,618 This plasticity may reflect remodeling of existing gray-white matter regions, refinement and selection of dendritic connections, rerouting of white matter tracts to circumvent obstructions, and development of alternative cortical processing strategies.618 Directed MR imaging studies in infants with white matter injury also show disturbances in cerebral growth, with a reduced volume of both gray and white matter.275 An autopsy study of PVL patients showed gray matter lesions in a third or more of cases, with neuronal loss in the thalamus, globus pallidus, and cerebellar dentate nucleus, and gliosis in the deep gray nuclei (thalamus and basal ganglia) and basis pontis.463 The authors suggested the term “perinatal panencephalopathy” to more accurately describe the scope of the neuropathology. Therefore, the focal subcortical white matter injury that we diagnose as PVL or subcortical visual loss should probably be viewed as a marker for more global neu-

rological injury rather than the isolated causative lesion for visual system dysfunction in these patients. A recent study using diffusion tractography imaging performed at termequivalent age41 found development of the white matter in the optic radiations to be the best correlate with visual development in preterm infants. Recent use of diffusion-weighted MR imaging has challenged our concept of the spastic diplegia that so often accompanies PVL. This condition has long been attributed to the location of the anterior periventricular white matter injury. Because the lower extremity axons course medially to the upper extremity axons, they are more affected by periventricular injury, and motor function is more affected in the lower extremities (spastic diplegia).34 However, diffusion tensor MR imaging has recently implicated interruption of sensory feedback from the posterior thalamic radiation, which connects the thalamus and the parieto-occipital lobe, and is mostly related to sensory dysfunction, in the pathogenesis of spastic diplegia.49,255 Thalamic injury may also play a direct role in the abnormal development of visual function in infants with PVL.477

Fig. 1.17 Periventricular leukomalacia. (a) In a mild case, axial FLAIR MR image shows focal high signal in the periatrial white matter compatible with gliosis. (b) Severe PVL in which the axial T1-weighted image

demonstrates thinning of the periventricular white matter with encephalomalacia of the striate cortex. In this case, there is decreased volume and increased signal within the thalami bilaterally. With permission from Brodsky et al76

Neuro-Ophthalmologic Findings Clinically, PVL can produce decreased visual acuity, inferior visual field constriction, visual cognitive impairment, ocular motility disturbances, optic nerve hypoplasia,

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dyskinetic strabismus, in which an exotropia changes to an esotropia on a moment-to-moment basis. Strabismus surgery for the esotropia in PVL is prone to overcorrection. Normal surgical doses should therefore be reduced. Unlike in infantile esotropia, some children with esotropia and PVL spontaneously convert to an exotropia.280,286 Given these complexities, and the minimal potential for fusion in children with PVL, the current trends for early strabismus surgery in children with infantile esotropia should not be loosely applied to premature children with PVL. Latent nystagmus also appears to be particularly common in PVL. Jacobson et al286 found nystagmus in 16 of 19 children with PVL, with latent nystagmus in 12 of these patients. It is unclear whether the latent nystagmus of PVL is simply a physiological epiphenomenon of infantile strabismus, a result of afferent injury to the optic radiations, or whether the bilateral white matter lesions of periventricular leukomalacia can anatomically disrupt efferent corticotectal pathways to the nucleus of the optic tract (the neural generator of latent nystagmus).79 Patients with dyskinetic cerebral palsy may display “dyskinetic” eye movements (difficulty with voluntary saccades, pursuit, and fixation, producing tiredness, illness, anxiety, Fig. 1.18 Tonic downgaze as a sign of periventricular leukomalacia. 76 stress, discomfort, and straining that adversely affect visual With permission from Brodsky et al performance.297 Premature infants with moderate-to-severe white matter injury have greater disruption in fixation and conpseudoglaucomatous cupping, spastic diplegia (Fig. jugate gaze that improves with time.196 Reduced accommoda1.18).76,280 PVL is associated with tonic downgaze in infancy tion is also common and often overlooked in children with (Fig. 1.19), esotropia more often than exotropia, latent or cerebral palsy.392,398 Reduced accommodation can impair manifest latent nystagmus, and optic nerve hypoplasia.76 The learning and requires dynamic retinoscopy to diagnose.392,508 Finally, PVL is a common cause of optic nerve hypoplaetiology of tonic downgaze may relate to the coexistent IVH and its associated hydrocephalus, or to thalamic hemorrhage sia77 and pseudoglaucomatous optic atrophy.284 Children (which produces tonic downgaze, esotropia, and pupillary may show increased retinal vascular tortuosity,243 suggesting constriction in adults).76,171,555 IVH is attributed to venous sta- that abnormal fetal development may influence endothelial sis rather than to the hypoxic-ischemic injury that character- cell function. Some patients with PVL show garden-variety izes PVL although the two mechanisms sometimes overlap optic nerve hypoplasia, suggesting that intrauterine retroin premature infants.598 However, associated pupillary miosis grade transsynaptic degeneration has diminished the optic is not seen in children with IVH.276 In one study,76 IVH did nerve size. However, the small optic nerves in children with not increase the prevalence of tonic downgaze in children PVL are not associated with pituitary deficiency. In 1996, with periventricular leukomalacia. Phillips et al462 noted a Jacobson et al284 recognized that PVL produced a unique high prevalence of esotropia in patients with grade 3 and 4 optic nerve configuration characterized by an abnormally IVH, whereas lower grade hemorrhage did not predict esotro- large optic cup and a thin neuroretinal rim contained in a pia, suggesting that the degree of parenchymal damage and normal-sized optic disc defect (Fig. 1.19). They attributed this morphologic characteristic to bilateral injury to the the ocular morbidity may be related. Children with PVL often have esotropia with associated optic radiation, with retrograde transsynaptic degeneration latent nystagmus, dissociated vertical divergence, and supe- of retinogeniculate axons after the scleral canals had estabrior oblique muscle overaction with binocular intorsion lished normal diameter. Because injury to oligodendrocytes (producing an A pattern). The age of onset of esotropia is may also affect synaptogenesis at the level of the geniculate variable, ranging from the first few months of life to many bodies, we now consider these optic disc changes to be more years later. This esotropia can usually be distinguished from properly designated as a form of congenital optic atrophy. In infantile esotropia on the basis of concurrent signs such as some cases, pseudoglaucomatous cupping is accompanied ROP, optic nerve hypoplasia or atrophy, and neuroimaging by pallor of the neuroretinal rim (Fig. 1.19). This pseudoglaufindings.468 More severely affected patients are said to exhibit comatous cupping of PVL is more properly designated as a exotropia rather than esotropia,76,280 and others display a form of optic atrophy.72,284

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Fig. 1.19 Periventricular leukomalacia in a child with 20/20 vision in both eyes. (a) and (b) Pseudoglaucomatous atrophy. Both optic discs are normal in size, with large, round cups. (c) and (d) Automated visual field examinations show bilateral constriction with symmetrical inferior depression that

Perceptual Difficulties Even when visual acuity is normal, children with PVL may have particular difficulties with interpretation of their visual environment that are impossible to predict with standard acuity testing.464 This central visual impairment is often

1 The Apparently Blind Infant

spares fixation. (e) and (f) MR imaging. (e) High signal intensity in the optic radiations and contiguous enlargement of the posterior ventricles. (f) Similar lesions involving the corticospinal pathways are shown. With permission from Brodsky et al72

incorrectly attributed to regressed ROP.101 Jacobson et al281 have emphasized the difficulties that children with PVL experience special difficulties with visual crowding, visuospatial orientation, and interpretation of complex visual patterns such as faces and words. In school, their inability to read is often puzzling to parents and teachers because their visual acuity, intelligence, and ambitions indicate higher

Subcortical Visual Loss (Periventricular Leukomalacia)

ability. These perceptual difficulties, together with their tendency toward reduced inferior visual fields, often necessitate educational reprogramming.280 In general, children with PVL are much more visually debilitated than expected from their optotype acuity. In new and unfamiliar surroundings, they often behave insecurely, have difficulty in finding their way around, wish to hold hands, and fail to recognize the familiar faces of others. Parents of younger children may report that, at one moment, they would spot a small crumb on a table and reach for it, while at another moment they would seem not to like looking at things. They like to listen and not to watch. Pictures and comic strips are seldom interesting to them. They prefer to sit closer to the television to eliminate crowding. They start to draw later than normal children.280,281 Perceptually, these children are confronted with a complex array of real-world difficulties. Although these children effectively see too much to be called visually impaired, they are still visually disabled.273 A number of strange perceptual consequences result. Some of these elusive visual symptoms that these children experience include the ability to recognize simple figures but not faces. Children with PVL may also display a striking inability to distinguish steps from flat ground, which seems to be a form of impaired visual guidance of the lower limbs because it can occur in the presence of intact stereopsis.510 Distortions in motion perception cause blurring or disappearance of objects when walking,273 cause cars and bicycles to appear from nowhere when they stop, and small dogs that move fast to be seen as large blurred balls that pop up out of nowhere. Informational “overload” from movement in the peripheral visual field causes these children to fall frequently. They have low tolerance to stress and sensory distraction, poor awareness of body concept and body parts (needing to touch their body frequently to make sure it still exists), difficulty seeing and talking at the same time, abnormal spatial awareness and impaired egocentric direction, impaired visual information in communication using lipreading, fingerspelling, and gestures, and difficulty with communication.273,397,398,509 In test situations, all children have difficulties in distinguishing forms but use a variety of cognitive strategies to overcome this obstacle.281 Although they may not be able to recognize faces, they know who is coming by the sound of footsteps and sound of voices. They often use colors to identify objects, symbols, and persons. They are able to guess the rest of the picture from parts and details. Guessing and use of memory serve as compensatory mechanisms. It takes a long time for them to sort out a complex visual scene. However, development of speech is often reported to start early, and the parents state that these children talk a lot and listen carefully. They have a poor visual memory and great difficulty copying, but auditory memory is often remarkably good.281 Concentration is a problem for some, and they are easily distracted by sound and visual stimulation. These difficulties are less conspicuous in children with definite cerebral palsy.

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Reading is especially difficult. Although they can often read short words, they have difficulty with long words, often lose track while reading, and have difficulty in finding the place where they left off. Many have difficulty with mathematics. When trying to read, they may see a few letters at a time but not the whole word. However, they can use the intelligence they have to piece words and sentences together. Hearing is intact, so it is helpful for them to learn their lessons verbally (or in Braille). It is important to listen to children with PVL, because intelligence is relatively spared, and these children will tell you about their vision what the children with cystic PVL would tell you if they could. For the ophthalmologist, these children are often hidden away in the strabismus group.424 However, screening with structured history taking using a question inventory can identify these children.257 According to Lena Jacobson, these children are often intellectually unhappy largely because they know themselves to be “normal,” yet when information is presented to them in a way that everyone else can handle, they cannot handle it and cannot understand why. Children with cerebral palsy may be less frustrated because these difficulties are more consonant with their self-image. These children tend to be in normal classes but lag behind despite having good verbal skills. Many have been evaluated for visual problems in the past, so parents are grateful just to know that their physician recognizes that something is wrong. Several classroom measures can be taken to accommodate the visual difficulties that these children experience. Teachers can be advised to have the child sit in front of the class, use large-print books, utilize their color vision, study in a space with reduced surrounding visual stimulation, teach lessons verbally (because the auditory system functions well), and use closed-circuit television.281 At home, parents can take additional steps to address these complex visual symptoms. Such steps include storing toys in clear compartments; using plain carpets, bedspreads and decorations; identifying caretakers through waving and speaking; using constant identifiers such as shoes; training in seeking and identifying landmarks; using a cane to walk over uneven surfaces; using enlarged double-spaced text and masking surrounding text with a piece of paper; limiting conversation while walking; limiting distractions by reducing background clutter and activity; training in tactile recognition; and visual orientation to surroundings.397

Dorsal and Ventral Stream Dysfunction From a functional point of view, there are two pathways, the dorsal stream, which links the visual cortex with the parietal lobes, and the ventral stream, which links the visual cortex

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with the temporal lobes.412,537 As a result of the seminal work of Ungerleider and Mishkin,576 visual cortex anatomy is considered to be composed of two parallel and interconnected pathways, both supplied by the primary visual cortex area V1.594 As mentioned earlier in our discussion of CVI, the dorsal pathway mainly subserves visuo-motor transformations, while the ventral pathway neurons represent information from low-level features to more and more abstract stages of identity processing, thus subserving object identification.137,412,594 Some operations in the dorsal pathway operate unconsciously, while the ventral pathway activity subserves phenomenal visual consciousness.594 More simplistically, the ventral stream is for object vision while the dorsal stream is for space vision (Fig. 1.20).309,310 Although these two parallel neural processing pathways systems are segregated, they have developmental and functional overlap.309,310 The ventral stream connects the occipital and temporal lobe territories and subserves recognition of geometric and biological form, route finding, and visual memory. The dorsal stream connects the occipital area with the posterior parietal cortex, which allows the mind to encompass the whole visual scene and to elect to pay attention to chosen components. The posterior parietal cortex is also thought to work in harmony with the motor cortex by subconsciously providing the “online” action plan for visually guided movement of the limbs and body through three-dimensional space. It also interacts with the frontal territory responsible for both choosing which elements of the visual scene to pay attention to and bringing about saccades to the object of interest. Dorsal

1 The Apparently Blind Infant

stream dysfunction caused by bilateral posterior parietal pathology gives rise to simultanagnosia, in which there is a profound difficulty in registering the presence and identity of any object that is not being attended to.133,142,194,509 The ventral stream thus provides a conscious analysis and understanding of the visual world, while the dorsal stream facilitates and brings about accurate movement of the body through visual space, ostensibly at a subconscious level. The functions of the dorsal stream comprise the analysis of the complexity of a visual scene, the ability to accord selective visual attention to specific elements, the ability to suppress other elements so that they do not distract, and the handling of other incoming data such as hearing and touch. The dorsal stream also determines the visual coordinates of elements within the visual scene, informs the motor cortex to facilitate visually guided movements of the body, and informs the frontal eye fields to bring about rapid eye movements to view objects of interest.137 The ventral stream is comprised of the fusiform gyri of the inferior temporal lobes, which ostensibly act as an image store for the wealth of imagery encountered. If the incoming data from the occipital lobes match what is already known, recognition takes place.140 Following injury, affected individuals have an inability to interpret the totality of the scene despite preserved ability to apprehend individual portions of the whole. If the ventral stream is selectively affected, a child with cerebral impairment and good acuities may therefore mistake a stranger for a parent. Because the ventral stream also subserves orientation and navigation, children with ventral stream dysfunction can easily become lost in known locations.140

Fig. 1.20 Graphic depiction of dorsal and ventral visual pathways (courtesy of Gordon Dutton, M.D.)

Subcortical Visual Loss (Periventricular Leukomalacia)

Children with PVL often display evidence of selective dorsal stream dysfunction, which selectively affects visuocognitive functions such as spatial awareness, attention, and visually-guided motion.21,139,140,141,397,398,509 Affected children may have difficulty distinguishing a line on the ground from a step, have difficulty combining tasks such as writing and listening, get frustrated if distracted while engaging in another activity, have difficulty choosing a toy in a toy box or against a cluttered background, get lost in the crowded visual scenes, and have difficulty walking down stairs or on uneven ground. These symptoms can sometimes be found even when MR imaging shows no evidence of periventricular leukomalacia or other abnormalities. Children with PVL and parietal/dorsal stream dysfunction often show visual field loss that is associated with an impaired ability to make accurate visually guided movements (or optic ataxia) especially of the lower limbs, accompanied by impaired simultaneous perception and, in some cases, with inaccurate saccades and, in others, impaired perception of movement. Cortical visual loss resulting from stroke can produce higher cognitive visual dysfunction, selectively affecting the dorsal or ventral stream.351 Selective dorsal stream dysfunction correlates with the finding that PVL shows a predilection for involving the lower visual fields.141,142,283 These findings could be explained by bilateral injury to the superior striate or extrastriate cortex. Galetta and Grossman found that horizontal meridian corresponds to the base of the calcarine fissures,186 which lie adjacent to the lesions of PVL. Horton and Hoyt256 observed that a lesion involving V2/V3 is uniquely able to produce a quadrantic visual field defect. If PVL involves higher cortical centers, associated injury to the primary visual cortex or dorsal stream injury involving higher cortical centers could obliterate the inferior visual fields bilaterally. Processing of biologic motion seems to be more severely affected.457 Although it is often written that the visual outcome of PVL is worse than that of CVI,210 many children in both groups have good visual acuity, and both groups show a large range of visual acuity. Because higher cortical dysfunction is what hobbles both groups, this distinction probably contributes little to the final visual prognosis.

Pathophysiology In the premature brain, the periventricular region represents a transient watershed zone between the ventriculopetal and ventriculofugal branches of deep-penetrating arteries (so the optic radiations are more involved). In preterm infants, ischemic brain damage tends to predominantly affect the subcortical white matter adjacent to the lateral ventricles (the optic radiations) and the anterior horns of the lateral

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ventricles (corticospinal tracts).35 Between the 27th and 34th week of gestation, a vascular watershed zone lies within the periventricular white matter, autoregulation is compromised in the immature vessels of the optic radiation. Until recently, periventricular leukomalacia was attributed to a watershed injury to periventricular white matter.35,76 This concept was based on the finding that ventriculofugal blood vessels in the brain (those coursing outward from the intraventricular and periventricular regions into the cerebrum) are poorly developed during the first two trimesters of gestation and that almost all blood supply comes from ventriculopetal arteries coursing inward from the surface of the brain.35,120,554,585 Recently, this watershed dogma has undergone progressive revision.330,435 Although vascular hypotension can produce ischemia within this subcortical arterial borderzone, recent evidence indicates that an increased metabolic activity, rather than vascular watershed distribution, may be primarily responsible for the selective ischemic injury to subcortical white matter. Several pathogenetic factors have now been shown to contribute to white matter injury in the preterm newborn.618 First, the arterial vascular supply to the immature brain leads to arterial end zones within the deep periventricular white matter.31,32,35,36,38,91,145,280,281,349,575 Second, the autoregulatory mechanisms within the cerebral vasculature are immature. 32,599 Autoregulation is often absent in premature neonates and, because of the high incidence of lung immaturity, patent ductus arteriosus, and sepsis, mild cerebral hypoperfusion is common. This implies that fluctuations in arterial blood pressure induced during intensive care may be transmitted directly to the cerebral blood vessels, causing marked variations in cerebral blood flow. Consequently, specific regions within the deep white matter become highly vulnerable to ischemic and hemorrhagic injury. Third, it is now believed that the periventricular white matter, which is the site of oligodendrocyte proliferation in preparation for myelination, has high metabolic activity (highest perfusion, most mature metabolism, greatest glucose uptake) and therefore the greatest vulnerability to injury.35,599 Fourth, periventricular leukomalacia may result from ischemic injury to late oligodendrocyte progenitors, which show selective vulnerability to hypoxic ischemic injury in the third trimester.25,26 Preoligodendrocytes and oligodendrocyte progenitor cells seem to be more vulnerable to ischemic injury551 and infection304,305 than are mature oligodendrocytes.238 Under conditions of hypoxia-ischemia551 or infection,303–305,593,594 proinflammatory cytokines such as tumor necrosis factor-a, chemokines, reactive oxygen/nitrogen species, and trophic factors, induce apoptosis. Tumor necrosis factor-a cytotoxicity has been shown to play a major role in the pathogenesis of periventricular leukomalacia.364,454 The pattern of brain injury detected on MR studies of newborns who have suffered profound hypotension correspond closely to the patterns of

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myelination, perfusion, and glucose uptake at the time of injury.35 Finally, a transient layer of deep subplate neurons may be selectively vulnerable to injury in PVL. These subplate neurons act as a way-station for axons that will ultimately connect with permanent cortical layers.191,523 Subplate neurons also appear transiently during brain development and play a critical role in the formation of connections between the thalamus and the visual cortex.306 In the term neonate with ischemic brain injury, however, certain neurons in the deep gray nuclei and perirolandic cortex are most likely to be injured, whereas other cells, such as neurons expressing nitric oxide synthase, seem resistant to ischemic injury.161 Neurons expressing nitric oxide synthase participate in processes of oxidative stress and excitotoxicity that lead to the death of neighboring cells.26,163,228 If an ischemic injury occurs early in gestation and the baby is born prematurely, some developing oligodendrocytes and subplate neurons are lost.26,399 Shatz and colleagues have shown that these subplate neurons, which lie below the cortical plate during development, are involved in cortical organization and are necessary for secondary guidance of axon collaterals from the cortex toward subcortical targets (e.g., other cortical sites, thalamus, corpus callosum).190,394 These subplate cells are generated in the subependymal germinative zones and migrate to the primitive subpial marginal zones before generation and migration of neurons in the cortical plate.600 The peak time for the development of subplate neurons corresponds to the times for PVL and IVH.600 Volpe600 has proposed that preterm injury to these subplate neurons, by secondarily affecting cortical organization and projections, could account for the complex cognitive and attentional deficits that are often seen in the preterm child. The periventricular white matter is particularly sensitive to inflammatory chorioamnionitis during a specific period of brain development, and maternal infection is now implicated in the pathogenesis of PVL.8,107,195,356,357,630 Our concept of injury has therefore changed from a monophasic ischemic birth injury to a more multifactorial mechanism in which similar factors may give rise to preterm labor and perinatal damage. Adverse perinatal events that correlate with the development of PVL include perinatal asphyxia, recurrent apnea, septicemia, hypocarbia, and prolonged mechanical ventilation.32,76,280 A range of pathogenetic factors, including free radicals, glutamate, and proinflammatory cytokines, have been shown to induce the death of immature oligodendroglial cell lines. In addition, the presence of free iron following germinal matrix or IVH may exacerbate the sensitivity of oligodendroglial cells to free radical injury. The result of these pathological processes is cystic tissue necrosis within the periventricular white matter regions and the development of PVL.32 The complex molecular mechanisms governing cell death in periventricular leukomalacia and involving inflammatory cells and associated cytokine upregulation,

1 The Apparently Blind Infant

apoptosis and, ultimately, white matter damage, continue to be elucidated.161,303 In summary, it is inadvisable to attribute PVL to perinatal perturbations that may lead to hypoxia because there is an abundant evidence for the role in a variety of contributory factors, and it is usually difficult to assess their relative roles.108 Maturational, circulatory, and inflammatory risk factors are all being studied as potential cocontributors to PVL.108 Moreover, multiple experimental studies support the claim that hypoxia without ischemia does not cause brain damage.355,358,478 While the evidence that hypoxia-ischemia can indeed cause brain lesions is indisputable,590 the legalistic inference that brain damage in human newborns must therefore be hypoxic-ischemic in origin is not well supported by solid observational evidence.216

Intraventricular Hemorrhage Periventricular and Intraventricular Hemorrhage Although the incidence of severe IVH has fallen with improvements in management and increased antenatal steroid use, it remains a major cause of brain injury, with consequent abnormal neurodevelopment.143 Most IVHs in preterm infants occur within the first few days of life. They arise from poorly supported small vessels in the subependymal germinal matrix (the metabolically active area within the ventricular wall in which the cells that compose the brain are produced), either spontaneously or as a result of hypoxia or hypertensive crisis. When ischemic brain tissue is reperfused, the weakened blood vessels frequently rupture, resulting in parenchymal hemorrhage. The hemorrhage extends into the ventricles and may eventually result in hydrocephalus and dissect into the brain parenchyma, causing direct damage to neural structures, including the posterior visual pathways. Because the germinal matrix diminishes in activity and begins to involute during the third trimester, germinal matrix hemorrhages are unusual after 34 weeks of gestation. Choroid plexus hemorrhages are common in premature infants, often accompanying hemorrhages of the germinal matrix. It should therefore be evident that the consequences of hypoxia-ischemia in premature infants result in injury represented largely by periventricular hemorrhages and leukomalacia.32 Periventricular and IVH in the premature infant has been divided into four grades related to its severity.455 Grade 1 refers to germinal matrix hemorrhage with little or no IVH. Grade II bleeds extend from the subependymal germinal zone into the ventricles (which remain normal in size). In grade III bleeds, IVH is associated with ventricular enlargement, which can result from either IVH or ex vacuo enlargement (Fig. 1.21).

Hemianopic Visual Field Defects in Children

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Fig. 1.21 Intraventricular hemorrhage. Sagittal ultrasound image shows dilated lateral ventricle filled with echogenic clot. Courtesy of Charles M. Glasier, M.D.

Grade IV bleeds were once thought to be extensions of germinal matrix bleeds into the surrounding parenchyma,215 but are now thought to result from venous infarction. They are termed periventricular hemorrhagic infarction.601 To the surprise of many, IVH is generally more benign than PVL. However, while patients with mild hemorrhage and normal ventricular size (grades I to III have less than a 10% incidence of neurological sequelae),612 patients with enlarged ventricles associated with IVH have a 50% incidence of neurological sequelae215,553 that are related to the location and extent of the parenchymal injury.114,583 In one large study,583 only 26% of patients with grade III or IV hemorrhages survived. Periventricular hemorrhage (PVH), a complication of IVH, is often conflated with PVL.74 Periventricular hemorrhage refers to the periventricular hemorrhagic necrosis caused by venous infarction.74,553,599 This lesion is distinguishable neuropathologically from PVL, an ischemic, usually nonhemorrhagic, and symmetrical lesion of the periventricular white matter. Unlike PVL, PVH results from early gestational injury and usually produces a unilateral lesion that is causally related to germinal matrix-IVH. The venous infarction associated with PVH is particularly prominent anteriorly, while PVL has a predilection for the arterial border zones, particularly the posterior region near the trigone of the lateral ventricles. Despite their pathological differences, in vivo distinction is confounded by the fact that PVL can also be associated with secondary periventricular hemorrhage (termed hemorrhagic periventricular leukomalacia). Consequently, some studies have used hemorrhagic periventricular leukomalacia

(ischemic arterial periventricular leukomalacia with secondary hemorrhage) to designate periventricular hemorrhagic infarction (the anterior hemorrhagic necrosis caused by venous infarction). The end stage of PVL and PVH (also an ischemic condition) cannot always be reliably differentiated although the changes of PVL are usually symmetrical and bilateral, whereas the opposite is true for PVH.596

Hemianopic Visual Field Defects in Children Children may display pure hemianopic defects, with normal fields on the contralateral side, or asymmetric (albeit bilateral) visual field involvement. Children with pure hemianopic defects usually have normal visual acuity, and if the defect is congenital, it may go unnoticed for many years. Congenital homonymous hemianopia is often discovered on a routine eye examination.572 Patients may have a history of being involved in accidents with automobiles approaching from the affected side, or of being tackled frequently by players approaching from the affected side when playing football, etc. Overall, patients with congenital hemianopia have minimal visual disability, whereas adults with acquired hemianopias are often severely disabled. This difference may hypothetically arise from the ability of the developing nervous system, but not the adult brain, to develop compensatory rewiring after prenatal damage, a phenomenon that has been well demonstrated in kittens.536,595 It may also arise from differences in the adaptive strategies that hemianopic patients develop to fixate targets within the blind areas of the

36

1 The Apparently Blind Infant

visual field (see below). Finally, an extrageniculostriate system could theoretically play a role.96 Trauma and tumors are the most common case of homonymous hemianopia in children.314 Most cases of congenital homonymous hemianopia are due to unilateral or asymmetric cerebral lesions, but congenital optic tract syndromes do rarely occur.381 Common structural causes are congenital lesions, such as porencephaly, arteriovenous malformations, and gangliogliomas. Cases of congenital hemianopia may be isolated or associated with other neurological abnormalities. Conversely, congenital hemiplegia is associated with a variety of visual problems.223,403 One study467 found that 75% of children with congenital hemiplegia had a homonymous hemianopia homolateral to the hemiplegic side. Associated lesions include a variety of hemispheric cortical lesions, including cerebral hemiatrophy, porencephaly of the posterior cerebral hemispheres, occipital lobe dysplasia,572 vascular malformations (e.g., Sturge–Weber syndrome, occipital arteriovenous malformations), colpocephaly, polymicrogyria, as well as prenatal injury to the periventricular white matter.259,473 Congenital homonymous hemianopia should be suspected in patients with congenital hemiplegia.467 Sturge-Weber syndrome may cause homonymous hemianopia due to leptomeningeal malformations involving one occipital lobe, with or without facial port-wine stains259 (Fig. 1.22). Congenital homonymous hemianopia with occipital porencephaly is a recognized complication ofneonatal isoimmune thrombocytopenia.111

Porencephalic cysts often show a distribution corresponding to a territory perfused by one of the major cerebral arteries, suggesting a vascular etiology (Figs. 1.6–1.8). They may also arise in areas of the brain into which intracerebral hemorrhages have dissected. Most of these abnormalities can be elucidated with CT, but occasionally, this modality may be falsely negative. Tychsen and Hoyt572 described two patients with congenital hemianopia in whom the results of CT were normal but MR imaging disclosed focal occipital dysplasia involving the striate cortex and underlying white matter. Highly characteristic optic disc and nerve fiber layer changes termed homonymous hemioptic atrophy may be seen in some patients as a result of transsynaptic degeneration.258,259,269 These consist of band-shaped pallor or atrophy of the contralateral disc; the ipsilateral disc shows temporal pallor. Corresponding hemiretinal patterns of nerve fiber layer dropout are characteristically present. The contralateral eye shows intact arcuate nerve fibers above and below the disc but absent or sparse nerve fibers in the retinal sectors nasal and temporal to the disc. The ipsilateral eye shows sparse nerve fiber layers in retinal sectors above and below the disc. Current evidence supports the notion that the presence of these disc changes attests to the timing of the cortical lesion as being prenatal259,411 or perinatal rather than acquired later in life. The clinical elucidation of transsynaptic degeneration of the retinogeniculate pathway has been used to ascribe a prenatal onset to associated cerebral lesions. For example, Fletcher et al172 described a 24-year-old patient

Fig. 1.22 MRI scan of 12-year-old girl with Sturge–Weber syndrome and right homonymous hemianopia. (a) Note severe atrophic foci over parietal and occipital areas with overlying

venous malformation. (b) The left globe shows thickened choroid (arrow) corresponding to choroidal venous malformation seen on fundus examination

Hemianopic Visual Field Defects in Children

with recent onset of seizures who was found to have homonymous quadrantanopia with underlying occipital lobe ganglioglioma. Because the patient showed transsynaptic atrophy of retinal nerve fibers, the authors reasoned that these findings indicated that gangliogliomas may arise in utero and exist for many years before causing symptoms. Patients with congenital homonymous hemianopia may show an afferent pupillary defect on the side contralateral to the cerebral lesion. These defects are rather small, measuring around 0.3 log units, with a neutral density filter. This afferent pupillary defect has been attributed to transsynaptic degeneration of the pupillomotor fibers. It appears that the pupillomotor fibers, which do not synapse at the lateral geniculate nucleus but at the pretectal area, may also be susceptible to transsynaptic degeneration.572 When an apparent defect is encountered in a patient with hemianopia, involvement of the contralateral lateral geniculate nucleus or optic tract should be considered.54,437 Generally, patients with congenital hemianopia appear to cope better with their deficit than those with lesions acquired in adult life. Patients with homonymous hemianopia may exhibit a variety of adaptive strategies to mitigate their visual handicap. Patients with either congenital or acquired lesions show diminished or absent head movements when fixating an eccentric target.622 The saccadic strategy for fixating eccentric targets appears somewhat different in patients with congenital lesions than in those with acquired lesions. Congenital hemianopes often produce a single large saccadic movement into the blind field that overshoots the intended visual target and then “finds” it as the eyes drift back. This may be a more effective adaptation than that is often seen in patients with acquired hemianopia, in which the patient makes multiple small saccades into the blind field until the target of interest is found.400 Acquired hemianopes, though, may also learn the single large saccade strategy. Patients with congenital, but not acquired, hemianopia frequently manifest a head turn.260,267 We examined a 12-yearold boy with a left homonymous hemianopia who turns his chin far over his left shoulder when batting right-handed during baseball games. Some authorities have noted that when such a child is forced to assume a normal head position, certain visual tasks, especially those related to mobility, become more difficult, which suggests that such head turns have a compensatory adaptive function. Because the fixation point of the eyes does not change with this maneuver, this adaptation could serve to centralize the remaining visual field with respect to the body, or to position the head so that saccades could be used to capture a wider angle of hemianopic space.131,199,267,459 Alternatively, this unique form of torticollis may represent a nonpurposeful postural tonus imbalance of hemispheric origin whereby early loss of visual input from one field increases neck muscle tonus on one side.73 Mechanistically, a postural tonus would circumvent any

37

element of will or choice on the part of the individual; the head simply goes where the neck muscles pull it. Many children with congenital hemianopia defects show an exotropic deviation.267 The exotropia may also be coincidental because neurologically damaged children are predisposed to strabismus.267 When the exotropic eye is on the side of the visual field defect, it serves a compensatory function by enabling the patient to have panoramic vision in the presence of harmonious anomalous retinal correspondence. Even when the exotropic eye is on the side of the intact visual field, a significant expansion of visual field results that may facilitate navigation. Thus, irrespective of whether the exotropia developed as a neurological defect or as an adaptation, we carefully check confrontation visual fields in children with constant exotropia and avoid strabismus surgery when a heminanopic defect is discovered.248 Patients with cortical visual loss from any cause may show asymmetric involvement of the cerebral hemispheres with corresponding asymmetry in their visual fields, with one hemianopic field allowing better visual function than the other. In infants and young children with lesions of the visual area of one cerebral hemisphere, a marked VEP asymmetry has been demonstrated for both flash and pattern testing.345 Patients suspected of hemianopic defects on the basis of cerebral lesions should be tested for the presence of smooth pursuit asymmetry, either with an optokinetic ROP (OKN) target, spinning of the patient, or eye movement recording. Saccadic tracking to the side of the lesion is a helpful diagnostic sign in patients with large lesions involving the parietal lobe.278 Increasingly, younger patients are prone to acquire cortical blindness or hemianopic defects as either a presenting feature or an associated symptom of AIDS. The causative lesion is most commonly progressive multifocal leukoencephalopathy, but opportunistic infections and neoplastic lesions are not unusual. Evaluation of the visual fields in infants and small children is more difficult than in adults, especially when neurological disorders, mental retardation, or illness coexist. Some useful information about the visual fields can be gleaned utilizing a modification of confrontational methods referred to as evoked saccadic techniques. When we suspect that an infant or young child with hemiplegia or neuroimaging evidence of posterior hemispheric injury harbors homonymous hemianopia, we introduce a colored toy into the superior or inferior portion of the potentially hemianopic field and move it toward the vertical meridian. If a saccade toward the toy is consistently seen as the object reaches the midline, the diagnosis of homonymous hemianopia is confirmed. Kinetic perimetry has also been performed in infants.218,416,588 Newer diagnostic techniques such as saccadic vector optokinetic perimetry may provide a more accurate means to test visual fields in neurologically-impaired children.424a

38

Mayer et al389 utilized a modified perimetric technique with LED stimuli and a forced-choice observation procedure to quantitatively record the visual fields of normal infants ages 6–7 months. They also demonstrated the applicability of this technique to infants at risk of harboring field defects, such as those with hydrocephalus. However, such methods have not received widespread application and remain investigational at this point. As mentioned earlier, VEP measurements with hemispheric recordings can help delineate preferential or asymmetric hemispheric disorders associated with hemianopic field defects.345 Some children with neglect may have a pseudohemianopia (a body- or gaze-dependent defect rather than a retinotopic defect). When looking leftward, these patients are unable to see objects in the left retinotopic field, but when looking rightward, they can see objects in the left field.327,429

Delayed Visual Maturation DVM is diagnosed when a child fails to show the expected visual function for his age but does so spontaneously after a period of time. These infants may initially appear to have cortical blindness, with poor or no fixation, normal pupillary responses, and no nystagmus, but neuroimaging studies show no underlying cerebral insult. Some of these children have a history of prematurity, delayed motor development, or small size for gestational age. Because improvement of vision is mandatory to make the diagnosis, the condition can only be suspected initially, with confirmation of the diagnosis made retrospectively following visual improvement. It should be evident then that there is no such entity as DVM that does not show visual improvement. When an ophthalmologist “hedges” when giving a visual prognosis to the parents of an apparently blind infant, he at least partially, acknowledges the entity of DVM.227,234,274 A brief summary of some developmental aspects of vision is relevant as background information for this topic.69 The globe reaches adult size only after the first decade of life. The fovea is not mature at birth. The cone photoreceptors are immature, and the ganglion cells have not moved aside to form the foveal pit. The fovea reaches full maturity at 4 years of age.245 Myelination of the optic nerves begins at the lateral geniculate nucleus, reaching the orbital part of the optic nerve at term, and continues over the following 2 years.378 Myelination of the geniculostriate pathway begins in the 10th fetal month and is fully mature about 4 months postnatally.620 The rate of myelination appears to be hastened by light exposure.401 Thus, a preterm infant, on reaching chronological term, has more advanced myelination than a full-term newborn.268 Other molecular mechanisms of retinal and retinocollicular synapse maturation522,552 are physiologically active during this

1 The Apparently Blind Infant

period. The parvocellular layers of the lateral geniculate nucleus (color vision and high-grade acuity) reach adult maturity at 6 months of age; the magnocellular layers (low-contrast sensitivity and motion detection) reach maturity at 2 years of age.249 Postnatal growth and development of the brain is not associated with an increase in cell number, but rather reflects an increase in the size of individual cells, synaptic density, and interconnections. Synaptic density in the striate cortex increases over the first 8 months and then begins declining, reaching adult density at age 11 years.272 Cortical ocular dominance columns become adultlike at 6 months.20 Functional, behavioral, and neurophysiological aspects of visual function emerge to some extent in a parallel manner with the aforementioned anatomical and physiological developmental aspects. Pupillary reaction to light becomes apparent in 30-week-old premature infants.276 Accommodation and stereopsis begin to emerge at about 3 months of age.20 Ocular pursuit movements in neonates are saccadic, becoming smooth at 2 or 3 months of age.2 Rapid changes in the configuration of VEPs occur in the first few months of life, so that abnormal-looking responses may be normal for age. Most newborn infants demonstrate fixation and following of a near object, such as the examiner’s face. However, some neonates show significant delays in developing fixation and following. It is these visual “late bloomers” that typify the entity of DVM. Lambert et al344 reported nine cases of “pure” DVM, excluding cases with ocular abnormalities, perinatal asphyxia, or structural cerebral abnormalities. With one exception, all infants showed normal VEPs to flash and pattern stimulation (despite being behaviorally blind), and all these showed normalization of vision at the end of the follow-up period, usually within a few months. Children with DVM exhibit normal acuity thresholds as measured by grating and vernier acuity.205 The authors concluded that intact pattern VEPs strongly indicate a good visual prognosis in such behaviorally blind infants. Skarf,528 in a discussion of the paper by Lambert and colleagues,344 advised that absence of a pattern or even a flash VEP in meeting the study’s criteria should not, however, necessarily be interpreted as a dismal prognostic sign. Lambert et al344 felt that the visual recovery could not be explained by foveal immaturity, delay in myelination, and synaptogenesis of the posterior visual pathway.344 Moreover, in view of the normal pattern visual evoked responses in all but the one patient who did not attain normal vision, delay in the maturation of the striate cortex was also considered an unlikely explanation of the poor vision. MR imaging of the optic nerve and chiasm in normal infants and those with delayed visual development showed no delay in myelination patterns, either in the neural visual pathways or elsewhere in the cortex. Lambert et al344 suggested immaturity of the higher visual association areas as the possible explanation. This suggestion may be supported by the observation that the phylogenetically older systems are myelinated first, with

Delayed Visual Maturation

myelination proceeding roughly in a rostral direction; the cortical association fibers are myelinated last.620 As a diagnostic label, DVM may be used in the narrow sense previously described or may be applied more broadly to include patients with various developmental abnormalities and ocular disorders. A trend for a broader application of the term emerged as experience has accumulated to justify this. Tresidder et al566 reported 26 cases of DVM but had a different inclusion criteria, including all cases of blindness without an ophthalmological cause. They subdivided the cases into three groups. Group 1 included infants with isolated DVM. This group was further subdivided on the basis of the presence or absence of perinatal problems. Group 2 included infants with neurodevelopmental abnormalities. Group 3 included infants with nystagmus. Visual recovery was fastest in group 1 infants without perinatal problems, of whom seven of eight recovered normal vision between the third and fourth month of life. None in group 2 attained normal vision, while patients in group 3 did so but later than group 1. All groups developed nystagmus concurrent with visual recovery; the nystagmus disappeared in group 1, with complete visual recovery, but persisted in group 3. The timing of visual recovery in this study (between the third and fourth month of life) has been noted to be synchronous with the emergence of geniculostriate-mediated visual functions, such as binocular vision, some orientation-specific responses, and smooth eye movements. Thus, while nystagmus is usually absent in DVM, both transient and persistent nystagmus are wellrecognized findings in some cases.59,207 As the foregoing studies indicate, DVM is most widely thought of as representing an isolated anomaly with total eventual recovery of vision. However, as early as 1947, Beauvieux48 pointed out that DVM may be further complicated by superimposed ocular or neurodevelopmental disorders that may render the eventual visual outcome variable. Fielder et al168,169 modified the classification of DVM provided by Uemura and colleagues573,574 and divided DVM into the following three types: Type 1. Isolated DVM is diagnosed when the child is otherwise healthy, with no associated ocular or systemic disease. Visual recovery usually occurs within a year of age. Type 2. This second type is diagnosed when the child has associated systemic disease, mental retardation, or other neurodevelopmental disorders. This type includes infants who may be small for gestational age or premature children321 with associated delays in their general motor development.94 Kivlin et al321 suggested that visual inattentiveness in a preterm infant is a harbinger of generalized neurological problems more so than in full-term infants. Also included are children with organic brain damage, such as anoxia, hypoglycemia, Aicardi syndrome, tuberous sclerosis. Infants in this group usually improve partially. Neonatal hyperbilirubinemia may depress the visual evoked responses within the

39

first year of life although the possibility of phototherapy as a confounding variable has not been definitively excluded.90 Infants exposed in utero to cocaine may similarly have DVM.204 Type 3. The third type is diagnosed when the child has associated ocular disease, such as bilateral cataracts, severe corneal opacities, colobomas, retinal dystrophy, optic nerve hypoplasia, or albinism. Affected children often have associated nystagmus. The visual impairment in such children may appear early on to be out of proportion to the ocular defect per se but improves proportionately with time. Not all patients with the aforementioned disorders show improved vision over time, and no clinical features help distinguish those who improve from those who do not.166 The visual improvement has been postulated to result from posterior visual pathway maturation.166 Infants with no visual responses can show dramatic normalization after correction of myopic refractive errors.615 In the same way, children with organic visual loss in one eye (organic amblyopia) often develop a superimposed functional amblyopia (visual loss on a cortical basis)335 many children with bilateral ocular causes for their vision loss (e.g., coloboma, optic nerve hypoplasia, albinism, myopia) may have a superimposed component of DVM, as attested to by the observation that the vision in many of these children improves surprisingly in the first year of life. Of 11 such patients, Fielder et al166 reported significant, albeit limited, visual improvement in eight. It is tempting in this context to speculate on the pathophysiologic basis of visual improvement reported in infants with unilateral ocular disease (e.g., optic nerve hypoplasia, congenital glaucoma) after patching therapy.335,336 Could the visual improvement be due, at least in part, to a maturational phenomenon of the posterior visual pathway? Stated differently, is the partial recovery of vision observed in some patients with significant ocular disorders limited to those with bilateral disease, or can it also occur in unilateral ocular disorders? It is impossible to answer this question without an appropriately designed clinical trial. Most patients with DVM have an unremarkable optic disc appearance. However, it has been noted that some patients with DVM may show gray discoloration of the optic discs (gray pseudo-atrophy of Beauvieux).48 Such children are usually either immature or have ocular albinism, with the grayish tint variably attributed to “the effect of contrast” between a normally pigmented disc and an albinotic fundus, or deficient myelin of the optic nerve. The gray appearance of the optic nerves originally led Beauvieux (1926, 1947) to speculate that this problem resulted from delayed myelination of the optic nerves. This discoloration should be distinguished from the grayish discoloration of the disc that may occur due to pigment on or within the disc substance that may be noted with melanocytoma or in several chromosomal abnormalities. Although Beauvieux attributed DVM to a

40

delay in myelination, he presciently used the term temporary visual inattention to describe this condition.50 In one study, MR imaging has shown that the overall myelination process appears delayed in infants with developmental delay as compared with normal age-matched infants.125 However, the overwhelming evidence suggests that the function of the retina, optic nerve, visual cortex, and saccadic eye movement systems are normal in infants with DVM.344,609 This hypothesis is supported by the observation that visual function of premature infants with cortical lesions is similar to that of infants without such lesions.134 This implies that a subcortical, subcortical, possibly collicular, extrageniculostriate system is responsible for vision in the neonate, a postulate supported by the clinical observation that vision is indeed abnormal in infants with subcortical lesions.135 According to this concept, visual recovery in DVM represents the emergence of a functioning geniculostriate system that takes place around 2–4 months of age.117 The notion of delayed myelination was reinforced by the finding that vision in infancy is subcortically mediated and that DVM may represent malfunction of the extrageniculostriate system (colliculus-pulvinar-parietal system), which subserves responses in neonates relating to detection, location, and orientation.167 Dubowitz et al135 suggested that lesions involving the thalamus have a more profound effect on the visual function than lesions of the visual cortex in infancy. This interpretation has been taken to imply that the extrageniculostriate system was responsible for early visual function and the striate system might not predominate until several months of age. The finding of a measurable delay in the development of pupillary responses implicates transient dysfunction of both cortical and subcortical visual systems in some patients.92 However, this interpretation appears to be incorrect. More likely, any profound visual disability associated with lesions of the thalamus in infants is due to their effect on visual attention mechanisms.234 Follow-up studies of children with DVM reveal a definite tendency toward the developmental problems, including global developmental delay as well as speech delay, hearing delay, and autistic tendencies, either concurrently or following visual improvement.11,88,169,212,268,495 For this reason, DVM has come to be viewed as a mild form of CVI by which injury to higher visual association centers that subserve visual attention may produce the behavioral profile observed clinically. Some neuroanatomic abnormalities may elude detection on the standard neuroimaging techniques used in infants, which are relatively insensitive to cortical abnormalities. Even in the absence of neuroimaging lesions, these children are at significant risk for neurodevelopmental and educational problems in the future. However, the much better visual prognosis than in patients with demonstrable cortical insults justifies a separate classification from the typical CVI.

1 The Apparently Blind Infant

Hoyt263 retrospectively reviewed 98 patients with isolated DVM who were followed for at least 3 years. Although 93 had 20/20 visual acuity, he found that 22 had a learning disability, 11 had attention-deficit hyperactivity disorder, 9 had seizures, 5 had cerebral palsy, 5 had psychiatric disorders, and 4 had autism. In nine children, repeat MR imaging showed minor gyral anomalies. Some children with a seizure focus in the frontal or parietal cortex appear to be “blind” despite the fact that no pathology can be identified in the eyes, the visual cortex, or the optic radiations.263 Hoyt concluded that DVM is attributable to a top-down injury (rather than the bottom-up injury that delayed myelination would imply) to higher cortical centers involved in processing visual attention and that the observed recovery is attributable to neural plasticity in the neonatal period.234 So, the notion that these are children who simply have 4 or 5 months of bad vision in early infancy is an oversimplification. Because of limited processing resources, multiple objects compete at the same time in the visual field for neural representation. The brain appears to handle this competition in two primary ways: a bottom-up, stimulus-driven process, and a top-down, feedback attentional network.263,479 The visual attention network can be divided into a posterior system that subserves visual spatial attention and an anterior system that selects the stimulus of attention by providing “executive functions.”121,310 Although competition among objects in the visual environment must be resolved within the visual cortex, the top-down signals arise from areas of the brain outside the visual cortex. While the complete details of these areas have yet to be defined, primate and human studies point to similar basic substrates.121,310 The anterior system involved in selection of stimuli (executive functions) depends on the frontal cortex (frontal eye field and supplemental eye field areas), globus pallidus, caudate, and putamen, although other areas, especially in the posterior thalamus, may also be involved in gating visual attention.310,484 The posterior system appears to involve the inferior parietal cortex (probably more predominantly on the right), superior colliculus, and pulvinar.185,479 The capacity of the visual system to process information about multiple objects at any given moment in time is limited.569 A selective deficit in visual attention would nicely explain the normal VEPs and the capacity for the development of good visual acuity that characterizes DVM. Some children who present with DVM may later prove to have congenital ocular motor apraxia. Infants with ocular motor apraxia may appear blind before acquiring head and neck control, which is a prerequisite to manifest the characteristic head thrusts.486 This is so because infants normally employ the saccadic system (which is defective in congenital ocular motor apraxia) to follow objects of regard (saccadic pursuit). Checking the vestibulo-ocular reflex by spinning such children around would produce only a slow phase of nystagmus; the fast phase would be expected to be defective.

Blindsight

Only when the neck musculature and head control are sufficiently mature, do the characteristic head thrusts emerge to strongly suggest the diagnosis. Unless associated with Joubert syndrome, children with congenital ocular motor apraxia would be expected to have normal VEPs and ERGs.

Blindsight There has been considerable controversy regarding the existence of an extrageniculostriate visual system that subserves a cruder form of visual discrimination (blindsight) in man.83,385,460,626,628 The precise function of such a system is debatable, but it is thought to be integrated with the geniculostriate system and to mediate the unconscious awareness of motion in the peripheral field, spatial localization, and visuospatial orientation.300 Neuro-anatomically, it is estimated that 20–30% of the optic nerve fibers in humans terminate in structures other than the lateral geniculate body.89 In primates, some such fibers go to the pretectal area and others to the superior colliculus which, in turn, project to the secondary, parastriate visual cortex (areas 18 and 19) and other areas of the brain via the pulvinar.71 The function of the pretectal fibers is to mediate pupillary reaction to light, while collicular-pulvinar-parastriate fibers are presumed to subserve a subcortical form of vision that bypasses the geniculostriate pathway (blindsight). The term blindsight refers to unconscious residual visual ability detected within a visual field defect corresponding to a lesion of the striate cortex. In humans, data supporting the existence of blindsight has been largely derived from studies demonstrating the ability of some patients with cortical blindness or hemianopia to detect and localize stimuli that they do not report seeing within a perimetrically blind hemifield, as well as the ability to determine the orientation, motion, or color of such stimuli.472 For example, when an image is flashed in the blind hemifield, affected patients are able to point to the location of the image or to guess correctly when it appeared. Despite insistence on seeing nothing, the typical patient scores better than what would be expected from chance alone. The results of such studies are open to question on the basis that some residual cortical function may still remain in the area subserving the blind fields due to incomplete destruction of the striate cortex30,71,83,157 or that they may represent an artifact of poor fixation or light scattering.83 In humans, neurologic injury to the striate cortex usually involves some degree of injury to the overlying visual association cortex.606 Even in experimental studies after bilateral occipital lobectomy in primates, residual visual function may stem from subtotal resection of the anterior striate cortex.119 The phenomenon of blindsight is unconscious. Conscious awareness of residual visual function in a patient with cortical blindness renders the possibility of an

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underlying blindsight mechanism, which is subcortically mediated, quite unlikely. Since the early reports of blindsight, a wide range of residual functions without an acknowledged awareness have been called “Type I” blindsight.605 These include target detection and localization by saccadic eye movements or manual pointing, movement direction detection, relative velocity discrimination, and stimulus orientation detection. Other subjects show “Type II” blindsight characterized by residual visual abilities with awareness such as consciously detecting a fast-moving stimulus and its direction607 or semantic priming from words presented in a blind field.380 One notion of blindsight revolves around the idea that the extrageniculostriate system may act as a backup visual system if the geniculostriate system is defective.70 Adults with acquired complete destruction of both areas 17 are usually totally blind,71,89 “despite a preserved tectal system.”109 Whether a similar generalization applies to prenatal or neonatal lesions in humans is unknown. The age at the time of insult is important because many animal studies have suggested that the immature brain has a greater potential for recovery than the adult brain.606 Evidence derived from experiments with cats indicates that visual cortex damage in neonatal kittens, but not in adult cats, is followed by the significant compensatory rewiring of the nervous system that reduces the otherwise expected visual handicap. A similar adaptability of the human embryonic CNS may underlie some cases that defy ready explanation on the basis of electrophysiologic and neuroimaging evidence. Summers and MacDonald550 described a 14-month-old infant who showed intact central vision despite the absent patterned VEPs and tomographic absence of the occipital cortex. The cerebral lesion might have resulted from a prenatal developmental defect. The authors speculated that the intact central vision may be explained on the basis of a heterotopic occipital cortex, a subcortical collicular system, or rewiring of the brain after the prenatal lesion. Adults who have sustained damage to the occipital lobes commonly have a degree of perception of movement that is either conscious or subconscious. Soldiers who sustained occipital injury during World War I were found by Riddoch (1917) to be aware of movement in the “blind” visual field. This statokinetic dissociation is known as the Riddoch phenomenon. Adults who are blind because of cerebral damage may manifest a relatively subconscious awareness of moving targets, lights, and colors in the blind area. When asked to guess the position of a moving target, they do so more frequently than is probable by chance alone.605 In monkeys, orientation to visual stimuli and visually guided movement takes place despite bilateral occipital lobectomy.270 The brain structures that subserve blindsight may include residual striate cortex, light scatter from the seeing hemifield, extrastriate cortex, and the superior colliculus and pulvinar.68,98,458,537,543,606

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Blindsight has only recently been studied in children. Boyle et al65 found evidence of blindsight in 19 of 541 children with profound visual impairment and four with hemianopia. They noted that helping the parents and caregivers to both recognize and make use of their child’s blindsight can facilitate bonding. When feeding children with profound cerebral visual impairment, for example, the child does not open his or her mouth when the spoon approaches the mouth from straight ahead. However, bringing the spoon in an arc moving through the peripheral visual field can result in the child’s mouth opening to receive the food. Adults with blindsight who see movement only may report improved conscious awareness of movement when rocking back and forth.137 In children who choose to rock to and fro when they want to see something, it may be counterproductive to discourage such behavior.192 While some success has been obtained in training adults to gain a conscious awareness of their blindsight,627 there is greater potential for improvement when the damage to the primary visual cortex is sustained early in life.458 Unlike in humans, primates show the preservation of visuospatial orientation and recognition of moving targets after bilateral destruction of both areas.270 The interspecies difference may be theoretically explained from a phylogenetic viewpoint; that is, the greater the development of the newer cortical visual structures, the less the contribution of the older tectal and collicular structures to visual function. In lower vertebrates, the superior colliculus is the major visual processing center. In humans, unconscious perceptual processes are subserved by the activity of subcortical visual pathways, including the superior colliculus and other pathways bypassing the primary visual cortex.353,594 In one patient, functional MRI demonstrated activation of the amygdala in response to a conditioned visual stimulus that correlated with activity levels in the superior colliculus and pulvinar, suggesting that a route that bypasses VI may remain intact for activation by emotional events.421,606 A study of diffusion tensor tractography in hemispherectomized patients demonstrated strong ipsilateral and contralateral projections from the superior colliculus to primary visual areas, visual association areas, precentral areas/frontal eye fields and the internal capsule of the remaining hemisphere in hemispherectomized patients with type I or “attention blindsight.”353 These results support an essential role for the superior colliculus in blindsight. In both humans and primates with V1 ablation, medial temporal cortex (MT) responsiveness is reduced but not eliminated and motion perception persists. Although it has long been believed that visual information could reach the extrastriate cortex without traversing V1 by going from retina to superior colliculus to pulvinar to MT, the region of the pulvinar receiving input from the superior colliculus may possess only a few neurons that project to MT.527 In infant

1 The Apparently Blind Infant

cats with cortical visual injury, one particular anatomical pathway that runs directly from the dorsal lateral geniculate nucleus to the posteromedial lateral suprasylvian cortex has been implicated in the superior visual recovery. This normally-transient pathway is retained and expanded after visual cortical injury in infancy but not in adulthood.219,220,535,564 Although Sorenson and Rodman534 could find no direct pathway from the dorsal lateral geniculate nucleus to MT or medial superior temporal cortex (MST) using retrograde tracers, Sincich et al527 found a direct projection in the macaque monkey, from the lateral geniculate nucleus to the motion-selective middle temporal area (MT or V5), a cortical area not previously considered primary. The constituent neurons sent virtually no collateral axons to the primary visual cortex (V1) and equaled about 10% of the V1 population innervating MT. The authors proposed that this pathway could explain the persistence of motion sensitivity in subjects following injury to V1 and suggested that residual perception after damage in a primary area may arise from sparse thalamic input to secondary cortical areas. In their book Sight Unseen, Milner and Goodale413 document how selective ventral stream injury can produce a syndrome of blindsight. Balint syndrome is caused by bilateral superior (dorsal stream) parieto-occipital lesions in the watershed areas resulting from anoxia, hypotension, or infarction.240 The features of Balint syndrome that may occur together or separately592 include the following: (1) despite the normal range of ocular movements, the patients seem unable to fixate an object voluntarily, and, if fixated, gaze tends to involuntarily drift away (“psychic paralysis of gaze”); (2) inability to guide arm and hand movements by using visual feedback, with inaccurate reaching and grasping (“optic ataxia”); and (3) inability to attend to more than one visual stimulus in the whole visual field at a time (“piecemeal vision”) and, often, unawareness of extramacular stimuli (bilateral visual neglect). The visual acuity is intact, and visual agnosia is absent (i.e., the patient recognizes what he sees), because the parietal and temporal association areas are intact. Balint syndrome has recently been described in children.133,194 However, the diagnosis is usually missed, possibly due to difficulties in testing. While Balint syndrome represents the extreme variant of dorsal stream dysfunction, mild variants are much more common. In summary, most investigators now acknowledge the existence of an extrageniculostriate system that persists and expands following early injury to the visual cortex.83 This pathway probably involves projections from the superior colliculus as well as direct projections form the dorsal lateral geniculate nucleus to extrastriate area MT. These pathways may normally function to subconsciously mediate body orientation during traveling.83 The selective neuroanatomic pathways subserving blindsight are still being elucidated, and this controversial phenomenon has led to some intriguing

The Effect of Total Blindness on Circadian Regulation

questions about the nature of consciousness and the potential role of the extrageniculostriate system in visual performance. These pathways may also play a role in modulating the normal visual processing that occurs in the absence of conscious awareness.606 The observation that visual attention still has a determining impact on unconscious processing demonstrates that visual attention cannot be loosely equated with visual consciousness.428a

The Effect of Total Blindness on Circadian Regulation In the current cost-conscious climate of medical practice, the contribution of expensive and complicated surgical procedures to the overall quality of life comes under increasing scrutiny. A case in point would be the patient with stage 5 ROP who undergoes extensive vitreoretinal surgery only to achieve “anatomical success,” sometimes with no better than light perception vision. A question then arises whether the low functional vision attained with surgery contributes sufficiently to the patient’s overall quality of life to justify the total cost. While questions like this are difficult to answer, there is an increasing evidence to suggest that restoring any visual input may have significant impact on the overall wellbeing of the child in a manner unrelated to the meager improvement in visual function.506 This evidence derives from studies demonstrating the importance of light input in the entrainment of circadian timing systems.322 From the clinical standpoint, these adverse effects of blindness may manifest as sleep disturbances or depression following the visual loss, among other disorders.373 Light input to the eye controls a panorama of life’s major functions, such as fertility, seasonal gestation, sleep/wake rhythms, adrenal behavior, hibernation, and mood itself.373 Systemically, the circadian pacemaker (or biological clock) regulates the timing of a host of physiologic parameters across the biological day.420,582,602 Free-running circadian rhythms can cause problems with sleep/wake cycles, mood, growth, reproductive functioning and other endocrine systems, cell division, and aging.387 Circadian rhythms may even impact maturation, developmental milestones, and longevity. Even though a blind person has no light perception, he or she may indeed have a functioning retinohypothalamic tract pathway because the level of light needed to stimulate the system and synchronize the suprachiasmatic nucleus may be very low. Thus, minimal vision (and perhaps the intact eye in patients with no light perception) should be preserved in individuals with eye disease in order to avoid disturbances in circadian rhythm and clinical symptoms related to gonadal dysfunction, sexual maturation, infertility, mood disturbances, and the daily sleep/wake cycle.373

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Research on circadian timing systems in mammals have shown that three components of such a system exist: (1) a visual pathway connected to the circadian pacemaker, (2) a pacemaker (which in mammals, including possibly, humans, is the suprachiasmatic nucleus of the hypothalamus), and (3) efferent pathways coupling the pacemaker to effector systems that display circadian function.417 Disruption in any of these components would result in circadian dysfunction. Total elimination of environmental light input may result in loss of circadian entrainment with subsequent free-running circadian rhythms. The endogenous, free-running, sleep-wake rhythms of humans is about 25 h, a shift of 1 h from the normal, entrained rhythm.104,503 This shift results in sleep disturbances, wherein affected patients are periodically awake at night and sleep during the day. Therefore, the pacemaker needs to be synchronized or entrained to the external 24-hour day. Light through the eyes has been shown to be the primary synchronizer.103,503,611 The anatomical locus for the biological clock is the hypothalamic suprachiasmatic nuclei,84 and its molecular “clockwork” within individual neurons that form the basis for pacemaker rhythmicity.57,136,476 Photic information conveyed from the retina via the retinohypothalamic tract to the suprachiasmatic nuclei provides the daily phase shifts necessary to maintain entrainment).322 Timing,317 intensity,62,624 and wavelength68,368 have all been shown to be important factors in the resetting effects of light. The importance of retinohypothalamic connections in circadian rhythm regulation has been amply demonstrated in experimental animals. Bilateral transection of the optic nerves in rats resulted in loss of synchronized endogenous circadian rhythm, while bilateral transection of the optic tracts had no such effect. Retinohypothalamic fibers project directly from the optic nerves to the suprachiasmatic nucleus of the hypothalamus, the circadian pacemaker (Fig. 1.23). These findings are also applicable to humans. In mammals, retinohypothalamic projections to the pineal gland provide the primary stimulus that serves to regulate melatonin secretion. Plasma melatonin levels rise at night and plummet during the day. Melatonin free running may explain why many blind patients have chronic insomnia. Blind patients without chronic insomnia maintain normal melatonin levels, while those with insomnia are found to have lost their ability to regulate these levels. Melatonin is available in a synthetic form for oral use. Recent studies have shown promising results for the possibility of treating certain sleep disorders by entraining the circadian pacemaker with external administration of melatonin.289,499,501 Of all the parameters with endogenous circadian variation, the rhythm of melatonin secretion has proved to be the most reliable marker of circadian phase.362 Melatonin is secreted by the pineal gland, and levels are high during the night and low during the day.360 This pattern of secretion is the same in both nocturnal (night-active) and diurnal (day-active) species, and so melatonin secretion can be thought of as a marker for the

44

1 The Apparently Blind Infant

Fig. 1.23 Graphic overview of visual pathways influenced by melanopsin. CG ciliary ganglion; SCN suprachiasmatic nucleus; PVN periventricular nucleus; LGN lateral geniculate nucleus, IGL intergeniculate leaflet;

OPN olivary pretectal nucleus; EW Edinger-Westphal nucleus; SCG superior cervical ganglion; IML intermediolateral nucleus of the spinal cord. With permission from Berson et al57

Table 1.3 Characteristics of photoreceptors and melanopsin-containing retinal ganglion cells

cones, by intrinsic activation via melanopsin-mediated phototransduction, or both.311 Melanopsin is a novel opsin-based photopigment that renders these cells intrinsically photosensitive. Melanopsin-containing retinal ganglion cells are intrinsically photosensitive, with peak sensitivity in the short wavelength (around 480 nm), so they are particularly sensitive to blue light,57,237 which, when used during pupillary examination, can isolate the contribution of the ganglion cells to the pupillary light reflex in various retinal degenerations.311 In patients who are blind from retinitis pigmentosa, use of a blue light may therefore elicit some detectable pupillary response.311 Although melanopsin-deficient mice entrain normally to bright light-dark cycles, under constant darkness their oscillator is less sensitive to discrete pulses of light, thus establishing an important role for melanopsin in circadian photoentrainment.57,237,453,493 These novel retinal ganglion cell photoreceptors are far less sensitive and far more sluggish than rods and cones, with latencies as long as one minute.57 Selective sparing of these cells may help to explain the puzzling phenomenon of disabling photophobia responses that accompany the congenital retinal dystrophies. Because melanopsin-containing cells are inhibited by blue cones and stimulated by red and green cones, it may also explain the paradoxical pupillary phenomenon. In retinal dystrophies causing loss of red and green cones, turning off the room lights may remove blue-cone inhibition from melanopsin-containing photoreceptors, allowing them to constrict the pupils.311 Photoentrainment of circadian rhythms can occur in the absence of classical photoreceptors (rods and cones)179,180 but not in animals without eyes.453 Selective genetic ablation of melanopsin abolishes the intrinsic light response (the ability of individual ganglion cells to respond to light), it has surprisingly little effect on circadian photoentrainment.453,493 Thus, under normal circumstances, classical photoreceptors

Photoreceptor cell Rods and cones Location Photopigment Total number Receptive field Sensitivity Function

Melanopsin-expressing Ganglion Cells

Outer nuclear layer Ganglion cells, inner nuclear layers Rhodopsin, cone Melanopsin opsin 92 million rods, 5 Several thousand million cones Very small Very large (photoreceptive net) All visible Broad band, most sensitive wavelengths to blue wavelength Image formation Circadian clock, pupillary light reflex

Adapted, with permission, from Kawasaki et al312

b iological night. Melatonin levels are suppressed by light but are relatively unperturbed by other types of stimuli.361 The recent discovery of melanopsin, a novel vertebrate opsin in ganglion cells of the retina, provided a missing explanation of why eyes are necessary for circadian photoentrainment but the photoreceptors are not (Table 1.3).312 In rodents, only 1–3% of all retinal ganglion cells contain melanopsin.237 These melanopsin-containing ganglion cells are scattered throughout the retina, with somewhat higher density superiorly.230,237 This novel vertebrate opsin is directly photosensitive, redistributing pigmented organelles when illuminated.57 Melanopsin-containing ganglion cells in the retina do not project to the lateral geniculate nucleus but to the suprachiasmatic nucleus to maintain the nonvisual functions of photoentrainment of the circadian system.461 They also project directly to pupillary centers to modulate the pupillary light reflex. These neurons depolarize either from transsynaptic activation initiated by phototransduction in the rods and

Horizons

also help to synchronize the circadian clock57 and help to drive the suprachiasmatic nuclei,8 and light continues to affect circadian phase (albeit less effectively) when the direct photosensitivity of intrinsically-photosensitive retinal ganglion cells is eliminated by knockout of melanopsin.57 This and other nonvisual responses are lost only when the melanopsin deficiency is coupled with mutations that disable classical rod and cone photoreceptors, suggesting that melanopsincontaining retinal ganglion cells also receive rod and cone driven synaptic inputs.239 Suprachiasmatic nuclei-projecting retinal ganglion cells can respond to light both via an intrinsic melanopsin-based signaling cascade and a synaptic pathway driven by classical rod and/or cone photoreceptors. Recently, a medium-wavelength opsin has also been found to contribute.129,453 It is unclear how the retinal ganglion cells integrate these temporally distinct inputs to generate the signals that mediate circadian photoentrainment and other nonvisual responses to light. Blind people have a high incidence of sleep complaints, with some suffering intractable sleep disorders, suggesting that circadian disruption may be at fault.406,407,453,505 Patients with congenital blindness have been shown to have abnormalities of other circadian rhythm regulation.430,453,603 In these patients, excessive daytime napping may be a sign of circadian dysfunction.370,603 In addition, many totally blind people have free-running temperature, cortisol, melatonin, and sleep-activity rhythms. In addition to sleep propensity and alertness, circadian variation can be seen in clinical phenomena such as fasting glucose level and myocardial infarction.427,500,503,568 However, some blind human patients continue to suppress melatonin production when exposed to light.105,505 In patients with congenital retinal or optic nerve blindness, sleep disturbances may be secondary to an absent melanopsin function, while in others with CNS disease, it may be secondary to associated hypothalamic injury. Sleep disturbances in visually impaired infants are often responsive to melatonin,299 although there are concerns that this hormonal medication may interfere with normal progression of puberty.589 Although most individuals lacking light perception have free-running circadian rhythms, some maintain circadian entrainment,369 albeit sometimes with an abnormal phase.502 It remains unclear what zeitgebers (time cues) mediate entrainment among blind persons who are without light perception and yet are able to maintain synchronization to the 24-hour day. Furthermore, light has been shown capable of constricting pupils, suppressing plasma melatonin levels, and resetting circadian phase in some individuals lacking subjective light perception. The quantity of light needed may fall below the level of conscious visual perception (which is estimated to have as a threshold the loss of 95–97% of photoreceptors).505 In summary, the intrinsic melanopsin photoreceptive system within the ganglion cells that mediates the circadian

45

resetting effects of light is distinct from the rods and cones that mediate vision.150 Total elimination of light input into the hypothalamus may, accordingly, have far-reaching consequences on various circadian systems with potentially significant negative impact on the patient’s health and wellbeing. Sadun et al505 prophetically state that “In the future, ophthalmologists may consider the potential impact on the neuroendocrine system when assessing the relative risks and benefits of therapy. Salvaging light perception vision may be of greater significance than previously thought.”

Horizons Our understanding of the major retinal and CNS disorders that produce blindness in infancy continues to be refined by new diagnostic techniques. Although neuroimaging is relatively insensitive to identifying dysfunction of the visual cortex and higher cortical areas, newer diagnostic modalities using high-strength magnets, diffusion tractography, diffusion-weighted imaging, and functional imaging change our understanding of many neurological disorders that affect the visual system.221 Although the role of the clinician has traditionally been limited to providing information, counseling, and support, a number of new and promising therapies are on the horizon. Gene therapy has achieved early success in patients with LCA.28,379,369a Pharmacological treatments, growth factors, and neuroprotective factors are all being used to tip the scales toward neuronal survival in children with perinatal brain injury.160 Stem cells, nanoparticles, and agents to promote neural plasticity should also find application in the near future. Refinement of preventive measures and early treatment of underlying causes to prevent neuronal damage in premature infants will hopefully reduce the incidence of periventricular leukomalacia.160 Rescuing sick axons to prevent their death is assumes an important role in areas of research concerned with brain injury.43,246 Research to prevent transsynaptic degeneration after brain damage also holds promise,517 although it is not clear whether such prevention would have a clinically desirable outcome. Older therapeutic interventions such as placement of a shunt for hydrocephalus or antibiotic treatment for meningitis are of obvious importance to limit the extent of neuronal damage. Visual stimulation is a therapeutic modality that is, generally speaking, not popular with ophthalmologists. However, some authorities who work regularly with visually impaired children believe that certain techniques of visual stimulation may result in visual improvement but acknowledge that this reflects their clinical experience rather than results of scientific research. Visual stimulation rests on the premise that vision is a learned skill, and like physical therapy, good

46

visual stimulation helps the child use his residual sight more efficiently. This may occur as a result of recruiting neurons, increasing the synapses, or other means.532 Given its impressive efficacy in treating amblyopia (with occlusion therapy), we should not be pessimistic about its therapeutic potential.

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Chapter 2

Congenital Optic Disc Anomalies

Introduction Congenital anomalies of the optic disc underlie many cases of decreased vision, strabismus, and nystagmus in childhood.125 A comprehensive evaluation necessitates an understanding of the ophthalmoscopic features, associated neuro-ophthalmologic findings, pathogenesis, and appropriate ancillary studies for each anomaly.40 The subclassification of different forms of “colobomatous” defects on the basis of their ocular and systemic associations has further refined our ability to predict the likelihood of associated central nervous system (CNS) anomalies solely on the basis of the appearance of the optic disc.40 The widespread availability of modern neuroimaging has refined our ability to identify subtle associated CNS anomalies and to prognosticate neurodevelopmental and endocrinological problems.40 Genetic analysis has now advanced our understanding of some anomalies. Four clinical axioms can be used to guide the general evaluation and management of children with congenital optic disc anomalies: 1. Children with bilateral optic disc anomalies generally present with poor vision and nystagmus in infancy, while those with unilateral optic disc anomalies may present later in the preschool period with sensory esotropia. 2. CNS malformations are common in patients with malformed optic discs. Small discs are associated with a variety of malformations involving the cerebral hemispheres, pituitary infundibulum, and midline intracranial structures (e.g., septum pellucidum, corpus callosum). Large optic discs of the morning glory configuration are associated with the transsphenoidal form of basal encephalocele.40 The finding of a discrete V- or tongue-shaped zone of infrapapillary retinochoroidal depigmentation in an eye with an anomalous optic disc should prompt a search for a transsphenoidal encephalocele.55 3. In contradistinction to the severe dyschromatopsia that characterizes most acquired optic neuropathies, color vision is relatively preserved in eyes with congenital optic disc anomalies.

4. Any structural ocular abnormality that reduces visual acuity in infancy may lead to superimposed amblyopia.191 A trial of occlusion therapy may be warranted in some patients with unilateral optic disc anomalies and decreased vision.

Optic Nerve Hypoplasia Optic nerve hypoplasia is an anomaly that, until recently, escaped the scrutiny of even the most meticulous observers.39 It was not until the late 1960s that its clinical description became commonplace. Optic nerve hypoplasia is now unquestionably the most common optic disc anomaly encountered in ophthalmologic practice.40 This dramatic increase in prevalence primarily reflects a greater recognition by clinicians. Many cases of optic nerve hypoplasia that previously went unrecognized or were misconstrued as congenital optic atrophy are now correctly diagnosed. In addition, some investigators believe that parental drug and alcohol abuse, which have become more widespread in recent years, may also be contributing to an increasing prevalence of optic nerve hypoplasia.39,192 Teratogenic agents and systemic disorders that have been associated with optic nerve hypoplasia are summarized in Table 2.1. Ophthalmoscopically, optic nerve hypoplasia appears as an abnormally small optic nerve head that may appear gray or pale in color and is often surrounded by a yellowish, mottled peripapillary halo, bordered by a ring of increased or decreased pigmentation (“double-ring” sign) (Fig. 2.1).192 The major retinal veins are often tortuous.139 When the nystagmus precludes accurate assessment of the optic disc size, this selective venous tortuosity provides an important clue to the diagnosis. Borchert and Garcia-Filion have noted that optic nerve hypoplasia may also be accompanied by unusually straight retinal vessels with decreased branching.35 This nonbranching pattern is also found in patients with primary growth hormone deficiency,138 raising the intriguing possibility that this variant vascular pattern may turn out to correlate with endocrine dysfunction in children with optic nerve hypoplasia.35

M.C. Brodsky, Pediatric Neuro-Ophthalmology, DOI 10.1007/978-0-387-69069-8_2, © Springer Science+Business Media, LLC 2010

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Table 2.1 Systemic and teratogenic associations with optic nerve hypoplasia. (Modified from Zeki and Dutton)333 Systemic associations Teratogenic agent Albinism Aniridia Duane syndrome Median facial cleft syndrome Klippel–Trenauney–Weber syndrome Goldenhar syndrome Linear sebaceous nevus syndrome Meckel syndrome Hemifacial atrophy Blepharophimosis Osteogenesis imperfecta Chondrodysplasia punctata Aicardi syndrome Apert syndrome Trisomy 18 Potter syndrome Chromosome 13q Neonatal isoimmune thrombocytopenia Fetal alcohol syndrome Dandy–Walker syndrome Delleman syndrome

Dilantin Quinine PCP LSD Alcohol Maternal diabetes

Fig. 2.1 Optic nerve hypoplasia. (a) Optic nerve hypoplasia with selective retinal venous tortousity. (b) Pseudo-normal optic disc in a child with optic nerve hypoplasia and no light perception. The disc appears normal at first glance, but shows complete absence of retinal nerve fiber layer. It is difficult to tell whether central white area corresponds to lamina cribrosa or to hypoplastic and atrophic

Histopathologically, optic nerve hypoplasia is characterized by a subnormal number of optic nerve axons with normal mesodermal elements and glial supporting tissue.25,153,225 The double-ring sign has been found histopathologically to consist of a normal junction between the sclera and lamina cribrosa, which corresponds to the outer ring, and an abnormal extension of the retina and pigment epithelium over the outer portion of the lamina cribrosa, which corresponds to the inner ring.25,153 Visual acuity in optic nerve hypoplasia ranges from 20/20 to no light perception, and the affected eyes show localized visual field defects, often combined with a generalized constriction of the visual fields.107 Because visual acuity is determined primarily by the integrity of the papillomacular nerve fiber bundle, it does not necessarily correlate with the overall size of the disc. The association of astigmatism with optic nerve hypoplasia warrants careful attention to correction of refractive errors.331 A classic Pulfrich phenomenon (illusory perception of elliptical motion in the frontal plane) was detected in a 12-year-old girl with normal acuity and asymmetrical optic nerve hypoplasia.141

optic disc. Surrounding area represents extension of retinal pigment epithelium over normal-sized lamina cribrosa, producing double-ring sign. (c) Optic nerve hypoplasia with nasal pallor and extension of RPE and choroid over temporal aspect of disc. (d) Black optic disc caused by optic nerve hypoplasia with congenital optic disc pigmentation

Optic Nerve Hypoplasia

Optic nerve hypoplasia has recently been implicated in the pathogenesis of amblyopia.196 Using optic disc photographs corrected for magnification, Lempert found smaller optic discs and smaller axial lengths in amblyopic eyes compared with their fellow eyes, and suggested that vision impairment in presumed amblyopia may be caused by optic nerve hypoplasia with relative microphthalmos.196 Archer10 questioned whether a small optic disc area could be associated with amblyopia by being correlated with hyperopia and anisometropia rather than being the cause of the decreased vision. In other words, small eyes may have small optic discs, and further study is needed to determine whether the small optic nerves or the associated hyperopia or anisometropia is causal.10 In a follow-up study, Lempert197 factored axial length into the calculation and found the optic disc areas of eyes with hyperopic strabismus (with and without amblyopia) to be smaller than those in hyperopic eyes without amblyopia or esotropia. More recently, OCT has demonstrated a normal nerve fiber layer in amblyopic eyes, effectively refuting the Lempert hypothesis.252a Visual acuity remains stable throughout life unless amblyopia develops in one eye. However, Taylor has documented mild optic nerve hypoplasia in children with congenital suprasellar tumors, which can slowly enlarge to produce the confusing diagnostic picture of acquired visual loss in the child with optic nerve hypoplasia.301 While moderate or severe optic nerve hypoplasia can be recognized ophthalmoscopically, the diagnosis of mild hypoplasia continues to be problematic in infants and small children, whose visual acuity cannot be accurately quantified. Several techniques have been devised to directly measure fundus photographs of the optic disc in an attempt to apply quantitative criteria to the diagnosis of optic nerve hypoplasia. Jonas et al174 have defined “microdiscs” statistically as the mean disc area minus two standard deviations. In their study of 88 patients,174 the mean optic disc area measured 2.89 mm2 and the diagnosis of a microdisc corresponded to a disc area smaller than 1.4 mm. Romano256 has advocated the simple method of directly measuring the optic disc diameter using a hand ruler and a 30° transparency (both under magnification) and has concluded that a horizontal disc diameter of less than 3.4 mm constitutes optic nerve hypoplasia. This quick and simple technique is limited to eyes with minimal spherical refractive error. Zeki et al332 have found that a disc-to-macula/disc diameter ratio of 2.94 provides a one-tailed upper population limit of 95%, while individuals with optic nerve hypoplasia have a mean ratio of 3.57. Calculation of this ratio has the important advantage of eliminating the magnification effect of high refractive errors (myopic refractive errors can make a hypoplastic disc appear normal in size, whereas hyperopic refractive errors can make a normal disc appear abnormally small). While the Zeki technique is especially useful in patients with high refractive errors, the notion that one can establish an unequivocal dividing line between the normal

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and hypoplastic disc strictly upon the basis of size is inherently flawed. As discussed later, large optic discs can be axonally deficient,211,249 and small optic discs do not preclude normal visual function. In evaluating small optic discs, we have grown accustomed to drawing inferences about axon counts on the basis of size. While it is reasonable to infer that an extremely small disc must be associated with a diminution in axons, the application of this reasoning to mild or borderline cases is limited by additional variables, including the size of the central cup, the percentage of the nerve occupied by axons (as opposed to glial tissue and blood vessels), and the cross-sectional area and density of axons. Furthermore, segmental forms of optic nerve hypoplasia (described later) may affect a sector of the disc without producing a diffuse diminution in size. As such, it would seem prudent to reserve the diagnosis of optic nerve hypoplasia for patients with small optic discs who have reduced vision or visual field loss with corresponding nerve fiber bundle defects. The use of the term “hypoplasia” to describe a congenitally small, axonally deficient optic nerve implies that this abnormality necessarily results from a primary failure of optic axons to develop.156 The timing of other CNS anomalies, which often coexist with optic nerve hypoplasia, would suggest that some cases of optic nerve “hypoplasia” represent an intrauterine degenerative phenomenon rather than a primary failure of axons to develop. In human fetuses, Provis et al246 found a peak of 3.7 million axons at 16–17 weeks of gestation, with a subsequent decline to 1.1 million axons by the 31st gestational week. This massive degeneration of supernumerary axons (termed apoptosis) occurs as part of the normal development of the visual pathways and may serve to establish the correct topography of the visual pathways.192 Toxins or associated CNS malformations may, in some instances, augment or interfere with the usual processes by which superfluous axons are eliminated from the developing visual pathways.192 A recent study by Garcia-Filion et al111 confirmed young maternal age and primaparity as significant risk factors. Preterm labor, gestational vaginal bleeding, low maternal weight gain, and weight loss during pregnancy were also prevalent in mothers of patients with optic nerve hypoplasia.111 Optic nerve hypoplasia is often associated with a wide variety of CNS abnormalities. Septo-optic dysplasia (de Morsier syndrome) refers to the constellation of small anterior visual pathways, absence of the septum pellucidum, and thinning or agenesis of the corpus callosum.85 The clinical association of septo-optic dysplasia and pituitary dwarfism was documented by Hoyt et al158 in 1970. Growth hormone deficiency is the most common endocrinologic abnormality associated with optic nerve hypoplasia, followed by thyrotropin, corticotropin, and antidiuretic hormone (Fig. 2.2).2,35,40,111,278 Hypothyroidism, panhypopituitarism, diabetes insipidus, and hyperprolactinemia may also occur.11,156,163,212 Hyperprolactinemia is said to occur in 62%

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Fig. 2.2 Magnetic resonance imaging in optic nerve hypoplasia. (a) T1-weighted coronal MR imaging in patient with left optic nerve hypoplasia. Black arrow denotes normal right optic nerve. White arrow denotes thin, attenuated signal corresponding to hypoplastic left optic nerve. Used, with permission, from Williams et al 322

(b) T1-weighted coronal MR imaging demonstrating diffuse thinning of optic chiasm (arrow) in patient with absence of septum pellucidum and bilateral optic nerve hypoplasia. Used, with permission, from Brodsky et al 54 Copyright 1990, American Medical Association

of cases, and does not cause galactorrhea but contributes to the high incidence of obesity in these children.35 Neonatal hypothyroidism is a significant risk factor for developmental delay.110 Growth hormone deficiency may be clinically inapparent in the first 3–4 years of life because high prolactin levels may stimulate normal growth over this period.3,79 Growth hormone surrogates such as insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein (IGFBP-3) can also be decreased in patients with growth hormone deficiency.35 Puberty may be precocious or delayed in children with hypopituitarism.133 Because subclinical hypopituitarism can manifest as acute adrenal insufficiency following general anesthesia, it may be prudent to empirically treat children who have optic nerve hypoplasia with perioperative intravenous corticosteroids.273 Although the incidence of clinical hypopituitarism has been estimated at 15%,52 in a recent analysis of multiple hormone levels in children with optic nerve hypoplasia, Ahmad et al3 recently found a 72% prevalence of endocrinopathies, suggesting that subclinical pituitary involvement is common. Other retrospective studies support this higher incidence.129,251 According to Borchert and Garcia-Falion,35 “endocrinological workup should include fasting morning cortisol and glucose, thyroid-stimulating hormone (TSH), free T4, IGF-1, IGFBP-3, and prolactin. If the child is less than 6 months of age, luteinizing hormone, follicle-stimulating hormone, and/or testosterone levels should be checked in order to anticipate delayed sexual development. Beyond 6 months of age, sex hormones are not normally produced until puberty

and thus cannot be tested. Micropenis can be treated with testosterone injections during infancy but is a harbinger of delayed puberty.” In an infant with optic nerve hypoplasia, a history of neonatal jaundice suggests congenital hypothyroidism, while neonatal hypoglycemia or seizures suggest congenital panhypopituitarism.192 A serum thyroxine level may be normal in children with secondary hypothyroidism. Because the adverse developmental effects associated with secondary hypothyroidism are irreversible by 15 months of age, it is advisable to also obtain the serum TSH level to rule out this treatable problem. Because of inherent difficulties in measuring normal physiologic growth hormone levels, which vary widely over a 24-h period, most patients with optic nerve hypoplasia are followed clinically and only investigated biochemically if growth is subnormal. However, when MR imaging shows posterior pituitary ectopia, or when a clinical history of neonatal jaundice or neonatal hypoglycemia is obtained, anterior pituitary hormone deficiency is probable, and more extensive endocrinologic testing becomes mandatory.241 The eyes and neurohypophysis probably evolved as a single receptor which developed a complex of integrating and crosslinking external and internal stimuli. The pituitary gland serves as the neurochemical interface between internal homeostasis and the external world. The fact that it controls the critical survival functions of the organism (to eat, drink, reproduce, and respond to stress within the environment) may explain why it is seated in the middle of the head in a

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boney cage, where it is well protected. The electrochemical responses of the melanopsin-containing ganglion cells provide an external continuum to this function. Pituitary hormone levels show active circadian regulation that is controlled by the hypothalamus. Some patients with optic nerve hypoplasia have sleep disturbances with increased daytime napping.319 It remains to be determined whether some of these sleep disturbances are directly attributable to absence of melanopsin-containing retinal ganglion cells or to hypothalamic injury.320 These sleep disturbances are often responsive to oral melatonin167 (although it has been reported that oral melanopsin may interfere with normal progression of puberty).311 Children with septo-optic dysplasia and corticotropin deficiency are at risk for sudden death during febrile illness.51 This clinical deterioration appears to be caused by an impaired ability to increase corticotropin secretion to maintain blood pressure and blood sugar in response to the physical stress infection. These children may have coexistent diabetes insipidus that contributes to dehydration during illness and hastens the development of shock. Some also have hypothalamic thermoregulatory disturbances signaled by episodes of hypothermia during the period when they are feeling healthy and high fevers during illnesses, which may predispose to lifethreatening hyperthermia. Children with septo-optic dysplasia

who are at risk for sudden death have usually had multiple hospital admissions for viral illnesses. These viral infections can precipitate hypoglycemia, dehydration, hypotension, or fever of unknown origin.51 Because corticotropin deficiency represents the preeminent threat to life in children with septooptic dysplasia, a complete anterior pituitary hormone evaluation, including provocative serum cortisol testing and assessment for diabetes insipidus, should be performed in children who have clinical symptoms (history of hypoglycemia, dehydration, or hypothermia) or neuroimaging signs (absent pituitary infundibulum with or without posterior pituitary ectopia) of pituitary hormone deficiency. Magnetic resonance (MR) imaging provides an excellent noninvasive neuroimaging modality for delineating associated CNS malformations in patients with optic nerve hypoplasia.54 MR imaging can be used to provide specific prognostic information regarding the likelihood of neurodevelopmental deficits and pituitary hormone deficiency in the infant or young child with unilateral or bilateral optic nerve hypoplasia.52 It also provides high-contrast resolution and multiplanar imaging capability, allowing the anterior visual pathways to be visualized as distinct, well-defined structures.54 In optic nerve hypoplasia, coronal and sagittal Tl-weighted MR images show thinning and attenuation of the corresponding prechiasmatic intracranial optic nerve (Fig. 2.2). Coronal TI-weighted MR

Fig. 2.3 Cerebral hemispheric abnormalities associated with optic nerve hypoplasia. (a) Axial T1-weighted inversion recovery MR image demonstrating schizencephaly in patient with optic nerve hypoplasia. Schizencephalic cleft (arrows) consists of abnormal band of dysmorphic gray matter in left cerebral hemisphere extending from cortical surface to lateral ventricle. (b) T2-weighted axial MR image demonstrating asymmetrical periventricular leukomalacia, worse in right

hemisphere (left side of picture), in child with optic nerve hypoplasia. Note enlargement and irregular contour of posterior aspect of lateral ventricle. Black arrow denotes loss of posterior periventricular white matter, with direct apposition of cortical gray matter to trigone of lateral ventricle. White arrow indicates greater volume of posterior periventricular white matter in the left hemisphere. Used, with permission, from Brodsky et al52 Copyright 1993, American Medical Association

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Fig. 2.4 Posterior pituitary ectopia. (a) T1-weighted sagittal MR image demonstrating normal hyperintense signal of posterior pituitary gland (lower black arrow), normal pituitary infundibulum (lower white arrow), optic chiasm (upper right arrow). Open arrow denotes normal corpus callosum. (b) T1-weighted sagittal MR image demonstrating posterior pituitary ectopia (upper white arrow), which appears as abnormal

focal area of increased signal intensity at tuber cinereum. Note absence of pituitary infundibulum and absence of normal posterior pituitary bright spot (lower arrow). Upper white arrow denotes ectopic posterior pituitary gland. Child had normal septum pellucidum and corpus callosum (open arrow). Used, with permission, from Brodsky et al52 Copyright 1993, American Medical Association

imaging in bilateral optic nerve hypoplasia shows diffuse thinning of the optic chiasm in bilateral optic nerve hypoplasia (Fig. 2.2) and focal thinning or absence of the side of the chiasm corresponding to the hypoplastic nerve in unilateral optic nerve hypoplasia.54 When MR imaging shows a decrease in intracranial optic nerve size accompanied by other features of septo-optic dysplasia, a presumptive diagnosis of optic nerve hypoplasia can be made.54 Because MR imaging often shows associated structural abnormalities involving the cerebral hemispheres and the pituitary infundibulum, septo-optic dysplasia can no longer be considered a monolith and is best viewed as a heterogenous malformation syndrome.52,243 Cerebral hemispheric abnormalities are evident in about 45% of patients with optic nerve hypoplasia (Fig. 2.3).52 They may consist of hemispheric migration anomalies (e.g., schizencephaly, cortical dysgenesis) or intrauterine or perinatal hemispheric injury (e.g., periventricular leukomalacia, porencephaly),52 and other rare conditions such as intracranial arachnoid cysts.207 A recent prospective study found developmental delay in 78% of children with bilateral optic nerve hypoplasia and 39% of children with unilateral optic nerve hypoplasia at 5 years of age, with hypoplasia of the corpus callosum and hypothyroidism standing out as independent correlates.111 Evidence of perinatal injury to the pituitary infundibulum (seen on MR imaging as posterior pituitary ectopia) is found in about 15% of patients with optic nerve hypoplasia.52,180,217

Normally, the posterior pituitary gland appears bright on TI-weighted images, probably because of the chemical composition of the vesicles contained in it.52,243 In posterior pituitary ectopia, MR imaging demonstrates absence of the normal posterior pituitary bright spot, absence of the pituitary infundibulum, and an ectopic posterior pituitary bright spot where the upper infundibulum is normally located (Fig. 2.4).52,241 In the patient with optic nerve hypoplasia, posterior pituitary ectopia is virtually pathognomonic of anterior pituitary hormone deficiency, whereas cerebral hemispheric abnormalities are highly predictive of neurodevelopmental deficits.52 Absence of the septum pellucidum alone does not portend neurodevelopmental deficits or pituitary hormone deficiency.322 Thinning or agenesis of the corpus callosum is predictive of neurodevelopmental problems,52 probably by virtue of its frequent association with cerebral hemispheric abnormalities. The finding of unilateral optic nerve hypoplasia does not preclude coexistent intracranial malformations.52

Segmental Optic Nerve Hypoplasia Optic nerve hypoplasia can be segmental.228 A superior segmental optic hypoplasia with an inferior visual field defect occurs in children of insulin-dependent diabetic mothers (Fig. 2.5).183,240 Despite the multiple teratologic effects of

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Fig. 2.5 Superior segmental optic hypoplasia. (a) Right optic disc demonstrating abnormal superior entrance of central retinal artery, relative pallor of superior disc, and superior peripapillary halo. Superior nerve fiber layer is absent, while inferior nerve fiber layer is

clearly seen. (b) Corresponding Humphrey 60-2 visual field demonstrating nonaltitudinal inferior defect with mild superior constriction. Used, with permission, from Brodsky et al58

maternal diabetes early in the first trimester, superior segmental optic hypoplasia is usually diagnosed in patients with no other systemic anomalies.193 The incidence of superior segmental optic hypoplasia has been estimated at approximately 8%.193 Kim et al183 have noted that the inferior visual field defects in superior segmental optic hypoplasia differ from typical nerve fiber bundle defects and questioned whether a regional impairment in retinal development could play a role in the pathogenesis. Superior segmental optic hypoplasia has also been documented in Japanese patients whose mothers were not diabetic, demonstrating that this anomaly is not pathognomonic for maternal diabetes.136 The teratologic mechanism by which insulin-dependent diabetes mellitus selectively interferes with the early gestational development of superior retinal ganglion cells or their axons is not established.58 Mice lacking EphB receptor guidance proteins exhibit specific guidance defects in axons originating from the dorsal or superior part of the retina,31 suggesting that developmental mechanisms that control the expression of axon guidance molecules along the dorsal-ventral axis of the retina may eventually explain this segmental hypoplasia.31 Congenital lesions involving the retina, optic nerve, chiasm, tract, or retrogeniculate pathways are associated with segmental hypoplasia of the corresponding portions of each optic nerve (Fig. 2.6).228 Chiasmal hypoplasia produces focal loss of the nasal and temporal nerve fiber layer, with hypoplasia of corresponding portions of the optic nerve (Fig. 2.7). Hoyt et al159 coined the term “homonymous hemioptic hypoplasia” to describe the asymmetrical form of segmental optic nerve hypoplasia seen in patients with unilateral congenital hemispheric lesions involving the postchiasmal afferent visual pathways. In this setting, the nasal and temporal aspects of the optic disc contralateral to the hemispheric lesion show segmental hypoplasia

and loss of the corresponding nerve fiber layer. This hypoplasia may be accompanied by a central band of horizontal pallor across the disc. The ipsilateral optic disc may range from normal in size to frankly hypoplastic.228 Homonymous hemioptic hypoplasia in retrogeniculate lesions results from transsynaptic degeneration of the optic tract that is usually seen in the setting of a congenital hemispheric lesion.159, 228 Periventricular leukomalacia produces another segmental form of optic nerve hypoplasia. In 1995, Jacobson et al165 recognized that periventricular leukomalacia produces a unique form of bilateral optic nerve hypoplasia characterized by an abnormally large optic cup and a thin neuroretinal rim contained in a normal-sized optic disc (Fig. 2.8). They attributed this morphologic characteristic to intrauterine injury to the optic radiations with retrograde transsynaptic degeneration of retinogeniculate axons after the scleral canals had established normal diameters. The large optic cups can simulate glaucoma, but the history of prematurity, normal intraocular pressure, and characteristic symmetrical inferior visual field defects all serve to distinguish periventricular leukomalacia from glaucomatous optic atrophy.44 Most authorities believe that this anomaly warrants classification as a prenatal form of optic atrophy because of its normal optic disc diameter.44 Patients with periventricular leukomalacia can also have typical optic nerve hypoplasia with small optic discs.40

Pathogenesis Several distinct mechanisms may be involved in the embryogenesis of optic nerve hypoplasia. Early investigators attributed optic nerve hypoplasia to a primary failure of retinal ganglion cell differentiation at the 13- to 15-mm stage of

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Fig. 2.6 Segmental optic nerve hypoplasia. (a) Segmental hypoplasia of temporal optic disc with focal absence of the temporal nerve fiber layer in patient with “macular coloboma.” (b) Subtle segmental hypoplasia of temporal portion of disc. Child was thought to have amblyopia with 20/400 OS but was refractory to occlusion therapy. (c and d) Chiasmal hypoplasia with congenital bitemporal hemianopia. Note segmental

hypoplasia of nasal and temporal nerve fiber layer bilaterally Courtesy of William F. Hoyt, M.D. (e and f) Homonymous hemioptic hypoplasia in patient with right occipital porencephalic cyst. Both optic discs are hypoplastic. Left optic disc (f) shows relative loss of disc substance and peripapillary nerve fiber layer nasally and temporally. Used, with permission, from Novakovic et al228 Photographs courtesy of William F. Hoyt, M.D.

embryonic life (4–6 weeks of gestation).267 Recent experiments have shown that a deficiency of axon guidance molecules at the optic disc can lead to optic nerve hypoplasia. Netrin-1 is an axon-guidance molecule that is involved in development of

spinal commissural axons and is expressed by neuroepithelial cells at the developing optic nerve head. Retinal ganglion cells in vitro respond to netrin-1 as a guidance molecule. Mice with a targeted deletion of the netrin-1 gene exhibit

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pathfinding errors at the optic disc, whereas retinal ganglion cells fail to exit into the optic nerve and instead grow inappropriately into the other side of the retina. As a result of this aberrant pathfinding, these mice exhibit optic nerve hypoplasia.86,232 In addition to defects in optic nerve formation, the lack of netrin-1 function during development also results in abnormalities in other parts of the CNS, such as agenesis of the corpus callosum and cell migration and axonal guidance defects in the hypothalamus.232 Thus, elimination of specific axon guidance molecules during development of the mouse nervous system results in a phenotype that bears striking resemblance to septo-optic dysplasia.232 The timing of coexistent CNS injuries would also suggest that some cases of optic nerve hypoplasia may result from intrauterine destruction of a normally developed structure (i.e., an encephaloclastic event), whereas others represent a primary failure of axons to develop.279 In human fetuses, Provis et al248 found a peak of 3.7 million optic axons at 16 or 17 weeks of gestation, with a subsequent decline to 1.1 million axons by the 31st gestational week. This massive degeneration of supernumerary axons, termed “apoptosis,” occurs as part of the normal development of the visual pathways and may serve to establish the correct topography of the visual pathways.192 Toxins or associated CNS injury could augment the usual processes by which superfluous axons are eliminated from the developing visual pathways.52,192,279 The common association of optic nerve hypoplasia with periventricular leukomalacia,52 which clearly cannot be reconciled with a deficiency of axon guidance molecules at the optic disc, demonstrates the importance of retrograde transsynaptic degeneration in the development of some forms of optic nerve hypoplasia.44,165

Genetics Reported cases of optic nerve hypoplasia in siblings have all been bilateral and without consanguinity.24,128,180,223 These cases are sufficiently rare that parents of a child with optic nerve hypoplasia can reasonably be assured that subsequent siblings are at little or no additional risk. While genetic mutations in the human netrin-1 and DCC genes have not been described, homozygous mutations in the HESX1 gene has been identified in two siblings with optic nerve hypoplasia, absence of the corpus callosum, and hypoplasia of the pituitary gland.37 Numerous additional mutations in HESX1 have recently been observed in children with sporadic pituitary disease and septo-optic dysplasia.75,82,217,305 Mutations have clustered in the DNA-binding region of the protein consistent with a presumed loss in protein function. Formal examination of homeobox genes with expression patterns similar to HESX1, such as SOX2 and SOX3, may yield additional genes responsible for both sporadic and familial septo-optic dysplasia.83,180 The targets and partners of the transcriptional

factors involved in the development of forebrain structures involved in septo-optic dysplasia are unknown.180 Optic nerve hypoplasia may accompany other ocular malformations in patients with mutations in the PAX6 gene.25 Recent studies suggest that mitochondrial disease may underlie some cases of optic nerve hypoplasia.30,36,295 Taban et al295 retrospectively reviewed 80 patients with nonsyndromic mitochondrial cytopathies and found 10 cases of optic nerve hypoplasia, leading them to question whether excessive apoptosis during embryonic ganglion cell and/or axonal development could result from abnormal mitochondrial function and cellular energy metabolism. Superoxide dismutase (SOD)-deficient mice with inactivation of SOD2 (the mitochondrial form of superoxide dismutase) produces multiple ocular and systemic abnormalities that are accompanied by optic nerve hypoplasia.262

Excavated Optic Disc Anomalies Excavated optic disc anomalies include optic disc coloboma, morning glory disc anomaly, and peripapillary staphyloma, megalopapilla, and optic pit. Recently, two new excavated optic disc anomalies have been associated with periventricular leukomalacia (discussed in the previous section) and the “vacant optic disc” associated with papillorenal syndrome. In the morning glory disc anomaly and peripapillary staphyloma, an excavation of the posterior globe surrounds and incorporates the optic disc, while in coloboma, the excavation obliterates the inferior portion of the optic disc. The inevitable transposition of the terms morning glory disc, optic disc coloboma, and peripapillary staphyloma has propagated tremendous confusion regarding their diagnostic criteria, associated systemic findings, and pathogenesis.40 It is now clear that optic disc colobomas, morning glory optic discs, and peripapillary staphylomas are distinct anomalies, each with its own specific embryological origin, and not simply clinical variants along a broad phenotypic spectrum.40 Genetic mechanisms producing optic disc excavation have been associated with papillorenal syndrome,237 and others have been mapped to specific chromosomal sites.100

Morning Glory Disc Anomaly The morning glory disc anomaly is a congenital, funnel-shaped excavation of the posterior fundus that incorporates the optic disc.244 It was so named by Kindler184 in 1970 because of its resemblance to the morning glory flower. Ophthalmoscopically, the disc is markedly enlarged, orange or pink in color, and may appear to be recessed or elevated centrally within a funnelshaped peripapillary excavation (Fig. 2.7).175 A wide annulus of chorioretinal pigmentary disturbance surrounds the disc

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Fig. 2.7 Morning glory optic disc. Large optic disc is surrounded by annular zone of pigmentary disturbance. Retinal vessels appear increased in number, emerge from periphery of disc, and have abnormally straight, radial configuration. There is radial folding of peripapillary retina. Note characteristic central white glial tuft. Arrow denotes focal yellowish discoloration that corresponds to macula lutea pigment (macular capture). Used, with permission, from Goldhammer et al123 Copyright 1975, American Medical Association. Photograph courtesy of Stephen C. Pollock, M.D.

within the excavation.244 A white tuft of glial tissue overlies the central portion of the disc. The blood vessels appear increased in number and often arise from the periphery of the disc.244 They often curve abruptly as they emanate from the disc, and then run an abnormally straight course over the peripapillary retina. It is often difficult to distinguish arterioles from venules. Close inspection occasionally reveals the presence of small peripapillary artenovenous communications (Fig. 2.8).59 The macula may be incorporated into the excavation (macular capture).244 Computed tomography (CT) scanning shows a funnel-shaped enlargement of the distal optic nerve at its junction with the globe (Fig. 2.9).208,308

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Fig. 2.9 CT scan of morning glory disc anomaly. Note calcified, funnelshaped enlargement of distal optic nerve at its junction with globe. Used, with permission, from Brodsky40

The morning glory disc anomaly is usually unilateral but can be bilateral.28,244 Visual acuity usually ranges from 20/200 to finger counting in the morning glory disc anomaly, but cases with 20/20 vision as well as no light perception have been reported. The fact that visual acuity tends to be near normal in bilateral cases suggests that functional amblyopia may contribute to visual loss in unilateral cases.191 Unlike optic disc colobomas that have no racial or gender predilection, morning glory discs are conspicuously more common in females and rare in African-Americans.130,245,289 With rare exceptions,13,230 the morning glory disc anomaly does not present as part of a multisystem genetic disorder.245

Fig. 2.8 Morning glory disc anomaly with multiple retinal arteriovenous communications (denoted by arrows). Child was later found to have neurofibromatosis 2. Used, with permission, from Brodsky and Wilson59 Copyright 1995, American Medical Association

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The association of morning glory disc anomaly with the transsphenoidal form of basal encephalocele is well established.28,66,123,150,187,244,307 Transsphenoidal encephalocele is a rare midline congenital malformation in which a meningeal pouch, often containing the chiasm and adjacent hypothalamus, protrudes inferiorly through a large, round defect in the sphenoid bone (Fig. 2.10). Children with this occult basal meningocele have a wide head, flat nose, mild hypertelorism, midline notch in the upper lip, and sometimes a midline cleft in the soft palate (Figs. 2.11 and 2.12). The meningocele protrudes into the nasopharynx, where it may obstruct the airway. Symptoms of transsphenoidal encephalocele in infancy may include rhinorrhea, nasal obstruction, mouth breathing, or snoring.89,244,328 These symptoms may be overlooked unless the associated morning glory disc anomaly or the characteristic facial configuration is recognized. A transsphenoidal encephalocele may present as a pulsatile posterior nasal mass or as a “nasal polyp” high in the nose; surgical biopsy or excision can have lethal consequences.243 Transsphenoidal encephalocele can present initially by interfering with intubation during general anesthesia.275 Associated brain malformations include agenesis of the corpus callosum and posterior dilatation of the lateral ventricles. Absence of the chiasm is seen in approximately one-third of patients at surgery or autopsy. Most of the affected children have no overt intellectual or neurological deficits, but panhypopituitarism is common.89,244 Surgery for transsphenoidal

encephalocele is considered by many authorities to be contraindicated, because herniated brain tissue may include vital structures, such as the hypothalamic-pituitary system, optic nerves and chiasm, and anterior cerebral arteries, and because of the high postoperative mortality reported, particularly in infants.40,55 As with other dysplastic optic discs (see Fig. 2.23 below), the finding of a discrete V- or tongueshaped zone of infrapapillary depigmentation can be considered a clinical sign of transsphenoidal encephalocele.55 With the advent of MR angiography, numerous reports have found ipsilateral intracranial vascular dysgenesis (hypoplasia of the carotid arteries and major cerebral arteries with or without Moyamoya syndrome) in patients with morning glory disc anomaly (Fig. 2.13).16,134,195,198,214 A retrospective multicenter study by Lenhart et al198 found cerebrovascular anomalies in nine of 20 patients (45%) with morning glory optic disc anomalies. Some patients also have duplication of the pituitary stalk.206,300 These findings underscore the need for MR angiography in the routine neurodiagnostic evaluation of patients with morning glory disc anomaly. It is unknown whether this congenital unilateral form of Moyamoya syndrome carries the same risk for progressive stenosis and cerebral ischemia that characterizes the more common bilateral progressive form in children.281 The coexistence of these intracranial vascular anomalies implicates a primary vascular dysgenesis with regional mesodermal dysgenesis.16

Fig. 2.10 Transsphenoidal encephalocele. (a) T1-weighted sagittal MR image shows an encephalocele (delimited by open arrows) extending down through the sphenoid bone into the nasopharynx with impression on the hard palate (white arrow). (b) T1-weighted coronal MR

image shows the third ventricle and hypothalamus (white arrowheads) extending inferiorly into the encephalocoele (delimited inferiorly by open arrows). Used, with permission, from Barkovich.18 Photographs courtesy of A. James Barkovich, M.D.

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Fig. 2.11 Transsphenoidal encephalocele. (a) Infant with transsphenoidal encephalocele. Note hypertelorism, depressed nasal bridge, and mid upper lip defect. Photograph courtesy of Thomas P. Naidich, M.D. (b) Infant with cleft palate and intraoral transsphenoidal encephalocele. Note midline cleft in upper lip. Photographs courtesy of William F. Hoyt, M.D.

Holmström and Taylor148 documented the association of morning glory disc anomaly with ipsilateral orofacial hemangioma. Metry et al suggested that this association falls within the spectrum of the PHACE syndrome (posterior fossa malformations, large facial hemangiomas, arterial anomalies, cardiac anomalies and aortic coarcation, and eye anomalies),

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which occurs only in girls.220,221 We have confirmed that girls with infantile hemangiomas and ipsilateral morning glory disc anomalies (or peripapillary staphylomas) have PHACE syndrome with dysplasia of the ipsilateral carotid vasculature (Fig. 2.14).186 The morning glory disc anomaly has been reported in patients with neurofibromatosis 2 (Fig. 2.8),186 and in Okihiro syndrome.23 Patients with morning glory disc anomaly are also at increased risk for acquired visual loss. Serous retinal detachments have been estimated to develop in 26–38% of eyes with morning glory anomalies optic discs.130,288 These detachments typically originate in the peripapillary area and extend through the posterior pole, occasionally progressing to total detachments.314 Although retinal tears are rarely evident, several reports have identified small retinal tears adjacent to the optic nerve in patients with morning glory disc-associated retinal detachments.7,135,314 Subretinal neovascularization may occasionally develop within the circumferential zone of pigmentary disturbance adjacent to a morning glory disc.81,285 In addition to retinal detachments, careful fundus examination reveals nonattachment and radial folding of the retina within the excavated zone in a substantial percentage of the remaining cases.244 The sources of subretinal fluid may be multiple.161 Irvine et al reported a patient with a morning glory disc-associated retinal detachment who was treated with optic nerve fenestration followed by gas injection into the vitreous cavity.161 Following the procedure, gas was seen to bubble out through the dural window, demonstrating an interconnection between the vitreous cavity and the subarachnoid space through the anomalous disc. Chang et al70 also reported resolution of a morning glory-associated serous retinal detachment following optic nerve sheath fenestration. Spontaneous resolution of morning glory-associated retinal detachments have also been reported.130 We and others have documented contractile movements in a morning glory optic disc.47,123,244 Pollock245 attributed the contractile movements in his case to fluctuations in subretinal fluid volume altering the degree of retinal separation within the confines of the excavation (Fig. 2.15). One child47 and one adult125a with unilateral morning glory disc anomalies had ipsilateral episodes of amaurosis accompanied by transient dilation of the retinal veins in an eye with a morning glory disc. In another child with a morning glory disc anomaly, MR angiography showed marked narrowing of the ipsilateral distal carotid artery, which resolved 6 months later, suggesting vasospasm.226 The embryogenesis of the morning glory disc anomaly is poorly understood.125 Histopathological reports have, unfortunately, lacked clinical confirmation.244 Older reports mistakenly attributed the morning glory disc anomaly to defective closure of the embryonic fissure and considered it to be a phenotype a colobomatous (i.e., embryonic fissure-related) defect.112,208 More recent investigators have interpreted the

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Fig. 2.12 (a) Older patient showing midline cleft in the upper lip, depressed nasal bridge, and mild hypertelorism. (b) Close-up view showing characteristic midline cleft in the upper lip. Used with permission from Brodsky et al55 Photographs courtesy of William F. Hoyt, M.D.

sclera in presumed cases of the morning glory disc, to signify a primary mesenchymal abnormality.244,306 According to this interpretation, the associated midfacial anomalies in some patients further support the concept of a primary mesenchymal defect, because most of the cranial structures are derived from mesenchyme. Dempster88 attempted to reconcile these two views by proposing that the basic defect is mesodermal but that some clinical features of the defect may result from a dynamic disturbance between the relative growth of mesoderm and ectoderm. The observation that neural guidance molecules such as netrins also regulate angiogenesis may provide a clue to the molecular pathomechanism for this neurovascular anomaly.313 Pollock244 has argued that the fundamental symmetry of the fundus excavation with respect to the disc implicates an anomalous funnel-shaped enlargement of the distal optic stalk at its junction with the primitive optic vesicle as the primary embryological defect. According to this hypothesis, the glial and vascular abnormalities that characterize the morning glory disc anomaly would be explainable as the secondary effects of a primary neuroectodermal dysgenesis on the formation of mesodermal elements that arise later in embryogenesis.244

Fig. 2.13 (a) Morning glory disc anomaly in a child with NF-2. Both eyes MR angiography shows hypoplasia of the ipsilateral internal carotid artery (large arrow) with Moyamoya vessels (small arrow). Used with permission from Massaro et al214

clinical findings of a central glial tuft, vascular anomalies, and a scleral defect, together with the histological findings of adipose tissue and smooth muscle within the peripapillary

Optic Disc Coloboma The term coloboma, of Greek derivation, means curtailed or mutilated.62,233 It is used only with reference to the eye. In optic disc coloboma, a sharply delimited, glistening white, bowl-shaped excavation occupies an enlarged optic disc (Fig. 2.16). The excavation is decentered inferiorly, reflecting

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Fig. 2.14 PHACE syndrome. (a) Large facial hemangioma. (b) Morning glory disc anomaly. (c) MR angiogram showing tortuousity of the right internal carotid artery (open arrow) and narrowing of the proximal right middle cerebral artery (closed arrow). Used with permission from Kneistedt et al186

Fig. 2.15 Contractile morning glory optic disc. (a) Morning glory disc prior to contraction. Note minor retinal elevation with radial folding of the peripapillary retina. (b) Same morning glory disc during contrac-

tion. There is now greater elevation of retina and encroachment of peripapillary retinal folds on central glial tuft. Used with permission from Pollock.244 Photographs courtesy of Stephen C. Pollock, M.D

the position of the embryonic fissure relative to the primitive epithelial papilla.244 The inferior neuroretinal rim is thin or absent, while the superior neuroretinal rim is relatively spared. Rarely, the entire disc may appear excavated; however,

the colobomatous nature of the defect can still be appreciated ophthalmoscopically because the excavation is deeper inferiorly.244 The defect may extend further inferiorly to involve the adjacent choroid and retina, in which case

Excavated Optic Disc Anomalies

Fig. 2.16 Optic disc coloboma. (a) Disc is enlarged. Deep white excavation occupies most of disc but spares its superior aspect. Note chronic serous retinal elevation (seen best at 11 o’clock) that has caused subretinal fibrosis. Otherwise, there is minimal peripapillary pigment disturbance in contrast to morning glory disc anomaly. Used with permission from

Fig. 2.17 CT scan showing coloboma extending into left optic nerve

microphthalmia is frequently present.26,104 Optic disc colobomas may contain focal pit-like excavations.312 Iris and ciliary colobomas often coexist. Axial CT scanning shows a large crater-like excavation of the optic nerve at its junction with the globe (Fig. 2.17).112,208

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Brodsky.40 (b) Massively-enlarged colobomatous optic disc. Courtesy of Paul Phillips, M.D. (c) Vertically oval colobomatous disc with atypical vascular dysplasia. Courtesy of Stephen C. Pollock, M.D. and William F. Hoyt, M.D. (d) Colobomatous disc with infrapapillary defect simulating a “double optic disc.” Courtesy of William F. Hoyt, M.D.

Visual acuity, which depends primarily on the integrity of the papillomacular bundle, may be mildly to severely decreased and is difficult to predict from the appearance of the disc.40 Unlike the morning glory disc anomaly, which is usually unilateral, optic disc colobomas occur unilaterally or bilaterally with approximately equal frequency.244 As with uveal colobomas, optic disc colobomas may arise sporadically or be inherited in an autosomal dominant fashion. Ocular colobomas may also be accompanied by multiple systemic abnormalities in myriad conditions including, the CHARGE association,72,234,259 Walker-Warburg syndrome,233 Goltz focal dermal hypoplasia,233 Aicardi syndrome,67,155 Goldenhar sequence,200,318 and linear sebaceous nevus syndrome.233 Rarely, large orbital cysts can occur in conjunction with atypical excavations of the disc, which are probably colobomatous in nature.65,280,322 A communication between the excavation and the cyst was documented ultrasonographically in one case.280 Histopathological examination in optic disc coloboma has demonstrated the presence of intrascleral smooth muscle strands oriented concentrically around the distal optic nerve.101,324 This pathological finding may account for the contractility seen in rare cases of optic disc coloboma.102

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Eyes with isolated optic disc colobomas are prone to develop serous macular detachments, (Fig. 2.16) while those with retinochoroidal colobomas develop complicated rhegmatogenous retinal detachments.201,265 In a clinicopathologic study of an optic disc coloboma and associated macular detachment in a rhesus monkey, Lin et al201 noted disruption of the intermediary tissue of Kuhnt, with diffusion of retrobulbar fluid from the orbit into the subretinal space. A variety of treatment modalities have been applied to the associated sensory retinal detachments, including patches, bedrest, corticosteroids, vitrectomy, scleral buckling procedures, gas-fluid exchange, and photocoagulation.33,265 Some have advocated waiting 3 months before treating coloboma-associated macular detachments, because spontaneous reattachment may occur.33,265 In patients with atypical optic disc colobomas, intraoperative drainage of subretinal fluid through the disc anomaly may be possible, or gas or silicone oil may be seen to migrate subretinally. The pressure differential required for migration of gas through a small defect in the roof of a cavitary lesion is within the range of expected fluctuations in cerebrospinal fluid pressure, suggesting the presence of interconnections between the vitreous cavity, subarachnoid space, and subretinal space.169 Perkins et al described three patients with macular schisis cavities who developed (noncolobomatous-appearing) optic disc cavitations concurrent with the resolution of the macular fluid.239,240 They proposed that a communication through dysplastic tissue could either allow liquified vitreous to migrate posteriorly into the perineural space or CSF to migrate intraretinally. They cautioned that, in cases of macular schisis in which an optic nerve excavation is not initially apparent, spontaneous resolution of the macular schisis cavity is possible.238,239 Colobomatous malformations of the optic disc produce an inferior segmental hypoplasia of the optic nerve, with a C-shaped or quarter-moon-shaped neuroretinal rim confined to the superior aspect of the optic disc (Fig. 2.16).40 Colobomas constitute the most common segmental form of optic nerve hypoplasia encountered in clinical practice.42 Coronal T1-weighted MR imaging confirms that the intracranial portion of the optic nerve is reduced in size.42 The nosological overlap between colobomatous derangement of the optic nerve and segmental hypoplasia reflects the early timing of colobomatous dysembryogenesis, which results in primary failure of inferior retinal ganglion cells to develop. Unfortunately, many uncategorizable dysplastic optic discs are indiscriminately labeled optic disc colobomas. This practice continues to complicate the nosology of coloboma-associated genetic disorders. It is therefore crucial that the diagnosis of optic disc coloboma be reserved for discs that show an inferiorly decentered, white-colored excavation with minimal peripapillary pigmentary changes.40,244 For example, the purported association between optic disc coloboma and basal encephalocele199,244,291 is deeply entrenched in the literature; however, a critical review reveals only two photographically

2 Congenital Optic Disc Anomalies

documented cases.78,291 In striking contrast to the numerous well-documented reports of morning glory optic discs occurring in conjunction with basal encephaloceles, cases of optic disc coloboma with basal encephalocele are conspicuous by their absence. In the early 1900s, von Szily,316 in his monumental study of colobomas, stated “with certainty” that “all the true morphological malformations of the optic disc, including true colobomas … are only different manifestations of the same developmental anomaly, namely, a different form and degree of malformation of the primitive or epithelial optic papilla.” Despite the multiple ophthalmoscopic findings that distinguish optic disc coloboma from the morning glory disc anomaly (Table 2.2), many authors continue to treat these two anomalies as merely different phenotypic expressions of the same embryological defect, namely, failure of closure of the superior aspect of the embryonic fissure. Although the phenotypic profiles of optic disc coloboma and the morning glory disc anomaly may occasionally overlap, the ophthalmoscopic features of optic disc coloboma (Table 2.2) are most consistent with a primary structural dysgenesis involving the proximal embryonic fissure, as opposed to an anomalous dilatation confined to the distal optic stalk in the morning glory disc anomaly.244 The profound differences in associated ocular and systemic findings between the two anomalies (Table 2.3) lend further credence to this hypothesis.41 Although anomalous optic discs with overlapping features of

Table 2.2 Ophthalmoscopic findings that distinguish the morning glory disc anomaly from optic disc coloboma153 Morning glory disc anomaly

Optic disc coloboma

Optic disc lies within the excavation Symmetrical defect (disc lies centrally within the excavation) Central glial tuft Severe peripapillary pigmentary disturbance Anomalous retinal vasculature

Excavation lies within the optic disc Asymmetrical defect (excavation lies inferiorly within the disc) No central glial tuft Minimal peripapillary pigmentary disturbance Normal retinal vasculature

Table 2.3 Associated ocular and systemic findings that distinguish isolated optic disc coloboma from the morning glory disc anomaly14 Morning glory disc anomaly

Optic disc coloboma

More common in females, rare in blacks Rarely familial Rarely bilateral No iris, ciliary, or retinal colobomas Rarely associated with multisystem genetic disorders Basal encephalocele common

No sex or racial predilection Often familial Often bilateral Iris, ciliary, and retinal colobomas common Often associated with multisystem genetic disorders Basal encephalocele rare

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the morning glory disc anomaly and optic disc coloboma are occasionally seen, these “hybrid” anomalies could easily represent instances of early embryonic injury involving both the proximal embryonic fissure and the distal optic stalk. Their existence should not obscure the fact that colobomatous and morning glory optic discs appear as clinically distinct anomalies in the great majority of cases. The concept of “an optic disc coloboma with a morning glory configuration” should be abandoned. Coloboma can be sporadic or transmitted as an autosomal recessive, dominant, or X-linked trait.318 Mutations have been identified in the following genes: PAX6,13,119 CHX10,20,98 MAF,165 SHH,269 CHD7,176 GDF6,248 and SOX2.317 However, these genes account for only a fraction of colobomas,318 so there is no high-yield genetic test. In CHARGE syndrome, 60% have a mutation in CHD7 genetic testing is high yield.177 Because chromosomal abnormalities are more common in cases where coloboma is clearly syndromic, it is in the child who has systemic malformations involving the CNS, ears, spine or ribs, digits, or urogenital syndrome that genetic testing is most fruitful.

Peripapillary Staphyloma Peripapillary staphyloma is a rare, usually unilateral anomaly, in which a deep fundus excavation surrounds the optic disc.62,277 In this condition, the disc is seen at the bottom of the excavated defect and may appear normal or shows temporal pallor (Fig. 2.18).244,326 The walls and margin of the defect may show atrophic pigmentary changes is the retinal pigment epithelium (RPE) and choroid.326 Unlike the morning

glory disc anomaly, there is no central glial tuft overlying the disc, and the retinal vascular pattern remains normal, apart from reflecting the essential contour of the lesion.244 The staphylomatous excavation in peripapillary staphyloma is also notably deeper than that seen in the morning glory disc anomaly. Several cases of contractile peripapillary staphyloma have been documented.69,188,189,326 One patient had transient visual obscurations in an eye with an atypical peripapillary staphyloma.272 Visual acuity is usually markedly reduced, but cases with normal acuity have also been reported.64 Affected eyes are usually emmetropic or slightly myopic.62 Eyes with decreased vision frequently have centrocecal scotomas.62 Although peripapillary staphyloma is clinically and embryologically distinct from morning glory disc anomaly, these conditions are frequently transposed in the literature.40 Table 2.3 contrasts the ophthalmoscopic features that distinguish these two anomalies. Although peripapillary staphyloma is usually unassociated with systemic or intracranial disease, it has been reported in association with transsphenoidal encephalocele,146 PHACE syndrome,186 linear nevus sebaceous syndrome,56 and 18q- (de Grouchy) syndrome.163 The relatively normal appearance of the optic disc and retinal vessels in peripapillary staphyloma suggests that the development of these structures is complete, prior to the onset of the staphylomatous process.244 According to Pollock,244 the clinical features of peripapillary staphyloma are consistent with diminished peripapillary structural support, perhaps resulting from incomplete differentiation of sclera from posterior neural crest cells in the fifth month of gestation. Staphyloma formation presumably occurs when establishment of normal intraocular pressure leads to herniation of unsupported ocular tissues through the defect.244 Thus, peripapillary staphyloma and the morning glory disc anomaly appear to be pathogenetically distinct both in the timing of the insult (5 months gestation vs. 4 weeks gestation) as well as the embryological site of structural dysgenesis (posterior sclera versus distal optic stalk).

Megalopapilla

Fig. 2.18 Peripapillary staphyloma ipsilateral to an orofacial hemangioma in a child with PHACE syndrome. Used with permission from Kniestedt et al186

Franceschetti and Bock originally assigned the term megalopapilla to a patient who had enlarged optic discs with no other morphological abnormalities.103 Since that time, megalopapilla or congenital macrodiscs have become generic terms that connote an abnormally large optic disc that lacks the inferior excavation of optic disc coloboma or the numerous anomalous features of the morning glory disc anomaly. In its current usage, megalopapilla comprises two phenotypic variants. The first is a relatively common variant in which an abnormally large optic disc (greater than 2.1 mm in diameter) retains an otherwise normal configuration.62,173 This form of megalopapilla

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is usually bilateral and often associated with a large cup-to-disc ratio, which almost invariably raises the diagnostic consideration of normal-tension glaucoma (Fig. 2.16). However, the optic cup is usually round or horizontally oval with no vertical notching or encroachment, so that the quotient of horizontalto-vertical cup-to-disc ratio remains normal, in contradistinction to the decreased quotient that characterizes glaucomatous optic atrophy. Jonas et al have emphasized that the most important parameter in distinguishing megallopapilla from glaucoma may be the inferior-superior-nasal-temporal rule of the normal physiologic shape of the neural retinal rim.170,174,176 Because the axons are spread over a larger surface area, the neuroretinal rim may also appear pale, mimicking optic atrophy.63 Less commonly, a unilateral form of megalopapilla is seen in which the normal optic cup is replaced by a grossly anomalous noninferior excavation that obliterates the adjacent neuroretinal rim (Fig. 2.19). The inclusion of this rare variant under the rubric of megalopapilla serves the nosologically useful function of distinguishing it from a colobomatous defect with its attendant systemic implications. Cilioretinal arteries are more common in megalopapilla.175 A high prevalence of megalopapilla has been observed in natives of the Marshall Islands.209 Two reports have documented large optic discs in patients with optic nerve hypoplasia associated with a congenital homonymous hemianopia.211,246 This combination of findings suggests that a prenatal loss of optic nerve axons leading to optic nerve hypoplasia may not always alter the genetically predetermined size of the scleral canals.246 Visual acuity is usually normal but may be mildly decreased in some cases of megalopapilla. Visual fields are usually normal, except for an enlarged blind spot, allowing the examiner to effectively rule out normal tension glaucoma or compressive optic atrophy. However, Jonas et al170 reported the exceptional case of a three-year-old boy with congenital megallopapilla and normal neuroretinal rims who developed

2 Congenital Optic Disc Anomalies

a glaucomatous optic neuropathy 10 years later. Colobomatous discs are distinguished from megalopapilla by their predominant excavation of the inferior optic disc. Aside from glaucoma and optic disc coloboma, the differential diagnosis of megalopapilla includes orbital optic glioma, which in children can cause progressive enlargement of a previously normalsized optic disc.126 Pathogenetically, most cases of megalopapilla may simply represent a statistical variant of normal. However, it is likely that megalopapilla occasionally results from altered optic axonal migration early in embryogenesis, as evidenced by a report of megalopapilla in a child with basal encephalocoele.123 The rarity of this association, however, would suggest that neuroimaging is unwarranted in megalopapilla, unless midfacial anomalies (e.g., hypertelorism, cleft palate, depressed nasal bridge) coexist.

Optic Pit An optic pit is a round or oval, gray, white, or yellowish depression in the optic disc (Fig. 2.20). Optic pits commonly involve the temporal optic disc but may be situated in any sector.60 Temporally located pits are often accompanied by adjacent peripapillary pigment epithelial changes. One or two cilioretinal arteries are seen to emerge from the bottom or the margin of the pit in greater than 50% of cases.62,303 Although optic pits are typically unilateral, bilateral pits are seen in 15% of cases.62 Histologically, optic pits consist of herniations of dysplastic retina into a collagen-lined pocket extending posteriorly, often into the subarachnoid space, through a defect in the lamina cribrosa.62,99,161 Numerous reports of familial optic pits suggest an autosomal dominant mode of transmission.172,249,287

Fig. 2.19 Megalopapilla. (a) Massively enlarged optic disc within a peripapillary staphyloma. Courtesy of Kenneth Wald, M.D. (b) Common variant of megalopapilla in which an abnormally large optic disc contains large central cup

Excavated Optic Disc Anomalies

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Fig. 2.20 Optic pit showing each stage in evolution of serous macular detachment. (a) Abnormal radial striations between disc and macula (delimited by large arrows) correspond to schisis-like inner-layer retinal separation. There is also outer-layer hole (open arrow) surrounded by outer-layer macular detachment (delimited by small arrows).

(b) Black and white photograph demonstrating inner-layer separation (delimited by large arrows), macular hole (open arrow), and outer-layer sensory detachment (delimited by small arrows). Used with permission from Lincoff et al203 Copyright 1988, American Medical Association. Photograph courtesy of Harvey Lincoff, M.D.

In unilateral cases, the involved disc is slightly larger than the normal disc.62 Visual acuity is typically normal in the absence of subretinal fluid. Although visual field defects are variable and often correlate poorly with the location of the pit, the most common defect appears to be a para-central arcuate scotoma connected to an enlarged blind spot.60,190 With rare exceptions,312 optic pits do not portend additional CNS malformations. Acquired depressions in the optic disc that are indistinguishable from optic pits have been documented in normal-tension glaucoma.167 Serous macular elevations have been estimated to develop in 25–75% of eyes with optic pits.34,60,190,293 Optic pit-associated maculopathy generally becomes symptomatic in the third or fourth decade of life. Vitreous traction on the margins of the pit and tractional changes in the roof of the pit may be the inciting events that ultimately lead to late-onset macular detachment.34,99,303 Until recently, all optic pit-associated macular elevations were thought to represent serous detachments. Studies by Lincoff et al have led to a better understanding of optic pit-associated maculopathy.203 These investigators have proposed that careful stereoscopic examination of the macula in conjunction with kinetic perimetry demonstrates the following progression of events:

3. An outer-layer retinal detachment develops around the macular hole (presumably from influx of fluid from the inner-layer separation). This outer-layer detachment ophthalmoscopically resembles an RPE detachment but fails to hyperfluoresce on fluorescein angiography. 4. The outer-layer detachment may eventually enlarge and obliterate the inner-layer separation. At this stage, it is no longer ophthalmoscopically or histopathologically distinguishable from a primary serous macular detachment.

1. A schisis-like inner-layer retinal separation initially forms in direct communication with the optic pit, which produces a mild, relative, centrocecal scotoma. 2. An outer-layer macular hole develops beneath the boundaries of the inner-layer separation and produces a dense central scotoma.

Figure 2.20 depicts the retinal findings that can be observed in the evolution of an optic pit-associated macular detachment. The finding of a sensory macular detachment in histopathologically studied eyes with optic pits presumably represents the end stage of this sequence of events. Optical coherence tomography has confirmed this mechanism.202 The risk of optic pit-associated macular detachment is greater in eyes with large optic pits and in eyes with temporally located pits.60 Perhaps because of age-related differences in vitreopapillary traction, optic pit-associated serous maculopathy in children may have a tendency toward spontaneous resolution.45,330 Spontaneous reattachment is seen in approximately 25% of adult cases.60,284 Early reports of spontaneous resolution of most optic pit-associated macular detachments with good visual recovery294 differ from the experience of subsequent investigators who have noted permanent visual loss in untreated patients, even when spontaneous reattachment occurs.113,285 Bedrest and bilateral patching have led to retinal reattachment in some patients, presumably by decreasing vitreous traction.80,265

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Laser photocoagulation to block the flow of fluid from the pit to the macula has been largely unsuccessful, perhaps due to the inability of laser photocoagulation to seal a retinoschisis cavity.34,80,113,194,203,265,284 Vitrectomy with internal gas tamponade laser photocoagulation has produced long-term improvement in acuity.8,113,142,203,216,265 Although the aim of this treatment is to compress the retina at the edge of the disc to enhance the effect of laser treatment, Lincoff et al204 have postulated that internal gas tamponade functions to mechanically displace subretinal fluid away from the macula, allowing a shallow, inner-layer separation to persist, which is associated with a mild scotoma and relatively good visual acuity. On the basis of clinical and perimetric observations following treatment, Lincoff et al have concluded that laser photocoagulation probably does not contribute to the success of this procedure.204 The source of intraretinal fluid in eyes with optic pits is controversial. Possible sources include (1) vitreous cavity via the pit, (2) the subarachnoid space, (3) blood vessels at the base of the pit, and (4) the orbital space surrounding the dura. Although fluorescein angiography shows early hypofluorescence of the pit followed in many cases by late hyperfluorescent staining, optic pits do not generally leak fluorescein, and there is no extension of fluorescein into the subretinal space toward the macula.60 The finding of late hyperfluorescent staining has been shown to correlate strongly with the presence of cilioretinal arteries emerging from the pit.304 Careful slit-lamp biomicroscopy and OCT91a often reveal a thin membrane overlying the pit60 or a persistent Cloquet’s canal terminating at the margin of the pit.6 Although active flow of fluid from the vitreous cavity through the pit to the subretinal space has been demonstrated in collie dogs, this mechanism has never been conclusively demonstrated in humans.61 Friberg and McLellan106 demonstrated a pulsatile communication of fluid between the vitreous cavity and a retrobulbar cyst through an optic pit. Theodossidadis et al306 described a similar optic nerve sheath cyst that compressed and displaced the nerve, producing optic pallor. On the other hand, Dithmar et al91 reported progressive migration of oil into the subretinal space following retinal detachment surgery in an eye with a pit, suggesting that a communication between the vitreous cavity and the subretinal space through the pit can also cause retinal detachment. Rarely, macular holes can develop in eyes with optic pits or optic disc colobomas and lead to rhegmatogenous retinal detachment.29,293 Although the pathogenesis of optic pits is unclear, they have historically been viewed as the mildest variant in the spectrum of optic disc colobomas.9,60,113,161,190,201,208,253,258,265,292,293 It should be noted, however, that this widely accepted hypothesis is inconsistent with the preponderance of clinical evidence: 1. Optic pits are usually unilateral, sporadic, and unassociated with systemic anomalies. Colobomas are bilateral as often

2 Congenital Optic Disc Anomalies

as unilateral, commonly autosomal dominant, and may be associated with a variety of multisystem disorders. 2. It is rare for optic pits to coexist with iris or retinochoroidal colobomas. 3. Optic pits usually occur in locations unrelated to the embryonic fissure. Following a review of 75 eyes with optic pits, Brown et al concluded that “the sparsity of inferonasal pits (none among our cases) casts doubt as to whether the pits are truly colobomas resulting from incomplete closure of the embryonic fissure. Certain authors have thought that pits are colobomas, and the finding of pits in three of our patients in association with true optic nerve colobomas, along with similar reports by others, indicates more than an incidental relationship. However, if pits are colobomatous defects, they are certainly atypical.”60 While it is true that colobomas may contain focal crater-like deformations that resemble optic pits,9,122 and that the distinction between an inferiorly located pit and a small optic disc coloboma is difficult at times, there appears to be sufficient evidence to conclude that most optic pits are fundamentally distinct from colobomas in their pathogenesis. The observation that one or more cilioretinal arteries emerge from the majority of optic pits suggests that this finding must somehow be pathogenetically related.60,140

Papillorenal Syndrome (The Vacant Optic Disc) The papillorenal syndrome, previously known as renalcoloboma syndrome, was first described by Rieger in 1977.254 This syndrome was initially considered to be a rare autosomal dominant disorder consisting of bilateral optic disc anomalies associated with hypoplastic kidneys.230 Associated retinal detachments were described, as was eventual renal failure. In 1995, Sanyanusin et al discovered mutations in the developmental gene PAX2, the human homologue of the mouse gene PAX2 in two affected families.263 Schimmenti et al268 identified three additional families with PAX2 mutations with similar ophthalmologic features and a wider spectrum of renal abnormalities, which may include hypoplasia, variable proteinuria, vesiculoureteral reflux, recurrent pyelonephritis, microhematuria, echogenicity on ultrasound, or high resistance to blood flow on Doppler ultrasound. Parsa et al have since determined that the papillorenal syndrome is characterized by a distinct optic disc malformation that bears no relationship to coloboma.237 In this syndrome, the excavated optic disc is normal in size, and may be surrounded by variable pigmentary disturbances.237 Unlike in colobomatous defects, the excavation is centrally positioned (Fig. 2.18). According to Parsa et al, the defining feature is the presence of multiple cilioretinal vessels that emanate from the periphery

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Congenital Tilted Disc Syndrome

Fig. 2.21 Papillorenal syndrome. Right and left discs show central excavation with multiple cilioretinal vessels and absence of central retinal vasculature. Courtesy of Erika Levin, M.D.

of the disc, and variable attenuation or atrophy of the central retinal vessels (Fig. 2.21).236,237 Color Doppler imaging has confirmed the absence of central retinal circulation in patients with papillorenal syndrome.237 Visual acuity is usually 20/20 but may occasionally be severely diminished secondary to choroidal and retinal hypoplasia and, in some cases, to later-onset serous retinal detachments.237 Peripheral visual field defects corresponding to areas of retinal hypoplasia are often present. The central optic disc excavation and peripheral field defects can simulate coloboma as well as normal tension glaucoma. Follow-up examination has shown renal disease in some patients who were originally reported as having isolated familial autosomal dominant “coloboma.”237,264 In infants, the bilateral optic disc excavation can simulate congenital glaucoma, but the diagnosis can be established clinically by recognizing the characteristic optic disc morphology.181 This malformation is attributed to a primary deficiency in angiogenesis involved in vascular development.237 In these patients, there is a failure of the hyaloid system to convert to normal central retinal vessels. The absence of a well-defined central retinal artery or vein in several adult mammalian species, including lemurs and cats, suggests that this malformation could be considered analogous to an evolutionary regression to a feline pattern of circulation.237 Because ocular tissues and renal cortex are the most highly perfused tissues of the body, both develop a significant portion of their vasculature by means of angiogenesis (budding) in addition to vasculogenesis.237 These tissues may thus be particularly susceptible to anomalies in vascular development, resulting in hypoplasia or anomalies of associated structures. Many patients with papillorenal syndrome have no detectable mutations in the PAX2 gene.96,237 Honkanen et al149 recently described a four-generation pedigree with progressive optic nerve head cupping, anomalous

vasculature (often emerging from the periphery of the disc), and serous macular detachments in some patients and mapped the chromosomal location of the disease-causing gene to chromosome 12q.100 These patients may have had undiagnosed papillorenal syndrome. In patients with the vacant optic disc, we routinely check blood pressure and order serum BUN and creatinine levels, urinalysis for hematuria, and Doppler renal ultrasound to look for structural defects such as renal hypoplasia.

Congenital Tilted Disc Syndrome Nonspecific tilting of the optic discs is a rather frequent anomaly found in 1.6–1.7% of population-based surveys.117,316 The tilted disc syndrome is a nonhereditary bilateral condition in which the superotemporal optic disc is elevated and the inferonasal disc is posteriorly displaced, resulting in an oval-appearing optic disc, with its long axis obliquely oriented (Fig. 2.22).40 This configuration is accompanied by situs inversus of the retinal vessels, congenital inferonasal conus, thinning of the inferonasal RPE and choroid, and bitemporal hemianopia.329 The anomalous optic disc appearance is secondary to a posterior ectasia of the inferonasal fundus and optic disc. Because of the regional fundus ectasia, affected patients have myopic astigmatism, with the plus axis oriented parallel to the ectasia. Corneal topography studies indicate that an irregular corneal curvature contributes to the associated astigmatism.17 The cause of the condition is unknown, but the inferonasal or inferior location of the excavation is at least vaguely suggestive of a pathogenetic relationship to retinochoroidal coloboma.9

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Fig. 2.22 Congenital tilted disc syndrome. (a) and (b) Optic discs appear obliquely oval. There is elevation of superonasal discs and posterior displacement of inferonasal disc. Note subtle inferonasal peripapillary crescent, albinotic appearance of inferonasal retina, and situs inversus of vessels as they emerge from disc. (c and d)

Goldmann visual field of right eye demonstrates superotemporal visual field defect confined to midperipheral isopter that does not respect horizontal meridian. (e and f) Axial CT scan showing “tilted eyeballs” with posterior protrusion of both globes. Courtesy of Klara Landau, M.D.

Familiarity with the tilted disc syndrome is crucial for the ophthalmologist, because affected patients may present with bitemporal hemianopia or optic disc elevation that simulates papilledema.9,40 The bitemporal hemianopia in affected patients, which is typically incomplete and confined primarily to the superior quadrants, represents a refractive

scotoma, secondary to regional myopia localized to the inferonasal retina. Unlike the visual field loss from chiasmal lesions, the field defects seen in the tilted disc syndrome fail to respect the vertical meridian on careful kinetic perimetry. Furthermore, the superotemporal depression is selectively confined to the midsize isopter, while the large and small

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Congenital Optic Disc Pigmentation

isopters remain fairly normal due to the marked ectasia of the midperipheral fundus. Repeat perimetry after addition of a −4.00 lens often eliminates the visual field abnormality, confirming the refractive nature of the defect. In some cases, retinal sensitivity may be decreased in the area of the ectasia, and the defect persists to some degree despite appropriate refractive correction.329 It should be emphasized that the tilted disc syndrome has been associated with true bitemporal hemianopia in several patients who were found to harbor a congenital suprasellar tumor. As with optic nerve hypoplasia, these two seemingly disparate findings may reflect the disruptive effect of the suprasellar tumor on optic axonal migration during embryogenesis.301 This sinister association makes neuroimaging mandatory in any patient with a tilted disc syndrome whose bitemporal hemianopia either respects the vertical meridian or fails to preferentially involve the midperipheral isopter on kinetic perimetry.178,231 Tilted discs without retinal ectasia occur in patients with transsphenoidal encephalocele.55,64 The tilted disc syndrome has also been reported in patients with X-linked congenital stationary night blindness.137,144 In eyes with tilted discs or the full tilted disc syndrome, anomalies at the junction of the staphyloma or at the junction between the peripapillary retina and the altered disc margin may cause serous macular detachments.43,76,307 Crowding and elevation of the superotemporal portion of the tilted disc may predispose to the formation of optic disc drusen118 and to central retinal vein occlusion.117 The congenital tilted disc syndrome can also be complicated by choroidal neovascularization, which develops at the inferotemporal edge of the staphyloma,116 serous macular detachment and subretinal leakage,76 and polypoidal choroidal vasculopathy.215

Optic Disc Dysplasia The term optic disc dysplasia should be viewed not as a diagnosis but as a descriptive term that connotes a markedly deformed optic disc that fails to conform to any recognizable diagnostic category (Fig. 2.23). The distinction between an uncategorizable “anomalous” disc and a “dysplastic” disc is somewhat arbitrary and based primarily on the severity of the lesion. In the past, the term optic disc dysplasia has been applied to cases that are now recognizable as the morning glory disc anomaly.123,132 Conversely, many dysplastic optic discs have been indiscriminately labeled optic disc colobomas.40 It is likely that additional variants of optic disc dysplasia will be recognized and identified as distinct anomalies. A discrete infrapapillary zone of V- or tongue-shaped retinochoroidal depigmentation has been described in five patients with dysplastic optic discs and transsphenoidal

Fig. 2.23 Optic disc dysplasia. Optic disc is vertically elongated and grossly anomalous. Retinal vessels emerge from disc in anomalous pattern. Used with permission from Brodsky.40 Photograph courtesy of Stephen C. Pollock, M.D.

encephalocele (Fig. 2.24).55 These juxtapapillary defects differ from typical retinochoroidal colobomas, which widen inferiorly and are not associated with basal encephalocele. Unlike the typical retinochoroidal coloboma, this distinct juxtapapillary defect is associated with minimal scleral excavation and no visible disruption in the integrity of the overlying retina. In patients with dysplastic optic discs, the finding of this V- or tongue-shaped infrapapillary retinochoroidal anomaly should prompt neuroimaging to look for transsphenoidal encephalocele.55

Congenital Optic Disc Pigmentation Congenital optic disc pigmentation is a condition in which melanin deposition anterior to or within the lamina cribrosa imparts a gray or black appearance to the optic disc (Fig. 2.25).50 True congenital optic disc pigmentation is extremely rare, but it has been described in a child with an interstitial deletion of chromosome 17 and in Aicardi syndrome.50 Congenital optic disc pigmentation is compatible with good visual acuity but may be associated with coexistent optic disc anomalies that decrease vision.50 Silver and Sapiro276 have demonstrated that, in developing mice and rats, a transient zone of melanin in the distal developing optic stalk influences migration of the earliest optic nerve axons. The effects of abnormal pigment deposition on optic nerve embryogenesis could explain the frequent coexistence of congenital optic disc pigmentation with other anomalies, particularly optic nerve hypoplasia. In some cases, congenital optic disc pigmentation may be

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Fig. 2.24 Infrapapillary retinochoroidal depigmentation associated with transsphenoidal encephalocele. (a) V-shaped defect with inferior segmental optic hypoplasia. Photograph courtesy of

William F. Hoyt, M.D. (b) Tongue-shaped infrapapillary depigmentation with dysplastic optic disc. Used with permission from Brodsky et al55

Fig. 2.25 Congenital optic disc pigmentation. (a) Right optic disc. Circular area of patchy pigmentation surrounds severely hypoplastic, elevated, central tuft of optic nerve substance, producing appearance of gray optic disc. Arteries and veins overlying disc are anomalous.

(b) Left optic disc. Disc is elevated and uniformly gray in appearance. Note anomalous superior vasculature and anomalous venous trunk along 2 o’clock meridian of disc. Used with permission from Brodsky et al50

difficult to distinguish from melanocytoma of the optic disc. This distinction is assisted by the fact that melanocytoma is generally a unilateral condition and rarely associated with other optic disc anomalies.46

The great majority of patients with gray optic discs do not have congenital optic disc pigmentation. For reasons that are poorly understood, optic discs of infants with delayed visual maturation and albinism may have a diffuse gray tint when

Aicardi Syndrome

Fig. 2.26 Optic disc from infant with albinism and delayed visual maturation demonstrating diffuse gray cast unrelated to pigmentation. Used with permission from Brodsky40

viewed ophthalmoscopically (Fig. 2.26). In these conditions, the gray tint often disappears in the first year of life without visible pigment migration. Beauvieux observed gray optic discs in premature infants and in albinotic infants who were apparently blind but who later developed good vision as the gray color disappeared.21,22 He attributed the gray appearance of these neonatal discs to delayed optic nerve myelination with preservation of the “embryonic tint.” It should be noted, however, that gray optic discs may also be seen in normal neonates and are therefore a nonspecific finding of little diagnostic value, except when accompanied by other clinical signs of delayed visual maturation or albinism. Despite their fundamental differences, “optically gray optic discs” and congenital optic disc pigmentation have, unfortunately, been lumped together in many reference books. These two conditions can usually be distinguished ophthalmoscopically, because melanin deposition in true congenital optic disc pigmentation is often discrete, irregular, and granular in appearance.50

Aicardi Syndrome The Aicardi syndrome is a cerebroretinal disorder of unknown etiology. Its salient clinical features are infantile spasms, agenesis of the corpus callosum, a characteristic electroencephalographic pattern termed hypsarrhythmia, and a pathognomonic optic disc appearance consisting of multiple

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Fig. 2.27 Aicardi syndrome. Cluster of peripapillary lacunae surround enlarged, anomalous right optic disc. Used with permission from Brodsky40

de-pigmented “chorioretinal lacunae” clustered around the disc (Fig. 2.27).67,92,155 Histologically, chorioretinal lacunae consist of wellcircumscribed, full-thickness defects limited to the RPE and choroid. The overlying retina remains intact, but is often histologically abnormal.67 Congenital optic disc anomalies, including optic disc coloboma, optic nerve hypoplasia, and congenital optic disc pigmentation, may accompany chorioretinal lacunae.67,73 Other ocular abnormalities include microphthalmos, retrobulbar cyst, pseudoglioma, retinal detachment, macular scars, cataract, pupillary membranes, iris synechiae, and iris colobomas.73,155 The most common systemic findings associated with the Aicardi syndrome are vertebral malformations (e.g., fused vertebrae, scoliosis, spina bifida) and costal malformations (e.g., absent ribs, fused or bifurcated ribs).67,73,155 Other systemic associations include muscular hypotonia, microcephaly, dysmorphic facies, auricular anomalies, and gastrointestinal dysfunction.120 A constellation of facial anomalies, including a prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows may assist in the diagnosis of the Aicardi syndrome.293 Various skin lesions are also present in 20% of cases.293 Severe mental retardation is almost invariable.67,155 CNS anomalies in the Aicardi syndrome include agenesis of the corpus callosum, cortical migration anomalies (e.g., pachygyria, polymicrogyria, cortical heterotopias), and

84

2 Congenital Optic Disc Anomalies

multiple structural CNS malformations (e.g., cerebral hemispheric asymmetry, Dandy–Walker variant, colpocephaly, midline arachnoid cysts) (Fig. 2.28).5,15,67,121,131,152,160 An overlap between the Aicardi syndrome and septo-optic dysplasia has been recognized in several patients.67 The intriguing

association between choroid plexus papilloma and the Aicardi syndrome has been documented in five patients.297 No gene has been identified for the Aicardi syndrome, but several observations support the hypothesis that the Aicardi syndrome is caused by de novo mutations of a gene on the

Fig. 2.28 MR imaging in Aicardi syndrome. (a) Sagittal T1-weighted MR image demonstrating agenesis of corpus callosum (upper solid arrow denotes normal position of corpus callosum), arachnoid cyst in region of quadrigeminal cistern (open arrow), and hypoplasia of cerebellar vermis with cystic dilatation of fourth ventricle (Dandy–Walker variant) (white arrow). (b) Coronal T1-weighted image demonstrating absent corpus callosum (black arrow denotes normal position of corpus callosum) and chiasmal hypoplasia (white arrow). (c) Coronal inversion

recovery image (arrow) demonstrating pachygyria (thickened dysmorphic cortex with decreased cortical gyri and sulci). (d) Axial T1-weight MR image demonstrating gray matter heterotopias in right temporal lobe (upper arrow), small areas of probable polymicrogyria just medial to occipital poles (greater in left hemisphere), dilatation of posterior horns of lateral ventricles (also known as colpocephaly) (open arrows), and arachnoid cyst in region of quadrigeminal cistern (lower arrow). Used with permission from Carney et al67

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Doubling of the Optic Disc

X-chromosome that is subject to X-chromosomal inactivation and that is lethal in males.73,228,293,309 Parents should therefore be asked about a previous history of miscarriages. All but four affected individuals have been female70 and, except for one pair of sisters,225 all reported cases are sporadic. At least six pairs of twins that are discordant for Aicardi syndrome are known. Five of these are confirmed to be dizygotic, which excludes the possibility that the etiology is a prenatal toxic or other disruptive event. With a single exception,71 all males confirmed to have Aicardi syndrome had a 47XXY karyotype.4,151 In 1986, Chevrie and Aicardi suggested that all cases of Aicardi syndrome represent fresh gene mutations, because no cases of affected siblings had been reported.73 A report of Aicardi syndrome in two sisters challenged the notion that Aicardi syndrome always results from a de novo mutation in the affected infant and indicates that parental gonadal mosaicism for the mutation may be an additional mechanism of inheritance.224 Although early infectious CNS insults can lead to severe CNS anomalies, tests for infective agents have been consistently negative. No teratogenic drug or other toxin has yet been associated with the Aicardi syndrome.67 On the basis of the pattern of cerebroretinal malformations in the Aicardi syndrome, it is speculated that an insult to the CNS must take place between the fourth and eighth week of gestation.73 The neurodevelopmental prognosis of Aicardi syndrome is extremely poor, with most children having seizures that are intractable despite therapy, and 91% attaining milestones no higher than 12 months.218,219 However, some do well; one girl reportedly never had seizures, and her psychomotor and language development were normal for her age.245 One study found the presence of large chorioretinal lacunae to correlate with poor neurodevelopment.219 The ability of new medications

such as vigabatrin and lamotrigine, which are more effective in controlling infantile spasms, have also improved the neuro developmental outcome and obviated the need for treatment with adrenocorticotropic hormones and prednisone. Persistence of fetal vasculature between gestational weeks 9 and 12 may provide a unifying hypothesis for the embryogenesis of the Aicardi syndrome. On the basis of the presence of associated intraocular malformations such as microphthalmos, persistent pupillary membrane, persistent hyperplastic primary vitreous, vascular loops on the optic disc, and epiretinal glial tissue,109 a persistence of fetal vasculature between gestational weeks 9 and 12 may provide a unifying hypothesis for the embryogenesis of the Aicardi syndrome.

Fig. 2.29 Doubling of optic disc (a) Note superior retinal vasculature arising from upper disc and inferior retinal vasculature arising from lower disc, with interconnecting vessels between two discs. (b) Major

optic disc and superotemporal “accessory optic disc” (right eye). Note “bridging tissue” between discs. Used with permission from Donoso et al93 Photographs courtesy of Larry Donoso, M.D.

Doubling of the Optic Disc Doubling of the optic disc is a rare anomaly in which two discs appear to be in close proximity to one another.62 This ophthalmoscopic finding is presumed to result from a duplication or separation of the distal optic nerve into two fasciculi.62 Most reports describe a “main” disc and a “satellite” disc, each with its own vascular system (Fig. 2.29). Doubling of the optic disc is usually unilateral and associated with decreased vision in the involved eye.93 Most clinical reports antedate the era of high-resolution neuroimaging and have relied upon the roentgenographic demonstration of two optic nerves in the same orbit, results of fluorescein angiography, synchronous pulsations of each major disc artery, dual blind spots, and angioscotomas to provide indirect evidence of optic nerve diastasis.93 In many cases, an apparent doubling of the optic disc results from a

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focal, juxtapapillary retinochoroidal coloboma that displays an abnormal vascular anastomosis with the optic disc.93,312 Separation of the optic nerve into two or more is rare in humans but common in lower vertebrates.93 However, separation of various portions of an intracranial or orbital optic nerve has been documented in a handful of autopsy cases.77,108,230,279,282 High-resolution orbital MR imaging should allow in vivo confirmation of optic nerve diastasis. In one recent case, retinal examination disclosed distinct vasculatures, OCT and ultrasound permitted in vivo imaging confirmation of two distinct optic nerve heads.252 Acquired optic nerve splitting has been described after trauma and penetration by an aneurysm.90,178 Occasionally, coronal MR imaging can produce the appearance of optic nerve diastasis.114

Optic Nerve Aplasia Optic nerve aplasia is a rare nonhereditary malformation that is usually seen in a unilaterally malformed eye of an otherwise healthy person.320 In its current usage, the term optic nerve aplasia comprises complete absence of the optic nerve (including the optic disc), retinal ganglion and nerve fiber layers, and optic nerve vessels.213a Histopathological examination usually demonstrates a vestigial dural sheath entering the sclera in its normal position, as well as retinal dysplasia with rosette formation (Fig. 2.30).320 Some early reports of optic nerve aplasia actually described patients with severe hypoplasia at a time when the latter entity was not clearly recognized.205,213a Ophthalmoscopically, optic nerve aplasia may take on any of the following appearances32: • Absence of a normally defined optic nerve head or papilla in the ocular fundus, without central blood vessels or macular differentiation • A whitish area corresponding to the optic disc, without central vessels or macular differentiation • A deep avascular cavity in the site corresponding to the optic disc, surrounded by a whitish annulus Optic nerve aplasia seems to fall within a malformation complex that is fundamentally distinct from that seen with optic nerve hypoplasia, as evidenced by its tendency to occur unilaterally and its frequent association with malformations that are otherwise confined to the involved eye (microphthalmia, malformations in the anterior chamber angle, hypoplasia or segmental aplasia of the iris, cataracts, persistent hyperplastic primary vitreous, colobomas, and retinal dysplasia), as opposed to the brain.32,115,154,250 The pathogenesis of optic nerve aplasia is unknown. When it occurs bilaterally, optic nerve aplasia is usually associated with other CNS

Fig. 2.30 Optic nerve aplasia. Left Retinal photograph shows absence of the optic nerve and vessels, and only rudimentary development of the retinal vessels. Used with permission from Brodsky et al.49 Right Histopathologic section of eye with optic nerve aplasia. Note mass of gliotic retina (arrows) filling vitreous cavity. RPE ends abruptly (open arrow) in area in which optic nerve should be. The choroid (solid arrow) is replaced with gliotic tissue. Residual tag of dura (asterisk) is attached to outer sclera. Courtesy of Curtis Margo, M.D.

malformations,19,289,327 although rare exceptions exist.262 One infant with bilateral optic nerve aplasia was found to have congenital hypopituitarism and posterior pituitary ectopia.49 In patients with unilateral optic nerve aplasia, the intracranial course of the “intact” optic nerve may vary. One patient with unilateral anophthalmos had optic nerve aplasia associated with a congenital giant suprasellar aneurysm.147 The remaining optic nerve was identified at craniotomy as passing posteriorly as a single cord to form an optic tract with no adjoining chiasm. It was speculated that the absent optic nerve and chiasm may have formed initially and then degenerated in a retrograde fashion. Autopsy findings from a patient with a Hallerman–Streiff-like syndrome and left optic nerve hypoplasia showed normal geniculate bodies and optic tracts with only a single nerve that emerged anteriorly from a chiasm that deviated to the right.153 In another patient with unilateral optic nerve aplasia and microphthalmos, MR imaging disclosed optic nerve aplasia and hemichiasmal hypoplasia on the

Myelinated (Medullated) Nerve Fibers

affected side.213a Visual evoked cortical responses demonstrated increased signals over the occipital lobe contralateral to the intact optic nerve, suggesting chiasmal misdirection of axons from the temporal retina of the normal eye, as seen in albinos. The authors speculated that this abnormal decussation may represent an atavistic form of neuronal reorganization.213a Optic nerve aplasia and its associated chorioretinal lacuna may occasionally overlap with the autosomal dominant microcephalylymphedema-chorioretinal dysplasia syndrome.68,127

Myelinated (Medullated) Nerve Fibers Myelination of the afferent visual pathways begins at the lateral geniculate body at 5 months of age and terminates at the lamina cribrosa at term or shortly thereafter.222 Oligodendrocytes, which are responsible for myelination of the CNS, are not normally present in the human retina.222 Histological studies have confirmed the presence of presumed oligodendrocytes and myelin in areas of myelinated nerve fibers and their absence in other areas.290 Myelinated retinal nerve fibers have been found in approximately 1% of eyes examined at autopsy307 and in 0.3–0.6% of routine ophthalmic patients.222 Ophthalmoscopically, myelinated nerve fibers usually appear as white striated patches at the upper and lower poles of the disc (Fig. 2.31). In this location, they may simulate papilledema, both by elevating the involved portions of the disc and by obscuring the disc margin and the underlying retinal vessels.222,322 Distally, they have an irregular fan-shaped

Fig. 2.31 Myelinated nerve fibers

87

appearance that facilitates their recognition. Small slits or patches of normal-appearing fundus color are occasionally visible in an area of myelination.222 Myelinated nerve fibers are bilateral in 17–20% of cases, and clinically, they are discontinuous with the optic nerve head in 19%. Isolated patches of myelinated nerve fibers in the peripheral retina are rarely found nasal to the optic nerve head.322 The pathogenesis of myelinated nerve fibers remains largely speculative, but several recent hypotheses advanced by Williams322 provide a useful conceptual framework and seem particularly plausible in light of recent reports. It is known that animals with little or no evidence of lamina cribrosa tend to have deep physiological cups and extensive myelination of retinal nerve fibers, while animals with a well-developed lamina cribrosa tend to show fairly flat nerve heads and no myelination of retinal nerve fibers. Williams322 has used this animal model to question whether the following factors could play a critical role in the pathogenesis of myelinated nerve fibers: 1. A defect in the lamina cribrosa may allow oligodendrocytes to gain access to the retina and produce myelin there. 2. There may be fewer axons relative to the size of the scleral canal, producing enough room for myelination to proceed into the eye. In eyes with remote, isolated peripheral patches of myelinated nerve fibers, an anomaly in the formation or timing of formation of the lamina cribrosa permits access of oligodendrocytes to the retina. These cells then migrate through the nerve fiber layer until they find a region of relatively low nerve fiber layer density, where they proceed to myelinate some axons.322 3. Late development of the lamina cribrosa may allow oligodendrocytes to migrate into the eye. The sclera begins to consolidate in the limbal region, then proceeds posteriorly toward the lamina cribrosa. As Williams stated, “in a sense, it is possible to imagine a race going on, with the oligodendrocytes myelinating their way toward the retina and the mesodermal tissue consolidating its way to make the lamina cribrosa. If scleral consolidation is retarded, then some retinal myelination may occur.”322 Extensive unilateral (or, rarely, bilateral) myelination of nerve fibers can be associated with high myopia and severe amblyopia (Fig. 2.32). Unlike other forms of unilateral high myopia that characteristically respond well to occlusion therapy, many children with myelinated nerve fibers are notoriously refractory to rehabilitation.97 In such patients, myelin envelops most or all of the circumference of the disc, and the disc may have a dysplastic appearance.299 In addition, the macular region (although unmyelinated) usually appears abnormal, showing a dulled reflex or pigment dispersion.143 The appearance of the macula may be the best direct correlate of response to occlusion therapy.143 Schmidt et al proposed that myelinated retinal nerve fibers could blur

88

Fig. 2.32 Diffuse myelination of nerve fibers in eye with high myopia and refractory amblyopia

retinal images and induce visual deprivation.270 Regarding the pathogenesis of the syndrome, it is unclear whether increased axial length of the eye predisposes to retinal myelination or whether retinal myelination causes myopia.269,299 Myelinated nerve fibers may be familial, in which case the trait is usually inherited in an autosomal dominant fashion.105 Isolated cases of myelinated nerve fibers have also been described in association with abnormal length of the optic nerve (oxycephaly),27 effects in the lamina cribrosa (tilted disc),74 anterior segment dysgenesis,322 and NF-2.125 Although myelinated nerve fibers are purported to be associated with neurofibromatosis,125 many authorities feel that this association is questionable at best.322 Myelinated nerve fibers also occur in association with the Gorlin (multiple basal cell nevi) syndrome.84 This autosomal dominant disorder can often be recognized by the finding of numerous tiny pits in the hands and feet that produce a “sandpaper” irregularity. Multiple cutaneous tumors develop in the second or third decade, but they may occasionally develop in the first few years of life. When present in childhood, these lesions remain quiescent until puberty, then increase in number and demonstrate a more rapid and invasive growth pattern.179 Additional features include jaw cysts (which are found in approximately 70% of patients and often appear in the first decade of life) and mild mental retardation.84 Rib anomalies (bifid ribs, splaying, synostoses, and partial agenesis) are found in approximately 50% of patients. Facial characteristics include hypertelorism, prominent supraorbital ridges, frontoparietal bossing, a broad nasal root, and mild mandibular prognathism.84 Ectopic calcification, especially of the falx cerebri, is an almost

2 Congenital Optic Disc Anomalies

constant finding. Medulloblastomas have developed in several children with this condition. This disorder should be considered in children with myelinated nerve fibers, because small lesions can be treated with curettage, electrophotocoagulation, cryosurgery, and topical chemotherapy to forestall the development of aggressive and invasive lesions.1,179 Traboulsi et al307 described an autosomal dominant vitreoretinopathy characterized by congenitally poor vision, bilateral extensive myelination of the retinal nerve fiber layer, severe vitreal degeneration, high myopia, a retinal dystrophy with night blindness, reduction of the electroretinographic responses, and limb deformities. Rarely, areas of myelinated nerve fibers are acquired after infancy and even in adulthood.1,14 Trauma to the eye (a blow to the eye in one patient and an optic nerve sheath fenestration in the other) seems to be a common denominator in these cases. Williams has suggested that “perhaps there was sufficient damage to the lamina cribrosa in these patients to permit oligodendrocytes to enter the retina, whereupon they moved to the nearest area of relatively loose nerve fibers and myelinated them.” Myelinated nerve fibers have also been known to disappear as a result of tabetic optic atrophy, pituitary tumor, glaucoma, central retinal artery occlusion, and optic neuritis.222

The Albinotic Optic Disc The optic discs of albinos have a number of distinct ophthalmoscopic appearance that has gone largely unrecognized. Albino optic discs often have a diffuse gray tint when viewed ophthalmoscopically in the first few years of life. This discoloration must somehow be related to optical effects resulting from surrounding chorioretinal depigmentation, because it is no longer evident in older children and adults. Schatz and Pollock266 have identified the following five ophthalmoscopic findings that characterize most albino optic discs: (1) small disc diameter; (2) absence of the physiological cup; (3) oval shape with long axis oriented obliquely; (4) origin of the retinal vessels from the temporal aspect of the disc; and (5) abnormal course of retinal vessels consisting of initial nasal deflection followed by abrupt divergence and reversal of direction to form the temporal vascular arcades (Fig. 2.33). The purported association between albinism and optic nerve hypoplasia is controversial. Although histopathological verification is lacking in humans, some circumstantial evidence supports this association. Clinically, it has been observed that the optic discs appear small in some human albinos.286 Because the macula is poorly developed in albinos, it is plausible that a decreased number of macular ganglion cells would reduce the total number of optic nerve axons from the papillomacular nerve fiber bundle.

References

Fig. 2.33 Albinotic optic disc. Note small size, situs inversus of vessels and abnormal course of retinal vessels (Courtesy of Stephen C. Pollock, M.D.)

Optic nerve hypoplasia would then be inevitable, unless other nerve fiber bundles contained a proportionately larger number of axons. Several histological studies have estimated that animals with albinism have approximately 7% fewer optic nerve fibers than their normally pigmented counterparts.38,95 These findings raise the possibility that optic nerve hypoplasia is a component of albinism. In one study, highresolution MR imaging of the intracranial optic nerves in human albinos shows no diminution in size,53 while a more recent study detected hypoplasia anterior visual pathways.271 Clinically, the diagnosis of mild optic nerve hypoplasia is usually predicated on finding either subnormal visual acuity or visual field abnormalities, which are usually present in albinos by virtue of the associated macular hypoplasia and nystagmus. Because neither ophthalmoscopy nor MR imaging alone can definitively distinguish mild forms of optic nerve hypoplasia from variants of normal, resolution of this controversy awaits neuropathological examination of human albino optic nerves.

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95 299. Tarabishy AB, Alexandroiu TJ, Traboulsi EI (2007) Syndrome of myelinated retinal nerve fibers, myopia, and amblyopia: a review. Surv Ophthalmol 52:588–596 300. Taskintuna I, Oz O, Teke MY et al (2003) Morning glory syndrome: association with moyamoya disease, midline cranial defects, central nervous system anomalies, and persistent hyaloid artery remnant. Retina 23:400–402 301. Taylor D (1982) Congenital tumors of the anterior visual pathways. Br J Ophthalmol 66:455–463 302. Theodossiadis G (1977) Evolution of congenital pit of the optic disc and macular detachment in photocoagulated and non-photocoagulated eyes. Am J Ophthalmol 84:620–631 303. Theodossiadis GP, Lollia AK, Theodossiadis PG (1992) Cilioretinal arteries in conjunction with a pit of the optic disc. Ophthalmologica 204:115–121 304. Theodossiadis PG, Strigaris K, Papdopoulos V et al (2005) Optic nerve cyst associated with optic disk pits. Graefe’s Arch Clin Exp Ophthalmol 243:718–730 305. Thomas PQ, Dattani MT, Brickman JM et al (2001) Heterozygous HESX mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 10:39–45 306. Tosti G (1999) Serous macular detachment and tilted disc syndrome. Ophthalmology 106:1453–1454 307. Traboulsi EI, Lim JI, Pyeritz R et al (1993) A new syndrome of myelinated nerve fibers, vitreoretinopathy and skeletal malformations. Arch Ophthalmol 111:1543–1545 308. Traboulsi EI, O’Neill JF (1988) The spectrum in the morphology of the so-called “morning glory” disc anomaly. J Ped Ophthalmol Strabis 25:93–98 309. Van den Veyver IB (2002) Microphthalmia with linear skin defects (MLS), Aicardi, and Goltz syndromes: are they related X-linked dominant male-lethal disorders? Cytogenet Genome Res 99:289–296 310. Van Nouhuys JM, Bruyn GW (1964) Nasopharyngeal transsphenoidal encephalocele, craterlike hole in the optic disc and agenesis of the corpus callosum: pneumoencephalographic visualization in a case. Psychiat Neurol Neurochir 67:243–258 311. Vanecek J (1999) Inhibitory effect of melatonin on GnRH-induced LH release. Rev Reprod 4:67–92 312. Vedantham V (2005) Double optic discs, optic disc coloboma, and pit: spectrum of hybrid disc anomalies in a single eye. Arch Ophthalmol 123:1450–1452 313. Vogel G (2005) The unexpected brains behind blood vessel growth. Science 307:665–666 314. von Fricken MA, Dhungel R (1984) Retinal detachment in the morning glory syndrome: pathogenesis and management. Retina 4:97–99 315. von Szily A (1924) Die Obntogenese der idiopathiachen (erbbildlichen Spaltbildungen des Auges des Mikrophthalmus und der Orbitalcysten). Z Anat Entwicklungsgesch 74:1–230 316. Vongphanit J, Mitchell P, Wang JJ (2002) Population prevalence of tilted optic disks and the relationship of this sign to refractive error. Am J Ophthalmol 133:679–685 317. Wang P, Liang X, Yi J, Zhang Q (2008) Novel SOX2 mutation associated with ocular coloboma in a Chinese family. Arch Ophthalmol 126:709–713 318. Warburg M (1992) Update of sporadic microphthalmos and coloboma. Ophthalmic Pediatr Genet 13:111–122 319. Wee R, Van Gelder RN (2004) Sleep disturbances in young subjects with visual dysfunction. Ophthalmology 111:297–303 320. Weiter JJ, McLean IW, Zimmerman LE (1977) Aplasia of the optic nerve and disk. Am J Ophthalmol 83:569–576 321. Wiggins RE, von Noorden GK, Boniuk M (1991) Optic nerve coloboma with cyst. A case report and review. J Pediatr Ophthalmol Strabismus 28:274–277

96 322. Williams TD. Medullated retinal nerve fibers: speculations on their cause and presentation of cases. Am J Optom Physiol Opt 1986;63:142-151. Ophthalmol 1972;88:139-146. 323. Williams J, Brodsky MC, Griebel M et al (1993) Septo-optic dysplasia: clinical significance of an absent septum pellucidum. Dev Med Child Neurol 35:490–501 324. Willis R, Zimmerman LE, O’Grady R et al (1972) Heterotopic adipose tissue and smooth muscle in the optic disc, association with isolated colobomas. Arch Ophthalmol 88:139–146 325. Wilson BD, Ii M, Park KW, et al. Netrins promote developmental and therapeutic angiogenesis. Science Express June 29, 2006; pp 1-9. 326. Wise JB, Maclean AL, Gass JD (1966) Contractile peripapillary staphyloma. Arch Ophthalmol 75:626–630 327. Yanoff M, Rorke LB, Allman MI (1978) Bilateral optic system aplasia with relatively normal eyes. Arch Ophthalmol 96:97–101

2 Congenital Optic Disc Anomalies 328. Yokota A, Matsukado Y, Fuwa I et al (1986) Anterior basal encephalocele of the neonatal and infantile period. Neurosurgery 19:468–478 329. Young SE, Walsh FB, Knox DL (1976) The tilted disc syndrome. Am J Ophthalmol 82:16–23 330. Yuen CH, Kaye SB (2002) Spontaneous resolution of serous maculopathy associated with optic disc pit in a child: a case report. J AAPOS 6:330–331 331. Zeki SM (1990) Optic nerve hypoplasia and astigmatism: a new association. Br J Ophthalmol 74:297–299 332. Zeki SM, Dudgeon J, Dutton GN (1991) Reappraisal of the ratio of disc to macula/disc diameter in optic nerve hypoplasia. Br J Ophthalmol 75:538–541 333. Zeki SM, Dutton GM (1990) Optic nerve hypoplasia in children. Brit J Ophthalmol 74:300–303

Chapter 3

The Swollen Optic Disc in Childhood

Introduction Because of its potentially ominous implications, the discovery of optic disc elevation in a child is a cause for urgent neuroophthalmologic referral. The nature of the underlying disorder can often be predicted from the wording of the referring physician’s telephone call. Bilateral optic disc elevation without visual loss in a child with headaches, nausea, and vomiting of several months duration creates a high index of suspicion for papilledema (i.e., swelling of the optic discs secondary to elevated intracranial pressure). Blurring of the nasal disc margins that is noted as an incidental finding in an otherwise healthy child is usually found to be pseudopapilledema (i.e., real or apparent elevation of the optic discs due to local structural factors that simulates swelling of the discs). Optic disc swelling in the setting of acute visual loss usually signifies optic neuritis. When the child arrives for consultation, we first examine the optic discs with a direct ophthalmoscope through undilated pupils. Often, the diagnosis of pseudopapilledema is readily apparent. In this setting, parents and siblings should also be examined, because anomalously elevated discs are often inherited as a dominant disorder. One can then reassure the concerned parents that their child is well. In the child with additional systemic anomalies, one must consider the possibility that the pseudopapilledema may be related to an underlying genetic disorder. In the child with swollen optic discs and other symptoms of increased intracranial pressure, we obtain magnetic resonance (MR) imaging to look for an intracranial mass lesion. If no lesion is found, we perform a lumbar puncture to determine the opening pressure, rule out meningitis, and examine the protein and cell count. Optic disc elevation in children may be associated with a wide variety of systemic disorders. Some conditions, such as neurosarcoidosis or leukemia, can produce optic nerve infiltration with visual loss in some cases and papilledema with little or no visual loss in others. Disorders such as mucopolysaccharidoses can be associated with either papilledema or pseudopapilledema.

Swelling of the optic disc is caused by interruption of axonal transport in the optic nerve head. Experimentally, interruption of axoplasmic transport can be associated with pressure changes at the level of the disc resulting from increased cerebrospinal fluid (CSF) pressure around the retrolaminar optic nerve. Anoxia, ischemia, cyanide toxicity, decreased temperature, methanol toxicity, and antimitotics also can cause optic disc swelling.228 Clinically, the terms optic disc swelling and optic disc edema are used interchangeably. We prefer the term swelling to edema because, histopathologically, the degree of axonal distension usually exceeds the degree of edema (exceptions to this rule are seen in diabetic papillopathy and Leber idiopathic stellate neuroretinitis, in which severe edema may occur). Swelling of the optic disc may result from increased intracranial pressure, local inflammation or ischemia, local metabolic effects, compression of the retrobulbar optic nerve, hypotony, intraocular inflammation, infiltration, or inflammation. Narrowing of the scleral canal with crowding of axons is associated with diabetic papillopathy (a form of disc swelling) as well as with pseudopapilledema. Although the acute ischemic infarction characteristic of ischemic optic neuropathy does not occur in children,70 a recurrent form of anterior ischemic optic neuropathy has been described in young adults with small cupless discs.224 Interruption of axonal transport with prelaminar accumulation of cytoskeletal elements does not appear to be a primary cause of visual loss, because severe papilledema is compatible with normal vision. The underlying pathogenetic mechanism (inflammatory, vascular, infiltrative) determines the nature and severity of visual loss, and interruption of axonal transport and swelling of the disc occur as epiphenomena. Swelling of the optic disc may or may not lead to optic atrophy and visual loss. Visual loss as a chronic effect of optic disc edema seems to depend, at least in part, on the severity and duration of the disc edema. Conceptually, the effects of papilledema can be likened to those of elevated intraocular pressure. An intraocular pressure of 30 mmHg may be toler-

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ated for years with no adverse effect. An intraocular pressure of 60 mmHg inevitably produces axonal loss. Both ocular hypertension and chronic papilledema can exist for years without optic nerve injury; however, each condition is assumed to have a threshold above which axonal loss occurs. There is likely a duration threshold for each level of severity of disc swelling, as well as a severity threshold for any given duration. As with elevated intraocular pressure, severity and duration probably act as independent parameters. This chapter focuses primarily on the differential diagnostic considerations of optic disc elevation in children. Its primary purpose is to delineate the broad spectrum of neurologic and systemic conditions that may manifest with optic disc swelling or pseudopapilledema.

Papilledema By convention, the term papilledema has been assigned to optic disc swelling caused by elevated intracranial pressure. Ophthalmoscopic signs of papilledema include optic disc elevation, venous distension, obscuration of the major retinal vessels (particularly at the disc margin), hyperemia of the disc, opacification of the peripapillary nerve fiber layer, and absent venous pulsations. Later signs include flame-shaped hemorrhages, peripapillary subretinal hemorrhages, and cotton wool spots (Fig. 3.1). From the ophthalmoscopic appearance of the disc alone, one cannot reliably distinguish papilledema

Fig. 3.1 Papilledema. Note optic disc elevation, papillary and peripapillary hemorrhage, venous congestion, and cotton wool spots

3 The Swollen Optic Disc in Childhood

from other forms of optic disc edema. Ophthalmoscopic signs of chronic papilledema and chronic atrophic papilledema have been detailed elsewhere.380 Elevated intracranial pressure produces a rise in CSF pressure surrounding the optic nerves, which increases tissue pressure within the nerves, leading to interruption of axonal transport at the lamina cribrosa and swelling of axons.228 Vascular changes in papilledema are secondary to axonal distension, which compresses the retinal veins, leading to venous engorgement as well as capillary leakage and extracellular fluid accumulation.228,550 Fluorescein angiography in papilledema shows dilated capillaries, microaneurysms, and flame-shaped hemorrhages in the arteriovenous phase, followed by diffuse prelaminar capillary leakage and late staining of the nerve head and adjacent tissues (Fig. 3.2). Interestingly, intraocular protrusion of the optic discs in papilledema does not produce a visible signal differential with the vitreous gel when viewed with routine MR imaging.63 Occasionally, the swollen disc can be visualized within the globe on MR imaging following gadolinium enhancement (Fig. 3.3).62 Unilateral papilledema is rare in children but not uncommon in adults.341,494 Headaches and transient visual obscurations are the major neuro-ophthalmologic symptoms of elevated intracranial pressure. Nausea, vomiting, persistent visual loss, and diplopia are less common. A historical clue to the nature of these headaches is that they are often present on awakening. Transient visual obscurations consist of “grayouts” or “fuzz-outs” of vision, each lasting a few seconds. They occur from one or two to several hundred times per day and often occur on bending over or standing up or with Valsalva pressure. Although purported to result from momentary ischemia, an electrochemical perturbation seems more plausible. Diplopia, when present, is usually horizontal and incomitant, reflecting the presence of unilateral or bilateral sixth nerve palsy. Sixth nerve palsies caused by elevated intracranial pressure are typically incomplete. Third and fourth nerve palsies have rarely been attributed to increased intracranial pressure, as have skew deviation and acute comitant esotropia. Such cases should be viewed as due directly to an intracranial mass lesion until proven otherwise. Rarely, idiopathic intracranial hypertension (IIH) with very elevated CSF pressures rarely produces diffuse ophthalmoplegia.67 Visual acuity is usually normal in the patient with papilledema, except in cases in which signs of chronic disc swelling or atrophy are present. However, visual field defects are common even in early papilledema. When tested with Goldmann perimetry, concentric enlargement of the blind spot is the most common, and often the only, visual field defect in patients with papilledema. Automated static perimetry is more sensitive and often demonstrates inferonasal field loss and constriction of isopters. Blind spot enlargement in

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Fig. 3.2 Fluorescein angiogram in papilledema. (a) Venous laminar phase demonstrating dilated capillaries, flame hemorrhages, and microaneurysms on surface of optic disc of adjacent retina. (b) Arteriovenous phase demonstrating fluorescein leakage from dilated surface capillaries on disc, which masks deeper fluorescence. (c) Venous

phase demonstrating increased leakage of fluorescein, which now obscures surface details on optic disc. (d) Late phase demonstrating intense, kidney-shaped staining that extends into peripapillary region. Fluorescein dye no longer fills arteries and veins

papilledema has been attributed to mechanical displacement of the peripapillary retina by the swollen disc. Corbett et al105 showed that the size of the enlarged blind spot could be reduced by the addition of plus lenses, demonstrating that blind spot enlargement in papilledema is partially refractive in nature. Accurate visual field testing can be problematic in younger children, although close attention and frequent rest periods often are helpful. Progressive visual field loss usu-

ally evolves over months in patients with chronic and/or atrophic papilledema. Once central visual loss begins, it can progress rapidly, and blindness can ensue over a period of weeks to months. Visual field loss is usually severe by the time acuity begins to drop. Therefore, a patient with papilledema whose visual acuity has decreased to 20/30 is at grave risk for future visual loss, and surgical treatment is often indicated.

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Fig. 3.3 MR imaging in child with IIH. (a) Bilateral papilledema. (b) Intraocular signal abnormalities corresponding to swollen discs are absent in unenhanced MR images. (c) Following Gadolinium administration,

hyperintense signal corresponding to swollen optic discs is visible in vitreous cavities. Also note flattening of posterior sclera. From Brodsky and Glasier64

It is important to document color vision whenever possible in children with papilledema. Secondary macular pathology (e.g., choroidal folds, macular star figures, macular edema, macular pigmentary changes) can compromise vision in patients with papilledema200,255,392 but tends to spare color vision. In contrast, an evolving optic neuropathy in the setting of chronic papilledema is virtually always associated with dyschromatopsia. Because decreasing visual acuity is an ominous sign in papilledema, the degree of dyschromatopsia helps to identify the rare cases in which decreased acuity is caused by macular pathology.

Intracranial mass lesions are the primary diagnostic consideration in children or adults with papilledema. Brain tumors elevate intracranial pressure by acting as space-occupying lesions, producing focal or diffuse cerebral edema, blocking the flow of CSF, or compressing a venous sinus.380 Rarely, brain tumors, such as choroid plexus papilloma, can elevate intracranial pressure by producing excess CSF. Papilledema is more likely to develop in children with infratentorial tumors than in those with supratentorial tumors. Papilledema from infratentorial tumors usually results from compression of the aqueduct but may also be caused by pressure

Papilledema

on the vein of Galen or occlusion of the posterior sagittal sinus.380 The most common tumors associated with childhood papilledema are midbrain and cerebellar glioma, medulloblastoma, and ependymoma.161 Pediatric brain tumors and their neuro-ophthalmologic sequelae are detailed in Chap. 11.

Idiopathic Intracranial Hypertension (IIH) in Children IIH is a condition characterized by symptoms and signs of increased intracranial pressure without evidence of a mass lesion or hydrocephalus.108 It differs from other causes of increased intracranial pressure in that the level of consciousness is not altered. The diagnosis of primary IIH is usually established when the modified Dandy criteria are met: ·· Signs and symptoms of increased intracranial pressure ·· Absence of localizing findings on neurologic examination ·· Absence of deformity, displacement, or obstruction of the ventricular system and otherwise normal neurodiagnostic studies, except for increased CSF pressure ·· Alert and oriented patient ·· No other cause of increased intracranial pressure present Older children with IIH may complain of headache, neck pain, diplopia, intracranial noises, or transient visual obscurations, whereas younger children may present with apathy or irritability.565 Although IIH headaches have been described as characteristically frontal, severe, pulsatile, and worse on lying down, most experts suggest that they are similar to migraine headaches, except that IIH headaches tend to be continuous, whereas migrainous headaches are generally more severe and intermittent.524 More precise criteria for diagnosis of elevated intracranial pressure are needed. For example, some consider the upper limit of normal opening CSF pressure in young children to be 180 mmHg,445 while others have found opening pressures of 275 mmHg in children who were identified as having pseudopapilledema.385

Pathophysiology The complex, multifactorial causes of IIH have been studied at both basic and clinical levels. There is no doubt that multiple contributory factors can downregulate CSF outflow and eventuate in elevated intracranial pressure. Johnson et al269 proposed a classification of IIH that reflects the concept of IIH as a disorder of CSF outflow. We have modified this model (Table 3.1) to apply it to the different forms of IIH of childhood. By expanding the diagnosis of IIH to include

101 Table 3.1 Classification of idiopathic intracranial hypertension in children (Adapted from Johnston et al272) Primary idiopathic intracranial hypertension · No recognized cause (idiopathic intracranial hypertension or benign intracranial hypertension) Secondary idiopathic intracranial hypertension · Idiopathic intracranial hypertension associated with neurological disease – Dural venous sinus thrombosis (associated with otitis media, mastoiditis, or head trauma) – Altered cerebrospinal fluid composition (meningitis) – Arteriovenous malformation draining into a venous sinus – Gliomatosis cerebri Idiopathic intracranial hypertension secondary to systemic disease · Malnutrition or renutrition · Systemic lupus erythematosis · Severe anemia (iron deficiency, aplastic, sickle cell) · Addison disease · Bone marrow transplantation · Retinal transplantation · Down syndrome · Sleep apnea Postinfectious (following chickenpox or measles) Idiopathic intracranial hypertension secondary to ingestion or withdrawal of exogenous agents · Corticosteroid withdrawal · Thyroxine replacement therapya · Nalidixic acid (used in the treatment of urinary tract infection and bacillary dysentery) · Tetracycline or minocycline therapy (used in teenagers to suppress acne) · Vitamin A intoxication – often in adolescents who take vitamin A or the synthetic vitamin A derivative isoretinoin for acne · Danazol, danocrine (used for endometriosis or autoimmune hemolytic anemia) · Recombinant growth hormone · All-trans retinoic acid · Chemotherapy (cyclosporine, cytarbine) Atypical idiopathic intracranial hypertension Occult idiopathic intracranial hypertension (no papilledema) Normal pressure idiopathic intracranial hypertension Infantile idiopathic intracranial hypertension

intracranial hypertension without ventriculomegaly from a defect of CSF absorption (of any cause), one can begin to synthesize the numerous and disparate causes into a single conceptual framework; in such a framework, the finding of clinical or neuroimaging abnormalities would not preclude the diagnosis of IIH as long as the mechanism of decreased CSF absorption is present. Until recently, the accumulated evidence best supported a blockage of CSF absorption that can occur at the level of the Pacchionian granulations or the venous sinuses. Decreased absorption at the level of the arachnoid villi has been demonstrated by radioisotope cisternography, although it is unclear whether it is secondary to compression of the arachnoid villi

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or the result of elevated intracranial pressure itself.355 This hypothesis is consistent with the absence of tight junctions in the ependymal cells surrounding the lateral ventricles, which allows high-pressure fluid to move transependymally into the extracellular space. The absence of tight junctions in pial cells that cover the cerebral convexities allows high-pressure fluid to communicate from the lateral ventricles to the subarachnoid space and vice versa. This flow may lead to the establishment of an equilibrium between raised CSF outflow resistance and increased brain stiffness (occurring as a consequence of increased cerebral blood volume, mild interstitial cerebral edema, or both), which would explain the absence of ventriculomegaly in IIH. The development of such a steady state of CSF fluid migration would also help explain the inability of some studies to demonstrate increased periventricular brain water content on MR imaging.99,512 Although some studies have found increased periventricular signal intensity (presumably signifying low-grade edema) in patients with IIH, the increased white matter signal intensity was demonstrable only by statistical analysis of periventricular signal intensities. It has now been shown that a significant portion of CSF passes through the olfactory bulb and through the foramina in the cribriform plate into an extensive network of lymphatic vessels in the nasal submucosa.267,268,595,597 These findings have refocused our attention on a possible predominant role of nasal lymphatic drainage pathways for intracranial and perioptic CSF. Elucidation of the relative contribution of these CSF pathways under normal and pathophysiologic conditions may change the way we conceptualize this condition and offer new avenues of treatment. Some CSF dysfunction may be attributable to changes of molecular flux and CSF flow rate.450,515 Corbett103 proposed that elevated levels of free vitamin A in obese patients may damage arachnoidal granulations and lead to decreased CSF absorption in primary IIH. Evidence of an adverse effect of high vitamin A intake on intracranial pressure is well-recognized. Acute swelling of the anterior fontanelle, with vomiting, agitation, and insomnia, develops in infants given large oral doses of vitamin A. These changes occur after only a few hours and usually subside 24–48 h later.367 Although 98% of vitamin A is said to be stored in the liver, there is evidence that this fat-soluble vitamin may be stored in fat to a greater degree than generally appreciated. Unbound vitamin A (retinyl esters) is a toxic agent that triggers cell death by activating lysosomal enzymes. Therefore, it is attached to different carrier proteins throughout the body. In the blood, it is bound to retinol-binding protein. In the CSF, it is attached to prealbumin (transthyretin), a carrier protein synthesized at the choroid plexus.

3 The Swollen Optic Disc in Childhood

Warner et al562 found increased levels of unbound retinal in the CSF of subjects with IIH, providing further evidence that vitamin A metabolism might be involved in the pathogenesis of IIH and that IIH could result from vitamin A toxicity localized to the CSF.349 Any condition leading to elevated levels of unbound vitamin A in the CSF, such as endogenous obesity, excess ingestion, or renal failure (which results in decreased excretion of retinol-binding protein and, secondarily, high levels of total vitamin A), could exceed the capacity of transthyretin to bind it. Free vitamin A in the CSF would then percolate into the Pacchionian granulations, where it damages the endothelial cells, which results in decreased CSF absorption. Because CSF transthyretin also binds thyroxine, the occurrence of IIH during thyroxine replacement in hypothyroidism (which would deplete CSF transthyretin and increase the level of unbound vitamin A in the CSF) is consistent with this hypothetical mechanism; the same is true for the association of IIH with obesity and its occurrence in women (who have more body fat). The changing hormonal status at menarche may contribute to vitamin A storage and binding. Drugs and toxins associated with IIH may affect absorption, binding, storage, or transmission of vitamin A. Recently, attention has been focused on the possible causative role of elevated venous sinus pressure in decreasing CSF absorption.445 MR venography has shown elevated venous sinus pressure in patients with IIH, which could be the primary cause, a contributory cause, or a secondary phenomenon. Elevated venous pressure may increase resistance to CSF absorption, causing the cerebrospinal pressure to increase as well. Karahalios et al276 found dural venous outflow obstruction in five of ten patients with IIH using angiography and manometry. The patients who had an obstruction had a high-pressure gradient across the stenosis. Angioplasty or thrombolytic infusion improved the outlet obstruction but not the clinical picture. Studies using cerebral venography and manometry showed elevated venous pressure in the superior sagittal and proximal transverse sinuses.309 However, King et al309 and other researchers31,243,374 have shown that venous sinus stenoses reverses with correction of the elevated intracranial pressure, suggesting that elevated venous pressure could be the effect rather than the cause of intracranial pressure.513 Bateman32 has proposed that reduced venous sinus pulsatility may be a marker for IIH secondary to elevated venous sinus pressure. Increased intraabdominal pressure that is transmitted through the thorax to the cerebral draining veins has also been proposed as the cause of IIH in morbid obesity, and bariatric surgery has shown to be efficacious in treating IIH in adults.534

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MR imaging is usually sufficient to rule out central nervous system disease, gliomatosis cerebri, leptomeningeal spread of lymphoma, leukemia, germ cell tumors (which may produce meningeal enhancement on MR imaging or CSF elevation in protein, pleocytosis, or abnormal CSF cytology)81,139 and spinal cord tumors, which usually produce back pain, upper motor neuron signs, or a sensory level. Although MR imaging does not show changes in the volume of the brain or ventricles in IIH, it is extremely helpful in identifying elevated intracranial pressure (Figs. 3.3 and

3.4).497 In a study of 20 patients with IIH, Brodsky and Vaphiades found flattening of the posterior sclera in 80%, empty sella in 70%, distension of the perioptic subarachnoid space in 45%, enhancement of the prelamnar optic nerve in 50%, vertical tortuousity of the orbital optic nerve in 40%, and intraocular protrusion of the prelaminar optic nerve in 30%65,268,557 (Fig. 3.4). MR imaging showed an empty sella in 71% of adults with IIH.373 Empty sella is thought to result from a pressure-induced, downward herniation of the suprasellar subarachnoid space into the sella, with secondary compression and flattening of the pituitary gland.373 Following normalization of intracranial pressure,

Fig. 3.4 MR imaging in IIH. (a) Enhanced T1-weighted MR image demonstrating distended perioptic nerve sheath (large open arrows), vertical tortuousity of the orbital optic nerve, and intraocular protrusion of the enhanced papilla (small open arrow). (b) Enhanced T1-weighted axial MR image demonstrating distension of the perioptic CSF space, vertical tortuousity of the optic nerves, and more severe protrusion of the papilla into

the globes (OS > OD). (c) Axial T1-weighted MR image demonstrating bilateral distension of the perioptic CSF space and flattening of the posterior sclera. (d) Empty sella. T1-weighted sagittal MR image shows compressed pituitary gland (lower arrow) assuming a concave shape within the lower sella. Upper arrow denotes chiasm, middle arrow denotes infundibulum. Used with permission from Brodsky and Vaphiades65

Neuroimaging

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the pituitary gland may reexpand to assume its normal configuration.596

Primary IIH in Children Although IIH is generally considered a disease of obese women of child-bearing age, its occurrence in children has been documented in numerous studies.23,25,343 Numerous studies have noted that the clinical profile of pediatric IIH differs in many respects from the adult variety (Table 3.2), suggesting that the precipitating factors may also be different. In younger age groups, there are more boys and nonobese children with IIH, and children may be more likely to be asymptomatic.93,128,445,492 Unlike adults, in whom there is a strong female predominance, the male-female ratio for IIH in prepubescent children is approximately equal.23,25,343 Starting at puberty, however, there is a distinct female predominance. A self-limited form of IIH may develop in girls following the onset of menstruation.213 Spontaneous remission appears to be more common in children and may even follow a diagnostic lumbar puncture.567 Some cases of IIH are familial.102 Infants and young children may present with irritability, listlessness, and somnolence.26,220,349 Dizziness or ataxia may also be evident.220,343 Irritability, nervousness, or apathy may be observed in older children.220 Generalized seizures have even been reported.220 Papilledema may still develop in infants with open fontanelles who have elevated intracranial pressure.343 Complaints of earache or roaring tinnitus are relatively common in children as well as adults.210 These associated symptoms should raise the diagnostic consideration of lateral venous sinus thrombosis.210 The incidence of certain neurologic deficits appear to be more common in children than in adults. Such deficits include lateral rectus paresis and atypical neurologic manifestations, such as skew deviation, facial paresis, and neck, shoulder, and back pain.343 Rarely, IIH can produce a comitant esotropia that is worse at distance without abduction deficits, internuclear ophthalmoplegia, transient bilateral oculomotor palsy,546 diffuse ophthalmoparesis, and nystagmus.175,595 It has been suggested that facial nerve paresis in IIH results from traction on the extra-axial facial nerves associated with small brainstem shifts caused by elevated intracranial pressure.501 Until recently, the consensus from clinical studies was that young patients with IIH tolerate chronic papilledema well and that visual loss from IIH is extremely rare in the pediatric age group.210–212,220,466,567 In summarizing 23 cases of childhood IIH, Rose and Matson466 concluded that “benign intracranial hypertension (in children) thus emerges as a clinical syndrome of varied etiology, generally with a short course, good prognosis, little tendency to

3 The Swollen Optic Disc in Childhood

recurrence, and only rarely requiring surgical intervention.” It is now established that permanent visual loss may occur in both the adult and the pediatric variants of IIH23,26,108,343 and that children and adults share similar risks.24,26,342 Recognition of this visual morbidity has led to discarding the term benign intracranial hypertension in favor of the term IIH. Optic atrophy as a consequence of chronic papilledema causes visual loss in IIH. In severe cases, loss of vision may evolve over a period of weeks; therefore, the finding of decreased vision demands aggressive, urgent intervention. In addition to chronic atrophic papilledema, rarer causes of visual loss, such as central retinal artery occlusion, peripapillary subretinal neovascularization, anterior ischemic optic neuropathy, and macular edema, should also be sought.26 Assessment of progressive visual loss is more difficult in children who are unable to cooperate for visual field testing. Although optical coherence tomography (OCT) has been reported to be of value in monitoring retinal nerve fiber layer in pediatric IIH (with increasing peripapillary nerve fiber layer thickness corresponding to worsening papilledema), the gradual development of optic atrophy can produce a significant confounding variable.142

Secondary IIH Once the diagnosis of IIH has been established, one must exclude the presence of associated neurologic disorders, systemic disease, or ingestion of vitamins or other medications that are known to precipitate IIH (Table 3.2). The latter two categories may merge in patients in whom an exogenous agent is used to treat a systemic disease (e.g., thyroid replacement for hypothyroidism),77,442 danazol therapy for anemia,223,343 or recombinant growth hormone for growth hormone deficiency94,113,169,315,464 (Table 3.1). The three most commonly recognized causes of childhood IIH are dural venous thrombosis, steroid withdrawal, and malnutrition associated with refeeding.

IIH Secondary to Neurological Disease The importance of otitis media, mastoiditis, and lateral sinus thrombosis in childhood IIH has long been recognized.211,539 Such cases of otitic hydrocephalus have decreased in recent decades as the incidence of mastoiditis has diminished with the advent of effective antibiotics.108,343 The differential diagnostic considerations of otitis media (with or without mastoiditis) associated with elevated intra cranial pressure include dural venous sinus thrombosis,

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Papilledema Table 3.2 Clinical and epidemiological differences between pediatric and adult IIH Pediatric

Adult

Potential for permanent vision loss Sex ratio

Yes 10:1 female predominance

Obesity Spontaneous remission Response to oral corticosteroidsa Corticosteroid withdrawalb Indications for surgical intervention

Yes 50:50 before puberty, female predominance thereafter Not a factor under age 10 Common Possibly better in children Possibly more causative in children Progressive visual loss regardless of whether a causative factor is defined

Rare in non-obese females Rare, often associated with residual intracranial pressure elevation even when papilledema resolves Fair Rarely causative in adults Same

Fig. 3.5 IIH following mastoiditis “otitic hydrocephalus” (a) Focal high-signal intensity area on T2-weighted MR imaging corresponds to thrombosis of left jugular vein (arrow). (b) Hyperintense signal (arrow) in same patient corresponds to left transverse sinus thrombosis

venous sinus compression by a regional abscess, and contiguous meningitis.211,539 The prevailing belief is that increased intracranial pressure may also follow an acute, uncomplicated otitis media.108,210,539 Several earlier studies identified otitis media with mastoiditis as a major cause.210,211 During mastoidectomy in 11 such children, Greer211 consistently found compression of the junction between the lateral and sigmoid sinus from overlying necrotic material or abscess. The primary channel for intracranial venous drainage is the sagittal sinus, which normally drains into the right lateral sinus. This

explains the preponderance of right-sided infections in children with otitis-associated IIH.211 Lateral sinus thrombosis, although less common today, remains an important consideration in childhood IIH because children with dural sinus thrombosis may be at increased risk for visual loss compared to those with primary IIH.26 Lateral sinus thrombosis, mastoiditis, and cerebral abscess can usually be identified on MR imaging (Fig. 3.5). Obstruction of the transverse, sagittal, or straight sinus may follow seemingly insignificant head trauma in children and cause intracranial hypertension.452,540 Surprisingly, a recent multicenter

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study of cerebral venous sinus thrombosis in children563 found papilledema in only 18%. However, we have seen several cases of hyperacute bilateral visual loss following venous sinus thrombosis, presumably reflecting a greater or more precipitous rise in intracranial pressure in this condition. Early investigators noted that IIH in children may develop after a symptom-free period of weeks following bacterial or viral infection. They speculated that IIH in such patients might be related to venous thrombosis in the pterygoid plexus, with propagation of the thrombus into the jugular vein (Fig. 3.5).466,540 It may also result from blockage of the arachnoid granulation with inflammatory material in predisposed individuals. Papilledema, with or without a macular star, may be seen in children with arteriovenous malformations who have no signs of hydrocephalus or recent subarachnoid hemorrhage.183,559 In this setting, papilledema probably results from decreased CSF absorption related to high pressure in the venous sinuses caused by arterial blood shunted directly into the cerebral veins, resulting in increased cerebral venous pressure.324,568 In theory, impairment of cranial venous outflow could elevate intracranial pressure in three ways: (1) an increase in venous intracranial pressure may distend the capacitance component of the intracranial vasculature, leading to an increase in cerebral blood volume; (2) brain edema with or without venous infarction; and (3) impairment of CSF absorption due to reduction or reversal of the normal pressure gradient between the subarachnoid space and the superior sagittal sinus, which drives the bulk flow of CSF across the absorptive channels in the arachnoid villi.272 Postoperative intracranial pressure elevation associated with cerebral edema and/or hemorrhage may also complicate embolization or surgical obliteration of large arteriovenous malformations.14,576 Papilledema may develop in children with meningitis or meningoencephalitis.380 In most cases, elevated intracranial pressure is presumed to result from a secondary IIH mechanism in which abnormal CSF composition impedes the absorption of CSF through cellular or macromolecular obstruction of channels in the arachnoid villi or by involvement of the narrow supracortical subarachnoid space over the cerebral convexities.272 Meningitis can also be associated with an inflammatory optic neuritis, which should be suspected in a child with swollen discs and decreased acuity. It is difficult to distinguish inflammatory disc swelling from papilledema on the basis of clinical findings alone.380 Only when a lumbar puncture is performed and a normal opening pressure with increased protein and cellular contents is found can the diagnosis of inflammatory optic neuritis be surmised.380 An association between Chiari malformations and IIH has recently been recognized.86a,150a,557a Disturbed CSF move-

3 The Swollen Optic Disc in Childhood

ment at the foramen magnum with increased resistance to outflow and venous flow abnormalities resulting in venous hypertension are likely to be contributory risk factors for the development of IIH in this setting.488 When both conditions coexist boney decompression of the posterior fossa can produce resolution of IIH.135,795 Other neuro-ophthalmologic symptoms and signs associated with Chiari I malformation often stabilize, improve, or resolve after suboccipital craniotomy.736,856 Conversely, decompressive surgery for Chiari 1 malformation can lead to IIH in children, although these patients tend to be asymptomatic and rarely require treatment.86a,150a,557a

IIH Secondary to Systemic Disease Malnutrition IIH has been recognized in malnourished children and immediately upon renourishment.10 Couch et al108 found this to be the underlying cause in 26% of children with IIH. They noted that nutritionally deprived children often display accelerated growth of the head when they are renourished. Animal models have shown malnutrition to severely impede bone growth. Refeeding presumably permits more rapid growth of the brain than the skull vault, which would explain the development of raised intracranial pressure.108 Couch et al described a transient type of “nutritional IIH” that occurs within days of starting treatment for cystic fibrosis.108 The rapid early onset and rapid resolution in this group suggests that some mechanism other than differential brain growth is occuring.108

Severe Anemia Papilledema is a rare but well-recognized complication of severe anemia in children as well as adults.551,589 Guiseffi and colleagues216 and Ireland and colleagues259 found similar frequencies of iron deficiency anemia in adults with IIH and controls, suggesting that the purported association of iron deficiency (a common condition) with IIH may be spurious. Nevertheless, some cases of childhood IIH associated with severe iron deficiency anemia have been reported to resolve following iron supplementation.214,258 While papilledema develops in few patients with iron deficiency anemia, this finding may be more common in patients with aplastic anemia.264,351,402 In a review of 120 patients with aplastic anemia, Wang et al561 found unequivocal optic disc swelling in 10 patients and blurred disc margins in another 34 patients. Papilledema in patients with immune hemolytic anemia may also be due to treatment with Danazol, an attenuated androgen derived from

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ethisterone.151,223 Although it has been suggested that optic disc swelling in such patients could also result from local hypoxia associated with anemia (i.e., an “energy-deficient” optic neuropathy),359 the cause of elevated intracranial pressure in the context of severe anemia is unknown. IIH can also complicate sickle cell disease.236

Addison Disease Although many purported cases of IIH in Addison disease have been incompletely documented, the association seems to be real.115 Alexandrakis et al7 provided convincing documentation of this association in a 12-year-old boy in whom papilledema resolved following corticosteroid replacement. The findings of weakness, weight loss, hypotension, cutaneous or mucous membrane pigmentation, and abdominal symptoms should suggest this diagnosis. Another case required acetazolamide.97 In both cases, glucocorticoid and mineralocorticoid replacement produced resolution of symptoms

Bone Marrow Transplantation Bone marrow transplantation is an increasingly successful treatment for aplastic anemia and for a variety of hematologic malignancies when chemotherapy has failed.536 Bone marrow transplantation has produced a marked improvement in long-term survival, especially in the pediatric population.536 When optic disc edema complicates bone marrow transplantation in children, it may be accompanied by vascular telangiectasias, retinal hemorrhages, lipid exudates, cotton wool spots, and macular edema.121,536 Kawase et al288 described these findings in a 4-month-old infant with acute lymphocytic leukemia, whose retinal neovascularization responded to oral prednisolone. Initially attributed to cyclosporin toxicity, the source of the optic disc swelling may be multifactorial, with graft-versus-host disease and total body irradiation also playing contributory roles.21,536 The differential diagnostic considerations of optic disc swelling in this setting must also include an intracranial mass lesion, optic nerve infiltration or metastasis, leptomeningeal carcinomatosis, infection (e.g., cytomegalovirus), and paraneoplastic optic neuropathy.

Down Syndrome Pseudopapilledema is the usual cause of optic disc elevation in children with Down syndrome.9,80,118 In these cases, the asymmetry in optic disc elevation in the two eyes can be quite striking. However, Esmaili and Bradfield148 reported four patients with Down syndrome and IIH. We have seen three similar cases (figure). Since children with Down syndrome may not be able to articulate symptoms of elevated intracranial pressure, papilledema must be carefully ruled out by ophthalmoscopy, and by MR imaging and lumbar puncture when necessary.

Gliomatosis Cerebri The development of gliomatosis cerebri in a 16-year-old who presented with signs and symptoms of IIH has recently been described.581 Gliomatosis cerebri is an uncommon central nervous system primary neoplasm characterized by proliferation of neoplastic glial cells, usually astrocytes with varying degrees of malignant potential. These cells infiltrate the cerebral cortex but do not destroy its cytoarchitecture.581 Because the clinical presentation is usually neurologically nonfocal, diagnosis is often delayed. Diffuse infiltration produces increased intracranial pressure and headache, nausea, vomiting, and papilledema. In the absence of a localized intracranial mass, these signs may lead to the diagnosis of IIH.581 The diagnosis of gliomatosis cerebri should be considered in a child with IIH in whom progressive, neurologic dysfunction or MR evidence of subtle signal abnormalities develop. The prognosis of gliomatosis cerebri is dismal, with survival ranging from a few weeks to several years after diagnosis. Responsiveness to radiation therapy presumably depends on the grade of the neoplasm. New chemotherapeutic regimens are currently under investigation.581

Systemic Lupus Erythematosis Systemic lupus erythematosis is sometimes complicated by IIH in children prior to commencement of corticosteroid therapy.343 IIH has also been described in a child as a feature of polyangiitis overlap syndrome.181 It is important to remember that IIH can occasionally be the presenting sign of systemic vasculitis, and to be attuned to associated signs of systemic vasculitis in children with IIH to enable early intervention.

Renal Transplantation IIH has been reported in 4.4% of children following renal transplantation.283 This condition must be distinguished from the apoplectic anterior ischemic optic neuropathy that may produce sudden blindness in children on continuous peritoneal dialysis.319

Sleep Apnea The association of sleep apnea with IIH, which is well recognized in adults, has rarely been reported in a child.401a Because sleep apnea produces a potentially curable form

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of pseudotumor, it is important to ask about snoring and other symptoms in the diagnostic evaluation of the child with IIH. Postinfectious IIH has been reported after varicella infection,316,323 measles infection,541 and Fisher syndrome.379 In one child, IIH was the presenting symptom of acute sinusitis.296

Childhood IIH Associated with Exogenous Agents The phenomenon of childhood IIH during or following corticosteroid withdrawal in children is well recognized.212,354 Multiple reports of IIH developing in children receiving thyroid replacement therapy leave little doubt that this association is valid. Nalidixic acid, a urinary tract antiseptic, has been reported to cause IIH.343 Numerous reports also implicate the bacteriostatic antibiotics tetracycline, doxycycline, and minocycline.86,185,343,441 Ciprofloxacin, a ubiquitous quinolone antibiotic derived from nalidixic acid, has precipitated IIH in a 14-year-old child with cystic fibrosis who was also receiving vitamin supplementation.579 Although IIH has been reported during treatment with lithium in a child, this association was probably not causal, since the condition persisted following discontinuation of the drug.292 Vitamin A intoxication is well established in the pathogenesis of some cases of IIH.125,126,261,500,562 This association should be considered in adolescents who take vitamin A for acne. Isotretoin, a synthetic retinoid used for the treatment of acne, has been implicated in the pathogenesis of IIH in adolescents. Because of these associations, it is crucial to obtain a history of medical treatment for acne in adolescents with IIH. In addition to vitamin A, other retinoids (e.g., isotretinoin, tretinoin, acitretin, etretinate) may cause intracranial hypertension.171 IIH among young children has also been associated with several new etiologies, including recombinant biosynthetic human growth hormone,315,447 and all-trans-retinoic acid (a vitamin A derivative used to treat acute promyelocytic leukemia [APML]).560 In a large database analysis, the prevalence of IIH in the population treated with growth hormone was about 100 times greater than in the normal population,315,447 IIH has been reported in a child receiving desmopressin (DDAVP) therapy.403 Several chemotherapeutic agents associated with IIH, including cyclosporine and cytarabine,127,166 can also produce elevated intracranial pressure in children.70

3 The Swollen Optic Disc in Childhood

Atypical IIH A syndrome of transient intracranial hypertension of infancy exists in which the affected infant presents with a febrile illness associated with a bulging anterior fontanelle and irritability. Some infants present with an abnormal rate of head growth and a head circumference above the 90th percentile.272 These infants are without neurological or developmental abnormalities and have normal imaging studies except for mild ventricular dilatation and distension of the subarachnoid space in some cases.272 Papilledema is infrequently present. Symptoms may abate following a single lumbar puncture, and intracranial pressure typically normalizes over days. This condition has been attributed to a nonspecific infectious illness that interferes with absorption of CSF by the arachnoid villi. When an infant with the diagnosis of transient intracranial hypertension fails to improve, the possibility of early meningitis that has failed to cause an initial pleocytosis must be considered, and a repeat lumbar puncture should be performed.365 There are occasional reports of IIH in the absence of headache, either because the child is too young to articulate symptoms or because headaches are completely absent.298,478,565 It has been suggested that children with IIH but no headaches have more neurological signs and visual loss at presentation and tend to have a poorer long-term prognosis.352 Conversely, some infants with IIH, especially those with open sutures, may lack papilledema.298,595 Killer et al have discovered lymphatic vessels in the dura of the optic nerve that may provide the drainage channels for CSF to egress the optic nerve sheaths. These authors have proposed that, in some cases, the perioptic CSF space forms a compartment that is isolated from the intracranial CSF, so that the biochemical composition between CSF obtained by lumbar puncture and that obtained during optic nerve sheath fenestration is distinctly different. The positive pressure front of CSF flowing into the perioptic CSF space may preclude drainage of CSF back to the brain.294,295,297 This neuroanatomy may explain the occurrence of unilateral papilledema and the failure of optic nerve sheath fenestration to produce bilateral resolution of papilledema in some cases. Unilateral and highly asymmetric dilatation of the perioptic subarachnoid space of the optic nerve could be similarly explained by a bigger resistance to influx of CSF on the side of the less marked papilledema or by reduced local drainage on the side of the greater papilledema.302a Killer et al have proposed that mechanical damage from local elevated pressure, as well as biochemical injury from an accumulation of biologically active metabolites, could contribute to the optic neuropathy in IIH.294,295,297,515

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Treatment of IIH in Children Spontaneous resolution of IIH appears to be more common in children than adults. In some children, IIH resolves following a single lumbar puncture. Because of the potential for permanent visual loss,25,26 however, children with IIH should be followed with the same vigilance as adults. Three caveats apply to the treatment of visual loss in IIH: (1) Although visual acuity usually remains normal, once it starts to decrease, it can drop precipitously over several weeks. Failing medical therapy, expeditious optic nerve sheath fenestration or lumboperitoneal shunting should be performed. (2) Children with IIH secondary to venous sinus thrombosis can experience hyperacute visual loss that simulates optic neuritis or neuroretinitis. (3) While it is considered axiomatic that visual loss is consequent to axonal injury from swelling of the disc, and it is known that superior venous sinus thrombosis and carotid cavernous fistula can cause a posterior optic neuropathy. It is therefore not inconceivable that the progressive optic atrophy in IIH could simultaneously be caused by vascular compromise of the posterior optic nerve in some cases. Regarding medical treatment, some have found the combination of furosemide and high-dose acetazolamide to be an effective nonsurgical intervention in children.489 Others believe that oral steroids are more efficacious in children than in adults with IIH and advocate their use.554 When these measures fail, topiramate may be used, especially in obese children.157 Topiramate is an antiepileptogenic medication with secondary carbonic anhydrase activity. It is unclear whether topiramate is superior to acetazolamide in reducing intracranial pressure. Because of the nonassociation of prepubertal IIH with obesity, gastric stapling and other bariatric procedures have found little application. Current surgical treatment of IIH is limited to optic nerve sheath fenestration and lumboperitoneal shunt. Numerous studies have suggested that optic nerve sheath fenestration is an effective way to restore or preserve vision in IIH,23 and it has become the surgical treatment of choice. Optic nerve sheath fenestration is also efficacious in cases in which lumboperitoneal shunting is unsuccessful. Optic nerve sheath fenestration relieves headaches in about two-thirds of patients.106 Optic nerve sheath fenestration has been shown to be safe and effective in children.332,547 Lumboperitoneal shunts have traditionally been the method of shunting in IIH, however, ventriculoperitoneal shunting has also been used.553 Although various shunting procedures have been devised, lumboperitoneal shunting seems to be the most successful in alleviating symptoms.436

Regardless of the shunt system used, patients with IIH are prone to shunt failure.186 Overdrainage is another important complication of CSF shunts. Thus, successful lumboperitoneal shunting relieves headaches from elevated intracranial pressure, this form of headache may be traded for another due to hindbrain herniation.23 Headache is the most common symptom, with a strong positional component akin to that seen after lumbar puncture.186 The overdrainage also common to all shunt systems can be responsible for iatrogenic Chiari malformation.186 Estimates of Chiari I malformation following lumboperitoneal shunting range from 0 to 70%.89,452 CSF shunting is advocated for children who have intractable headaches as well as visual loss and papilledema unresponsive to optic nerve sheath fenestration.23,89,452 Lumboperitoneal shunting is an effective means of reducing intracranial pressure, but shunt failures are frequent (particularly in obese individuals).23 Shunt infection may be life-threatening, and acquired Chiari type I tonsillar herniation commonly occurs. This procedure is also associated with various other complications, including shunt obstruction, lumbar radiculopathy, infection), and tonsillar herniation.69,88,140 Some have recently advocated venous sinus stenting of collapsed or stenotic venous sinuses.241,242,419 However venous sinus stenting is an irreversible, invasive procedure with the potential for serious complications.101 Notwithstanding its reported efficacy, longitudinal follow-up data are needed before it can be recommended. Furthermore, most investigators now believe that increased venous sinus pressure results from, rather than causes, increased intracranial pressure in IIH.101,173 The finding of a potentially reversible cause of IIH in a child (e.g., dural sinus thrombosis) should not lead to a false sense of security that the child is not at risk for blindness. Our indications for surgical intervention include the following: (1) Evidence of progressive optic neuropathy (i.e., loss of visual acuity or visual field despite maximal medical therapy, or worsening papilledema in a child who cannot cooperate with examination). (2) Severe optic neuropathy (i.e., chronic atrophic papilledema) that would seriously jeopardize the patient’s ability to function normally if further visual loss occured.25 If these criteria are met, we believe that optic nerve sheath fenestration should be performed despite the fact that the underlying condition is expected to eventually resolve. Prognosis of IIH in Children Stiebel-Kailash et al531 found pubertal age to carry a worse prognosis for visual outcome than other ages. While the long-term prognosis has not been determined with certainty, Kesler et al298 found the recurrence rate to be 40% and noted that recurrences occurred after stopping treatment.

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Optic Disc Swelling Secondary to Neurological Disease

discs (Fig. 3.6). The neuro-ophthalmologic signs of shunt failure are discussed in Chap. 11.

Hydrocephalus

Neurofibromatosis

Papilledema is absent in most infants with congenital hydrocephalus. Ghose197 reviewed optic nerve changes in 200 consecutive cases of congenital hydrocephalus examined before shunt surgery and found papilledema in 12%. The absence of papilledema in the remaining cases has been attributed to the fact that open sutures permit the head to enlarge in response to increased intracranial pressure. However, the low prevalence of papilledema in infantile hydrocephalus is still perplexing, because numerous studies have confirmed that infants with intracranial mass lesions still develop papilledema.380 Despite the ability of the infant skull to enlarge and act as a “release valve” for elevated intracranial pressure, large or rapid elevations in intracranial pressure may exceed this response. In making the diagnosis of papilledema in an infant who appears to have hydrocephalus, it is important to consider the association of megalencephaly (a large heavy brain with normal to slightly dilated ventricles and normal intracranial pressure) and optic disc drusen in the differential diagnosis.249 Once a patient with hydrocephalus is shunted, the situation changes. Shunting allows the intracranial sutures to fuse, and subependymal gliosis may develop, which can greatly reduce ventricular compliance. Subsequent shunt failure can produce marked papilledema, along with signs and symptoms of dorsal midbrain syndrome but no ventricular dilation.101 Visual loss associated with postpapilledema optic atrophy remains a major morbidity in shunted congenital hydrocephalus. For reasons that are poorly understood, the papilledema in acute shunt failure are may be accompanied by multiple splinter hemorrhages on the surface of the optic

Neurofibromatosis may produce optic disc swelling through several mechanisms. Most commonly, optic disc swelling in a child with neurofibromatosis signals the presence of an optic nerve glioma. Large chiasmal gliomas may also extend superiorly to compress the third ventricle and foramen of Monro and produce obstructive hydrocephalus.380 Children with neurofibromatosis are also at higher risk for aqueductal stenosis. Spinal cord tumors, which can elevate intracranial pressure and produce papilledema, occur with increased frequency in patients with neurofibromatosis (see below).371 Spinal Cord Tumors Spinal cord tumors are a well-recognized but easily missed cause of papilledema. Ependymomas constitute 40% of spinal cord tumors producing papilledema. Most spinal cord tumors associated with papilledema are located in the lumbar or thoracic region.362 Symptoms of backache or gait disturbance should lead the clinician to check carefully for evidence of sensory or motor deficits. If present, further diagnostic evaluation (CT scanning, myelography) should be directed toward the possibility of an underlying spinal cord tumor.371 The most likely explanation for elevated intracranial pressure in these cases may relate to the release of a tumor-generated chemical into the CSF that leads to failure of CSF absorption. Other proposed mechanisms are summarized in Table 3.3. The papilledema usually resolves following surgical excision of the lesion.299 Paroxysmal raised intracranial pressure can be associated with spinal meningeal cysts.219 Some extradural

Fig. 3.6 Papilledema with acute shunt failure. Note prominent optic disc hemorrhages bilaterally

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Papilledema Table 3.3 Potential causes of papilledema with spinal cord tumors Protein molecules released into the CSF by the tumor may mechanically block the arachnoidal pores and prevent CSF absorption. An aseptic arachnoiditis may develop secondary to protein leakage. CSF hyperviscosity may follow release of products of protein disintegration, which slows CSF circulation from the cranial circulation to the spinal spaces. Spinal cord tumors may hemorrhage into the subarachnoid space. The spinal cord normally acts as an “elastic reservoir” for cerebrospinal fluid. Spinal cord tumors may reduce the capacitance of this reservoir by mechanical blockage and thereby cause papilledema.

cysts can be associated with either intracranial hypertension or hypotension.505 Mechanistically, it is very unlikely that the tumor itself has any direct blocking effect on the absorption of the CSF.454

Subacute Sclerosing Panencephalitis Subacute sclerosing panencephalitis (SSPE) is a fatal neurological disease caused by the measles virus. It is more common in males than females and is usually associated with infection before 4 years of age.479 Neurovisual symptoms first become apparent in late childhood or early adolescence. The diagnosis is suggested by the clinical picture of mental deterioration, myoclonus and seizures, often with a characteristic maculopathy (see Chap. 10).479 Cortical visual loss, hemianopia, impaired visual spatial abilities, and visual hallucinations develop.503 The diagnosis is confirmed by elevated CSF and serum titers, measles titers, and immunoglobulin elevation. However, there is no evidence that the viral strains used for immunization cause SSPE.267 The classic electroencephalogram (EEG) changes are sharp wave complexes every 5–15 s in a “burst-suppression pattern.” MR imaging shows atrophy and high-signal T2 lesions scattered in the periventricular and subcortical white matter, as well as inflammatory changes in the splenium of the corpus callosum.16 These lesions asymmetrically involve parieto-occipital regions in the early stages, then involve the periventricular white matter symmetrically.420 Optic disc swelling has been reported frequently in SSPE and is generally ascribed to elevated intracranial pressure,136 though Hiatt et al239 found optic neuritis in 6% of patients. Although it is often described as a chorioretinitis, SSPE appears to preferentially affect the retina, with secondary involvement of the retinal pigment epithelium and the choroid.423 A ground-glass whitening of the macula with mottling of the underlying pigment epithelium is commonly found. Associated findings may include macular degeneration, which begins as chorioretinitis with macular edema, hemorrhages and white infiltrates, and leads to macular scarring, retinal

pigment epithelial atrophy, and epiretinal membrane formation.44 Over time, a gliotic retinal scar with contracture of the inner limiting membrane may develop. Although SSPE is uniformly fatal, intraventricular administration of interferonalpha, combined with oral inosine pranobex, appears to be the most effective regimen at present, producing remission or stabilization in approximately half of cases.187,591

Optic Disc Swelling Secondary to Systemic Disease Diabetic Papillopathy In 1971, Lubow and Makley360 reported on three young patients with juvenile-onset diabetes and bilateral optic disc edema, with an intricate capillary network on the surface of the disc. Visual disturbances were minimal (in two patients, the disc swelling was discovered on routine examination), and the disc edema resolved spontaneously in approximately 6 months. Twelve cases reported by Barr et al28 exhibited a similar picture: bilateral superior disc swelling that may be segmental, minimal reduction in visual acuity, mild visual field abnormalities (e.g., inferior arcuate scotomas, blind spot enlargement, inferior depression with involvement of fixation), excellent recovery, predominant occurrence in the second or third decades of life, no clear correlation with background diabetic retinopathy, and variable presence of dilated superficial radial capillaries on the surface of the disc (Fig. 3.7).28,425 Patients with diabetic papillopathy tend to have small, cupless discs, as seen in most adults with ischemic optic neuropathy. Some authors have hypothesized that optic disc edema in young patients with juvenile-onset diabetes represents a form of ischemic optic neuropathy.69,274,520 Slavin520 has suggested that younger patients may have sufficient collateral circulation to spare the axons from irreversible injury that would impair vision. According to this hypothesis, the dilation of the superficial peripapillary capillary network would represent a compensatory mechanism to ameliorate the ischemic process.69 Hayreh’s finding of asymptomatic optic disc swelling in the contralateral eye of adults with typical nonarteritic ischemic optic neuropathy lends support to the hypothesis that this self-limited form of disc edema is secondary to axonal stasis from low-grade ischemia, which is insufficient to produce visual dysfunction.229,281,520 Alternatively, disc swelling in young diabetics could result from a primary microangiopathy affecting the vascular bed subserving the distal optic nerve head, which would be influenced by local anatomic factors, such as axonal crowding due to the size of the surrounding scleral canal.281,425,557 Recently, it has been proposed that venous insufficiency and venous congestion underlies the chronic low-grade disc

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3 The Swollen Optic Disc in Childhood

Fig. 3.7 Diabetic papillopathy. Note optic disc edema and surface capillary dilation, which is mild in case (a) and severe in (b). Courtesy of William E Hoyt, M.D.

swelling that characterizes this condition.346 Although diabetes is associated with both arterial and venous disease, it also is associated with capillary endothelial leakage and would be expected to produce more vasogenic edema for a given level of venous pressure elevation.346 One report suggests that intravitreal triamcinolone may hold promise in the treatment of diabetic papillopathy.8

retinopathy and choroidopathy, a pathognomonic finding – focal intraretinal periarteriolar transudates (FIPTs) – has been identified by Hayreh et al.230 Blindness due to optic disc ischemia (AION) may occur if there is a precipitous reduction in blood pressure in patients with malignant hypertension.231,353 The finding of bilateral neuroretinitis with a macular star but without vitreous cells should also raise suspicion for this condition.331

Malignant Hypertension Sarcoidosis Malignant hypertension in children is seen in several settings, including severe glomerulonephritis, vasculitis (lupus, polyarteritis), and renal artery stenosis, and in transplant patients with severe rejection. In the most widely used classification of hypertensive fundus changes, the presence of optic disc edema separates grades III and IV, with grade IV hypertension associated with a grave systemic prognosis. Disc swelling in malignant hypertension has been attributed to elevated CSF pressure due to cerebral edema, particularly in patients with hypertensive encephalopathy. Accordingly, optic disc swelling in this setting has been equated with papilledema.233 However, Hayreh et al231 have demonstrated that the optic disc swelling in hypertensive retinopathy is caused by local ischemia rather than by elevated intracranial pressure. The swollen optic disc characteristically shows either hyperemia or pallor. It is believed that leakage of high levels of angiotensin II from the choriocapillaris produces vasoconstriction in the choroid and choroidal occlusion. Additionally, diffusion of angiotensin through the border tissue of Elschnig and into the optic nerve head causes ischemia in the axons that reduces axoplasmic transport proximal to the ischemic site. This process causes disc swelling and, secondarily, more ischemia and occlusion, with resultant swelling of the disc. In addition to the well-recognized signs of hypertensive

The evaluation of optic disc swelling in a child with sarcoidosis requires a detailed ocular and systemic evaluation. Optic disc edema in sarcoidosis may be due to infiltration of the disc (i.e., granulomatous optic neuritis), a local reaction to contiguous intraocular inflammation, or an indirect effect of neurosarcoidosis (hydrocephalus or mass effect) (Table 3.4). The characteristic irregular, cauliflower appearance of the infiltrated optic disc is a clue to the diagnosis of neurosarcoidosis (Fig. 3.8).34 However, neurosarcoidosis can present with bilateral optic disc edema and normal visual acuity, mimicking IIH.426 The protean systemic manifestations of sarcoidosis present differently in children than in adults.275,426 Among children younger than 4 years of age, a triad of maculopapular rash, uveitis, and arthritis predominates.238,468 Because the initial chest X-ray is abnormal in only 22%, children with sarcoidosis must be differentiated from those with juvenile rheumatoid arthritis.468 Children in the 8- to 15-year-old age range with sarcoidosis are often black and have symptoms of malaise, cough, and fever.293 Ocular lesions occur in 24%, manifesting primarily as uveitis.293 The initial chest radiograph is abnormal, displaying hilar adenopathy or, less commonly, a parenchymal infiltrate.293 Eighty percent of children have increased angiotensin-converting enzyme (ACE) levels

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at the time of diagnosis, whereas adults with sarcoidosis have increased ACE levels less often.463 Children with sarcoidosis also have higher ACE concentrations and less CNS involvement than adults. Relative to Caucasians, African-American patients with sarcoidosis tend to be younger when they first present to the ophthalmologist and to present with uveitis and/or adnexal granuloma.149 Radiological evidence of bilateral hilar adenopathy, with or without parenchymal involvement, is a hallmark of the disease. Serum ACE is elevated in approximately 80% of children aged 8–15 with sarcoidosis, but this figure may be lower for children younger than 5 years of age.248 Biopsy confirmation may be obtained from nodular areas of skin, conjunctiva, and lacrimal gland. Conjunctival biopsies yield positive results in only 10–28% of eyes without visible granulomas.248 Sarcoid optic neuropathy is a very nasty and unforgiving problem. While systemic corticosteroids are the mainstay of therapy for neurosarcoidosis, other immunosuppressive agents such as cyclosporine, azathioprine, cyclophosphamide, chlorambucil, and methotrexate provide useful alternative treatments.180 The acute form of meningitis responds favorably to corticosteroids, whereas chronic meningitis may go through a cycle of remissions and exacerbations that require Table 3.4 Causes of optic disc swelling in sarcoidosis Granulomatous infiltration of the optic nerve head Postlaminar granulomatous involvement of the optic nerve or surrounding meninges (retrobulbar neuritis) Papilledema secondary to intracerebral masses, hydrocephalus, or granulomatous meningitis Ischemic optic nerve infarction associated with perivascular inflammation Idiopathic intracranial hypertension associated with steroid withdrawal Disc swelling secondary to ocular hypotony Disc swelling secondary to contiguous intraocular inflammation

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long-term corticosteroid therapy.506 Surgical therapy is indicated in cases of hydrocephalus, expanding mass lesions, or mass lesions causing increased intracranial pressure.506 Seizure activity with neurosarcoidosis is a bad prognostic sign.194,318 Most patients with neurosarcoidosis achieve favorable outcomes with corticosteroids plus alternative corticosteroid therapy.493 Low-dose methotrexate therapy has been used as a corticosteroid-sparing therapy in childhood sarcoidosis.358 For neurosarcoidosis, agents other than corticosteroids show increased efficacy with lower morbidity. MR imaging and lumbar puncture combined with the evaluation of the anterior and posterior chambers of the eye are useful in determining which mechanisms are primarily responsible for the optic disc edema.146 Gadolinium increases the sensitivity of MR imaging if corticosteroids have not been given, permitting detection of meningeal, parenchymal, optic nerve, and ependymal sarcoid lesions not visible on unenhanced scans.133,502,602 Lumbar puncture serves to rule out elevated intracranial pressure and other infectious and granulomatous disorders (tuberculosis, coccidioidomycosis, parasites, and lymphoma). Diagnostic tests with the highest yield and common clinical usage include chest X-ray, ACE level, serum lysozyme levels, limited gallium scan, and tissue biopsy.42 The combination of a positive Gallium scan and an elevated ACE level carries a 73% sensitivity and a 100% specificity for the diagnosis of sarcoidosis.435 Neurological complications of sarcoidosis are said to occur in 5% of sarcoidosis patients, and autopsy studies have identified unrecognized CNS disease in 15%.42,318 Neurosarcoidosis has a predilection for the base of the brain.506 Granulomatous meningitis at the skull base with infiltration or compression of adjacent nerves is the most common intracranial manifestation.281,592 Neurological manifestations include cranial nerve palsies, meningitis, hypothalamic and pituitary lesions, granulomatous basal meningitis,

Fig. 3.8 Sarcoidosis. (a) Optic disc elevation secondary to granulomatous infiltration of disc. (b) Fluorescein angiogram demonstrating nodular hyperfluorescence of disc. Courtesy of William F. Hoyt, M.D.

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space-occupying masses (mimicking gliomas and meningiomas), peripheral neuropathy, spinal cord involvement, and progressive multifocal leukoencephalopathy.339,490,506,602 Facial nerve palsy is the most common neurological manifestation of sarcoidosis, followed by involvement of the optic nerves and chiasm and, in descending order of frequency, the glossopharyngeal, vagus, and auditory nerves.426,506 Localized granulomatous lesions have been found in practically every part of the CNS, including the meninges, the floor of the third ventricle, the lateral ventricle, the occipital, frontal, and temporal lobes, the optic chiasm, the optic nerves, the basal ganglia, the cerebellum, and the spinal cord.490 The epidemiology of sarcoidosis gives strong evidence for a potential transmissible factor.433 Increasing evidence has implicated a hypersensitivity response to an endemic mycobacteria in the development of sarcoidosis.115 With the use of polymerase chain reaction techniques, mycobacterial and propionobacterial DNA and RNA have been recovered from sarcoidal tissue.257 The histopathology of sarcoidosis reveals the classic noncaseating granuloma, consisting of multinucleated epitheliod cells typically surrounding a noncaseating core of debris. This pattern is reminiscent of granulomas caused by certain infections. Tuberculosis forms granulomas that typically caseate. Foreign bodies can also form noncaseating granulomas. All of these conditions have in common the presence of a localized antigen inciting this type of immune response from the innate immune system. It is likely that a combination of a normally benign trigger, and an altered, hyperreactive system, results in the observed disease.180

Leukemia The diverse spectrum of ocular involvement in childhood leukemia can be divided into three groups: neuro-ophthalmologic features associated with CNS involvement, vascular abnormalities reflecting changes in hematological status, and direct infiltration of ocular tissues.452 The acute forms of leukemia are responsible for most of these ocular and CNS complications.11,116,487 Since modern chemotherapy has prolonged survival and provided a possibility of cure in leukemic children, it has also increased the incidence of leukemic cell infiltration, especially of the CNS.415 While optic nerve infiltration is usually related to CNS involvement, anterior segment infiltration frequently occurs in the absence of CNS disease.411,452 Optic nerve infiltration occurs mainly in children with acute leukemia, with a proclivity for acute myelocytic leukemia.469 Several mechanisms have been defined by which leukemia can produce swelling of the optic nerve head (Table 3.5).144 The differentiation between leukemic infiltration of the optic nerve and disc swelling due to increased CSF pressure

3 The Swollen Optic Disc in Childhood Table 3.5 Causes of optic disc swelling with leukemia Leukemic infiltration of the optic nerve head Papilledema secondary to leukemic CNS infiltrate, intracranial hemorrhage, steroid withdrawal following prolonged treatment, or opportunistic CNS infection Papilledema related to leukemic infiltrates in the CNS Ischemic optic neuropathy secondary to local vascular compromise from tumor infiltration of the optic nerve or orbit, to sludging of blood flow secondary to hyperviscosity, or to small vessel thrombosis in the microcirculation of the optic nerve in patients with thrombocytosis Optic neuropathy secondary to opportunistic infections of the CNS that are more common in patients with leukemia Intracranial hypertension secondary to treatment with all-trans retinoic acid

remains the fundamental clinical distinction to be made, as early cases of leukemic infiltration can be reversed with local irradiation.116,144,250,457 Optic nerve infiltration may be predominantly prelaminar or retrolaminar.469 Prelaminar leukemic infiltration of the optic nerve head appears as an elevated, fluffy, whitish swelling of the disc that progressively obscures the retinal vessels and is associated with edema and varying degrees of hemorrhage (Fig. 3.9).469 Larger infiltrates may extend into the peripapillary retina and produce sheathing of the contiguous retinal vessels. The leukemic cells are characteristically most numerous in the perioptic meninges and peripheral portions of the nerve, and then they extend along the optic septa to accumulate about the blood vessels within the optic nerve.116,250 Direct leukemic invasion of the optic nerve head usually causes slowly progressive visual loss that occurs late in the course of the infiltration, although it can occasionally proceed rapidly.116 When leukemic infiltration is primarily posterior to the lamina cribrosa, a profound decrease in vision is usually accompanied by swelling of the disc without visible infiltrate.469 Leukemic infiltration of the optic nerve is a visual emergency requiring immediate local irradiation (approximately 2,000 rads over a 1- to 2-week period), usually combined with intrathecal injection of cytotoxic drugs.408 Optic atrophy is a frequent sequel of irradiation therapy, whether or not it is used in conjunction with chemotherapy. Following bone marrow transplantation, leukemic patients may develop optic disc edema.21 This condition is generally attributed to cyclosporine toxicity since it usually resolves without consequence, following a decrease or discontinuation of cyclosporine.21 Nevertheless, lumbar puncture is essential, because irradiation therapy would not improve papilledema due to increased CSF pressure; orbital irradiation is the treatment of choice for direct optic nerve infiltration.469 Monoclonal typing of CSF lymphocytes may aid in the difficult clinical task of differentiating insidious optic nerve infiltration from infectious optic nerve damage.116

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Fig. 3.9 Leukemia. (a) Optic disc infiltration with peripapillary depositions of leukemic infiltrate. (b) Severe leukemic infiltrate obliterating the optic disc in a child with megaloblastic leukemia. (c) Peripheral infiltrate with peripapillary flame-shaped hemorrhages in a 14-year-old boy with T cell leukemia. Courtesy of William F. Hoyt, M.D.

MR imaging can delineate leukemic optic nerve infiltration. Perineural enhancement within the subarachnoid space and leptomeninges has been accomplished with gadolinium and orbital fat suppression in a patient with leukemic invasion of the optic nerve.250 As mentioned earlier, there have been reports on the development of IIH in patients with APML treated with alltrans retinoic acid (ATRA), a vitamin A derivative.170,215,363,482,558 Children under 8 years of age seem particularly sensitive to this drug.363,521 ATRA is used in the treatment of acute promyelocytic leukemia in children.119 Immunosuppression may give rise to opportunistic infections. Bhatt et al47 described a 16-year-old boy with acute lymphoblastic leukemia in whom

unilateral optic disc swelling was the presenting sign of cytomegalovirus retinitis. The major forms of leukemic optic disc swelling are summarized in Table 3.5. The prognostic implications of ophthalmic involvement in childhood leukemia are ominous.415 In a 15-year study, 28 of 131 children with leukemia developed ocular complications. Twenty-seven of these patients died within 28 months from the onset of the ophthalmic involvement. All patients with ophthalmic manifestations had either bone marrow relapse or CNS involvement. Ocular involvement would appear, then, to be the harbinger of a relapse.452 Newer investigational chemotherapeutic regimens may improve the morbid prognosis in this subgroup.

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Cyanotic Congenital Heart Disease A retinopathy consisting of dilated, tortuous retinal veins, and optic disc elevation has been described in patients with congenital heart disease. Petersen and Rosenthal427 found optic disc elevation in 12 of 52 patients with cyanotic congenital heart disease. The severity of the fundus changes was closely related to the patient’s arterial oxygen saturation and hematocrit, but not to arterial PCO2, pH, central venous pressure, type of cardiac malformation, or the patient’s age. The retinopathy of cyanotic congenital heart disease resembles that seen in patients with polycythemia. Local hypoxemia, which causes retinal vasodilation, may also play a major role.427 The role of elevated intracranial pressure, if any, has not been determined.In one 12-year-old girl with a brain abscess, a congenital superior vena cava draining into the left atrium contributed to the papilledema.195

Craniosynostosis Syndromes Craniosynostosis syndromes primarily involve the cranium and upper face.543 Each condition involves premature closure of one or more sutures that limits skull growth in the direction perpendicular to the suture. This closure results in compensatory growth in the unrestricted direction to minimize the compressive effect of the growing brain.542 When brain growth exceeds growth of the skull, elevated intracranial pressure develops. It should be remembered, however, that the craniofacial syndromes also comprise a variety of skull base anomalies and can be accompanied by other CNS anomalies such as ventriculomegaly, hydrocephalus, cal-

Fig. 3.10 Algorithm depicting causes of optic neuropathy in craniosynostosis. With permission from Nischal410

3 The Swollen Optic Disc in Childhood

losal anomalies, hypoplasia/absence of the septum pellucidum, hypoplasia/dysplasia of the hippocampus, dysplasias or distortions of the cerebral cortex, and parenchymal hemorrhage.548 Craniosynostosis syndromes are commonly associated with papilledema and optic nerve atrophy.178,201,237,410 In a series of 244 patients with craniosynostosis, Dufier et al134 found disc edema in 31% with Crouzon’s disease, 23% with oxycephaly, and 9.5% with Apert’s disease. Optic discs were considered either pale or atrophic in 50% with Crouzon’s disease, 34% with oxycephaly, and 24% with Apert’s disease. In some cases, vision-threatening papilledema is the only sign of hydrocephalus,30 while in others, the craniosynostosis may not be clinically apparent.130 Fishman et al160 have stressed that hydrocephalus appears to be independently associated with premature synostosis rather than occurring as a direct consequence of it. Thus, raised intracranial pressure may be present in the absence of reduced intracranial volume.163 Syndromic craniosynostosis patients often have breathing difficulties, and the associated hypercapnia may contribute to raised intracranial pressure.208 Finally, a wide variety of skull base anomalies are present in most patients with craniofacial syndromes.544 Consequently, complex syndromic craniosynostosis can be associated with decreased flow in the sigmoid-jugular sinus complex.410 Consequently, there is a florid collateral circulation through the stylomastoid emissary venous complex.544 Papilledema in these conditions can, therefore, result from elevated intracranial pressure related directly to premature synostosis, from hydrocephalus, or from compromised venous sinus outflow (Fig. 3.10). These abnormalities may help to explain the development of delayed, asymptomatic increases of intracranial pressure with papille-

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dema in children who have undergone cranial vault reconstruction for complex craniosynostosis.431 Moreover, the appearance of the optic disc may not correlate with either the presence or absence of elevated intracranial pressure or optic neuropathy.348,552 For example, Bertelsen46 noted that papilledema had not been observed in any of his children who developed optic atrophy. For this reason, some groups obtain baseline VEPs to follow if visual function deteriorates.348,544 The presence of exposure keratopathy, astigmatism, and amblyopia may further complicate any clinical assessment.544

Nonaccidental Trauma (Shaken Baby Syndrome) The shaken baby syndrome is a unique but common form of child abuse in which intracranial injury and intraocular hemorrhage may coexist in the absence of external signs of direct head trauma.325,574 Shaken baby syndrome occurs when a screaming child with elevated jugular venous pressure is squeezed and forcefully shaken. This action produces dramatic acceleration–deceleration forces within the brain, eye, and orbit.389,390,588 The infant brain is particularly prone to whiplash injuries because of the proportionately larger and unsupported head, the pliability of sutures and fonta-

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nelles that allows stretching of the calvarium, the greater deformability of the unmyelinated brain, and the greater percentage of CSF.75,285 The common finding of subdural hemorrhage in infants with shaken baby syndrome is thought to result from tearing of the bridging cerebral vessels.198 Contusion, laceration, and edema of the brain may also occur.389 It is the characteristic retinal hemorrhages that provide the crucial diagnostic sign and warrants systemic evaluation for other physical signs such as midsternal ecchymosis, boney fractures, inconsistent or absent explanatory history, and other social risk factors.228,389 The finding of multiple hemorrhages surrounding the optic disc that become more sparse toward the retinal periphery favors shaken baby syndrome over the numerous systemic diseases that can also produce retinal hemorrhages (Fig. 3.11). White, ring-shaped retinal folds that encircle the macula outside the vascular arcades are also highly suggestive of shaken baby syndrome.193 The severity of the intraocular hemorrhages correlates with the severity of the acute neurological injury.390,574 The autopsy finding of hemorrhage within the optic nerve sheath seems to be a relatively specific retrospective marker for this mechanism of injury.68,372,588 As there are many causes of retinal hemorrhages in infancy, it is the cumulative clinical evidence along with social factors that enable one to make the diagnosis of shaken

Fig. 3.11 Shaken baby syndrome. Retinal photographs (a and b) depict multiple retinal hemorrhages. Courtesy of Gregory Griepentrog, M.D.

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baby syndrome.284 The ophthalmologist should resist the temptation to draw judgmental conclusions prematurely when examining infants with retinal hemorrhages. Although the findings of shaken baby syndrome are fairly specific, it is important to be remember that systemic or neurologic disease can rarely simulate this condition.184,571 Subdural hematoma, the most common intracranial finding in shaken baby syndrome, can be missed on CT scanning because of volume averaging of the hematoma with the overlying bone.310,389,390 In this setting, retinal hemorrhages may precede the subdural hemorrhage by days, so repeat neuroimaging is therefore warranted if clinical deterioration is observed.198,389 Diffusion-weighted MR imaging seems to be the optimal neuroimaging study for suspected shaken baby syndrome, demonstrating diffuse or posterior cerebral ischemia in addition to subdural hematomas in most cases.49 In a series of 75 shaken baby syndrome victims with or without impact head trauma, Morad et al390 found subdural hemorrhage in 93%, cerebral edema in 44%, and subarachnoid hemorrhage in 16%. Other, less common, findings included parenchymal contusion, epidural hemorrhage, and vascular infarction. Similar findings have emerged from other studies.310 Postmortem examination shows intradural and subarachnoid (most common near the sclera), and hemorrhages into the orbital fat in the most severe cases.587 The fact that these findings are much more common in shaken baby syndrome than in accidental head trauma without orbital fracture suggest that the unique acceleration–deceleration forces and vitreoretinal interface shearing caused by shaking are the major causes of retinal hemorrhages.587 Other proposed mechanisms such as elevated intracranial or intrathoracic pressure, direct tracking of blood from the intracranial space, or direct impact trauma are now considered unlikely to be responsible for the retinal hemorrhages.390,587 Intracranial vascular malformations, severe systemic hypertension, congenital cytomegalovirus infection, congenital protein C deficiency, subdural hematoma, hemophagocytic lymphohistiocytosis, and glutaric aciduria are rare causes of retinal hemorrhage that should be considered.560,584,521a For reasons that are poorly understood, papilledema is surprisingly rare in children with shaken baby syndrome.389,390 Furthermore, it appears that the presence or absence of papilledema carries no diagnostic significance except that one must be sure that retinal hemorrhages due to papilledema are not incorrectly attributed to shaken baby syndrome. It has also never been shown that the presence of papilledema per se imparts a worse neurologic prognosis in the child with shaken baby syndrome. Given the strong vitreoretinal shearing forces generated by shaking injuries, it is surprising that vitreopapillary tractional forces have not been implicated as a mechanism of injury.

3 The Swollen Optic Disc in Childhood

Because severe CNS injury often coexists, the diagnosis of shaken baby syndrome imparts a poor neurological prognosis.37,56,390 Cortical visual loss and macular pucker, macular hole, and epiretinal membrane formation are common residua that often limit the ultimate visual prognosis.418 Cortical visual loss is the most common cause of permanent visual loss.372 Dilated pupils at presentation and ventilator dependency seem to confer a worse prognosis.372 Mental retardation and other permanent neurological dysfunction are common.75,389,390 Shaken baby syndrome constitutes a major cause of pediatric stroke.389,390 Indeed, Caffey75 emphasized the deleterious effects of even mild whiplash and swinging activities in young children and conjectured that many cases of mental retardation, cerebral palsy, and congenital hydrocephalus represent undiagnosed “shaken baby” injuries to the CNS.

Cysticercosis Cysticercosis is a common worldwide parasite that affects the CNS.282 Humans serve as intermediate hosts in the life cycle of the pork tapeworm Taenia solium when eggs are ingested with contaminated food.535 The disease is endemic in Mexico, Central and South America, India, and China.118 In Mexico, the prevalence of neurocysticercosis may be as high as 2–3%, based on patients autopsied at general hospitals.118 Neurocysticercosis can develop in children and adults, but symptoms occur most often in young adults. Before modern neuroimaging, neurocysticercosis was included in the differential diagnosis of IIH.432 Many patients remain asymptomatic until degenerating parenchymal cysts produce contiguous inflammation, at which time seizures, increased intracranial pressure, altered mental status, and focal neurological signs develop.118,282,291 Degenerating parenchymal cysts may produce chronic meningitis. Papilledema and pretectal signs (associated with hydrocephalus) are the usual neuro-ophthalmologic manifestations of neurocysticercosis, although other brainstem and cerebellar signs, such as cranial nerve palsies, internuclear ophthalmoplegia, facial myokymia, upbeat nystagmus, periodic alternating nystagmus, and oculopalatal myoclonus, have been reported.52,78,265,266,291,306 Blindness from postpapilledema optic atrophy occurs in some cases. MR imaging and CT scanning are now considered to be complementary in the diagnosis of neurocysticercosis (Fig. 3.12). Suh et al535 found MR imaging to be more sensitive than CT scanning for visualization of the scolex within the cystic lesions but less sensitive for detection of small calcifications. Because it has been estimated that dead cysticercal larvae take 4–7 years to calcify (and become visible on CT scanning), MR imaging appears to be preferable in children.74 The location of cysticerci can be intraventricular, cisternal, parenchymal, or meningeal.74 In the neurologically symptomatic patient,

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Table 3.6 Causes of optic disc elevation with mucopolysaccharidosis (Information from ref193) Narrowing of the scleral canal by thickened, infiltrated peripapillary sclera Increased intracranial pressure associated with hydrocephalus Accumulation of acid mucopolysaccharides in retinal ganglion cells Compression of the optic nerve by thickened infiltrated meninges

Fig. 3.12 Neurocysticercosis. CT scan demonstrates multiple intracranial cysts

the diagnosis of neurocysticercosis is almost always made presumptively on the basis of neuroimaging studies. An enzyme-linked immunosorbent assay (ELISA) test is available that, when applied to the CSF of people with active disease, has a sensitivity of over 80% and a specificity of over 90%. More recently, the Centers for Disease Control and Prevention developed an immunoblot test that detects both IgM and IgG antibodies to cysticercosis antigens and has a specificity close to 100% and a sensitivity of about 98% in both serum and CSF.118 Treatment of active neurocysticercosis consists of praziquantel, which kills the organism through a mechanism that is poorly understood.118 Patients with inactive disease and dead cysts do not respond to praziquantal. Surgical removal is occasionally indicated for intraventricular cysts, which may have become dislodged and produced obstructive hydrocephalus. Patients with multiple cystic lesions may develop increased CNS symptoms shortly after praziquantel is started, which appears to result from intense reactive inflammation in the surrounding brain following death of the cysticerci. During treatment, patients must therefore be observed closely for worsening of papilledema, which may necessitate acetazolamide and/or optic nerve sheath fenestration.

Mucopolysaccharidosis Optic disc swelling is a common ocular finding in patients with systemic mucopolysaccharidosis.19 In a study of 108 patients with optic disc edema, Collins et al97 found a greater

than 40% incidence of optic disc edema in patients with Hurler syndrome, Hurler–Scheie syndrome, Maroteux–Lamy syndrome, and Sly syndrome; 19.7% in Hunter syndrome; and 4.6% in Sanfilippo syndrome. No patient with Scheie syndrome or Morquio syndrome had optic disc edema. Optic disc swelling in mucopolysaccharidosis can result from any one or a combination of several mechanisms97 (Table 3.6). Beck and Cole40 provided ocular histopathology from a patient with Hunter syndrome who had optic disc swelling without raised intracranial pressure. They confirmed deposition of abnormal mucopolysaccharides within the sclera and lamina cribrosa that produced gross thickening of these structures and compression of the optic nerve. Bone marrow transplant can lead to resolution of optic disc edema.217

Infantile Malignant Osteopetrosis Osteopetrosis describes a group of hereditary metabolic bone diseases in which osteoclast dysfunction results in abnormal bone resorption, thickened cortical bone, structural skeletal defects, and frequent bone fractures.473 Reduced bone marrow space and replacement of its normal contents by chondroosseous tissue in the sclerotic bones results in anemia, hepatosplenomegaly, thrombocytopenia, leukopenia, and increased susceptibility to infection.473,583 Infantile malignant osteopetrosis is an autosomal recessive subtype of the juvenile-onset variety that develops in utero or in the first months of life.473 Clinical signs in malignant infantile osteopetrosis include reduced vision in the first months of life, an enlarged skull with parietal and frontal bossing, hepatosplenomegaly, recurrent infections, failure to thrive, and bruising.4 Neurologic abnormalities, including extreme irritability, cranial nerve palsies, developmental delay, hydrocephalus, mental retardation, and cerebral atrophy, are often the first manifestation of the disease.473 Hydrocephalus in osteopetrosis may result from obstruction of cerebral venous outflow secondary to narrowed venous foramina.311 Neuro-ophthalmologic findings are common in malignant infantile osteopetrosis. They include optic atrophy, papilledema, nystagmus, strabismus, nasolacrimal duct obstruction, limited extraocular movements, and proptosis.4,583 Papilledema in osteopetrosis has been attributed to hydrocephalus, although a IIH mechanism related to venous outflow obstruction also seems plausible. Optic atrophy with severe visual loss is seen

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in approximately 80% of cases. Optic atrophy may be caused by either the compressive effects of narrowed optic canals or by long-standing papilledema.473 Visual loss in osteopetrosis may also result from a primary retinal degeneration associated with diminished electroretinographic amplitudes. Some affected infants develop multiple lacunar areas of macular depigmentation.473 The recent association of infantile malignant osteopetrosis with neuronal storage disease suggests that the degenerative retinal changes in osteopetrosis may be secondary to neuronal storage disease. Lysosome dysfunction has been identified in both infantile malignant osteopetrosis and neuronal storage diseases. Infantile malignant osteopetrosis is lethal if untreated within the first decade of life.473 Bone marrow transplantation is the only definitive therapy, with a success rate approaching 50%.583 Bone marrow transplantation has been reported to lead to reversal of optic canal stenosis and preservation of vision may be associated.297 In one child, the electroretinogram reportedly normalized following bone marrow transplantation, while the visual evoked response remained undetectable.4 Optic canal decompression may result in improved visual function when visual loss is associated with CT evidence of narrowing of the optic canals, a normal electroretinogram, and subjective or objective evidence of decreased optic nerve function (e.g., progressive abnormality on serial visual evoked potential [VEP] examinations).10,583 In rare cases, visual loss can result from obstruction of cerebral venous outflow at the jugular foramina, leading to elevated intracranial pressure.498

3 The Swollen Optic Disc in Childhood

Uveitis Intraocular inflammation and hypotony are well-recognized causes of optic disc swelling. These two conditions often coexist in children with uveitis (juvenile rheumatoid arthritis, sarcoidosis, pars planitis) (Fig. 3.13). Postoperative hypotony, particularly following glaucoma surgery, is also a common cause of transient optic disc swelling in children. Visual acuity is thought to be unaffected by disc swelling alone in inflamed or hypotonous eyes.380 The finding of optic disc swelling and decreased acuity in an eye with uveitis should suggest the possibility of an associated anterior optic neuritis, whereas decreased acuity in a hypotonous eye is usually attributable to coexistent macular edema.380 Beardsley et al34 and Minckler and Bunt383 have demonstrated compromised axoplasmic transport anterior to the lamina cribrosa in ocular hypotony, just as in increased intracranial pressure. Interestingly, elevated intraocular pressure is also rarely associated with optic disc swelling.384 The biochemical mechanisms by which any of these conditions eventuate in optic disc swelling are speculative.228

Blau Syndrome Blau syndrome is an autosomal dominant condition characterized by a triad of dermatitis, arthritis, and uveitis that mimics childhood sarcoidosis but is less responsive to immunosuppressive treatment. It is caused by a mutation in the

Malaria Although rarely seen in western countries, malaria remains an important cause of papilledema worldwide. In children with papilledema, laser Doppler flowmetry shows an increase in the microvascular blood volume of the optic nerve head.35

Paraneoplastic Cancer-associated retinopathy (CAR) is a well-recognized paraneoplastic syndrome that is mediated by antiretinal antibodies is adults. Inflammatory changes such as optic disc edema and retinal vasculitis have not been reported in CAR. However, several purported cases of paraneoplastic optic neuropathy have recently been reported in children. Scott et al491 ascribed bilateral papilledema in a child without elevated intracranial pressure or hypertension to the paraneoplastic effect of a pheochromocytoma. Paraneoplastic optic disc edema with retinal periphlebitis has been reported in two children with pineal germinoma.153 In both cases, the inflammatory fundus changes resolved after removal of the tumor.

Fig. 3.13 Disc swelling and macular edema in 12-year-old girl with pars planitis and 20/25 vision

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NOD2 gene, a regulatory molecule that acts as a receptor for microbes on monocytic cells.52,321,523 CINCA Chronic infantile neurological cutaneous articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a rare congenital inflammatory disease characterized by cardinal signs that include a variable congenital maculopapular urticarial rash, chronic noninflammatory arthropathy with abnormal cartilage proliferation, and chronic meningitis with progressive neurological impairment associated with polymorphonuclear and, occasionally, eosinophilic infiltration.545 Neurologic abnormalities are characterized by chronic meningitis and secondary cerebral atrophy. Sensorineural hearing loss leading to deafness occurs in 22% of patients. Morphologic features include macrocephaly, saddle nose, and short, thick extremities, with clubbing of fingers.129 The CINCA syndrome is associated with childhood uveitis and papillitis with chronic disc swelling.477 The appearance of swollen optic discs, the presence of increased white blood cells without evidence of infection,129 and the absence of elevated intracranial pressure in most patients suggests an infiltrative etiology for the swollen optic discs,246 which may evolve into optic atrophy.129 CINCA syndrome results from mutations of the CIAS1 gene, which results in reduced apoptosis of the inflammatory cells with upregulation of interleukin 1 (IL1). Neutrophilic infiltration of multiple organs, including the skin, lymph nodes, spleen, and synovium, has been documented.339 Therapeutically, it responds poorly to immunosuppressives, including steroids, but seems to respond to recombinant human IL1 receptor antagonists (rHuI1, 1Ra), and anakinra (Kineret, Amgen).203 Matsubayashi et al370 noted resolution of papilledema with use of anakinra when treating a patient with intractable arthopathy.

gammaglobulin and high doses of aspirin are administered within the first days following the onset of illness.29,404,471

Poststreptococal Uveitis In addition to acute bilateral nongranulomatous uveitis, children with poststreptococcal syndrome uveitis may develop vitritis, focal retinitis, optic disc swelling, and multifocal choroiditis in up to one third of cases. An elevated antistreptococcal lysin O titer can be used to establish the diagnosis when a history of recent tonsillitis is obtained.449

Posttraumatic Optic Disc Swelling In addition to its well-known association with posterior uveitis, optic disc edema can accompany anterior uveitis. It does not significantly affect visual function, and resolution of the optic disc edema can trail resolution of the anterior uveitis for up to 6 weeks.387 This section emphasizes systemic uveitis syndromes that produce optic disc edema in children. Traumatic optic neuropathy typically involves the intracanalicular segment of the optic nerve and is not associated with optic disc swelling. We have examined three young patients (two children and one young adult) in whom blunt ocular trauma caused an unusual form of optic neuropathy, characterized by prolonged optic disc swelling, negative orbital imaging studies, and slow visual recovery over weeks to months (Fig. 3.14).66 The associated findings of choroidal ruptures and peripapillary subretinal hemorrhages suggest a

Kawasaki Disease Kawasaki disease is an acute multisystem vasculitis of infancy and early childhood.287 It is characterized by fever, bilateral conjunctival injection, mouth changes (dry, fissured lips; prominent tongue papillae (i.e., strawberry tongue); diffuse reddening of the oropharyngeal mucosa), extremity changes (reddening of the palms and soles, indurative edema of the hands and feet, desquamation of the hands and feet), polymorphous nonvesicular rash of the trunk or face, and cervical lymphadenopathy.51 In addition to conjunctival injection, iridocyclitis, vitritis and optic disc edema may complicate the clinical picture.15 Because of its strong association of lifethreatening coronary artery aneurysms, it is important to recognize and treat this condition early.260 The risk of complications can be decreased if a single, large dose of intravenous

Fig. 3.14 Posttraumatic optic disc swelling. Note peripapillary hemorrhages, choroidal ruptures and segmental pallor of inferior disc

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contrecoup mechanism of injury to the optic nerve at its junction with the globe. The pathogenesis of this rare form of posttraumatic optic disc swelling is speculative. Possible inciting factors include chronic, low-grade ischemia secondary to traumatic posterior ciliary artery occlusion, axonal crowding secondary to edema of the peripapillary sclera, and posttraumatic posterior vitreous detachment in a young patient with strong vitreopapillary adhesions to the disc. The delayed visual recovery may relate to the ability of young patients to withstand chronic, low-grade optic disc ischemia. CT scanning should be obtained to rule out an intrasheath hemorrhage in any child with decreased vision and optic disc edema following blunt ocular trauma, as vision can be restored by optic nerve sheath fenestration in this setting.218,256 Optic disc swelling secondary to intraocular inflammation or to hypotony (due to a cyclodialysis cleft or ciliary body hyposecretion) should also be considered in the context of posttraumatic optic disc swelling.

Intrinsic Optic Disc Tumors Optic Disc Hemangioma Capillary hemangiomas may occur within the substance of the disc as an isolated tumor (von Hippel’s disease) or in association with cerebellar and visceral tumors (von Hippel–Lindau disease). “Endophytic” hemangiomas appear as reddish, spherical, slightly elevated “knobs” that lie anterior to the disc vasculature (Fig. 3.15). The “endophytic” type of capillary hemangioma does not appear as a distinct mass but is typically seen as blurring and elevation of the disc margin, often associated with a serous detachment of the peripapillary retina.380 Hemangiomas of the optic disc may leak lipoprotein exudates into the retina and may be mistaken for either neuroretinitis or juxtapapillary choroidal neovascularization (Fig. 3.15).189,380 Fluorescein angiography shows early and diffuse filling confined to the area of the tumor, with late staining (Fig. 3.15). Histopathologically, the disc hemangioma consists of multiple thin-walled interconnecting aneurysms of variable size.189

Tuberous Sclerosis Astrocytic hamartomas of the optic disc or peripapillary retina may produce optic disc elevation in tuberous sclerosis.412,575 These lesions typically protrude or overlie the optic disc and evolve from a gray or grayish-pink translucent appearance in infancy to a glistening, yellow, mulberry appearance later in childhood. Small calcified astrocytic hamartomas of the optic disc may be impossible to distinguish from disc drusen.189

Fig. 3.15 (a) Endophytic optic disc hemangioma in patient with von Hippel–Lindau disease. Area of fibrovascular proliferation overlies superior disc margin. (b) Early phase fluorescein angiogram showing discrete filling of lesion. Courtesy of Stephen C. Pollock, M.D. (c) Exophytic optic disc hemangioma with retinal exudate simulating neuroretinitis. Courtesy of Stephen P. Christiansen, M.D.

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Retrobulbar Tumors

Fig. 3.16 Optic disc tuber. This unusual patient with tuberous sclerosis had a slowly enlarging tuber within left optic disc. Visual acuity remained 20/20 over 10 years of observation. With permission from Brodsky and Safar64

Fig. 3.17 Optic disc glioma in a patient with NF2 (courtesy of Klara Landau, M.D.)

Fluorescein angiography shows a prominent network of fine “filigree” blood vessels in the superficial portion during the venous phase, and intense late staining of the tumor.189,191,507 Depending on their stage of evolution, these tumors are composed of either spindle-shaped astrocytes or acellular, laminated calcific concretions.189,380 Although these lesions rarely only enlarge, Shields et al described visual loss secondary to massive enlargement of astrocytomas of the retina and optic disc in four patients with tuberous sclerosis.508 In contrast, Brodsky and Safar64 described an enlarging tuber that was contained within the optic disc of one eye (Fig. 3.16). Despite its impressive enlargement and increasing surface vascularity, this lesion remained visually inconsequential over 10 years of observation. Intracranial lesions in children with tuberous sclerosis may cause obstructive hydrocephalus, papilledema and, eventually, optic atrophy.145,412 The associated CNS and systemic signs of tuberous sclerosis are discussed in Chap. 11.

lesions characterized by a proliferation of the retinal pigment epithelium (RPE), retina, and overlying vitreous. They have a predilection for the juxtapapillary area and are often accompanied by significant wrinkling and distortion of the retina. Combined hamartomas may elevate a portion of the optic disc and leak fluorescein. Conversely, chronic papilledema rarely produce a constellation of juxtapapillary pigmentary, vascular, and glial changes that is indistinguishable from a combined hamartoma.255 Gass189 described an older adult in whom a small depigmented juxtapapillary CHRPE produced elevation of the disc, with segmental leakage on fluorescein angiography, simulating ischemic optic neuropathy. Landau et al328 established the association of CHRPE with NF-2 that has been confirmed in subsequent studies.209,289,518

Optic Disc Glioma Optic disc glioma (Fig. 3.17) is an extremely rare tumor that appears as a mass of whitish, gray, or yellow tissue protruding from the disc surface.380 Visual acuity is variably affected. Dossetor et al132 recently reviewed all previously reported cases and established the strong association of optic disc glioma with NF-2.

Combined Hamartoma of the Retina and RPE Combined hamartomas of the retina and retinal pigment epithelium (CHRPE) are irregular, elevated, variably pigmented

Retrobulbar Tumors The finding of optic disc swelling in a proptotic eye (usually with decreased acuity) is highly suggestive of a retrobulbar tumor. Intrinsic optic nerve tumors may compress and/or infiltrate the optic nerve and interrupt axonal transport, leading to swelling of the optic disc. Optic nerve glioma is the most common retrobulbar tumor associated with optic disc swelling in children. While it has been found experimentally that extrinsic optic nerve compression must occur in close proximity to the globe to produce optic disc edema, many clinical exceptions to this rule have been documented.380 Orbital venous stasis may be a predominant mechanism whereby mass lesions in the posterior orbit lead to optic disc edema. Optic nerve sheath meningioma is rare in children. When present, it produces gradual visual loss, optic disc swelling, and proptosis. This tumor can usually be differentiated from

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orbital optic glioma on the basis of its neuroimaging characteristics (see Chap. 4). Optic nerve sheath meningioma is classically held to exhibit a more aggressive course in children than in adults, especially with regard to early intracranial extension.13,587 However, there is no evidence that it this has any significant effect on prognosis for life or vision in the contralateral eye. Children with optic nerve sheath meningioma should be evaluated by chromosome analysis for the possibility of occult NF-2 (see Chap. 11).

also precipitate optic neuritis in children. The delayed onset of pediatric optic neuritis after recent infection or immunization and the bilateral involvement in most cases of postinfectious optic neuritis suggest a generalized mechanism of injury (i.e., a systemic autoimmune demyelination) rather than random, viral invasion of each optic nerve.499 Hierons and Lyle240 noted that encephalomyelitis typically occurs in the wake of viral infections and suggested that optic neuritis in children be viewed as a localized form of encephalitis.

Optic Neuritis in Children

Acute Disseminated Encephalomyelitis

Pediatric optic neuritis is fundamentally different from adult optic neuritis in the following ways:

When childhood optic neuritis is accompanied by multiple neurological signs, the primary diagnostic considerations are acute disseminated encephalomyelitis (ADE), MS, and Devic’s disease (Table 3.7). The terms postinfectious encephalomyelitis and acute disseminated encephalomyelitis are used interchangeably to describe an uncommon, inflammatory, demyelinating disease of the CNS that usually follows a viral illness or vaccination by days to weeks.33,269 Children 6–10 years of age are most commonly affected, presenting with acute onset of motor signs and symptoms, seizure activity, and sometimes, altered consciousness, headache, fever, and ataxia.33 CSF analysis may show pleocytosis154,499,514 The histopathological hallmark of ADE is a zone of demyelination (with relative sparing of axons) around veins in association with infiltration of vessel walls and perivascular spaces by lymphocytes, plasma cells, and monocytes.33 ADE is believed to result from an

(1) Pediatric optic neuritis is commonly bilateral whereas adult optic neuritis is usually unilateral.294,375 (2) Pediatric optic neuritis is usually associated with optic disc swelling294,375 whereas adult optic neuritis is more often retrobulbar.375 (3) Pediatric optic neuritis is usually a postinfectious condition that does not presage multiple sclerosis (MS)375 whereas adult optic neuritis is usually a demyelinative event that augurs the onset of MS.460

History and Physical Examination It is often difficult or impossible to obtain an accurate history of the onset of visual symptoms in children. Young children may not notice unilateral visual loss and may blithely accept bilateral visual loss until it is so severe as to be incapacitating.294 In older children, a sense of panic may lead to denial of symptoms.294 The vagaries of subjective symptoms in children detract from the overall reliability of the history. Headache appears to be more common in pediatric optic neuritis.294,317 As in adults, a history of pain with eye movements supports the diagnosis.

Postinfectious Optic Neuritis A febrile or flu-like illness commonly precedes pediatric optic neuritis by days or weeks. Diseases that have been specifically associated with optic neuritis in children include measles, mumps, chickenpox, rubella, brucella, pertussis, infectious mononucleosis, cat scratch disease, toxoplasmosis462 Q fever, viral ebola virus, mycoplasma, enterovirus, herpes simplex, and Lyme disease.57,131,264,374,389,390,399,427,453,458,470,484,485 Diphtheria, pertussis, and tetanus vaccines or other immunizations may

Table 3.7 Differential diagnosis of optic disc swelling with visual loss in children Isolated visual loss Postinfectious optic neuritis Early neuroretinitis Leber hereditary neuroretinopathy Nutritional deficiency Pseudopapilledema with cortical visual loss Pseudopapilledema with psychogenic visual loss Systemic vasculitis (e.g., lupus) AMPEE, MEWDS, and related disorders

Visual loss with additional neurological signs Acute disseminated encephalomyelitis Multiple sclerosis Devic disease Meningitis Neurosarcoidosis Leukemia Optic glioma Craniopharyngioma

Shunt failure with hydrocephalus Adrenoleukodystrophy Drug toxicity AMPEE acute multifocal placoid pigment epitheliopathy, MEWDS multiple evanescent white dot syndrome

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autoimmune reaction to myelin triggered by a virus or vaccine, because no virus has consistently been isolated.33 Also, the temporal framework and pathological features of postinfectious encephalitis closely resemble those of experimental allergic encephalitis, a prototypical autoimmune demyelinating disease.499 MR imaging in ADE shows moderate to large areas of increased signal intensity on T2-weighted images corresponding to the inflammation and edema associated with demyelination (Fig. 3.18).20,33 These lesions involve subcortical white matter in a patchy distribution, but cortical and deep gray matter are also involved to a lesser extent. The lesions are bilateral but usually asymmetrical. Brain stem and cerebellar lesions are common.20 Despite the large size and subcortical location of the lesions, MR imaging findings in ADE show significant overlap with those of MS.33 Conclusive differentiation of ADE from the initial presentation of childhood MS is not possible, even when combining clinical features, CSF analysis, and MR imaging.33 Although ADE is classically considered to be a monophasic illness, a small but significant fraction of patients have relapses, establishing the diagnosis of MS.33 Recent reports suggest that thalamic involvement may be a useful neuroimaging sign of ADE, because it is rarely seen in children with MS.33,225 Acute disseminated encephalitis is an emergent condition, with mortality estimated at 10–20%. Systemic corticosteroids are the mainstay of treatment.

Fig. 3.18 Acute disseminated encephalomyelitis. MR image shows patchy areas of prolonged T2 relaxation involving subcortical white matter and cortex. Courtesy of A. James Barkovich, M.D.

MS and Pediatric Optic Neuritis Clinical and experimental evidence has demonstrated that the distinction between postinfectious childhood optic neuritis and MS may not be absolute. Riikonen458 believes that a combination of abnormal immunological responses, possibly precipitated by infectious agents in a genetically susceptible individual, may lead either to MS or to optic neuritis. Riikonen et al456 studied 18 children with optic neuritis, 10 of whom eventually developed MS. More than half of the children had suffered a bacterial or viral infection within 2 weeks prior to the first symptoms of optic neuritis. Vaccinations with live or attenuated viruses (e.g., polio, vaccinia, rubella, influenza) preceded the first episode of optic neuritis in six patients. Subsequent vaccinations caused exacerbations of optic neuritis in several cases. Five of the recently vaccinated children eventually developed MS. Killed virus components, such as those used for influenza vaccines, do not produce this effect. Riikonen has recommended avoiding immunizations with live or attenuated viruses in children with MS. Bye et al73 described five similar children with chronic, recurrent optic neuritis, three of whom had encephalomyelitis with optic neuritis as their initial episode. These findings corroborate those from the Riikonen study and confirm that postinfectious optic neuritis, with or without encephalomyelitis, may be a harbinger of MS in some children.73 It is currently unclear whether concurrent encephalomyelitis affects the likelihood that MS will develop in the child with optic neuritis or whether the severity of the encephalomyelitis influences this prognosis.417 Controversy persists regarding the incidence of MS and its relative association with unilateral versus bilateral optic neuritis. Morales et al391 found that: (1) Children typically have bilateral involvement with papillitis following an antecedent viral illness; (2) Although visual prognosis is poorer in children than adults, the development of MS is less common in children; (3) Children who present with unilateral involvement have a better visual prognosis, however, they also develop MS at a greater frequency than children with bilateral involvement; and (4) Patients who developed MS were, on average, older than those who did not develop MS. Studies of childhood optic neuritis with long clinical observation periods show the rate of subsequent diagnosis of multiple diagnosis to be 26–56%.361,458 A second demyelinating event can occur more than 10 years following an initial episode of optic neuritis.361 Wilejto et al573 found that the risk of MS was high (36%) at 2 years in children with optic neuritis. This retrospective study found that 13 of 36 (36%) children with pediatric optic neuritis developed MS. Contrary to other studies,326,391 this study found that bilateral optic neuritis was associated with a greater likelihood of having or developing MS. MR imaging

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abnormalities and the presence of clinical findings extrinsic to the visual system at baseline correlated with the diagnosis of MS. Morales et al391 and Wilejto et al573 found more MS in bilateral cases. Morales et al391 tried to debunk the notion that unilateral optic neuritis is supportive of the diagnosis of MS. In a retrospective analysis of 25 patients, Brady et al58 found that pediatric optic neuritis is usually associated with visual recovery, but a significant number (22%) remain visually disabled. The occasional poor visual outcome emphasizes the guarded prognosis of this disorder. Younger age at presentation and normal neuroimaging seem to impart a better visual prognosis, perhaps owing to a greater capacity for remyelination.79 Other studies have found that, compared with adults, the risk for development of MS after childhood optic neuritis is lower. In a 15-year follow-up of adult optic neuritis, the LONS found the cumulative probability of MS to be 50% at 15 years.416 Lucchinetti et al361 performed a life-table analysis of 79 patients and found that clinically or laboratory-suggested definite optic neuritis would develop in 13% after 10 years of follow-up. By 20 years, the risk rose to 19%. Not surprisingly, there was increased risk of development of MS in patients with sequential or recurrent optic neuritis compared with those who had unilateral or bilateral simultaneous involvement. Repka and Green454 described a 5-year-old girl who developed severe macular distortion due an epiretinal membrane in one eye following bilateral papillitis.221 Schilder disease is a severe form of MS that can present with cortical blindness and bilateral occipital lesions.327,495 The centrum semiovale is the typical location of the large plaque-like lesions of Schilder disease.434

Devic Disease (Neuromyelitis Optica) The diagnosis of early neuromyelitis optica Devic disease should be considered in any child or adult who presents with acute bilateral optic neuritis. Such patients should be cautioned to return immediately if they develop a gait disturbance or bladder dysfunction. Unlike MS, Devic disease is usually an acute and often self-limiting disorder (a “once and for all” demyelination). Subsequent attacks of demyelination are rare. When relapses involve other neurological signs, the patient must be considered to have MS. The relative incidence of Devic disease to MS is much higher in Asia, particularly in Japan.320 It is most common in young adults but may appear at any age from 5 to 60 years.375 Most cases start with bilateral visual symptoms. Visual loss occurs acutely and becomes severe within a few days.324 The optic discs may be normal or swollen.375 Pediatric Neuromyelitis Optic (PMO) may be difficult to distinguish from multiple sclerois

3 The Swollen Optic Disc in Childhood

in the early stages of the disease.357a Although many adults remain permanently blind after an attack of Devic disease, Jeffery and Buncic found that children with Devic disease have an excellent prognosis for visual and neurological recovery with no recurrences or long-term sequelae.263 However, a recent report of a 23-month-old child with Devic disease described severe sequelae with a poor outcome.589 Occasionally, visual system and spinal cord involvement are separated by months or years.364 Rarely, positive NMO antibodies are found in patients with recurrent optic neuritis without clear evidence of transverse myelitis.113 Neurological involvement consists of a progressive and often ascending sensorimotor myelitis affecting either the lower limbs or all four limbs and sometimes causing a complete transverse lesion of the cord.375 Urinary retention or incontinence are common. The CSF typically shows a pleocytosis and increased total protein. Patients with Devic disease have a high CSF albumin level with a low serum/CSF albumin ratio, suggesting a permeability defect in the blood-brain barrier. Most affected individuals are found to have absent oligoclonal bands, in contrast to the increased daily CSF IgG synthesis and oligoclonal bands that typify MS.364 Devic disease is fatal in approximately 20% of cases.320 Immunosuppressive therapies generally fail to benefit patients.364 Until recently, the clinical diagnosis of Devic disease was predicated on the diagnosis of concurrent acute optic neuritis and spinal cord dysfunction, with absence of brain white matter signal abnormalities on MR imaging.199 MR imaging in Devic disease typically demonstrates a normalappearing brain with enlargement and cavitation of the spinal cord.364 Unlike in MS, the cerebral hemispheres, brain stem, and cerebellum are generally unaffected in Devic disease.364 The usual absence of white matter MR signal abnormalities within the brain hemispheres in Devic disease helps to distinguish it from MS.364 The final diagnosis is established by finding antiNMO antibodies within the CSF (reference from below). Recently, a serum antibody that targets the aquaporin-4 molecule has been identified in adults with Devic disease.341 Devic disease, which is now considered to be an aquaporin channelopathy, may represent the first molecularly defined autoimmune optic neuropathy. Researchers at Mayo Clinic have identified an immunoglobulin marker of neuromyelitis optica (the “NMO antibody”) that binds selectively to the aquaporin-4 water channel and may play a causative role.114 NMO-IgG is a serum autoantibody marker that is both sensitive and specific for NMO and is generally absent in patients whose clinical course is otherwise indistinguishable from prototypical MS. This marker has also been found in Japanese patients with opticospinal MS, prompting the suggestion that neuromyelitis optica and Japanese opticospinal MS are the same disorder.340

Optic Neuritis in Children

The NMO antibody, which predicts frequent relapse of myelopathy and optic neuritis, is also found in patients with lupus erythematosus and Sjögren’s syndrome who also have severe optic neuritis and longitudinally extensive myelitis. Because this antibody is also found in patients with optic neuritis and myelitis who have brain signal abnormalities atypical of MS, the diagnosis of NMO has been revised to allow inclusion of these brain imaging abnormalities. However, a positive marker is not universal in patients who have classic Devic disease. It continues to be a subject of debate whether NMO is a separate disease or merely a form of MS and whether the natural history of NMO is always worse than that of conventional MS.202 No single clinical characteristic is adequate for defining NMO. Diagnostic confirmation using antiNMO antibody testing has led to revised diagnostic criteria by demonstrating the occasional presence of additional MR signal abnormalities in the brain is still compatible with the diagnosis of neuromyelitis optica196,578 Thus, while the presence of CNS symptoms outside the optic nerves and spinal cord formerly excluded the diagnosis of Devic disease,110,364,413 such lesions are now recognized as compatible with Devic disease. Similarly, the term NMO was applied to patients who experienced a monophasic event consisting of bilateral simultaneous optic neuritis and acute myelitis.122 The NMO spectrum is now recognized to typically evolve as a relapsing disorder that also includes patients with unilateral optic neuritis with index events of optic neuritis and myelitis occurring weeks or even years apart.577 A relapsing type of NMO is clinically characterized by two index events (optic neuritis and transverse myelitis) separated by an interval of days, weeks, months, or even years, with variable remission followed by new clinical events restricted to the optic nerve and spinal cord.421,422,577 Currently recommended diagnostic criteria for Devic disease require optic neuritis, myelitis, and at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion three or more segments in length, onset brain MRI nondiagnostic for MS, or NMO-IgG seropositivity.578 A necrotizing (rather than demyelinating) myelopathy is the histopathological hallmark of Devic disease.364 Autopsy examination of the optic nerves and chiasm shows demyelination, with gliosis and cavitation in some cases.364 The remainder of the brain is normal. Autopsy examination of the spinal cord shows a severe necrotizing myelopathy with involvement of both gray and white matter, thickening of blood vessels walls, and no lymphocytic infiltrate.364 These findings contrast sharply with those of MS, in which multiple demarcated plaques are scattered throughout white matter in the brain and spinal cord.

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Prognosis and Treatment Proper distinction between NMO and MS is important both prognostically and therapeutically, as NMO has a worse prognosis than MS. Within 5 years of onset, 50% of patients are blind in both eyes and cannot walk unassisted, and 20% die of respiratory failure due to cervical myelitis.577 The visual prognosis for Devic’s disease optic neuritis is also worse than that for patients with MS.378 Therapeutically, the two disorders may respond differently to immune modulatory therapy and to plasmapheresis, whereas the currently promoted treatment of MS includes immune-modulating agents such as interferon b.114 Mitoxantrone, which potentially suppresses both T-helper lymphocytes and the humoral immune system via both macrophage and B-cell attenuation, shows promise in the clinical treatment of this devastating condition.566

Course of Visual Loss and Visual Recovery Initial visual loss in pediatric optic neuritis is often profound; acuities of light perception and no light perception are not unusual. Despite the severity of visual loss, the prognosis for visual recovery is generally regarded as excellent.294,317,375,499 Kennedy and Carroll294 noted that “in most instances, improvement begins before the end of the third week after onset and reaches a maximum by 6 months”.21 Kriss et al317 found the pattern-evoked VEP latency to be normal in 55% of children with recovered optic neuritis, as compared to a previously established figure of 10% in adults and suggested that the greater potential for remyelination in the young than in the old may account for these findings. In most children, vision spontaneously recovers to 20/20, but some degree of optic disc pallor usually persists.317,375,499 Meadows375 stated that “the slower and more insidious the loss of function, the less the likelihood of visual improvement, and if this does occur, it tends to be equally slow. In contrast, a more abrupt and catastrophic onset is sometimes followed by surprising recovery.” In offering an optimistic prognosis to the parents and child, it should be kept in mind that most series include descriptions of a few children whose vision either failed to improve or improved minimally.234 Some children in the older series may have had a mutation for Leber hereditary neuroretinopathy. It is not known whether children who sustain permanent visual loss have a distinct form of optic neuritis or whether their failure to improve represents the low end in a broad spectrum of recovery.

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Systemic Prognosis It is classically held that optic neuritis is less likely to lead to MS in children than in adults.317 In adults, Rizzo and Lessell460 reported that 58% of optic neuritis patients (69% of women and 33% of men) were diagnosed as having MS during an average follow-up of 14.9 years. The incidence of MS following childhood optic neuritis has ranged from 5.2 to 55.5% in different studies.295,317,460 There seems to be a greater predisposition for children with unilateral rather than bilateral optic neuritis to develop MS.222,317,460 Conversely, optic neuritis is commonly reported in studies of children with MS; in a recent report by Bye et al,73 all five children with MS had this early sign. Because the incidence of MS continues to increase with long-term follow up in adults with optic neuritis, and the length of follow up is less than 15 years in most pediatric studies, one cannot conclude on the basis of present data that the incidence of demyelinating disease is less in children with optic neuritis than in adults. Kriss et al317 found that MS developed in 3 of 29 children with bilateral optic neuritis and 3 of 10 children with unilateral optic neuritis, suggesting that, while bilateral cases have a lower incidence of MS than unilateral cases, the risk in bilateral cases is not negligible (Table 3.8). In the 8 of 30 patients from the Kennedy and Carroll series294 who developed MS, four had simultaneous bilateral disc swelling. In the Riikonen study,458 MS developed in seven of eight patients with unilateral optic neuritis and in only 2 of 13 patients with bilateral optic neuritis. Riikonen noted that all patients who later developed MS had a second attack of optic neuritis within 1 year of the first attack.

Systemic Evaluation of Pediatric Optic Neuritis The diagnosis of bilateral optic neuritis is established by the finding of bilaterally decreased vision, decreased color vision, an afferent pupillary defect (if the visual loss is asymmetrical), swollen or normal discs, and the absence of

Table 3.8 Incidence of MS in unilateral versus bilateral childhood optic neuritis MS in MS in Mean unilateral bilateral follow up cases (Ratio/ cases (years) [%]) (Ratio[%]) Study Kennedy and Carroll294 Haller and Patzold222

4/18 (22.2) 4/10 (40)

4/12 (33.3) 3/9 (33)

Kriss et al317 Riikonen et al458 MS multiple sclerosis

3/29 (10.3) 2/13 (15.4)

3/10 (30) 7/8 (87.5)

8 0.5 to 30 (no mean) 4.6 7

space-occupying intracranial lesions, such as optic nerve glioma, craniopharyngioma, or hydrocephalus, on MR imaging. Using kinetic perimetry, cecocentral scotomas and large central scotomas are the most common visual field defects. Once the diagnosis of optic neuritis is established, a diagnostic evaluation is undertaken to determine an underlying cause (Table 3.9). The MR imaging is exquisitely sensitive to the periventricular ovoid lesions that characterize MS in adults.60 In the Optic Neuritis Treatment Trial,38 unenhanced MR imaging of the brain was performed as part of baseline diagnostic testing with a standardized protocol in 440 adults. The MR images in 418 of these patients were deemed acceptable for evaluation of signal intensity abnormalities. At the 2-year follow up, the initial MR imaging findings were compared with the neurologic course in each patient to determine whether any association could be established. Results of this study showed initial MR imaging findings to be a powerful predictor of MS.416 At 15 years, 25% of patients with no lesions on baseline MRI developed MS during followup compared with 72% of patients with 1 or more lesion.416 After 10 years, the risk of developing MS was very low for patients without baseline lesions, but it remained substantial for those with lesions. In patients without lesions, baseline factors associated with a lower risk for MS included male sex, optic disc swelling, and atypical features of the optic neuritis. These findings are consistent with results of the earlier study by Morrissey et al393 which suggested that, with long-term follow up, the risk of developing MS may approach 100% in adults with abnormal MR images, whereas the risk in patients with normal MR images is likely to remain low. Evidence from the Riikonen study459 suggests that MR imaging may be as useful in children as it is in adults for predicting which patients will subsequently develop MS. In children, a lumbar puncture is usually performed to rule out elevated intracranial pressure, meningitis, leukemia, Table 3.9 Infectious and noninfectious causes of childhood optic neuritis Infectious or postinfectious Noninfectious Rubeola (measles) Paramyxovirus (mumps) Varicella zoster (chicken pox) Pertussis (whooping cough) Boriella burgdorferi (Lyme disease) Epstein-Barr virus (infectious mononucleosis) Rochalimaea (cat scratch disease) Treponema pallidum (syphilis) Toxocara canis Toxoplasmosis Tuberculosis Rickettsia Coxsiella burnetti Brucella Vaccinations

Multiple sclerosis Devic’s disease Sarcoidosis Bee venom Vasculitis (e.g., lupus) Etanercept or Inflixamab

Optic Neuritis in Children

or a coexistent encephalitis. Riikonen and von Willebrandt459 found normal peripheral blood lymphocyte counts and function in most children with optic neuritis and MS. A thorough history of recent infection or systemic disease, illness, recent immunizations, bee stings,45 tick bites,582 or neurological symptoms suggestive of MS should be obtained. Symptoms of headache, malaise, lethargy, seizures, or fever should suggest the possibility of a coexistent encephalomyelitis. The findings of lymphadenopathy, hepatomegaly, or splenomegaly should suggest the possibility of infectious mononucleosis or cat scratch disease.154 A chest X-ray (to rule out sarcoidosis and tuberculosis) and a tuberculin skin test can be predicated on the index of suspicion. Systemic signs of vasculitis should be sought because systemic lupus erythematosis can occasionally cause a bilateral simultaneous optic neuritis in children that is usually associated with a poor visual outcome.3 In children with a discrete white inflammatory mass on the disc or prominent vitreous inflammation, serological testing for toxoplasmosis and toxocariasis should be obtained.109,164 Bilateral, multifocal chorioretinitis with circular “target-like” lesions scattered in the mid-periphery and often arranged in a radial, linear pattern has been a consistent feature. Other intraocular findings include mild iridocyclitis, vitritis, occlusive vasculities, and optic disc edema.17,26,401 The increasing use of etanercept and infliximab for juvenile rheumatoid arthritis and other autoimmune diseases is now a recognized cause of pediatric optic neuritis.600 Table 3.9 summarizes the recognized infectious and noninfectious causes of childhood optic neuritis.

Treatment There has been no controlled study to determine the efficacy of oral or intravenous corticosteroids in the treatment of childhood optic neuritis.234 Recommendations in the literature are largely anecdotal.154 In typical demyelinating optic neuritis in adults, the Optic Neuritis Treatment Trial38 has found that neither oral nor intravenous steroids change the final visual outcome as measured 1 year after onset of symptoms. However, adults who received intravenous steroids in high doses had more rapid recovery of vision. Adult patients who received oral corticosteroids alone for acute optic neuritis had twice the number of recurrent attacks of optic neuritis over the following 2 years.39 In contrast, patients who were treated with intravenous corticosteroids had only half the number of systemic demyelinative episodes as the placebo or oral corticosteroid treated groups over the same 2-year period.39 The protective effect of intravenous corticosteroids was seen only in the subgroups with abnormal MR scans.60 On the basis of these results, some adults with optic neuritis and/or MS are now treated at 2-year intervals with intravenous

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high-dose corticosteroids. These results may also be applicable to children with optic neuritis and signal abnormalities on MR imaging suggestive of MS or to children with MS. MR imaging is also crucial to define the multiple bilateral large signal abnormalities of ADE, which responds to corticosteroids.225

Leber Idiopathic Stellate Neuroretinitis In 1916, Theodor Leber described the clinical syndrome of unilateral visual loss, optic disc swelling, macular star, and spontaneous resolution in otherwise healthy patients.190,332 He referred to this condition as an idiopathic stellate neuroretinopathy, emphasizing the star figure that surrounded the fovea (Fig. 3.17). The onset of visual loss usually follows a viral prodrome by 2–4 weeks.424 Visual loss may be accompanied by symptoms of floaters and ocular pain. Ophthalmoscopic examination at onset shows a swollen optic disc with peripapillary retinal striae extending from the disc toward the macula or extending radially from the fovea, frequent serous detachment of the peripapillary retina, and cells in the anterior vitreous. An associated iridocyclitis is seen in some cases. Within weeks, the disc swelling and peripapillary edema begin to subside, and a yellowish star-shaped pattern of macular exudate appears and becomes more prominent190,475 (Fig. 3.19). In most cases, visual acuity ranges from 20/50 to 20/200, and an afferent pupillary defect is present.190 Visual field testing shows a central or centrocecal scotoma.133 Fluorescein angiography shows evidence of abnormal capillary permeability, particularly from the capillaries deep within the optic disc.190 The disc swelling clears over 2 or 3 months, but the macular exudate may persist and be associated with retinopathic deficits for a longer period. A minority of patients with Leber stellate neuroretinitis have either focal neurological symptoms or elevated intracranial pressure at presentation; fulminant encephalitis or meningitis is not seen.424,569 The ultimate level of visual recovery seems to be the same in Leber idiopathic stellate neuroretinitis as in optic neuritis, but the course of visual recovery is prolonged in neuroretinitis. During the months between the resolution of disc edema and the resolution of macular exudates, a dissociation between color vision and visual acuity may be apparent, with the former normalizing first. Following resolution, patients are left with varying degrees of optic atrophy and mild macular pigmentary changes and, sometimes, macular hole formation.6 As with optic neuritis, most patients recover near-normal vision but, occasionally, patients fail to recover or recover only minimally.555 The distinction between Leber stellate neuroretinitis and anterior optic neuritis bears tremendous prognostic significance,

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Fig. 3.19 Leber stellate neuroretinitis. (a) Scratches from a kitten on a girl with unilateral visual loss. (b) Vitritis, optic disc swelling, and a macular star in the same patient. Note the characteristic yellowish, white

nodular lesion which occupies the inferonasal portion of the optic disc. (c) Swelling of optic disc and macular star-shaped exudates in another patient

because the diagnosis of Leber stellate neuroretinitis virtually rules out the possibility of MS.424 This fundamental difference can be predicted from the known pathophysiology of the disease. Gass originally suggested that Leber stellate neuroretinitis is due to a prelaminar disc vasculitis that results in a leakage of lipid and protein-rich exudate from the disc capillaries into the outer plexiform layer.133,188,424 As the serous component is resorbed over days to weeks, lipid precipitates within Henle’s fiber layer, forming a star figure.133 Leber stellate neuroretinitis is thought to be fundamentally different from optic neuritis in that Leber stellate neuroretinitis presumably represents an autoimmune vasculitis confined to the nonmyelinated prelaminar optic disc.569 In anterior optic neuritis, the target tissue is primarily retrolaminar myelin.133 Although anterior optic neuritis can indirectly produce disc swelling, it does not cause the profuse leakage from the prelaminar disc capillaries necessary to produce a macular star.

Cat scratch disease has emerged as the most common infectious cause of neuroretinitis.525 Cat scratch disease is a self-limited illness caused by a gram-negative bacillus, Bartonella henselae (now synonymous with Rochaliaea hensalae). The disease is transmitted by the bite or scratch of an infected animal, often a young cat or kitten.599 However, dogs, monkeys, and porcupines can also harbor the agent,206 and recent evidence suggests that cat fleas may also play a role as an arthropod vector.313 The infected individual often develops an erythematous pustule at the site of inoculation, followed by a systemic reaction in days to weeks. Typical symptoms include regional lymphadenopathy, fever, malaise, and fatigue. More severe systemic complications may develop, including splenomegaly or splenic abscesses, encephalopathy, granulomatous hepatitis, pneumonia, or osteomyelitis.525 The finding of angiomatous skin lesions (bacillary angiomatosis) resembling Kaposi’s sarcoma in the child with neuroretinitis or hepatosplenomegaly should also suggest the

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possibility of cat scratch disease.207,448,571 Weiss and Beck569 noted that the swollen optic disc usually had a yellowishwhite nodular region located at the temporal aspect of the swollen disc (Fig. 3.19). Fish et al158 documented peripapillary angiomatosis on the surface of a swollen disc of a child with cat scratch disease. Papillary angiomatosis may turn out to be a unique ocular manifestation of cat scratch disease that is analogous to the skin lesions of bacillary angiomatosis. In the past, a cat scratch skin test and/or a lymph node biopsy were the methods most commonly employed to establish the diagnosis. Previously reported cases of cat scratch–associated neuroretinitis must be considered at least somewhat presumptive, because a positive skin test only demonstrates acquired immunity to the infection, which could have occurred months to years before.29 In patients with lymphadenopathy from cat scratch disease, a lymph node biopsy typically shows noncaseating necrosis and gram-negative coccobacilli with Warthin-Starry silver stain.87,158 The cat scratch skin test was never approved by the U.S. Food and Drug Administration and has now been replaced by serological testing of acute and chronic IgG and IgM. Rochalimaea can also be cultured from blood or skin lesions.207 Although some authors have recommended oral antibiotics207,247,347,446 or oral corticosteroids for the treatment of cat scratch disease, most patients recover fully without treatment.525 Despite a lack of proven benefit, systemic corticosteroids are often empirically added in patients with optic neuritis or neuroretinitis.158,554 Lyme disease is another recognized cause of Leber stellate neuroretinitis.345 Lyme disease is caused by the spirochete Borrelia burgdorferi, which is transmitted by Ixodidae ticks.1 Serological testing is therefore particularly important in children who have recently been camping or have a history of a tick bite. Clinical signs of erythema migrans, carditis, arthritis, or facial palsy should raise suspicion for this diagnosis.1 Unfortunately, currently available serology for Lyme disease has problems with both false–positive and false–negative results, causing overdiagnosis and underdiagnosis, respectively.529,580 Patients with syphilis can have positive Lyme serology.580 Patients with Lyme disease who have early skin, joint, or

cardiac involvement are often treated with oral antibiotic therapy, while those with neuroborreliosis (encephalitis, neuroretinitis, facial palsy) or chronic arthritis require longer-term intravenous third-generation cephalosporins. Other infectious and parainfectious causes of Leber stellate neuroretinitis in childhood include mumps,167 leptospirosis,133 infectious mononucleosis,53,172 exudative tuberculous retinitis,135 a toxocaral granuloma within the nerve head,48,109 toxoplasmic neuroretinitis,159 syphilis,156,165 and influenza.369 It also is important to remember that macular stars rarely accompany disc swelling due to elevated intracranial pressure.200 Tables 3.10 and 3.11 summarize the recognized infectious causes of Leber stellate neuroretinitis, along with suggested medical evaluations. Other forms of childhood neuroretinitis include posterior scleritis and diffuse unilateral subacute neuroretinitis (DUSN). Posterior scleritis is an autoimmune disorder that is often associated with ocular pain, conjunctival injection, and ocular motility disturbances. Ophthalmoscopic abnormalities include optic disc edema, retinal and choroidal striae, exudative retinal detachment, annular choroidal detachment, and cystoid macular edema.43 The disc swelling in posterior scleritis may be caused by narrowing of the scleral canal due to contiguous scleral inflammation and edema. The diagnosis can be confirmed by ultrasonography, which demonstrates a fluid-filled space in Tenon’s tissue behind the globe or by CT scanning, which demonstrates enhancement and thickening of the posterior sclera. Diffuse unilateral subacute neuroretinitis occurs in healthy patients and, in its acute stage, is characterized by mild to moderate swelling of the optic disc, vitreous cells, and transient crops of focal, gray-white or yellow-white lesions that involve the deep or external layers of the retina and retinal pigment epithelium (RPE).190,192 DUSN can rarely be associated with a macular star.188 Over weeks to months, depigmentation of the overlying RPE occurs, along with severe optic atrophy and marked retinal arteriolar attenuation.188 DUSN is now considered a multietiologic syndrome caused by different species of nematodes.204 It is believed that larval excretory–secretory products, including various enzymes and metabolic wastes produced by nematode larvae, cause localized toxic effects

Table 3.10 Infectious causes of Leber idiopathic stellate neuroretinitis in childhood Bartonella hensalae (cat scratch disease) Mumps Boriella burgdolferi (Lyme disease) Toxocara optic neuritis Toxoplasma optic neuropathy Tuberculosis Syphilis Leptospirosis Chicken pox Diffuse unilateral subacute neuroretinitis

Table 3.11 Suggested medical evaluation for neuroretinitis in childhood Cat scratch skin test Tuberculin skin test FTA-ABS (syphyllis test) Serum testing for · Bartonella · Lyme disease · Toxoplasmosis · Toxocara canis · Epstein-Barr virus · Leptospirosis · West Nile virus

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and/or stimulate an inflammatory response, especially one mediated by eosinophils.204 Direct photocoagulation has proven successful in eradicating the nematode and halting the progression of visual loss.192 Oral treatment with the antihelminthic agent thiabendazole has met with success in some patients and has been recommended for use in cases in which the worm cannot be located.192 In many Latin American countries, such as Venezuela, DUSN is seen primarily in young patients without a significant gender predilection.107,527 Occasionally, ocular involvement may be bilateral.123 In the United States, DUSN secondary to Baylisascaris procyonis (raccoon roundworm) should also be considered. West Nile virus is a newly recognized cause of optic neuritis and optic atrophy that should be considered when accompanied by multifocal choroiditis and occlusive vasculitis.82,400 Ocular symptoms such as photophobia, retrobulbar pain, and diplopia have also been reported.570 Noninfectious disorders can mimic neuroretinitis. These etiologies should be suspected when atypical features such as bilaterality, lack of vitreous cells, lack of infectious risk factors, or no significant visual recovery are noted.559 It is important to check the blood pressure and rule out hypertensive retinopathy, particularly in bilateral cases.334,353 Bilateral neuroretinitis can also result from unruptured intracranial arteriovenous malformations (AVMs).559 The most common infectious etiology, by far, is cat scratch disease, but numerous other infectious and noninfectious disorders have been described. Both neuroretinitis and acute retinal necrosis occasionally follow chickenpox in children.340 Shoari and Katz509 described recurrent neuroretinitis in an adolescent with ulcerative colitis. Gass190 described acute visual loss with optic disc swelling, peripapillary exudate, and a macular star in two children with progressive facial hemiatrophy (Parry–Romberg syndrome). One of these children had angiographic evidence of increased peripheral retinal vascular permeability. Both patients developed optic atrophy as the peripapillary and macular exudation cleared, but neither demonstrated progressive loss of visual field. Similar cases have since been reported.474 The pathogenesis of this acute neuroretinopathy is not known.190 Lecleire-Collet et al333 described a stellate neuroretinitis in an 11-year-old girl with tubulointerstitial nephritis and uveitis (TINU) syndrome. It is important to bear in mind that children with hypertensive retinopathy can present with bilateral disc edema with a macular star, which may thereby simulate neuroretinitis.334 Bartonella can induce sudden bilateral blindness without systemic signs of cat scratch disease.124 In 1983, Kincaid and Schatz307 formally described the idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome. The most common ocular findings are the characteristic aneurysmal dilatations of the retinal and optic nerve head arterioles. This condition typically occurs in young patients.226 These aneurysmal dilatations generally

3 The Swollen Optic Disc in Childhood

leak on fluorescein angiography but tend not to cause subretinal, retinal, or vitreous hemorrhages.226 Peripapilary subretinal fluid and lipid deposition, along with peripheral capillary nonperfusion are common findings and can lead to retinal neovascularization. Vitritis may also be present. The pathophysiology is unclear, although an autoimmune mechanism has been suggested.592 The IRVAN syndrome can be associated with optic disc swelling in children.83,226,307 In 1973, Karel et al278 reported a series of children with uveitis. Among these children, a 15-yearold girl had fluorescein angiographic evidence of vasculitis and numerous aneurysmal changes on the optic nerve head and along the first- and second-order arteriolar bifurcations. Visual loss is due to a combination of exudative maculopathy and sequelae of retinal ischemia. Capillary nonperfusion is often present, necessitating panretinal photocoagulation. One of the most characteristic features is the presence of numerous aneurysmal dilatations of the retinal and optic nerve head arterioles. These vascular abnormalities are present on the optic nerve head as well as on the retinal arterioles, either at or near the major branching sites. They typically have a triangular or “Y”-shaped morphology, but also are seen in a coiled configuration, resembling knots in the arteriolar tree. This process starts around the optic disc and marches out toward the periphery, eventually causing peripheral retinal ischemia. Poor vision results in about 50% of cases.83 Papilledema from elevated intracranial pressure rarely coexist.226 Systemic corticosteroids have little effect on the progression of the disease, and associated systemic disease is not found.83

Ischemic Optic Neuropathy Classic spontaneous anterior ischemic optic neuropathy (AION) is rare in children. There is new evidence that the spontaneous optic nerve infarction of adulthood may actually be precipitated by venous insufficiency in adults, with venous congestion causing initial disc edema with creation of a compartment syndrome.346 Anterior ischemic optic neuropathy in children usually occurs under pathologic circumstances, as in diabetic papillopathy.90 Secondary nonarteritic ischemic optic neuropathy is a rare event in childhood, occurring mostly in the setting of spinal surgery or peritoneal dialysis, and hypovolemia was postulated to be the major etiology.67,330,519 Children subjected to vigorous treatment of accelerated hypertension and children with migraines and prothrombotic disorders have also developed AION.90 Those children capable of cooperating for visual field examination typically show an altitudinal defect in the affected eye. Treatment of pulmonary hypertension with sildenafil may have led to the development of ischemic optic neuropathy in one 5-year-old child.519

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Pseudopapilledema

AION rarely occurs in children with optic disc drusen.406,440 Rare cases of AION may complicate cranial vault reconstruction. Lee et al338 described a 5-year-old boy who developed bilateral blindness following cranial vault reconstruction for nonsyndromic sagittal synostosis. Prone positioning, intraoperative blood loss, controlled hypotension during surgery, and eyelid edema may have contributed to this blindness. However, his visual acuity gradually recovered to 3/200 in the right eye and 20/20 in the left eye. Ischemic optic neuropathy may produce sudden blindness in children on continuous peritoneal dialysis.325 Patients generally present with light perception and bilateral mydriasis, unreactive to bright light. Retinal examination discloses bilateral disc swelling, edema, and hemorrhages. Blood pressure is generally low, and dehydration may or may not be present. Hypovolemia is suspected to be the cause. Partial improvement of vision may occur over several months. Kim et al304 described a 2-year-old child with end-stage renal disease on continuous peritoneal dialysis who lost vision bilaterally and had unreactive pupils bilaterally secondary to AION. He was dehydrated and received intravenous fluid on admission, as well as methylprednisolone and levodopa. On day 3, his pupils again became reactive to light, and his vision improved. A combination of acute and chronic ischemia may also cause AION in patients with autosomal recessive polycystic kidney disease who are not on dialysis. One of these patients had massive blood loss secondary to esophageal varices from associated portal venous hypertension.91 Posterior ischemic optic neuropathy (PION) following spine surgery has been reported in both adults and children.69,305 Most patients initially have normal-appearing discs without swelling, with gradual development of optic atrophy.69 Although younger patients have a better prognosis for visual recovery, some patients fail to recover.305 Special features of complex spinal surgery that may predispose to PION include long operating times, substantial intraoperative blood loss, deliberate hypotensive anesthesia, prone positioning and, possibly, direct pressure on the globe from a badly positioned headrest.305

Autoimmune Optic Neuropathy Autoimmune optic neuropathy was first described by Dutton et al.137 His three patients were defined by a recurrent corticosteroid-dependent optic neuropathy.180 Elevated antinuclear antibodies without defined collagen-vascular disease were the early markers for this disorder. Kupersmith’s subsequent series319 included anticardiolipin antibody in their evaluation and found four of six patients to be positive for the disorder. Bielory et al48 found that 82% of their patients with autoimmune optic neuropathy were positive for the IgM idiotype. Skin biopsy usually demonstrated abnormalities on

light microscopy, immunofluorescence, or both.48 It is unclear whether anticardiolipin antibodies represent a marker for the condition or whether they are immunogenic. Most patients do not demonstrate the classic triad of thrombocytopenia, vasoocclusion, and recurrent miscarriage, and rarely develop a defined collagen disease. Frohman et al180 described autoimmune optic neuropathy in a 4-year-old girl who experienced four episodes of bilateral optic neuritis with mild concurrent weakness, ataxia, or dizziness. Autoimmune optic neuropathy was diagnosed because of the presence of anticardiolipin antibody and an abnormal skin biopsy with thrombin and immunoreactant deposition. Although autoimmune optic neuropathy in adults is usually treated with immunosuppression, she was treated with corticosteroids, gammaglobulin (because of the risk of long-term immunosuppression in a child), and aspirin, which diminished the intensity of her attacks. Optic disc swelling can accompany the autoimmune polyendocrinopathy syndrome, type 1 (also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED] syndrome).84 This rare immune disorder causes progressive endocrine tissue destruction, cell-mediated immunity deficiency, and ectodermal dystrophies. Clinical manifestations usually appear in childhood and consist of hypoparathyroidism, oral candidiasis, and adrenocortical insufficiency, chronic malabsorption, and diarrhea. Ocular complications include dry eye, iridocyclitis, cataract, retinitis pigmentosa, optic disc swelling, and optic atrophy.377 Antibodies against the retina and optic nerve have been found in one patient with autoimmune polyendocrinopathy syndrome.586

Pseudopapilledema Anomalous elevation of the optic disc is a primary diagnostic consideration in the child referred for papilledema.252 Buried drusen in the optic disc is the most common form of pseudopapilledema in childhood and must be distinguished from other causes of pseudopapilledema, such as hyperopia, myelinated nerve fibers, epipapillary glial tissue, and hyaloid traction on the disc.484

Optic Disc Drusen The word drusen, of Germanic derivation, originally meant tumor, swelling, or tumescence.357 According to Lorentzen,357 the word was used in the mining industry approximately 500 years ago to indicate a crystal-filled space in a rock. Other terms such as hyaline bodies and colloid bodies are occasionally used to describe drusen of the optic disc.174

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The fact that drusen may closely simulate early or chronic papilledema, that they are associated with visual field defects, and that they occasionally show solitary hemorrhages often serve to complicate the diagnostic picture and impart a sense of urgency to the diagnosis.479 If buried drusen go unrecognized, the elevated optic discs may precipitate inappropriate diagnostic studies.467 The conceptual problem that persists in understanding the evolution of disc drusen comes from viewing drusen as the cause rather than the effect of an underlying configurational anomaly of the disc. This tendency carries over into our analysis of associated complications (e.g., the lack of correspondence between visual field abnormalities with the position of visible drusen on the disc has puzzled many). It is helpful to recognize at the outset that the time course of the evolution of optic disc drusen and the histopathological findings suggest that disc drusen actually result from axonal degeneration rather than encroaching upon adjacent axons to cause their degeneration. Disc drusen signify a chronic, low-grade optic neuropathy measured over decades.

Epidemiology Lorentzen356 examined 3,200 routine cases from an ophthalmological practice in Denmark and found that 11 had drusen of the optic disc (for a prevalence of 0.34%). This prevalence increased by a factor of 10 in family members of patients with disc drusen.357 Friedman et al176 examined 737 cadavers and found disc drusen in 15. The drusen were often minute and situated deep within the optic nerve tissue. Francois,168 and later Lorentzen, concluded that familial drusen are transmitted as an autosomal dominant trait. Subsequent studies

3 The Swollen Optic Disc in Childhood

have confirmed the familial nature of this anomaly.254,356,517 Disc drusen are rare in blacks.254,366,467 The early notion that disc drusen are associated with hyperopia has not been substantiated.254,398,467 In one large study,467 visible disc drusen were bilateral in about two-thirds of cases, whereas pseudopapilledema associated with buried drusen was bilateral in 86% of cases. Although Erkkila147 found a high prevalence of clumsiness, learning disabilities, and neurological problems in her Finnish population of children with drusen, subsequent studies have failed to substantiate these findings.

Ophthalmoscopic Appearance in Children In our experience, most childhood cases present initially with pseudopapilledema secondary to buried drusen (Fig. 3.20). In this setting, the disc appears elevated, and its margins are blurred or obscured.174 The elevated disc may have a gray or a yellow-white discoloration. Disc drusen tend to become more ophthalmoscopically conspicuous with age.381 In older children, there is often a scalloped contour to the disc margins, due to the presence of partially buried drusen protruding from the edge of the disc into the peripapillary retina.174 Buried drusen are most visible at the margin of the disc, where they impart an irregular lumpy-bumpy contour to the line of demarcation between the elevated disc and the retina (Fig. 3.21). Exposed drusen are more frequently found on the nasal side of the optic disc. Surface drusen appear as yellowish, globular, hemitranslucent formations on the optic disc, often accumulated in larger or smaller conglomerations357 (Fig. 3.2). They may occur singularly, in grape-like clusters, or as fused conglomerations, varying in size from small dots to several vein widths in diameter.174 With direct illumination,

Fig. 3.20 (a, b) Two examples of pseudopapilledema with buried drusen. Note cupless discs, anomalous vasculature, and crescentic circumpapillary light reflexes. A few surface drusen are visible in (b)

Pseudopapilledema

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Fig. 3.21 (a, b) Two examples of pseudopapilledema with surface drusen. Note peripapillary pigment atrophy in (b)

Fig. 3.22 (a) Buried disc drusen with superior and inferior juxtapapillary subretinal neovascular membranes. (b) Fluorescein angiogram demonstrates typical patchy hyperfluorescence of disc drusen,

along with late peripapillary staining corresponding to juxtapapillary subretinal neovascular membranes. Courtesy of Stephen C. Pollock, M.D.

the central portion of each druse shines uniformly, while the border may appear as a glistening ring. With indirect illumination of the druse from light focused on the peripapillary retina, the druse shines uniformly, except for a brighter, semicircular marginal zone on the side opposite the spot of light (known as inverse shading). In addition to the small size of the optic disc and the absence of a central physiological cup, the disc vasculature is anomalous (Fig. 3.21). The major retinal vessels are increased in number and often tortuous (Fig. 3.21). They tend to branch early and sometimes trifurcate or quadrificate. The prevalence of cilioretinal arteries is also increased, with estimates ranging

from 24.1%400 to 43%.147 Mustonen398 found peripapillary atrophy or pigment epithelial derangement in 29.7% of eyes (Fig. 3.22). Retinal venous loops or anomalous retinociliary shunt vessels are occasionally seen.

Distinguishing Buried Disc Drusen from Papilledema The distinction between pseudopapilledema associated with buried drusen and papilledema (or other forms of optic disc edema) is sometimes difficult, but there are several clinical signs that serve to distinguish these two conditions (Table 3.12).252

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Table 3.12 Ophthalmoscopic features useful in differentiating optic disc swelling from pseudopapilledema associated with buried drusen in children Optic disc swelling Pseudopapilledema with buried drusen Disc vasculature obscured at disc margins Elevation extends into peripapillary retina Graying and muddying of peripapillary nerve fiber layer Venous congestion ± exudates Loss of optic cup only in moderate to severe disc edema Normal configuration of disc vasculature despite venous congestion No circumpapillary light reflex Absence of spontaneous venous pulsations

Disc vasculature remains visible at disc margins Elevation confined to optic disc

The late phases may be characterized by some minimal blurring of the drusen that may either fade or maintain fluorescence (staining). Unlike in papilledema, however, there is no visible leakage along the major vessels.480,517 Venous anomalies (venous stasis, venous convolutions, and retinociliary venous communications) and staining of the peripapillary vein walls are occasionally seen.278

Sharp peripapillary nerve fiber reflexes No venous congestion No exudates Small, cupless disc

Increased major retinal vessels with early branching and anomalous trifurcations and quadrifurcations Crescentic circumpapillary light reflex Spontaneous venous pulsations may be present or absent

In papilledema, the swelling extends into the peripapillary retina and obscures the peripapillary retinal vasculature. In pseudopapilledema, there is a discrete, sometimes grayish or straw-colored elevation of the disc without obscuration of vessels or opacification of peripapillary retina. Hoyt and Knight253 have called attention to the graying or muddying of the peripapillary nerve fiber layer that occurs with swelling of the optic disc from papilledema or other causes. In pseudopapilledema associated with buried drusen, light reflexes of the peripapillary nerve fiber layer appear sharp, and the elevated disc is often haloed by a crescentic peripapillary ring of light that reflects from the concave internal limiting membrane surrounding the elevation (Fig. 3.20). This crescentic light reflex is absent in papilledema, due to diffraction of light from distended peripapillary axons.147,244,253 Single splinter or subretinal optic disc hemorrhages are occasionally seen with disc drusen, but exudates, cotton wool spots, hyperemia, and venous congestion are conspicuously absent.244,357 OCT studies have generally shown a thickening of the peripapillary nerve fiber layer in papilledema and in pseudopapilledema with drusen.162,277,376,464,485

Neuroimaging The distinction between papilledema and pseudopapilledema has been aided by CT scanning and ultrasonography, which readily demonstrate calcification within the elevated optic disc.37,179 It is not uncommon to see a child referred for possible papilledema arrive for consultation with their “negative” CT scan in hand, only to find undetected calcification of the optic discs on review of the scan (Fig. 3.23). One large study322 found that drusen of the optic disc are more reliably diagnosed using B-scan echography than CT scanning or B-scan echography. OCT has demonstrated that many cases of papilledema have peripapillary subretinal fluid and submacular fluid that is not clinically evident.251

Histopathology Optic disc drusen are situated anterior to the lamina cribrosa; they occur nowhere else in the brain. They consist of homogenous,

Fluorescein Angiographic Appearance Discs with ophthalmoscopically prominent drusen may exhibit autofluorescence in the preinjection phase.174 This is followed by a true nodular hyperfluorescence corresponding to the location of the drusen. Hyperfluorescence, which is typically mild, begins in the arteriovenous phase and continues into the late phases. The superficial disc capillary network may show prominence in areas overlying buried drusen (Fig. 3.22).174

Fig. 3.23 “Normal” CT scan showing posterior scleral calcification corresponding to optic disc drusen. Courtesy of Stephen C. Pollock, M.D.

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Pseudopapilledema

globular concretions, often collected in larger, multilobulated agglomerations. Individual drusen usually exhibit a concentrically laminated structure that is not encapsulated and contains no cells or cellular debris.357 Drusen are often most concentrated in the nasal portion of the disc. The optic disc axons are atrophic adjacent to large accumulations of drusen.56,177,357 Drusen take up calcium salts and must be decalcified before being cut into sections for histological study.357

OCT study162 failed to show this association. Alternatively, Antcliff and Spalton18 found optic disc drusen in only 1 of 27 relatives of 7 probands with bilateral optic disc drusen. However, 57% had anomalous vessels and 49% had no optic cup. They concluded that the primary pathology of optic disc drusen is likely to be an inherited dysplasia of the optic disc and its blood supply, which predisposes to the formation of optic disc drusen. Figure 3.24 summarizes our current understanding of the pathogenesis of optic disc drusen and their attendant complications.366

Pathogenesis The primary developmental expression of the genetic trait for drusen may be a smaller-than-normal scleral canal.367,396 The peripapillary sclera forms after the optic stalk is complete.396 Mesenchymal elements from the sclera then invade the glial framework of the primitive lamina, reinforcing it with collagen.396 An abnormal encroachment of sclera, Bruch’s membrane, or both, on the developing optic stalk would narrow the exit space of optic axons from the eye. The absence of a central cup in affected eyes is consistent with the existence of axonal crowding. Drusen are often first detected clinically and histopathologically at the margins of the optic disc, which raises the possibility that the rigid edge of the scleral canal may be an aggravating factor in producing a relative mechanical interruption of axonal transport.396 In 1962, Seitz and Kersting498 first suggested that disc drusen may be the product of chronic degenerative changes in ganglion cell axons. In 1968, Seitz496 concluded from a series of histochemical studies that drusen originate from axonal derivatives of disintegrating nerve fibers resulting from a slow degenerative process. Sacks et al476 advanced an alternative hypothesis that formation of drusen is secondary to the associated abnormal disc vascular pattern, which is conducive to leakage of nonformed elements such as plasma proteins from the blood. According to Sacks, these elements serve as a nidus for the deposition of other materials in the perivascular space, which then gradually increase in size and coalesce. Spencer528 hypothesized that axonal crowding may provide the anatomical substrate for impaired axoplasmic transport anterior to the lamina cribrosa that, over years, leads to intracellular mitochondrial calcification, axonal rupture, extrusion of mitochondria into the extracellular space, and the appearance of drusen on the surface of the disc. Tso favored a similar mechanism but believed that abnormal axonal metabolism, rather than axonal transport, was responsible for the accumulation of disc drusen.388,549 The lower prevalence of optic disc drusen in African Americans, who have a larger disc area with less potential for axonal crowding, is consistent with the notion of axonal crowding as a fundamental anatomical substrate for formation of disc drusen.286 Although previous studies have indicated that eyes with optic disc drusen have a small scleral canal,273,396 a more recent

Ocular Complications Optic disc drusen should not be viewed as an innocuous condition. While the finding of disc drusen is generally compatible with preservation of good visual function, patients rarely experience acquired progressive loss of visual field or visual acuity via a number of different mechanisms. Acquired visual loss in eyes with drusen is rare in childhood but may afflict young adults. As such, it is appropriate to inform patients that, while disc drusen rarely cause blindness, there

Fig. 3.24 Pathogenesis of optic disc drusen. Adapted from Tso549

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is a remote possibility that affected patients may develop visual symptoms later in life. Visual field defects have been detected in 71–87% of eyes with visible disc drusen and in 21–39% of eyes with pseudopapilledema but no visible drusen.357,400,486 In most cases, the asymptomatic nature of the defects reflects the insidious attrition of optic nerve fibers over decades.486 Less common but equally recognized is the abrupt visual field loss that may accompany vascular occlusions or hemorrhagic phenomena.486 Using Goldmann perimetry, Savino et al486 found field defects in 71% of patients with visible drusen, as opposed to only 21% with buried drusen. Visual field defects fall into three general categories: (1) nerve fiber bundle defects; (2) enlargement of the blind spot; and (3) concentric field constriction.174 Several studies noted inferonasal steps to be the most common nerve fiber bundle defect, but arcuate defects and sector defects are not uncommon.356,357,486,530 Mustonen found an afferent pupilary defect associated with asymmetrical visual field defects in 14 of 200 patients with optic disc drusen.398,399 Miller380 stated that an afferent pupillary defect is the rule rather than the exception in the setting of unilateral or asymmetrical visual field loss from optic disc drusen without visual acuity loss. Although concentric constriction of the visual field is recognized as a chronic phenomenon, three adults have recently been documented to have sudden severe visual field constriction with preservation of central vision.382,388 There was no disc swelling or retinal edema to suggest an ischemic process in these patients. Visual field defects are uncommon in eyes with buried optic disc drusen.284 The pathogenesis of visual field loss in eyes with disc drusen could involve one or more of the following mechanisms: (1) an abnormality in axoplasmic flow leading to dysfunction of nerve fibers (the formation of drusen has been postulated to be related to axonal degeneration from altered axoplasmic flow),528,549 (2) compression of nerve fibers by the drusen, or (3) ischemia in the optic nerve head.41 The visual field defects often fail to correspond to the position of the visible drusen on the disc.483,484 The presence of disc drusen also does not preclude superimposition of field defects from other ocular or intracranial diseases.486 Transient visual loss was reported in 8.6% of the patients with disc drusen in Lorentzen’s study.357 Episodes of transient visual loss may be a harbinger of vascular occlusions in some patients.407 Superficial splinter or flame-shaped hemorrhages on the surface of the disc or peripapillary area may be seen in eyes with optic disc drusen.398,481 Splinter hemorrhages associated with optic disc drusen tend to be single and prepapillary in location, in contrast to the multiple hemorrhages in the nerve fiber layer that characterize papilledema.244 They are not visually significant but may cause diagnostic confusion if they arouse suspicion of papilledema.174 Large superficial hemorrhages rarely extend into the vitreous.

3 The Swollen Optic Disc in Childhood

Deep peripapillary hemorrhages have been documented in children with disc drusen.147,467 These hemorrhages may be subretinal or subpigment epithelial and are typically circumferentially oriented around the disc. The question of whether these hemorrhages can be caused by compression of thinwalled veins by drusen conglomerates or by erosion of the vessel wall by the sharp edge of the druse remains unsettled.278 Wise et al584 postulated that enlarging disc drusen could result in circulatory compromise and local hypoxia, which might stimulate the growth of new vessels between the RPE and Bruch’s membrane, which are prone to hemorrhage. Peripapillary pigmentary disruption may remain following resolution of subretinal hemorrhage. Subretinal hemorrhage may also occur in papilledema, but its occurrence in early papilledema is rare and should suggest the possibility of disc drusen.244 Peripapillary subretinal neovascularization is a recognized complication in eyes with disc drusen (Fig. 3.25). Peripapillary subretinal neovascularization may manifest as a peripapillary subpigment epithelial hemorrhage and may be associated with either transient or permanent visual disturbances.584 In severe cases, this complication may simulate a neuroretinitis (Fig. 3.22). Harris et al227 found subretinal neovascularization in seven eyes of 57 patients with optic disc drusen. They also noted that hemorrhages occurring in the absence of choroidal vascularization produced no symptoms and resolved without sequelae, while hemorrhages resulting from choroidal neovascularization commonly produced visual symptoms. In their study, six of seven eyes with neovascular membranes retained visual acuities of 20/40 or better. On the basis of their findings, they recommended observation rather than laser photocoagulation for peripapillary choroidal neovascularization associated with disc drusen.

Fig. 3.25 Ten-year-old child with buried drusen and subretinal neovascular membrane simulating neuroretinitis. Courtesy of Stephen C. Pollock, M.D.

Pseudopapilledema

Vascular occlusions have been reported in patients with disc drusen. The most common of these causes ischemic optic neuropathy, which may occur as a single episode or as successive episodes of discrete visual loss over years.483 Karel et al278 documented ischemic optic neuropathy in three patients (including one 13-year-old boy) with optic disc drusen. Branch retinal artery occlusion, central retinal artery occlusion, and central retinal vein occlusion have also been reported. Retinal vascular occlusions can occur in young adulthood, and rare cases in children have been documented.407,437 The mechanism by which disc drusen produce vascular occlusion is uncertain.407 The following theories have been advanced: ·· Vascular anomalies are commonly associated with intrapapillary drusen, and it has been suggested that these tortuous vessels with abnormal branching patterns and loops are more susceptible to disrupted hemodynamics.407 ·· Disc drusen are associated with small, cupless discs, which may predispose to crowding of the vasculature and vascular compromise. The association of ischemic optic neuropathy with small, cupless discs is well established.483 ·· Drusen are hard, unyielding structures that may directly compromise adjacent vessels.407 Peripapillary central serous choroidopathy has been described in association with disc drusen.371 Fluorescein angiography showed a bright hyperfluorescent spot superonasal to the disc. The detachment resolved following focal laser photocoagulation of the RPE defect. Ischemic optic neuropathy. Ischemic optic neuropathy is a rare complication of optic disc drusen that seems to be confined to the adult population. It has been attributed to the small scleral canal that foreordains optic disc drusen.286,350,406,439 Loss of central acuity has been reported as a rare complication of disc drusen. In most cases, this follows a series of episodic, stepwise events that progressively diminish the peripheral visual field.41,312 Loss of visual acuity should only be attributed to disc drusen after potential intracranial causes have been ruled out.

Systemic Associations Retinitis pigmentosa. Globular excrescences of the optic nerve head are occasionally seen in patients with retinitis pigmentosa. They differ in appearance from typical disc drusen in that the disc does not appear elevated, and they often lie just off the disc margin in the superficial retina. Some investigators have documented an increase in size, leading to the conjecture that they may be hamartomas rather than drusen.119,430 More recent histopathological examination has confirmed that the globular excresences of the optic nerve in

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retinitis pigmentosa are indeed drusen.436 Children with retinitis pigmentosa and buried drusen may present with optic disc elevation and masquerade as having neurological disease.235 The combination of vitreous cells with optic disc elevation may masquerade as uveitis in a child with retinitis pigmentosa. In this setting, the finding of attenuated retinal arterioles provides an important (and easily overlooked) clue to the diagnosis, which is confirmed by electroretinography.235 A distinct autosomal recessive syndrome of nanophthalmos, retinitis pigmentosis, foveoschisis, and optic disc drusen caused by mutation in the MFRP gene has also been recognized.112 Pseudoexanthoma elasticum. The incidence of optic disc drusen in patients with pseudoxanthoma elasticum is 20–50 times greater than in the general population.95 Disc drusen may be the earliest clinical manifestation of pseudoxanthoma elasticum.95 Coleman et al95 postulated that an abnormal aggregation of macromolecules with a high affinity for calcium (which affects elastin in the dermis, arterial walls, and Bruch’s membrane) may also develop at the lamina cribrosa, disrupting axonal transport and leading to disc drusen formation. The association of angioid streaks with disc drusen should suggest the systemic diagnosis of pseudoxanthoma elasticum. Megalencephaly. Hoover et al249 found megalencephaly in 3 of 40 children with pseudopapilledema and cautioned that such children can be misdiagnosed as having hydrocephalus. Migraine headaches. Migraines are said to occur with increased frequency in patients with disc drusen.400,564 Some have pointed out that the concurrence of migraine and optic disc drusen probably reflects the frequent and often expedited referral of patients with headache and elevated discs for specialty evaluation.407 Pigmented paravenous retinochoroidal atrophy. Disc drusen were recently noted in a patient with pigmented paravenous retinochoroidal atrophy.593 This association may be fortuitous. Growth Hormone Deficiency. It has been proposed that pseudopapilledema may be associated with growth hormone deficiency and suggested that this association should be considered before diagnosing children receiving recombinant human growth hormone as having IIH.96 Miscellaneous. Pseudopapilledema with or without optic disc drusen may be seen in association with a variety of chromosomal syndromes.53,92,58a5

Natural History and Prognosis The evolution of disc drusen is a dynamic process that continues throughout life. It is rare to see visible drusen or significant optic disc elevation in an infant. During childhood, the involved optic discs begin to appear “full” and acquire a tan,

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yellow, or straw color.528 Gradually, buried drusen become apparent as they produce subtle excrescences that impart a scalloped appearance to the margin of the disc. Buried drusen gradually enlarge, calcify, and become visible on the surface of the disc.381 In adult years, the optic disc elevation diminishes, and the disc slowly becomes pale as the nerve fiber layer thins.528 It is rare to see optic disc elevation in elderly adults with drusen. This evolution reflects the slow attrition of optic axons over decades. Despite this process, most patients remain asymptomatic and retain normal acuity. Ultrasonography appears to be equally sensitive in demonstrating buried disc drusen.53 It has the advantage of not subjecting the child to radiation; however, it requires skilled personnel and has the relative disadvantage of not simultaneously imaging the brain.

Ocular Disorders Associated with Pseudopapilledema The small, cupless disc associated with optic disc drusen is the most common cause of pseudopapilledema. Other local causes include the following: ·· A persistent anterior hyaloid artery may produce anterior traction on the optic disc.303 ·· Epipapillary glial tissue associated with Bergmeister’s papilla may produce anterior traction that elevates the disc. Flat opaque epipapillary glial tissue may obscure visualization of the underlying disc margins and thereby simulate disc edema. ·· Hypermetropic or nanophthalmic eyes with small scleral canals may have elevated optic discs.542 Nanophthalmic eyes may also be associated with a solitary retinal fold extending from the disc to the macula. ·· Juxtapapillary myelinated nerve fibers are occasionally mistaken for papilledema.542

3 The Swollen Optic Disc in Childhood

intracranial pressure, the elevated optic discs did not appear to be swollen in these cases. Three children showed partial, complete, or intermittent resolution of the disc elevation. Children with Down syndrome may also develop true optic disc edema by several different mechanisms. Taylor542 has noted optic disc swelling in a child with Down syndrome that resolved after 2 weeks of using elbow splints. He attributed the disc edema to the compressive/decompressive effects of the severe eye poking that can be seen in this condition. Less, commonly, children with Down syndrome can develop IIH (Fig. 3.26).148 If ophthalmoscopic signs of papilledema (i.e., venous distension, obscuration of vessels at the disc margin, hemorrhages, exudates) are present, children with Down syndrome associated with optic disc elevation should not be relegated to a benign diagnosis until elevated intracranial pressure is ruled out by a lumbar puncture.

Alagille Syndrome The Alagille syndrome, or arteriohepatic dysplasia, is a wellrecognized multiple-malformation syndrome consisting of a paucity of intrahepatic biliary ducts, cholestatic facies, peripheral pulmonary artery hypoplasia or stenosis (often with other cardiac abnormalities), butterfly like vertebral arch defects, and variable ocular defects, most commonly posterior embryotoxon.5 Both sporadic and familial cases have been reported, and it has been suggested that Alagille

Systemic Disorders Associated with Pseudopapilledema Down Syndrome Children with Down syndrome are said to have a characteristic optic disc appearance consisting of a rosy plethoric disc, RPE attenuation surrounding the disc, and an increased number of major vessels emanating from the disc.2 Catalano and Simon80 have recently described optic disc elevation without venous engorgement or obscuration of vessels in five children with Down syndrome. Although two of these had congenital cardiac defects that cause right to left shunts that may cause elevated

Fig. 3.26 Down syndrome. This elevated left optic disc shows distended veins and peripapillary elevation. The opening CSF pressure of 24 cm H2O. We were unable to ophthalmoscopically distinguish papilledema from pseudopapilledema

Pseudopapilledema

syndrome is inherited as an autosomal dominant trait with variable expressivity and reduced penetrance.395,510 An interstitial deletion of the short arm of chromosome 20 recently has been found in some patients with the Alagille syndrome.601 It has been proposed that this condition is a contiguous gene syndrome assigned provisionally to the short arm of chromosome 20.488 The Alagille syndrome comprises a broad spectrum of ocular anomalies involving the cornea, iris, retina, and optic

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disc.62 Characteristic ocular anomalies include posterior embryotoxon, slightly small corneas, a peculiar mosaic pattern of iris stromal hypoplasia, anomalous optic discs, and streaky peripapillary depigmentation.62 Optic disc elevation has been described in numerous cases of Alagille syndrome (Fig. 3.27). The optic disc elevation in Alagille syndrome has been attributed to pseudopapilledema, because previous studies have found no leakage of fluorescein at the optic disc, no evidence of drusen by ultrasonography, and no change in

Fig. 3.27 (a) Characteristic optic disc anomalies in Alagille syndrome, including (a) horizontal elongation of disc, (b, c) pseudopapilledema, and (d) anomalous inferotemporal scleral crescent. Note streaky peripapillary depigmentation characteristic of Alagille syndrome

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3 The Swollen Optic Disc in Childhood

appearance in one patient who was observed over a 10-year period.190,465 These findings suggest that the optic disc elevation is a genetically determined anomaly that is unrelated to pulmonary vascular compromise or to metabolic imbalance.62 Patients with Alagille syndrome may also display horizontally elongated or obliquely oriented anomalous optic discs (Fig. 3.27). Three children with Alagille syndrome were recently reported to develop IIH.401

Kenny Syndrome Systemic findings in Kenny syndrome include low birth weight, dwarfism, delayed closure of the anterior fontanel, thickened long bone cortex with stenotic medullary cavities, transient hypocalcemia with hyperphosphatemia leading to tetany, and normal mentation.57 Ocular findings range from uncomplicated nanophthalmos with high hyperopia to severe pseudopapilledema, vascular tortuousity, and macular crowding.57 Autopsy examination of one patient with Kenny syndrome disclosed narrow scleral apertures, with elevation and lateral displacement of disc tissue.57 The patient also had a total absence of parathyroid tissue. Several small, calcified prelaminar drusen-like bodies were noted in one eye. The pseudopapilledema in this condition presumably results from local factors (interruption of axonal transport associated with nanophthalmos and small scleral canals), although the associated metabolic imbalance (i.e., hypocalcemia with or without associated hypoparathyroidism) may also play a role. Kenny syndrome should be suspected when pseudopapilledema and nanophthalmos occur in a child with a history of dwarfism, hypocalcemia, and tetany.

Fig. 3.28 Pseudopapilledema in Leber hereditary neuroretinopathy

permanent, although a subgroup of patients recover one or more small islands of central vision within their central scotoma up to a year or two after vision is lost. (The genetic and systemic aspects of this disorder are detailed in Chap. 4.)

Mucopolysaccharidosis As mentioned earlier, optic disc edema is a common finding in children with mucopolysaccharidosis. Pseudopapilledema may also occur, as documented in a patient with Scheie syndrome.555 The mechanisms of optic disc elevation in the mucopolysaccharidosis are summarized in Table 3.6.

Leber Hereditary Neuroretinopathy Leber hereditary neuroretinopathy is characterized by acute or subacute loss of vision in both eyes that can occur simultaneously or can be separated by weeks, months, or years. It is transmitted by mitochondrial inheritance. Several different mitochondrial mutations that appear to have differing prognoses have heretofore been identified.405 There is a definite male predominance. Visual loss usually occurs in the second to fourth decade but occasionally occurs in childhood. Patients with this disorder and many asymptomatic carriers display characteristic peripapillary retinal alterations consisting of (1) peripapillary microangiopathy, (2) pseudoedema of the nerve fiber layer, and (3) absence of staining on flourescein angiography409,522 (Fig. 3.28). Retinal vascular tortuousity may also be prominent.405 When the disease occurs for the first time in a family, it is often mistaken for papillitis. The disc often initially appears cupless, although cupping may develop as optic atrophy supervenes.405 Central visual loss is

Linear Sebaceous Nevus Syndrome Campbell and Patterson76 described unilateral pseudopapilledema in a child with linear sebaceous nevus syndrome.

Orbital Hypotelorism Awan22 has described an association between orbital hypotelorism and pseudopapilledema with situs inversus of the vessels.

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Chapter 4

Optic Atrophy in Children

Introduction Optic atrophy is a morphologic sequel to a multitude of anterior visual pathway insults that culminate in the loss of retinal ganglion cell axons.573,701,753 Histopathologically, it is characterized by a variable reduction of nerve diameter with loss of axons and little or no gliosis. Ophthalmoscopically, the disc retains its normal size and shows diffuse or segmental pallor. The pallor in optic atrophy has been attributed to thinning of the neural tissue of the optic disc and resulting changes in cytoarchitecture and decreased transmission of light, rather than to loss of optic disc capillaries or astrocytic proliferation.700,702 The ophthalmoscopic appearance of the atrophic disc alone occasionally suggests a specific mechanism of injury.872 In adults and older children with optic atrophy, results of the sensory visual examination (visual acuity, color vision, pupillary responses, visual field examination, and optic disc examination) often suggest certain mechanisms of optic nerve injury and definitively rule out others. In infants and toddlers, however, accurate subjective visual testing is often impossible, and clues to the underlying etiology must be sought in the associated systemic, neurological, and neuroimaging findings in addition to the information obtained in the family and medical history. Infants and children may present with optic atrophy with a known underlying diagnosis (e.g., hydrocephalus, optic glioma) or may require a complete evaluation to establish such diagnosis. Referral may be initiated due to poor vision in one or both eyes or due to the presence of other disorders that require neuro-ophthalmologic consultation as a part of a multidisciplinary workup. A thorough gestational, prenatal, birth, and neonatal history is essential. A history of perinatal head trauma, prematurity, perinatal asphyxia, meningitis, encephalitis, hydrocephalus, and related disorders should be specifically sought. A family history should be obtained, with appropriate examination of family members and pedigree analysis to establish the diagnosis and the mode of transmission of suspected heritable cases.

A thorough ophthalmologic examination should then be undertaken. Attention to the appearance of the optic discs, pupillary examination, visual field testing, color vision performance, and any related physical findings may provide clues to the diagnosis. Long-standing cases with a relatively stable course are often found in children with a history of hypoxia, prematurity, meningoencephalitis, congenital hydrocephalus, microcephaly, craniostenosis, or previous head trauma. The clinical identification of such cases usually obviates the need for further diagnostic workup. In contrast, a previously normal child who develops progressive optic atrophy poses an entirely different diagnostic problem. Such a patient should undergo a thorough neurologic evaluation and, if deemed appropriate, neuroimaging studies with specific views of the anterior visual pathways and posterior fossa should be obtained. Other investigations for neurodegenerative, genetic, and metabolic disorders are customized to fit the overall clinical picture. Optic atrophy is initially evaluated by observing the color of the discs. The disc appears pale, either in a diffuse or in a segmental pattern, and typically shows fewer than normal fine vessels on its surface. The optic discs of young infants may ordinarily appear gray and slightly pale in appearance, even when excessive pressure on the globe while prying the eyelids open (which may cause vascular blanching and apparent pallor) is avoided.441 The examiner must be cautious when concluding that optic atrophy is present in a young infant and should reconsider the diagnosis if it is incompatible with other clinical findings. Similarly, the finding of normal visual acuity in an older child does not exclude the possibility of optic nerve damage because the degree of optic atrophy is not tightly correlated with visual acuity. Certain parameters may impart a misleading appearance of pallor to a normal disc. These include a large optic disc size, a deep physiologic cup, and axial myopia. Ophthalmoscopic inspection of the atrophic disc should be accompanied by an attempt to evaluate the peripapillary nerve fiber layer, if examination conditions permit.683 Generalized thinning, sectoral atrophy, wedge-shaped or

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slit-like defects, and other patterns of nerve fiber layer dropout may be found in children with optic atrophy who are sufficiently cooperative or sedated. Abnormalities in the peripapillary nerve fiber layer often provide early clues regarding axonal loss in equivocal cases of optic atrophy. For instance, selective dropout of the nasal nerve fiber layer is a critical diagnostic sign of band atrophy. Other ophthalmoscopic correlates of nerve fiber layer loss include a more distinct appearance of the peripapillary retinal vessels, variable attenuation of retinal arterioles,272 loss of Gunn dots, and blunting of the macular reflex in children with optic atrophy.755 Although the appearance of the optic disc is usually unhelpful in localizing the site of visual system injury or defining its mechanism, important exceptions exist. Band atrophy is an important localizing sign in children because it signifies selective injury to axons that decussate in the chiasm to the contralateral hemisphere. Recognition of band atrophy is especially important in infants and young children, who commonly present with congenital suprasellar tumors and in whom accurate visual field testing is often impossible. Band atrophy appears as a horizontal stripe of pallor extending from the nasal to the temporal disc margin. Examination of the peripapillary nerve fiber layer shows selective dropout of the nasal sector. (The temporal sector is also absent; however, because the temporal nerve fiber layer is normally difficult to visualize, it cannot be used as a reliable gauge of nerve fiber dropout). The diagnosis of band atrophy can now be confirmed by optical coherence tomography (OCT).584 Bilateral band atrophy occurs exclusively in the setting of chiasmal injury (usually compression from a suprasellar tumor) and is accompanied by bitemporal hemianopia571 (Fig. 4.1). Unilateral band atrophy usually signifies intrauterine retrogeniculate injury with transsynaptic degeneration,369,376 but it may occasionally reflect a pregeniculate abnormality.539 The most common causes of congenital band atrophy in children are unilateral porencephaly, arteriovenous malformation, and ganglioneuroma, which involve the occipital lobe and lead to transsynaptic degeneration. A congenital optic tract syndrome may be a rare cause of congenital homonymous hemianopia and contralateral band atrophy539 (Fig. 4.2). Acquired band atrophy of one optic disc results from injury to the contralateral optic tract, and is usually accompanied by an afferent pupillary defect in the eye with the band atrophy.61a,504 The histology associated with band atrophy was discussed by Unsold and Hoyt.886 In cases purporting to show bilateral diffuse transsynaptic degeneration of the optic nerves due to bilateral cerebral lesions, coexisting primary damage to the optic nerves should be excluded.748 A congenital lesion involving the optic radiations may produce secondary neuronal loss in the lateral geniculate nucleus through the process of transsynaptic degeneration. This leads to a disorder termed homonymous hemioptic

4 Optic Atrophy in Children

hypoplasia, which is characterized by homonymous hemianopia, contralateral band atrophy of the optic disc, and corresponding changes in the nerve fiber layer bilaterally (Fig. 4.3).369,376 Transsynaptic degeneration of the retinogeniculate pathways is well documented to occur in nonhuman primates when the cerebral lesion occurs even during adulthood.208 In the case of humans, retrograde transsynaptic degeneration of the retinogeniculate pathways has been shown to occur following prenatal or perinatal lesions, but its occurrence after cerebral lesions in adults is considered rare.338,480,572 It is, however, well established that retrograde transsynaptic degeneration affects other neural systems in humans even when the injury occurs during adulthood.7,22,100,400,483,549 Some histopathological evidence points to the possibility of transsynaptic degeneration of the retinogeniculate pathway in humans even when the lesion occurs in adults, but the clinical significance is unknown.58 Congenital optic atrophy is uncommon. In infants, congenital disc anomalies are a much more common cause of optic nerve dysfunction than is optic atrophy.406 Many patients with clearly hypoplastic optic nerves show significant associated disc pallor. Hypoplastic nerves may also be misconstrued as atrophic when a white sector of the lamina cribosa is laid bare. In other cases, the hypoplastic disc can be confused with the optic cup, and the lamina cribosa with the neuroretinal rim. This interpretation is made more difficult when a yellowish rim of the retinal pigment epithelium extends over the border of the normal-sized lamina cribrosa. Prematurity is often associated with a unique form of pseudoglaucomatous cupping, which is probably a form of optic atrophy.96,371a Neuroimaging studies of the optic nerves are of limited use in differentiating optic nerve hypoplasia from optic atrophy because the dimensions of the optic nerves are generally reduced in either condition.95,664

Epidemiology Optic atrophy is a major cause of visual disability in children.330,440 In several studies, optic atrophy was found to be the leading cause of severe visual impairment among 2,527 Nordic children, followed by retinopathy of prematurity and amblyopia.330,350 It is also probably the leading cause of visual impairment in mentally handicapped children.89 The increasing survival rate of premature children in recent decades has resulted in an increased incidence of both cortical visual impairment and optic atrophy in infants, the latter largely explained by their greater predisposition to hydrocephalus and, to a lesser extent, associated perinatal hypoxiaischemia. Common infectious disorders, such as tuberculous

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Fig. 4.1 Chiasmal glioma. (a) Sagittal and (b) coronal MR images show diffuse enlargement of optic chiasm in 9-year-old boy who did not have neurofibromatosis. His optic discs (c, d) showed band atrophy more conspicuous on left disc (d)

meningitis, can produce primary optic atrophy.26 Disorders that are rarely encountered in the United States, such as onchocerciasis and intracranial hydatid cysts, may also cause optic atrophy.240 The reported incidence of diseases associated with optic atrophy differs according to series. Referral bias plays an important role, with large neurosurgical referral centers more likely to report higher incidences of compressive or postpapilledema optic atrophy in children who have intracranial tumors or shunt failure and with neurological referral centers more likely to accumulate neurometabolic cases. Not all

cases of optic atrophy in children are readily classifiable. The availability of high-resolution neuroimaging modalities, such as magnetic resonance (MR) imaging, and the increased availability of blood tests to identify genetic mutations and metabolic products of enzymatic defects, have increased the diagnostic yield.564,716 In 1968, Costenbader and O'Rourk176 were able to determine the cause of optic atrophy in a series of children so affected in only 50%, which is in contrast to 89% of children in the series by Repka and Miller.716 In the latter study of 218 children with optic atrophy, the underlying causes included tumors (29%), postinflammatory

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Fig. 4.2 Congenital optic tract syndrome. 11-year-old boy was found to have right homonymous hemianopia on routine testing. His optic discs revealed (a) band atrophy and (b) mild diffuse pallor. (c) MR imaging showed intact optic tract on right (arrow), but absent tract on left

(meningitis, optic neuritis) (17%), trauma (11%), undetermined (11%), hereditary (9%), perinatal disease (9%), hydrocephalus (6%), neurodegenerative disease (5%), toxic/ metabolic disease (1%), and miscellaneous (3%). They found that in 13 children less than 1 year of age with optic atrophy, five had a history of intrauterine infection, prematurity, or perinatal trauma; three had tumors, and five had optic atrophy of undetermined etiology. In the last decade, these authors have found that prematurity and hydrocephalus have become more important causes of optic atrophy.594 In patients without a history of prematurity, perinatal or postnatal trauma, meningitis, optic neuritis, or evidence of familial optic atrophy, the chance of an underlying tumor or hydrocephalus was 45%. The causative tumors included anterior visual pathway gliomas, craniopharyngiomas, other supratentorial tumors, pituitary adenomas, posterior fossa neoplasms, and orbital mass lesions. Rarely, optic atrophy occurs in children with autoimmune and col-

lagen vascular disease.75 Optic atrophy in children is therefore commonly accompanied by other neurological or systemic abnormalities. In this setting, intracranial, genetic, and neurometabolic diseases need to be ruled out. Although mitochondrial mutations account for most hereditary optic neuropathies, mitochondrial abnormalities have not been found in most nonhereditary cases of bilateral symmetrical optic atrophy.88 The natural history of visual loss due to optic atrophy or other causes in children can be difficult to ascertain due to the child's limited ability to provide an accurate history and greater capacity to compensate for handicaps. Children are probably more likely than adults to ignore unilateral visual loss. Many unclassifiable cases of childhood optic atrophy are undoubtedly caused by remote trauma, optic neuritis, neuroretinitis, or other disorders that went unrecognized during the acute phase. Most such cases are unilateral.

Optic Atrophy Associated with Retinal Disease

Fig. 4.3 Homonymous hemioptic hypoplasia. Eight-year-old girl with history of prematurity and perinatal asphyxia. (a) Ophthalmoscopy showed band atrophy of left optic disc with associated thinning of nasal

Optic Atrophy Associated with Retinal Disease Primary retinal disorders that involve the nerve fiber layer eventually lead to optic atrophy, and optic atrophy is a late finding in many diffuse degenerative retinal disorders. It is often possible to recognize optic atrophy associated with retinal disease by noting the concurrent retinal findings,

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nerve fiber layer; (b) Both optic discs were relatively hypoplastic, left one appearing more so. (c) MR scans showed periventricular leukomalacia with preferential involvement of parieto-occipital region bilaterally

especially marked arteriolar narrowing. An electroretinogram (ERG) is suggested in the case of optic atrophy with marked arteriolar constriction (Fig. 4.4). Retinal disorders associated with optic atrophy include the various congenital retinal dystrophies, tapetoretinal degenerations, neuronal ceroid lipofuscinosis (e.g., Batten disease), infectious/inflammatory retinopathies (e.g., diffuse unilateral subacute neuroretinitis, cytomegalovirus (CMV) retinitis, toxoplasmosis), and central retinal or ophthalmic artery occlusion. It should

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Fig. 4.4 Batten disease. Optic discs show bulls-eye maculopathy, temporal disc pallor, and severe arteriolar attenuation (Courtesy of Byron Lam, M.D)

be emphasized, however, that optic atrophy is not a typical feature of Leber congenital amaurosis, even in older patients.835 Optic atrophy, especially of the temporal aspect of the disc, may be the sole funduscopic finding in some patients with cone dystrophy.616,924 Severe optic disc and adjacent retinal atrophy has been reported in two brothers with incomplete congenital, stationary, night blindness associated with a mutation in the CACNA1F gene.602 Disproportionate involvement of color vision, photophobia, and hemeralopia should increase suspicion for cone dysfunction. Cases of old central retinal artery occlusion may be difficult to distinguish from primary optic atrophy because some cases of central retinal artery occlusion show eventual recanalization of the occluded vasculature after permanent inner retinal damage occurs. The two conditions may be distinguished with electroretinography that shows diminished b waves in cases of arterial occlusion. Although the ERG is reportedly normal in primary optic atrophy, full-field ERG has recently been demonstrated to show a selective reduction and loss of the photopic negative response (a response originating from the third-order neurons receiving their signals from cones.306 The pattern ERG, which reflects the activity of ganglion cells and their axons, is also abnormal.532,533

Congenital Optic Atrophy Vs. Hypoplasia Although most prenatal injuries to the developing visual system eventuate in optic nerve hypoplasia, some infants are born with atrophic-appearing discs that are normal in size. Histologically, optic nerve hypoplasia is characterized by a diminution in the number of axons, with normal blood vessels and glial tissue. Optic atrophy is characterized by a

similar histopathology, except that the diameter of the optic nerve may be mildly diminished in some cases and preserved in others. While we have grown accustomed to interpreting optic atrophy as a clinical marker for postnatal visual system injury and hypoplasia as a marker for prenatal injury, the notion that term birth can demarcate these outcomes is simplistic and contrary to clinical experience.374 For example, a congenital hemispheric lesion may be associated with either homonymous hemioptic hypoplasia with no pallor or band atrophy of the optic disc that is contralateral to the side of the lesion (Fig. 4.3). Why should some prenatal visual system injuries lead to hypoplasia and others lead to pallor? We believe that the timing of injury is the critical determinant of whether the injured optic nerve involutes or becomes pale. As gestation proceeds, the optic nerve may become “hardwired,” so that its size and structural integrity are relatively maintained despite a marked diminution of axons. An analogy may be drawn between this scenario and the brain's ability to mount a glial reaction to injury. This response seems to begin in the late second or early third trimester.51 In the fetal brain, there is limited capacity for glial reaction; therefore, necrotic tissue is completely reabsorbed (liquefaction necrosis), resulting in a porencephalic cyst.51 The mature brain, on the other hand, reacts to injury with significant gliosis; the resulting cavity contains glial septations and an irregular glial wall (multicystic encephalomalacia). Similarly, preservation of the structural integrity of the optic nerve in the face of exaggerated dying out (apostosis) of supernumerary axons may require a certain degree of developmental maturation of the glial system and other supporting structures. This notion is consistent with the observation that optic nerve hypoplasia is often associated with other central nervous system (CNS) malformations that occur early in gestation and are not associated with gliosis (e.g., schizencephaly).

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Causes of Optic Atrophy in Children

The prenatal visual system injury may exist as a spectrum ranging from optic nerve hypoplasia (signifying early gestational injury) to atrophy (signifying late gestational injury) (Fig. 4.5), with a mixture of atrophy and hypoplasia occurring with midgestational injuries (Fig. 4.6). This deve lopmental response to injury has been invoked to explain the pseudoglaucomatous cupping seen commonly in children with periventricular leukomalacia.401 The critical periods for developing hypoplasia vs. atrophy in response to prenatal injury have not been defined. The role of other factors, such as the nature of injury (e.g., ischemic vs. toxic) and its duration (acute vs. sustained), is also unclear.

Causes of Optic Atrophy in Children Compressive/Infiltrative Intracranial Lesions Bilateral optic atrophy diagnosed in the first 2 years of life is an ominous sign that may portend recurrent shunt dysfunction, in a hydrocephalic child, or anterior visual pathway compression from a congenital suprasellar tumor. These tumors include craniopharyngiomas, nonfunctional pituitary tumors, gliomas, meningiomas, arteriovenous malformations, aneurysms, metastatic tumors, and arachnoid cysts.

Fig. 4.5 Periventricular leukomalacia with bilateral pseudoglaucomatous cupping and temporal pallor

Fig. 4.6 Combined optic nerve hypoplasia and atrophy in a child with periventricular leukomalacia. Note that it is difficult to distinguish pallor of the temporal neuroretinal rim from visibility of the lamina cribrosa

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Rarely, optic atrophy is associated with suprasellar tumors of maldevelopmental origin, such as lipomas or lipodermoids,339 suprasellar aneurysms,382 or with ipsilateral compression, by an ectatic internal carotid artery.397 Bilateral band atrophy may be recognized when compression primarily involves the chiasm. Band atrophy is best detected with the red-free light on direct ophthalmoscopy, which shows selective loss of the nasal and temporal nerve fiber layer.369,683 Because the temporal nerve fiber layer is poorly visible on direct ophthalmoscopy, the selective absence of the nasal nerve fiber bundle relative to the superior and inferior nerve fiber bundles is used to establish the diagnosis. In the case of chiasmal compression, OCT measurement of the preoperative retinal nerve fiber layer thickness can be predictive of the degree of postoperative visual rehabilitation.766a In addition to optic atrophy, children with congenital suprasellar tumors may display congenital nystagmus (from bilateral sensory visual loss), nystagmus simulating spasmus nutans, see-saw nystagmus, or signs of dorsal midbrain syndrome. Systemic examination may provide some clues to the diagnosis in the form of café au lait spots or signs of emaciation in children with suprasellar glioma, signs of hypopituitarism in craniopharyngioma, and an abnormally large head size in hydrocephalus. Ipsilateral proptosis in a child with unilateral optic atrophy is highly suggestive of orbital optic glioma. The finding of nystagmus in an older child with bilateral optic atrophy is an important diagnostic sign that confirms that visual loss was present in the first 2 years of life. A suprasellar lesion should be excluded in this setting. Unilateral optic nerve compression generally presents with proptosis or sensory esotropia in the preschool years. Optic tract lesions (compressive or otherwise) produce homonymous hemianopia with contralateral band atrophy, but no associated nystagmus. Noncompressive retrogeniculate lesions that are congenital in origin can also produce this constellation of findings. For example, arteriovenous malformations, including those involving the vein of Galen, can present with band atrophy in combination with homonymous hemianopia.432 Macular thickness measurements using optical coherence tomography may prove useful in the evaluation of the amount of ganglion cell loss in patients with band atrophy.584 In compressive lesions of the anterior visual pathways, the degree of optic atrophy is a good predictive sign of the potential restoration of vision following neurosurgical decompression.

Optic Glioma Optic glioma is largely a tumor of childhood, with a mean age at presentation of 9 years (range: birth to old age).223 No gender predilection appears to exist. Seventy-five percent of cases present during the first decade of life, and 90% present during the first two decades.

4 Optic Atrophy in Children

Patients with neurofibromatosis type 1 have a predilection to develop CNS astrocytomas and to show a frequency of optic pathway gliomas of about 15%510 (Fig. 4.7). Most of these tumors are asymptomatic, with visual impairment in only about 20% of affected individuals. The frequency of neurofibromatosis type 1 in patients with optic pathway glioma varies in different series, from 10 to 70%. About onehalf of the tumors are intraorbital and the other half are intracranial. Café au lait spots are often absent or less conspicuous in young children. In patients with neurofibromatosis type 1, optic glioma is

Fig. 4.7 Optic nerve glioma in neurofibromatosis. Left: Bilateral optic glioma in child with NF1. Axial MR image shows characteristic fusiform enlargement of left right optic disc and kiniking of left optic disc. Area of high signal intensity (corresponding to perineural arachnoidal gliomatosis) surrounds core of low signal intensity (optic nerve). Used with permission from Seiff et al782. Right: Sagittal oblique MR shows characteristic fusiform enlargement and superior kinking of the nerve in another child with NF1. Area of high signal intensity (corresponding to perineural arachnoidal gliomatosis) surrounds core of low signal intensity (optic nerve). Used with permission from Brodsky95

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more often multifocal, occasionally affecting both optic nerves without apparent connection at the chiasm.223 Optic pathway glioma may exist in the absence of anterior visual pathway dysfunction. The absence of optic atrophy or papilledema, therefore, does not rule out chiasmal glioma in the child with neurofibromatosis. Lewis et al504 reviewed the ocular and intracranial features of neurofibromatosis in 217 patients, 15% of whom had tumors of the anterior visual pathways. In two-thirds of these, the tumors were not detected by ophthalmologic examination, underscoring the importance of neuroimaging studies in these patients. Due to the heterogeneity of optic pathway gliomas and their varying locations along the anterior visual pathway, a variety of clinical presentations have been noted. However, regardless of the location, most patients eventually develop some degree of visual loss. The visual loss is usually due to astrocytic proliferation, separation of longitudinal axonal bundles, axonal compression with subsequent demyelination, and mechanical disruption of axons.303 There is generally poor correlation between tumor growth and visual acuity.373 Optic nerve tumors commonly present as orbital mass lesions with axial proptosis, painless unilateral proptosis associated with disc edema, neoplastic infiltration of the disc, or optic atrophy. Optic atrophy is eventually noted in most, if not all, cases. Rarely, a congenital suprasellar glioma may be associated with optic disc dysplasia.846 An afferent pupillary defect is usually noted in unilateral or asymmetric cases. Visual field examination usually reveals a central scotoma or, with chiasmal involvement, temporal field defects. Temporal field defects are associated with loss of ganglion cells and nerve fiber layer nasal to the fovea. Optic atrophy is thus noted on the nasal and temporal sides of the disc in the classic “band” or “bowtie” distribution (Fig. 4.1). Proptosis is generally absent in chiasmal and hypothalamic tumors. Chiasmal gliomas usually present in childhood, with unilateral or bilateral (often asymmetric) optic atrophy and visual loss. Hypothalamic or endocrine dysfunction from hypothalamic involvement is also frequently present. This includes precocious puberty, obesity, panhypopituitarism, and dwarfism. Children with early invasion of the hypothalamus, present within the first several years of life with the diencephalic syndrome. Less commonly, hydrocephalus, seizures, cerebrospinal fluid (CSF) rhinorrhea, increased CSF protein, and tumor cells in the CSF have been reported with chiasmal gliomas. Occasionally, untreated patients with chiasmal gliomas may show spontaneous visual improvement despite the absence of tumor shrinkage on neuroimaging studies.512 If the chiasmal lesion expands to involve the nearby third ventricle, obstructive hydrocephalus may result. Spasmus nutans may occur, which may be distinguishable clinically from the benign variety by the presence of an afferent pupillary defect and/or optic atrophy. See saw nystagmus may also occur.

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Previously, plain skull X-rays show classic enlargement of the optic foramen and a J-shaped sella turcica. Computed tomography (CT) shows isodense enlargement of the optic nerve or chiasm, with variable enhancement. Fusiform enlargement of the optic nerve is characteristic. MR studies are now obtained in young children, in order to avoid exposure to ionizing radiation, and may be superior for imaging the intracanalicular and intracranial spaces.393 Optic nerve gliomas arise from astrocytes surrounding optic nerve axons. Histopathology of optic glioma usually reveals juvenile pilocytic astrocytoma with a benign cytologic appearance although mixed and malignant cases occur. An exuberant reactive proliferation of the surrounding meningeal tissues (termed arachnoidal gliomatosis) may accompany those gliomas associated with neurofibromatosis, occasionally causing diagnostic confusion with optic nerve sheath meningioma (Fig. 4.7). In addition to neoplastic growth and arachnoidal gliomatosis, the tumor mass may show enlargement as a result of intralesional hemorrhage, cyst formation, or accumulation of extracellular Periodic Acid Shiff (PAS)positive mucosubstance secreted by the glial cell.223 The malignant form of glioma occurs primarily in adults. Alvord and Lofton23 extensively reviewed the topic of optic glioma. In a review of optic pathway gliomas in neurofibromatosis type 1, Hoyt and Imes375 concluded that “It is agreed that the main bulk of an optic pathway glioma is a low grade neoplasm with unpredictable growth potential. It is not possible to demonstrate clear histological differences between tumors with limited growth and tumors that will grow.” Because most gliomas are benign and enlarge slowly, affected children generally show long-term survival,375 and treatment is controversial. Surgical amputation is considered when there is disfiguring proptosis in a blind eye. When the tumor is confined to the optic nerve, complete surgical excision with clear margin is curative, but many such children have sufficiently useful vision to suggest that conservative management with simple observation is a viable option. Removal or debulking of the orbital portion of the glioma is usually possible while leaving the globe in place. In this situation, the orbital portion of the tumor can be resected without adverse effect, even when the tumor involves the intracranial optic nerves or chiasm. In 1980, Stern and colleagues823 reviewed the histopathologic results of 34 tissue specimens from orbital optic gliomas. In 17 of 18 gliomas from patients with neurofibromatosis, a circumferential perineural pattern of growth in the subarachnoid space with minimal involvement of the intraneural compartment was found. They termed this pattern arachnoidal gliomatosis to signify that there was a marked proliferation of astrocytes over meningoepithelial cells and fibroblasts. In 14 of 16 gliomas from patients without neurofibromatosis, astrocytic proliferation was strictly intraneural with intact pial boundaries. The authors concluded that the perineural pattern of astrocytic proliferation was highly characteristic of neurofibromatosis-associated gliomas.

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Magnetic resonance imaging can often predict tumor histopathology in vivo, since gliomatosis tissue has a long T1 and T2 relaxation time due to its high water content, causing it to appear bright on T2-weighted images and dark on T1-weighted images. Because gliomatosis tissue is primarily perineural (confined to the subarachnoid space surrounding the optic nerve) in neurofibromatosis, MR imaging imparts a double signal to the contents of the expanded dural sheath, with an outer signal that is indistinguishable from CSF and a sharply demarcated inner signal corresponding to the optic nerve (Fig. 4.7). The peripheral CSF intensity signal in orbital optic glioma correlates with the histopathological finding of peripheral arachnoidal gliomatosis and serves as a neuroimaging marker for neurofibromatosis.95,782 When the tumor involves the optic chiasm, the overall prognosis for life diminishes due to hypothalamic or third ventricular involvement. Surgical intervention at this point does not appear to improve survival. Neurosurgical debulking of the tumor and/or ventriculoperotineal shunting procedures are necessary in children with large diencephalic tumors that produce obstructive hydrocephalus. The efficacy of radiation and chemotherapy in these tumors is a subject of debate. Any potential benefit of radiation should be weighed against the potential risks of irradiation to the developing brain. Reported complications after cranial irradiation in children include volume loss and atrophy of normal brain parenchyma, progressive calcification, white matter abnormalities,189,264 abnormalities in behavior, cognitive dysfunction, hypothalamic–pituitary dysfunction, growth retardation, acute lymphoblastic leukemia and other neoplasms,731 visual loss, ocular motor nerve palsy, neuromyotonia, and Moyamoya syndrome.646 Following surgical resection of an orbital optic glioma, several poorly understood phenomena may be observed. Ophthalmoscopic examination and fluorescein angiography may show a normal central retinal arterial circulation,502 and CT scanning and MR imaging may show an optic nerve-like structure that is normal in size and configuration (termed the “phantom” optic nerve).99,793 As detailed in Chap. 11, many optic gliomas have been reported to undergo spontaneous regression.665

Craniopharyngioma Craniopharyngioma is by far the most common supratentorial tumor as well as the most common nonglial intracranial tumor of childhood. It affects primarily children and young adults, but the age range extends from the neonatal period to the eighth decade of life.148 Craniopharyngioma is a histologically benign epithelial neoplasm thought to arise from epithelial vestiges found at the junction of the lower infundibular stem and the pars distalis. These tumors bear resemblance to

4 Optic Atrophy in Children

Rathke's pouch cysts and epidermoid cysts of the region, and the three tumors may be related. They frequently exhibit invasive, aggressive local growth. Despite the histological appearance of craniopharyngioma, its intimate association with the visual apparatus, the hypothalamus, and the ventricular system frequently predisposes children with these tumors to anterior visual pathway compression and endocrine dysfunction.921 Children often develop signs and symptoms of increased intracranial pressure and dysfunction of the hypothalamic–pituitary axis, manifesting as growth failure, delayed sexual development, infantilism, obesity, diabetes insipidus, disturbances in heat regulation, thalamic crises characterized by spontaneous pain, and vasomotor disturbances.47,57,118,190,546,956 Rarely, precocious puberty occurs. These tumors grow slowly and rarely present before 3–4 years of age. Craniopharyngioma is a particularly devastating tumor with respect to its long-term effects on the visual system. Most patients are admitted with visual problems as their presenting complaint.763 Children with craniopharyngioma develop gradual, progressive visual loss from compression of one or both optic nerves, chiasm, tract or, less commonly, as a result of chronic papilledema. Occasionally, visual loss may be rapid, and the child may be thought to have retrobulbar neuritis. It is not unusual for children with craniopharyngioma to complain of nonspecific symptoms and be assigned the diagnosis of psychogenic visual loss prior to the developing optic atrophy.576 The diagnostic goal is to detect neuro-ophthalmologic signs of craniopharyngioma before permanent injury to the visual system whenever possible. Therefore, in the examination of the preschool child with headaches, short stature, decreased visual acuity, diminished stereopsis, or symptoms of hemifield slide (described by young children as objects disappearing or suddenly appearing where they do not belong), or postfixational blindness (described as objects disappearing in the distance),926 we carefully examine pupil size (to look for increased diameter, afferent papillary defect, or light-near dissociation),270 color vision to look for dyschromatopsia, which is an early sign of compression, and confrontation visual fields to look for bitemporal desaturation. In our experience, Hand–Hardy–Rittler plates provide better sensitivity to acquired dyschromatopsia than Ishihara color plates. Difficulty with depth perception is often described in patients with chiasmal lesions, and diminished stereopsis has been shown to be a sensitive, albeit nonspecific, indicator of chiasmal dysfunction.362 Unfortunately, many children with craniopharyngioma already have profound optic atrophy by the time they are examined.3,576 Optic atrophy may occur consequent to compression by the tumor, surgical resection, or radiation therapy.260,332 In one series, optic atrophy developed in 81% of eyes.3,546 Poorer visual outcome was seen in children who were less than 6 years of age at presentation. Another recent

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study found ophthalmological problems in 96% of children at the time of diagnosis, with decreased acuity in 51%, strabismus in 27.6%, papilledema in 34.4%, and optic atrophy in 37.9%.195 Band atrophy is best detected with direct ophthalmoscopy, which shows selective loss of the nasal and temporal nerve fiber layer. Because the temporal nerve fiber layer is poorly visible on direct ophthalmoscopy, the selective absence of the nasal nerve fiber bundle relative to the superior and inferior nerve fiber bundles is used to establish the diagnosis, which can now be confirmed by OCT.584 Papilledema, secon dary to extension of the tumor into the third ventricle, may also occur in children and young adults with craniopharyngioma. Other presentations include see-saw nystagmus from compression of the mesencephalon and the interstitial nucleus of Cajal,450 sensory exotropia,3 and excessive tearing.915 The rare association of anomalous optic discs with craniopharyngioma and other congenital suprasellar tumors846 is attributed to the tumor’s proximity to the anterior visual pathways and its potential for disrupting optic axonal migration during embryogenesis. Associated signs include hypopituitarism (e.g., short stature, retarded sexual development, obesity, infantilism) and signs of hypothalamic involvement (e.g., thermolability), which are much more common after treatment. Diabetes insipidus is rare as a presenting sign, but it commonly develops following tumor resection.

Craniopharyngiomas are uniformly located, at least partially, in the suprasellar cistern. The symptoms and signs produced depend on the age of the patient, the size of the tumor, the direction of its growth, and the location of the optic chiasm (i.e., prefixed, fixed, and postfixed). The location of the chiasm determines whether the tumor compresses the optic nerves, the anterior chiasm (junctional syndrome), the chiasm, or the optic tract, each with its attendant visual consequences. The tumor may project into the third ventricle, causing hydrocephalus. Although craniopharyngioma usually occupies the suprasellar cistern in location, it may rarely originate beneath the sella, within the third ventricle, or even within the chiasm.100 Posterior extension of the tumor may compress the ventral brainstem and cerebellum. CT scanning often shows a lesion that is calcified, cystic, and suprasellar (Fig. 4.8).109,119 In the absence of calcification, however, the tumor can be isodense with CSF and easily go unrecognized unless the suprasellar cistern is enlarged and its normal pentagonal shape is distorted.915 On MR imaging, signal characteristics of craniopharyngioma may vary depending on the tumor composition, with high signal intensity on T1-weighted images correlating with high cholesterol content or the presence of methemoglobin, and low signal intensity on T1- or T2-weighted images, correlating with a bony trabecular network (Fig. 4.8).233,696

Fig. 4.8 Craniopharyngioma. (a) Axial CT scan shows low density suprasellar mass with calcification. (b) Coronal MR image of the same lesion shows an inhomogenous signal, reflecting both solid and cystic

components of the suprasellar mass. The calcification cannot be directly demonstrated on MR images

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Craniopharyngioma is a congenital tumor that may be solid, cystic, or both. The cyst is often filled with fluid that resembles machine oil, but the fluid may be straw colored. The fluid contains cholesterol crystals. Characteristic calcification within the tumor is readily demonstrated with plain skull films. CT is excellent for demonstrating the characteristic areas of calcification and cyst formation. On MR imaging, the calcification can be indirectly inferred (Fig. 4.8). The treatment of craniopharyngioma remains somewhat controversial. Surgical resection remains the treatment of choice for craniopharyngioma, but the issue of whether to attempt complete removal, with its potential morbidity and mortality or subtotal resection followed by radiotherapy, is not completely resolved. In a clinicopathological analysis of 56 patients operated on for craniopharyngioma, Weiner et al921 found that gross total resection was associated with a lower recurrence rate (17%) than subtotal resection with or without radiation therapy (58%). In this study, the histopathological subtype did not significantly influence the surgical outcome. Some tumors are extremely difficult to eradicate because of their adherence to the optic nerves, hypothalamus, and the vessels of the circle of Willis, necessitating local irradiation therapy. Interstitial irradiation (interstitial brachytherapy) is an additional option.892 Many patients enjoy a significant return of vision after treatment. Repka and colleagues717 assessed 30 patients with craniopharyngioma preoperatively and postoperatively to evaluate the degree of visual recovery. At the time of presentation, visual acuity was reduced in 42% of eyes; 20% of eyes had normal visual fields. One week postoperatively, acuity was reduced in 23% of eyes; 48% of eyes had normal fields, with a slight decrease to 44% on long-term follow-up. Patients with visual defects that were present after the first postoperative month showed no long-term improvement in acuity or field. Stark et al820 described a 9-year-old girl who recovered from no light perception vision to 20/25 in the right eye after subtotal surgical resection. The diagnosis of craniopharyngioma should be considered in patients with psychogenic visual loss and in those with amblyopia, particularly when no amblyogenic factors, such as anisometropia or strabismus, are present.3 The differential diagnosis of craniopharyngioma in children includes meningioma, pituitary adenoma, 595 dysgerminoma, Rathke's pouch cyst, and suprasellar epidermoid cyst.

Uncommon Compressive Lesions Causing Optic Atrophy in Children Pituitary adenoma is uncommon in childhood and adolescence.266a,489a,919a Most pediatric pituitary adenomas present after the onset of puberty with frequent headaches, changes in visual acuity, and, in girls, menstrual dysfunction.

4 Optic Atrophy in Children

Similarly to adults, 70% of children have evidence of pituitary hypersecretion at presentation,721 with prolactinomas being most common.266a,489a,919a A common presenting complaint is failure of sexual maturation. Pituitary adenomas in the prepubertal period may be more likely to exhibit extrasellar extension or invasiveness.266a,489a,919a Visual symptoms and signs may appear less commonly in children than in adults with pituitary adenomas. In a series of 25 children with pituitary adenomas,266a three showed optic atrophy, with two of these having visual failure as a part of the presenting symptoms. Pituitary apoplexy has been reported in children.688,787,833 Optic nerve sheath meningioma is rare in children.182,490 The diagnosis is suggested by the triad of optociliary shunt vessels, optic atrophy, and visual loss although this triad may less commonly be encountered in optic nerve glioma.576 Other features, common to both glioma and sheath meningioma, include proptosis, afferent pupillary defect, strabismus, limitations of eye movements, and visual field defects.404 These overlapping features and the purported rarity of optic nerve sheath meningioma in children may lead to diagnostic confusion with optic nerve glioma. The presence of optociliary shunt vessels may be a helpful diagnostic sign; they were present in only 1 of 22 patients with optic nerve glioma, but were identified in 10 of 47 patients with nerve sheath meningioma in one series.404 Neuroimaging findings may help differentiate optic nerve glioma from sheath meningioma. CT scans of orbital gliomas reveal fusiform enlargement and kinking of the optic nerve, with erosion and enlargement of the optic canal. The CT scans of meningiomas reveal diffuse enlargement, shaggy borders, frequent calcification, and hyperostotic thickening of the optic canalicular bone along with intraorbital “railroad tract sign” on axial images, representing abnormal enhancement of the periphery of the nerve. Gadolinium-enhanced MR may be particularly suited to delineate the extent of intracranial involvement of nerve sheath meningioma.960 In equivocal cases, a direct biopsy may be needed to establish the diagnosis. It is important to biopsy both the sheaths and the nerve itself to avoid a false-positive diagnosis on the basis of finding arachnoid hyperplasia that may surround a glioma, imparting a histological appearance of a meningioma. It is particularly important to establish the correct diagnosis of optic nerve sheath meningioma in children, as many authors consider this lesion to be more aggressive in children than in adults.182,490,941,942 There is some evidence that the childhood tumors have a higher propensity to show intracranial, intraneural, intraorbital, and intraocular spread than their adult counterparts. The treatment of optic nerve sheath meningioma is controversial.182 Dysgerminoma should be suspected in a child who presents with diabetes insipidus and who is found to have bitemporal hemianopia. With the exception of histiocytosis X, it is rare for children with other compressive lesions in this location

Causes of Optic Atrophy in Children

to present with diabetes insipidus. These usually solid tumors show similar histological features to pinealomas, but present in the perichiasmatic region. They occur in the first or second decade of life and may present with diabetes insipidus, visual loss, visual field defects, optic atrophy, or pituitary dysfunction. Similar lesions may be a part of the trilateral retinoblastoma syndrome. Suprasellar germinomas are divided equally between the sexes, unlike those in the pineal location, of which about 90% are in boys. Dermoids, epidermoids, and hamartomas are more uncommon and constitute the bulk of the remaining suprasellar masses. Osteopetrosis is an inherited metabolic bone disease characterized by a generalized increase in bone density due to reduction in osteoclast function. The disease is associated with narrowing of the foramina of the base of the skull, with resultant compressive neuropathy. Visual loss may arise from either optic nerve or retinal dysfunction. Optic atrophy may result secondarily either from papilledema or from compressive neuropathy due to narrowing of the optic foramen.335,371 Visual loss with optic atrophy may occasionally be the presenting symptom.655 Optic nerve decompression may result in stabilization or even improvement of vision. 556 It is important to perform electroretinography to exclude an associated retinal degeneration before undertaking optic nerve decompression.371,655 Craniosynostoses (e.g., Crouzon syndrome, Pfeiffer syndrome, Apert syndrome, plagiocephaly) are not uncommonly associated with visual failure due to optic atrophy.43,323,614 One retrospective study found optic atrophy in 16.7% of patients with craniosynostosis,845 whereas others have found optic atrophy in 7% with Crouzon disease315 and 5% of patients with Apert syndrome.442 The pathogenesis of optic atrophy in craniosynostosis may be related to (1) increased intracranial pressure and papilledema, (2) kinking and stretching of the optic nerve due to abnormal cranial and brain growth, (3) narrowed optic canals, or (4) a complication of craniofacial surgery.111 Papilledema may occur in otherwise asymptomatic patients.54,188 One study found that a 40% prevalence of visual loss from a combination of optic atrophy ametropia, exposure keratitis, and strabismic and anisometropic amblyopia continues to complicate this condition.845 When present, papilledema resolves after decompressive craniofacial surgery.682 Over the past decade, mutations in the fibroblast growth factor receptors (FGFR 1,2, and 3) genes, the TWIST gene, and the EFNB1 gene have been identified in craniosynostotic syndromes.597,882 Premature fusion of cranial sutures is commonly associated with optic atrophy in GAPO syndrome.769,773,912 GAPO is an acronym for the manifestations of growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy.391,596 It is a rare autosomal recessive disorder that also shows a peculiar geriatric facial appearance, short stature resembling rhizomelic dwarfism, muscular habitus, and a large fontanel

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in infancy. The hair is lost within the first few years of life, and the teeth are normal, but unerupted. Aside from progressive alopecia, these children may develop growth and mental retardation, large fontanelles, a puffy face, and swollen eyelids.493 As these findings are also seen in hypothyroidism, thyroid status should be examined in these children.493 Optic atrophy has been reported in 30% of affected children. The nature of the optic atrophy is unclear, with possible contributions from concurrent glaucoma or intracranial hypertension.588 Patients appear to have a shortened life expectancy, with death occurring in midlife. Craniodiaphysial dysplasia is another rare sclerosing bone disorder that is due to modeling errors of the long bones and the skull bones. Patients display widening and flattening of the nasal bridge, malformation of nasal cartilage, hypertelorism, and enlargement of the skull.106 Optic atrophy can result from narrowing of the optic canals due to sphenoidal boney overgrowth.447 Fibrous dysplasia is an abnormal fibro-osseous disorder of bone of unknown etiology. The disorder is considered to be a maturational arrest at the woven bone stage, with abnormal development of bony tissue, resulting in fibrous tissue proliferation and defective osteogenesis. Normal bone is gradually replaced with fibrous tissue. The process occurs primarily during childhood, but may continue into adulthood. Histological analysis shows areas of fibrous tissue interwoven with newly formed bone.585 The disorder most commonly involves a single bone (monostotic), but it may be disseminated throughout the body (polyostotic). Polyostotic fibrous dysplasia occurs in association with café au lait spots and precocious puberty in girls with Albright syndrome. In most patients, the lesions in fibrous dysplasia grow slowly and then stabilize in early adulthood. The most commonly affected calvarial bone is the frontal bone, then the sphenoid, temporal, parietal, and occipital bones, in that order. The most common presentation is a painless enlargement of the involved bone, causing facial asymmetry, orbital dystopia, or unilateral proptosis.703 Involvement of the bones at the base of the skull may cause narrowing of the neural foramina with compression of cranial nerves, causing hearing loss, tinnitus, and cranial nerve palsies. If the disorder affects the lesser wing of the sphenoid bone, the optic canal may become narrowed, with compression of the optic nerve and subsequent optic atrophy.585,686 Initially, such patients may be misdiagnosed as having retrobulbar optic neuritis, with the correct diagnosis subsequently suggested by neuroimaging studies obtained when spontaneous visual improvement fails to occur.922 Involvement of the sella turcica may compress the optic chiasm, leading to chiasmal syndrome and optic atrophy.928 Trigeminal neuralgia and increased intracranial pressure have also been described. Prompt surgical decompression of the optic canal in patients with compressive neuropathy may restore some optic nerve function and halt progression of the optic atrophy.703 Other rare causes

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of compressive optic neuropathy, such as intentional globe subluxation, should be also considered, even in nonpsychotic children.86

Noncompressive Causes of Optic Atrophy in Children with Brain Tumors In addition to the direct effect of the tumor itself, optic neuropathies may be seen in children with brain tumors due to several other potential etiologies (1) Toxic effect of chemotherapy (e.g., vincristine).799 Vincristine has been implicated in various ophthalmological disturbances including optic atrophy,799 transient cortical visual impairment, ptosis, and ophthalmoplegia. Disruption of the blood–brain barrier by both radiation and surgical manipulation may increase its toxic potential.799 (2) Paraneoplastic optic neuropathy. (3) Radiation optic neuropathy. Toxic optic neuropathy will be discussed later in this chapter.

Postpapilledema Optic Atrophy Postpapilledema optic atrophy is often associated with specific ophthalmoscopic findings that suggest the underlying mechanism of injury (Fig. 4.9). Any of the following findings in association with optic atrophy suggest previous optic disc swelling (1) a fine fibrous sheathing of the retinal vessels as they emanate from the disc, (2) opaque fibrous tissue overlying the disc and obscuring the peripapillary retina, (3)

Fig. 4.9 Postpapilledema optic atrophy in a patient with chronic pseudotumor cerebri. Note bilateral disc pallor with indistinct margins and circumpapillary “high-water” marks. There is prepapillary and

4 Optic Atrophy in Children

circumpapillary pigment changes (“high water marks”), and (4) optociliary shunt vessels. In addition to brain tumors (especially posterior fossa tumors, but also craniopharyngioma), major causes of postpapilledema optic atrophy in children include shunt failure, pseudotumor cerebri, and craniosynostosis, among others. These entities are detailed in Chap. 3. The efficacy of optic nerve sheath fenestration in preventing visual loss in patients with severe or intractable papilledema is now well established. The benefits of optic nerve sheath fenestration in children are now well established,858 and many cases of postpapilledema optic atrophy in children are now preventable with early intervention.

Paraneoplastic Syndromes Optic atrophy may rarely result from paraneoplastic axonal degeneration. Paraneoplastic retinal degeneration is much more common in adults than in children. In contrast, paraneoplastic ocular motility disorders (e.g., opsoclonus-myoclonus in neuroblastoma) are more common in children.40,773 Presumed paraneoplastic retinal degeneration and optic atrophy was recently described in a 6-year-old boy who had an embryonal rhabdomyosarcoma of the thorax.344 A few cases of presumed paraneoplastic optic neuropathy have been described in adult patients. In some such cases, retinal pigmentary abnormalities are absent, and marked arteriolar narrowing may be the only sign of underlying retinal dysfunction. The diagnosis is established by finding an attenuated or extinguished ERG signal.

peripapillary glial proliferation which produces a wispy vascular sheathing and radial peripapillary striae

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Paraneoplastic syndromes often have an autoimmune basis. Sera from patients with visual paraneoplastic syndromes have been shown to contain immunoglobulins that are reactive with both the tumor and with various retinal elements (e.g., photoreceptors, large ganglion cells, bipolar cells).140

Radiation Optic Neuropathy Radiation therapy is not infrequently administered for the treatment of various ocular (e.g., retinoblastoma) and intracranial (e.g., craniopharyngioma, dysgerminoma) tumors of childhood. Shielding the globes and the optic nerves from the field of radiation is not always possible. Patients receiving a cumulative dose of radiation of greater than 50–60 Gy or dose fractions greater than 200 cGy/day are particularly at risk of developing radiation retinopathy or optic neuropathy, depending on the path of administered radiation. Early radiation optic neuropathy can occur within several weeks of irradiation and is characterized by acute inflammation leading to optic nerve pallor.261,574 In contrast, late radiation optic neuropathy occurs years after treatment and has been characterized by irreversible vasculitis, necrosis, and optic disc pallor.574 Radiation retinopathy reveals findings similar to those seen in diabetes. Radiation optic neuropathy presents 1–6 years (peak: 18 months) after radiotherapy. Acute loss of vision occurs along with visual field changes that localize to various parts of the anterior visual pathways, depending on the site of involvement. Patients are often misdiagnosed as having optic neuritis or a recurrent tumor compressing the visual pathways. MR imaging in the acute phase of visual loss shows intense Gadolinium enhancement of the affected segments of the anterior visual pathway.326 Functional neuroimaging modalities (positron emission tomography, single photon emission computed tomography) may help delineate either metabolically active tumor or inactive necrotic neural tissue. The primary site of pathogenesis is the vascular endothelium, and the underlying pathologic changes are those of radiation-induced occlusive vascular disease: endothelial proliferation, fibrinoid necrosis, and reactive astrocytosis. Therapeutic trials of corticosteroids and hyperbaric oxygenation have been, with a few exceptions,86 unsuccessful. Treatments for radiation optic neuropathy have included corticosteroids, anticoagulation, and hyperbaric oxygen therapy. The most promising, hyperbaric oxygen therapy, is expensive, difficult to administer, and relatively ineffective.503 However, one adult treated with intravitreal bevacizumab showed improved visual acuity, with dramatic resolution of optic disc edema and hemorrhage without the development of optic atrophy.261

Hydrocephalus Hydrocephalus is a common cause of optic atrophy in children.171,284,290,542,883 It is difficult to determine with certainty which, if any, of the various types of hydrocephalus is more likely to result in optic atrophy. In contrast to optic atrophy arising from increased intracranial pressure in older patients, the childhood variety may or may not pass through a stage of papilledema. Optic atrophy and/or cortical visual impairment are the usual causes of bilateral visual defects in hydrocephalic children. Andersson and Hellström28 diagnosed optic atrophy in 10 of 69 (14%) children with hydrocephalus. If the optic disc area is significantly smaller in children with hydrocephalus it indicates a prenatal or perinatal disturbance in optic nerve development. The retinal arterioles were also straighter, with fewer branching points as compared to controls.28 The following mechanisms have been proposed as possible causes of optic atrophy in hydrocephalus (1) long-term papilledema or acute severe papilledema with subsequent atrophy. This typically arises after shunt placement with subsequent failure(s) because hydrocephalic infants tend not to develop significant papilledema due to their expansile cranium, (2) stretching of the chiasm and its blood supply as a result of intracranial displacement of the brainstem in an effort to accommodate increasing cerebral volume, (3) optic nerve stretching by an expanding skull. (4) Chiasmal compression by a dilated third ventricle. In such cases, bulging of the third ventricle anteriorly into the sella turcica can be demonstrated on CT or MR imaging (Fig. 4.10). Most cases of optic atrophy associated with hydrocephalus are bilateral although asymmetric and even unilateral cases do occur. Compression of one optic nerve, presumably against the internal carotid artery, with unilateral visual loss, has been reported in a child with an obstructed shunt.122 (5) Transsynaptic degeneration of the retinogeniculate pathway after cortical damage. (6) Optic tract damage by shunt placement.284,290,883 The major mechanism appears to be postpapilledema optic atrophy that occurs in children with poorly controlled hydrocephalus and repeated shunt failure. In our experience, children with hydrocephalus secondary to intraventricular hemorrhage are at particularly high risk of developing severe optic atrophy early in life. The specific mechanism of afferent visual system injury in these infants has not been determined.

Hereditary Optic Atrophy Hereditary optic neuropathies represent a heterogeneous group of disorders that generally manifest with bilateral optic atrophy and evidence of genetic transmission.610 The pathogenetic role of mitochondrial disease in many of the hereditary

170

Figure 4.10 Chiasmal compression by dilated third ventricle. Dilation of third ventricle in child with hydrocephalus may lead to stretching and ballooning of optic chiasm

4 Optic Atrophy in Children

optic neuropathies is now well-established.88,618,619 These optic hereditary optic neuropathies are often isolated, but may also occur in the context of more widespread mitochondrial disease, which can result from a mitochondrial or a nuclear gene defect.192 Four types of hereditary optic atrophy (autosomal dominant optic atrophy, autosomal recessive optic neuropathy, Costeff syndrome (Costeff syndrome), Leber hereditary optic neuropathy, and Charcot–Marie– Tooth (CMT2) disease), are now attributed to mitochondrial dysfunction. Many of the mitochondrial disorders produce isolated optic neuropathy without other neurological dysfunction. Other systemic mitochondrial disorders, such as the syndrome of mitochondrial encephalomyelopathy with ragged red fibers (MERRF) syndrome, may optic atrophy may show optic atrophy in the absence of ophthalmoplegia.319 All of these disorders show significant interfamilial and intrafamilial variability. A rare isolated form of X-linked optic atrophy is now recognized.34,430 An increasing number of hereditary neurologic and systemic diseases have been described with optic atrophy as a component.34,207,618,904 A single gene defect need not be responsible for each type of optic neuropathy. Some of these disorders have visual loss as the only clinical manifestation, and others are associated with neurologic or systemic abnormalities. Table 4.1 provides a partial listing of the genetic disorders that have optic atrophy as one of the clinical findings.377

Table 4.1 Genetic syndromes associated with optic atrophy in children Name of Syndrome

References

3-Methylglutaconic aciduria Acromesomelic-spondyloepiphyseal dysplasia (AD) Adrenoleukodystrophy Albers-Schönberg disease Alexander disease Allgrove (“4A”, or alacrima, achalasia, autonomic disturbance and ACTH insensitivity) syndrome Autosomal malignant osteopetrosis Autosomal recessive (malignant) osteopetrosis (AROP) Autosomal recessive cerebellar ataxia disorder Autosomal recessive spastic ataxia of Charlevoix-Saguenay Baraitser-Winter syndrome Behr optic atrophy Bilateral striatal necrosis, dystonia, and optic atrophy Biotinidase deficiency (AR) Blepharophimosis-mental retardation (BMR) syndromes Brooks-Wisniewski-Brown syndrome Brown-Vialetto-Van Laere syndrome Canavan disease Cerebro-oculo-facio-skeletal syndrome Cerebro-oculo-facio-skeletal syndrome (COFS) Cherubism Childhood lactic acidosis Chondrodysplasia punctata Chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease syndrome

14, 174, 461, 608, 794 785 163, 164, 408, 592, 865, 935 63 366, 449, 452, 902 581 581 559 322 277 59, 170, 253, 543, 774, 856 498 388, 920 898 587 764 13, 66, 304, 431, 548 560, 670 560, 671 132 357 244, 265 212 (continued)

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Causes of Optic Atrophy in Children Table 4.1 (continued) Name of Syndrome

References

Cockayne syndrome Combined methylmalonic aciduria and homocystinuria Complex I deficiency Complicated hereditary spastic paraplegia with peripheral neuropathy, optic atrophy and mental retardation Congenital disorders of glycosylation (CDG) Craniosynostosis Craniosynostosis (Crouzon, Apert, Pfeiffer syndromes) Deafness-dystonia-optic neuronopathy (DDON) syndrome Delleman (oculocerebrocutaneous) syndrome DIDMOAD syndrome (Table 4.3) Dominant optic atrophy Dysosteosclerosis Early-onset dystonia + optic atrophy Early-onset spinocerebellar ataxia, optic atrophy, internuclear ophthalmoplegia, dementia, startle myoclonus Familial agenesis of the corpus callosum Familial dysautonomia (Riley-Day syndrome) Familial optic atrophy with negative ERG Familial optic atrophy with white matter changes Familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia Fukuyama-type congenital muscular dystrophy Gait ataxia, dysarthria, dysmetria, adiadochokinesia, cramps, tremor, hypotonia, limited eye movements Ganglioside GM3 synthase deficiency GAPO syndrome (growth retardation, alopecia, pseudoanodontia, optic atrophy (AR) Hereditary motor and sensory neuropathy type VI with optic atrophy Heredodegenerative neurological disorders with optic atrophy (Table 4.4) Homocystinuria Infantile bilateral striatal necrosis Kabuki syndrome Kenny syndrome Late onset autosomal recessive optic atrophy Leber hereditary optic neuropathy Leukoencephalopathy + macroencephaly + mild clinical course Leukoencephalypathy with vanishing white matter Maple syrup urine disease (AR) Marble brain disease (AR) Marinesco-Sjogren syndrome Maroteaux-Lamy syndrome Marshall-Smith syndrome Menkes kinky hair disease (XLR) MERRF MICRO syndrome Microcephaly, microphthalmia, congenital cataract, optic atrophy, short stature, hypotonia, severe psychomotor retardation, and cerebral malformations Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) Mohr-Tranebjaerg syndrome Motor and sensory neuropathy, mental retardation, pyramidal signs, optic atrophy Mucolipidosis type IV Mucopolysaccharidoses Myoclonus epilepsy with ragged-red fibers Myotonic dystrophy N-Acetylaspartic aciduria N-Acetylaspartic aciduria (AR) Neuraminidase deficiency (sialidosis) Neurofibromatosis type I Neuronal storage disease (e.g., Batten disease) (Table 4.5) Numerous chromosomal abnormalities Oculocerebral hypopigmentation syndrome (Cross syndrome) Ohdo syndrome Optic atrophy +/- deafness +/- diabetes mellitis (Table 4.2 )

161, 271, 501, 509, 560, 606, 864, 873 162, 736, 867 243, 589, 885 579 279 54, 323, 614, 682, 845 43, 111, 323, 614 101 843 52, 83, 125, 757, 937 165, 370, 458, 462, 611, 617, 841 151 103 784 138 204, 727 903 175 953 433, 855 248 558, 596, 652, 769, 912 907 114, 162, 356, 736, 867, 874 56 203, 287 256 678 368, 385, 411, 413, 415, 613, 906 540 424 115 803 181, 210, 288 300, 910 817 281, 563, 609, 780, 940 319, 664 311, 558 558 117, 357 566 524 21 167, 435, 612 644 276 285 285 859 782 733, 816, 931 84, 390, 416 658 898 229 (continued)

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4 Optic Atrophy in Children

Table 4.1 (continued) Name of Syndrome

References

Optic atrophy in pansynostosis 639 Pantothenate kinase-associated neurodegeneration 8, 29, 135, 228, 433, 837, 855 PEHO syndrome (progressive encephalopathy, edema, hypsarrhythmia, optic atrophy) 812, 813 PEHO-like syndrome 259 Pelizaeus-Merzbacher disease 127, 211, 465, 705, 765, 971 Peroxismal D-bifunctional protein deficiency 265, 435 PHACE Syndrome 472 Primary oxalosis 804 Quantitative chromosomal abnormalities 82, 848 Sandhoff disease 955 Shaken baby syndrome 235, 534 Simple recessive optic atrophy 172, 268, 457, 911 Smith-Lemli-Opitz syndrome 36, 471 Spastic paraplegia, optic atrophy, and neuropathy linked to chromosome 11q13 525 Spastic paraplegia, optic atrophy, microencephaly with normal intelligence, and XY sex reversal 848 Spinocerebellar degenerations 181 Strumpell-Lorrain disease 535 Subacute sclerosing panencephalitis 69, 221 X-linked ataxia, weakness, deafness, early loss of vision, fatal course 32 X-linked seizures, acquired micrencephaly, agenesis of corpus callosum 690 X-linked severe mental retardation, blindness, deafness, epilepsy, spasticity, early death 325 Zellweger syndrome 15, 163, 328 PEHO, progressive encephalopathy with edema, hypsarrhythmia, and optic nerve atrophy PHACES, posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects and coarctation of the aorta, eye abnormalities, and sternal abnormalities or ventral developmental defects syndrome

The traditional classification of the hereditary optic neuropathies relies on the recognition of typical clinical characteristics and classic patterns of familial transmission, but genetic analysis now permits diagnosis of some of these disorders even in the absence of family history or in the setting of unusual clinical presentations.618,619 Nearly all of the inherited optic neuropathies eventually have symmetric, bilateral, central visual loss.679 In many of these disorders, the papillomacular bundle is affected, with resultant central or cecocentral scotomas.618,619 Optic nerve damage is usually permanent and, in many diseases, may be progressive. In classifying the hereditary optic neuropathies, it is important to exclude the primary retinal degenerations that may masquerade as primary optic neuropathies because of the common finding of optic disc pallor. Retinal findings may be subtle, especially among the cone dystrophies, in which optic nerve pallor may be an early finding. Retinal arteriolar attenuation and abnormal electroretinography should help to distinguish these diseases from the primary optic neuropathies. In addition, it is also customary to distinguish disorders in which optic neuropathy is the primary clinical feature, with or without associated neurologic or systemic findings, from neurologic and systemic multisystem diseases in which there may be optic nerve involvement.618,619

Dominant Optic Atrophy (Kjer Type) Dominant optic atrophy is the most common from of hereditary optic atrophy, with a disease frequency in the range of 1:50,000.458,617 It is transmitted as a dominant Mendelian trait with incomplete penetrance and variable clinical expression.165 The visual loss has an insidious onset within the first decade of life, typically between ages 4 and 8 years. Affected children are often unaware of their visual disorder until it is uncovered during routine visual screening. Visual acuity typically ranges from 20/70 to 20/100, but may be as good as 20/20 or as poor as counting fingers.370,462,611,841 The degree of vision loss varies considerably among members of the same family and may be asymmetric between fellow eyes in an affected individual. A mild degree of photophobia is often present. Affected children usually do not display nystagmus, even when the vision is reduced beyond the 20/200 level. It may thus be inferred that the acuity of such children must have been considerably better during early visual development. A characteristic blue-yellow color vision defect (tritanopia), best elicited with the Farnsworth–Munsell 100-hue test, is often seen,370,455,456,462,642,80 6,807 but is not necessary to make the diagnosis, as other studies have shown a more generalized dyschromatopsia.234,538,908 There is usually no clear correlation between the severity of the dyschromatopsia and the visual acuity. Many patients show

Causes of Optic Atrophy in Children

generalized nonspecific dyschromatopsia, and some patients may even show a deutan defect.538,908 Kinetic perimetry is often conspicuous for the absence of any apparent central scotoma. Static perimetry may be necessary to show central, paracentral, or centrocecal scotomas, or bilateral superotemporal hemianopia, which may raise concern about chiasmal compression.537,805,908 An isolated report of “hereditary chiasmal optic neuropathy” may actually represent dominant optic atrophy.685 Because of the tendency toward tritanopia, color visual fields are said to show a characteristic inversion of isopters in the peripheral visual field, being more constructed to blue than to red targets.494 In some patients, there is a mild, slow, insidious progression of visual dysfunction.617 The appearance of the optic disc ranges from mild but definite temporal pallor to complete atrophy.370,462,908 A “characteristic” focal temporal excavation of the disc is seen in some but not all patients (Fig. 4.11). An associated loss of the nerve fiber layer in the papillomacular bundle is present and is frequently dramatic. A few patients may show subtle macular pigmentary changes. The severity of disc pallor does not correlate with visual acuity, fields, or color vision. In patients with remote visual loss, it may be difficult to differentiate dominant optic atrophy from other conditions such as Leber optic neuropathy.403 Differentiation of mild cases of dominant optic atrophy from congenital tritanopia, another autosomal dominant disorder, requires blue cone ERG.578 The visual prognosis is generally good.234 These children function surprisingly well given the degree of their measured visual deficits. Some patients are even unaware of the visual deficit before the initial examination. Rarely do affected children attend schools for the blind. Long-term follow-up reveals either stabilization of visual function after the middle teens or minimal deterioration of vision (by a few lines) that is gradual and often unnoticed by the patient234 Kjer et al459 reported that all of his patients younger than 15 years of age had visual acuity better than 20/200, whereas 20% of patients beyond 45 years of age had acuities reduced to this level.

173

Visual evoked cortical potentials reveal reduced amplitudes and, in some patients, delayed latencies. The amplitude of the negative component of the pattern ERG is markedly reduced, whereas the positive component is normal.381 In some patients with normal electrophysiological studies, standard visual fields, and color vision (FM 100 hue), static perimetry with blue test spots may show enlarged central scotomas, indicative of subclinical dominant optic atrophy.72 Histopathologic studies have shown primary degeneration of the retinal ganglion cell layer, accompanied by loss of myelin and ascending optic atrophy, with intact cerebral hemispheres.459 Earlier suggestions that there are at least two genetic types of autosomal dominant optic atrophy, one congenital and one manifesting postnatally730 have not been borne out by genetic analysis, which suggest that these two types are probably a result of a single genetic defect, representing the variable expressivity so common in autosomal dominant disorders.670 Most patients with dominant optic atrophy are monosymptomatic. Affected patients are typically entirely healthy, with the exception of sight. Rare exceptions have included the association of mental retardation,417 hearing loss,569 and chronic progressive external ophthalmoplegia.561 Sensorineural hearing loss, which tends to cluster in families, may be congenital and severe or subclinical, requiring audiology for detection. It is unclear whether hearing loss signifies a phenotypic variant of dominant optic atrophy, a genetically distinct disorder, or a genetically heterogenous group of disorders with a similar phenotype.617 Two families with an autosomal dominant optic atrophy, hearing loss, and peripheral neuropathy have been described.334 This triad (optic atrophy +/ – hearing loss +/ – polyneuropathy) has been described as an autosomal dominant, autosomal recessive, and X-linked disorder; the various forms have been compared by Hagemoser et al334 In one remarkable family, in which ophthalmoplegia and ptosis accompanied dominant optic atrophy and hearing loss, a chromosome 3 missense mutation was found, a mutation which, in other pedigrees, resulted solely in nonsyndromic optic atrophy.669

Fig. 4.11 Dominant optic atrophy. This 7-year-old girl had failed the vision screening examinationat school, with acuities of 20/50 bilaterally. Note pronounced temporal pallor and excavation (a) right eye; (b) left eye

174

4 Optic Atrophy in Children

Also, a large family with an autosomal dominant disorder manifesting with progressive optic atrophy, abnormal ERGs without retinal pigmentary changes, and progressive sensori neural hearing loss has been reported.870 The disorder appears in the first or second decade of life, followed by the emergence of ptosis, ophthalmoplegia, ataxia, and a nonspecific myopathy in midlife.870 It has recently been found that mutations in the Wolfram’s syndrome gene (WFS1) can produce dominant optic atrophy with hearing loss.229 Table 4.2 lists the various genetic syndromes encompassing the findings of hearing loss and optic atrophy. Autosomal dominant optic atrophy is genetically heterogenous, with the OPA1 gene on chromosome 3q28 being the most prevalently mutated gene. More than 100 mutations have been described; however, the specific pathogenesis of the visual loss in this condition remains unclear.165 The major locus is OPA1 mapped in 3q28-q29.16,17,197,232,458,695 The penetrance of OPA1 mutations has been estimated at 82.5–98%.165 Additional loci are OPA3,718 OPA4,437 and OPA5,49 located at 10q13.2, 18q12.2, and 22q12.1-q13.1, respectively.229 Dominant optic atrophy appears to be a primary retinal ganglion cell

degeneration.197,908 The OPA1 gene encodes for a dynaminrelated GTPase that is made in the nucleus and imported into mitochondria, where it appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity,17,197,647 with a mutation leading to a deficit in oxidative phosphorylation.446,514 GTPase activity is particularly critical for retinal ganglion cell development and function.130,197,854 Downregulation of the OPA1 gene leads to fragmentation of the mitochondrial network and dissipation of the mitochondrial membrane potential, with cytochrome c release and caspase-dependent apoptosis.573,647 Certain OPA1 mutations exert a dominant negative effect, resulting in multisystemic disease closely resembling the mitochondrial cytopathies, by a mechanism involving mitochondrial DNA instability.24 The OPA1 gene polymorphism has also been associated with normal-tension glaucoma and high-tension glaucoma.523 Linkage analysis of patients with normal tension glaucoma has shown an association with polymorphisms of the OPA1 gene.38 Mutations in the OPA3 gene have been found to be responsible for the rare syndrome of autosomal dominant optic atrophy and cataract.718

Table 4.2 Hereditary syndromes with association of optic atrophy and deafness Degree of vision loss

Hearing loss

Autosomal Childhood or Progressive optic atrophy, dominant midlife congenital sensorineural deafness DIDMOAD (Wolfram Autosomal recessive First decade syndrome) mitochondrial First decade CAPOS syndrome (cerebellar Autosomal dominant ataxia, areflexia, pes cavus, optic atrophy, sensorineural deafness)

Moderate loss

Moderate, severe

None

Moderate to severe Progressive loss

Progressive

775

Optico-cochleo-dentate degeneration

Autosomal recessive

Infancy

? progressive

Progressive, severe

Diabetes mellitus, diabetes insipidus Weakness, muscle wasting, pes cavus, areflexia, ataxia, progressive hearing loss Progressive spastic quadriplegia, mental deterioration, death

734

Optic atrophy, peripheral neuropathy, hearing loss (Rosenberg–Chutorian syndrome) Optic atrophy, peripheral neuropathy, hearing loss Optic atrophy, peripheral neuropathy, hearing loss Optic atrophy, deafness, ptosis, ophthalmoplegia, dystaxia, myopathy Optic atrophy, dementia, sensorineural hearing loss Ataxia, weakness, deafness, blindness, fatal course

X-linked or autosomal recessive

Second decade

Moderate loss

Progressive, deafness by age 6 yrs

Autosomal recessive Autosomal dominant Autosomal dominant

First decade

Probable X-linked

Dysosteosclerosis

Autosomal recessive

Reference Syndrome 229 937 624

334 334 870 407 32 151

Inheritance

X-linked recessive

Age of onset of vision loss

Progressive, moderate to severe

Associated findings

Second decade

First decade

Severe

Mild to severe

First decade

Moderate to severe

Mild to severe

Second or third decade Early childhood

Moderate to severe loss Severe

Severe

Early childhood

Moderate to severe

Mild to moderate

Severe

Posterior column lack of myelin, death in first decade Skeletal dysplasia, intracranial calcifications, mental retardation

Causes of Optic Atrophy in Children

Leber Hereditary Optic Neuropathy Leber hereditary optic neuropathy (LHON) is a maternally inherited form of optic neuropathy that is associated with several mitochondrial DNA (mtDNA) mutations.367,385,613,906 Although five such mutations have been identified (nucleotide positions 11778, 3460, 14482, 15257, 4160),.411,413,415,604 over 95% of LHON cases are primarily the result of 1 of 3 mitochondrial DNA point mutations (G11778A [50–76% of families], G3460A [7–30%], T14484C [7–30%]). 529,536,627,788 It is likely that other mitochondrial dysfunction plays a role in nonhereditary cases of LHON-like optic neuropathy.5 It manifests typically in the second or third decade of life, but the age of onset may vary widely. The sex predilection varies in different geographic areas; the male-to-female ratio in the United States is 9:1, but in Japan it is about 6:4. On the basis of reported cases, 50–80% of males and 8–32% of females at risk experience significant visual loss. About 50% of the males and 10% of the females with the genetic defect develop optic neuropathy. The condition usually presents between ages 15 and 35 years (range: 1–80 years) as unilateral blurred vision that progresses rapidly, with sequential involvement of the other eye within days to a few months. Infrequently, the second eye involvement may occur simultaneously (after many years) or, rarely, not at all. The visual acuity commonly stabilizes at or below 20/200, but it varies widely, with a range of 20/40 to no light perception. Even after bilateral visual loss, patients may retain brisk pupillary responses,94,604,914 possibly attributable to selective sparing of melanopsin-containing retinal ganglion cells. Color vision is severely diminished. The time course of visual loss differs from that of optic neuritis in that it continues to evolve over several months. The characteristic visual field defect is a central or cecocentral scotoma that may extend superiorly in some patients. The visual loss is permanent in most cases but, occasionally, patients may show variable recovery of vision even years after the acute episode. This recovery is typically restricted to a few central degrees and appears to be more likely in patients with the 11,778 deletion.828 Patients whose acuity improves to the greatest degree are generally younger at the time of visual loss.107,411,528,545,627,725 Prior to and during the acute stages, the retinal examination usually shows a characteristic triad of signs: circumpapillary telangiectatic microangiopathy, pseudoedema of the disc and surrounding nerve fiber layer, and the absence of leakage on fluorescein angiography (Fig. 4.12).809 The discs are typically relatively cupless and crowded looking, with late branching vessels. These funduscopic changes may also be seen in presymptomatic cases and in asymptomatic maternal relatives. However, some patients with LHON never display these classic findings.620 Affected patients eventually

175

show optic atrophy with nerve fiber layer dropout, most notably in the papillomacular bundle. Several patients with the 15,257 mutation have been reported to show a macular degeneration resembling Stargardt disease.359 Because LHON may be associated with cardiac abnormalities, an electrocardiogram (EKG) or a 24-h Holter monitor should be performed. Preexcitation syndromes, including Wolff–Parkinson–White and Lown–Ganong Levine are found in 8–9% of patients with LHON.544,629,630 Prolongation of the QT interval has also been noted.654 Palpitations, syncope, myocardial hypertrophy, and sudden death have been reported in pedigrees with LHON.91,263,488,630,631,815,934 Histological changes in skeletal musculature, without clinical myopathy, may also occur.133 LHON is often misdiagnosed.368,412 In adults, it may be mistaken for dominant optic atrophy, anterior ischemic optic neuropathy,87 or tobacco-alcohol amblyopia.178 Because singleton cases are surprisingly common,620 it is common for LHON in children or adolescents to be diagnosed as optic neuritis, especially when CNS involvement coexists.668 Such associated neurologic involvement, if it occurs, is usually mild. Unusual cases may be associated with severe neurologic disease, making them difficult to differentiate from multiple sclerosis or Devic disease, especially if the characteristic fundus changes are absent. Rarely, a Leighlike encephalomyelopathy can accompany LHON.274,722 The extraocular muscles in LHON and chronic progressive external ophthalmoplegia (CPEO) show marked differences. A “mosaic-like” pattern caused by selective damage of muscle fibers was found in one patient with CPEO, whereas a diffuse increase in mitochondria with preservation of myofibrils characterized the LHON case. The increase in mitochondrial number may reflect a compensatory strategy for extraocular muscles and skeletal muscle.133 A Leber-like optic neuropathy has been associated with dystonia and basal ganglia lesions in several pedigrees.347,637 Although a disease that is clinically indistinguishable from multiple sclerosis may also coexist with LHON,72a191,255,491,526,626,628,661 studies of children with multiple sclerosis have not found Leber mutations.425,643,930 In that setting, genetic testing is needed to make the distinction. No treatment for LHON has been shown to be effective to date. Until recently, controversy existed regarding the existence of an X-chromosome-encoded modifying gene that is invoked to explain the male predominance.615,901 Recently, two optic neuropathy susceptibility loci have been reported.379,790 The cause for incomplete penetrance in LHON is poorly understood.129,790 Both environmental and genetic factors have been studied as potential modulators of the penetrance of the disease. Although the preeminent epigenetic factors are reported to be tobacco and alcohol,178 one large study found no significant association between tobacco and alcohol consumption and vision loss among individuals harboring

176

4 Optic Atrophy in Children

Fig. 4.12 Leber hereditary optic neuropathy. This 10-year-old boy developed bilateral loss of vision in both eyes to level of counting fingers. Optic discs appeared somewhat swollen (a) right disc; (b) left disc with peripapillary telangiectatic microangiopathy most apparent in

inferotemporal arcade below left disc. His mother showed similar optic disc appearance but was normally sighted. Four months later, his optic discs appeared diffusely pale; telangiectasia and swollen appearance were absent (c) right disc; (d) left disc)

LHON mutations.438 There is also some evidence that systemic illnesses may trigger the clinical disorder in a predisposed individual.220 The toxic/nutritional modulation of the clinical manifestation of LHON may, in a general sense, be bidirectional. Sadun et al753 investigated an epidemic of optic neuropathy in Cuba and found that nutritional and toxic factors were producing an acquired mitochondrial injury, with a resulting clinical syndrome that resembles LHON. Tobacco smoking and alcohol intake have been linked with the development of LHON in some, but not all, studies.438,750 The use of some prescription drugs, dietary supplements, or exposure to toxins have all been associated with the onset of disease in anecdotal reports.128,527,919 The male bias in LHON suggests that one or more genes on the X chromosome may be responsible for the incomplete penetrance. Although all descendents in a maternal lineage would inherit a mitochondrial mutation and be at risk for optic neuropathy, a digenic model would predict that only

those who also inherit an X-linked recessive mutation would actually develop the disease.790 The commonly observed intrafamilial phenotypic variability may also be explained on the basis of mtDNA heteroplasmy (the coexistence of normal and mutant mtDNA in variable combinations in different patients).810 Only when the percentage of affected mitochondria is high does the disorder become clinically manifested. However, epigenetic factors appear to play a role in the pathogenesis, as attested to by identical twins who are discordant for the disease.414 In LHON, the physical constraints near the lamina cribrosa may limit the size and transport of mitochondria, eventually leading to energy depletion and retinal ganglion cell degeneration.130,749,752 Although several theories have been advanced,130,226 it is not known why central visual loss occurs as an all-or-nothing event, what factors produce this ictus, why it never recurs, or how central vision, once extinguished, can spontaneously improve.

177

Causes of Optic Atrophy in Children

While there is no known treatment for LHON, experimental rescue of LHON cells with the 11778 mutation using adeno-associated viral vector containing the human mitochondrial superoxide dismutase (SOD2) gene offers promise that gene therapy may soon play a role in the treatment of LHON and other mitochondrial disease.326,697

arm of chromosome 8 in a French family.48 Given the rarity of this disorder, the diagnosis should be one of exclusion that carries with it the need for specific genetic counseling to prospective parents.

X-Linked Optic Atrophy

Recessive Optic Atrophy Recessively inherited optic atrophies are a heterogeneous group of disorders. One end of the spectrum is represented by complex and overlapping conditions such as Behr’s optic atrophy and Costeff syndrome, as well as various recessively inherited neurologic disorders that show optic atrophy as one of their manifestations. The other end of the spectrum is represented by a monosymptomatic, isolated, rare form of hereditary optic atrophy that occurs as an autosomal recessive disorder. Simple recessive optic atrophy is present at birth or develops at an early age.268,457,911 The visual deficit in this rare disorder is more pronounced than in dominant optic atrophy, with acuities worse than 2/200 and achromatopsia or severe dyschromatopsia being characteristic. The condition is therefore detected earlier in life than dominant atrophy, usually within the first several years of life, and is usually associated with nystagmus. Occasionally, the condition is noted in the neonatal period and labeled as congenital. Visual fields show variable constriction, often with paracentral scotomas. Because of the rarity of the condition, other, more common, disorders must first be excluded by thorough clinical, electrophysiological, and neuroimaging means.172 The optic discs show profound diffuse atrophy, often with deep cupping. Attenuation of the peripapillary retinal arteriolar vessels has been described, suggesting that at least some such cases might have represented undiagnosed retinal dystrophies such as Leber congenital amaurosis or autosomal recessive cone dystrophy with associated optic atrophy that went unrecognized in the pre-ERG era.267 Therefore, a complete retinal evaluation and a normal ERG are essential to make a diagnosis of autosomal recessive optic atrophy. In an infant with Leber congenital amaurosis, however, optic atrophy is distinctly unusual,745 and a compressive intracranial etiology should be sought. Also, histopathologic studies of eyes with Leber congenital amaurosis have revealed intact optic nerves, the outer nuclear layer and photoreceptors being the primary site of retinal pathology.744 Although some authors have cast doubt on the existence of simple, monosymptomatic, recessively inherited optic atrophy as a distinct entity,583 the locus for autosomal recessive isolated optic atrophy was recently mapped to the long

Several pedigrees with isolated X-linked optic atrophy have been documented. Assink et al34 analyzed four males from a Dutch pedigree with X-linked optic atrophy who had visual acuities between 20/80 and 20/1,000, with severe optic atrophy and severe color vision defects that differed from dominant optic atrophy by the absence of tritanopia. Katz et al430 found similar linkage in 15 members of an extended pedigree. Affected individuals have visual acuities ranging from 20/30 to 20/100 with significant optic atrophy, absence of nystagmus in most patients, and no other neurologic abnormalities. Obligate female carriers had normal acuity, color vision, perimetry, and normal disc appearances. The gene product for OPA2 has not yet been determined.363 Older reports of X-linked optic atrophy probably included a diverse group of patients, some of whom had Charcot–Marie–Tooth disease, with others having Rosenberg–Chutorian syndrome.430

Behr Syndrome In 1909, Behr59 described a variant of recessive optic atrophy that also occurs in early childhood (1–8 years). It differs from the simple variety previously described in that it is associated with other abnormalities, including ataxia, pyramidal and extrapyramidal dysfunction, hypertonia, juvenile spastic paresis, mental retardation, urinary incontinence, and pes cavus. Muscle contractures, mainly of the hip adductors, hamstrings, and soleus, are progressive and become more prominent in the second decade.170 Although usually autosomal recessive, pseudodominant and autosomal dominant inheritance do occur.253,774,856 The visual disability and optic atrophy are severe, showing a variable period of progression that does not usually extend beyond childhood. Sensory nystagmus occurs in over half of the patients. MR neuroimaging in a 6-year-old girl with this syndrome demonstrated diffuse, symmetric white matter abnormalities, including the optic radiations, internal capsule, and centrum semiovale.543 It is doubtful that Behr optic atrophy is a distinct entity, with recent evidence suggesting that the syndrome may represent a number of nosologically and genetically separate disorders. Some cases may represent undiagnosed

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adrenoleukodystrophy or hereditary ataxia during the era when diagnostic testing for these entities was not available. Other cases may represent undiagnosed cases of 3-methylglutaconic aciduria,175,794 a syndrome with similar clinical features to Behr syndrome. Sheffer794 examined three patients who fulfilled the diagnostic criteria of Behr syndrome and who excreted excessive amounts of 3-methylglutaconic acid and 3-methylglutaric acid in their urine. This autosomal recessive disorder, also known as methylglutconic aciduria type III or Costeff syndrome, is characterized by early bilateral optic atrophy, later-onset spasticity, extrapyramidal dysfunction, ataxia, and occasional cognitive defects.174,175,236,363 Patients with Costeff syndrome tend to have extrapyramidal dysfunction without ataxia, whereas those with Behr syndrome tend to have ataxia without extrapyramidal dysfunction, although some overlap exists.175 It is caused by a homozygous mutation in the optic atrophy 3 gene (OPA3), which encodes a protein that is localized to the mitochondrial inner membrane.363 Homozygous mutations with complete absence of the OPA3 gene produce Costeff syndrome, whereas missense mutations in one copy of the OPA3 gene produce autosomal dominant optic atrophy with cataract.363 Straussberg et al829 reported seven Iraqi Jewish children with 3-methyl glutaconic aciduria who were initially misdiagnosed as having cerebral palsy and cautioned that this diagnosis should be considered in the differential diagnosis of cerebral palsy, especially when neurologic symptoms are slowly progressive. Because the two disorders may be clinically indistinguishable, testing for elevated urinary excretion of 3-methylglutaconic acid should be included in the diagnostic evaluation of Behr syndrome. The diagnosis of Behr syndrome should be considered in patients with heredofamilial ataxia and optic atrophy.253 Its differential diagnosis includes NARP (nyctalopia, ataxia, retinitis pigmentosa) syndrome,292 Marinesco–Sjogren syndrome (a rare autosomal recessive disorder featuring cataracts, cerebellar ataxia, and mental retardation)288 and other spinocerebellar degenerations,181 and other rare congenital cerebellar ataxias such as CAMOS (cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities) syndrome,196 CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome,624 and Nyssen–Van Boegaert syndrome.484 Because there are no hallmarks, the diagnosis of Behr’s syndrome is based on exclusion criteria.253

Wolfram Syndrome (DIDMOAD) Originally described as an association of diabetes mellitus and optic atrophy by Wolfram,937 the spectrum of this syndrome was subsequently expanded to include central diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural

4 Optic Atrophy in Children Table 4.3 Neurologic manifestations of Wolfram (DIDMOAD) syndrome Diabetes insipidus Optic atrophy Nystagmus Ptosis Lacrimal hyposecretion Pupillary abnormalities (e.g., internal ophthalmoplegia) Sensorineural deafness Seizures Anosmia Psychiatric disorders Low IQ Ataxia Hypogonadotrophic hypogonadism Neurogenic bladder

deafness (hence, the acronym DIDMOAD).22,680,747,757,893 Other, less common, phenotypic features include ptosis, brachydactyly, anosmia, ataxia, nystagmus, seizures, mental retardation, psychiatric disorders, abnormal ERG, elevated protein and cell count in the spinal fluid, small stature, congenital heart disease, myocarditis, and genitourinary abnormalities (Table 4.3).497,708 The typical urinary tract abnormalities include muscular atony with bilateral hydronephrosis and hydro ureters. The mode of inheritance is generally considered autosomal recessive or sporadic, but recently, some cases of Wolfram syndrome have been proposed to represent a mitochondrial-mediated disorder.100,738 It has been suggested that the constellation of findings in Wolfram syndrome fulfill the criteria for a genetic defect of the mitochondrial energy supply. 108 These criteria include the following (1) an unexplained association of symptoms and signs, (2) with an early onset and a rapidly progressive course, and (3) which involves seemingly unrelated organs that share no common embryological origin or biological function.598 Alternatively, a combination of mitochondrial and nuclear genetic defects have been postulated to explain the pleiotropic features of DIDMOAD syndrome.108 Some have proposed that the DIDMOAD syndrome results from an inherited abnormality of thiamine metabolism.83 The optic atrophy initially shows rapid progression then plateaus before complete blindness occurs in most cases. Vision is usually reduced to less than 20/200. Pigmentary retinopathy and abnormal ERGs have been described in some cases, indicating the possibility of a more widespread retinal abnormality. The ages of most patients described in the literature are under 25 years, with many under 15 years. The onsets of the various manifestations of the syndrome are usually temporally separated from each other by months to years. The mean age at diagnosis of diabetes mellitus is 9 years, optic atrophy at 12 years, and diabetes insipidus at 15–20 years. Hearing loss may be detectable only by audiography before the age of 20 years. The fact that diabetes mellitus occurs first in most patients led to the earlier impression that many

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Toxic/Nutritional Optic Neuropathy

of the features of the syndrome represent diabetic microvascular complications. This now seems unlikely.453 Optic atrophy and other neurologic abnormalities may appear before diabetes mellitus and usually develop in the absence of any complications related to hyperglycemia.321 The syndrome may remain unrecognized in many patients because the symptoms, except diabetes mellitus and optic atrophy, occur with varying expressivity.159,217 The occurrence of optic atrophy and diabetes mellitus without other manifestations of the syndrome makes the diagnosis difficult to establish, especially in sporadic cases. The DIDMOAD syndrome should be suspected in diabetic children with unexplained visual loss or persistent polyurea and polydipsia (due to unsuspected diabetes insipidus) in the presence of adequate blood sugar control. The associated hearing loss may be subtle, often a mild highfrequency loss, and must be investigated. Atonia of the efferent urinary tract, which is said to occur in half of patients, is associated with recurrent urinary tract infections and even fatal complications.52 Other systemic and neurologic abnormalities may include regression of milestones, seizures, myoclonus, choreiform movements, ataxia, abnormal behavior, and a bleeding diathesis (Table 4.3).23,137,555 Median age at death is 30 years, most commonly attributable to central respiratory failure with brainstem atrophy.137 MR imaging is highly abnormal, with widespread atrophic changes involving the brainstem, middle cerebellar peduncle, and cerebellum, along with the absence of the high-intensity signal of the posterior pituitary that is consistent with degeneration of the supraoptic and paraventricular nuclei of the hypothalamus.398,660,708,778 In one 12-year-old girl, however, T2-weighted and proton density images showed high signal in the right substantia nigra with no evidence of atrophy.275 Differentiation from simple recessive optic atrophy is made on the basis of the congenital onset and the isolated nature of simple recessive optic atrophy. DIDMOAD is readily distinguished from complicated forms of recessive optic atrophy (such as Behr or Costeff syndrome) on the basis of the serious CNS dysfunction (mental retardation, spasticity, hypertonia, ataxia) and the early age of onset of Behr syndrome. The disorder should be readily differentiated from other disorders showing a combination of diabetes mellitus and optic atrophy, namely Friedreich ataxia, infantile Refsum disease, Alstrom syndrome, and Bardet–Biedl syndrome. The DIDMOAD syndrome can be distinguished from other syndromes showing a combination of optic atrophy and hearing loss, such as Sylvestor syndrome,840 Jensen syndrome,407 or a recently described syndrome showing a triad of optic atrophy, hearing loss, and peripheral neuropathy334 on the basis of other clinical characteristics, the time course of emergence of the various stigmata, and the modes of transmission. Mutations in the WFS1 gene at 4p16.3 are associated with either optic atrophy as part of the autosomal recessive

Wolfram syndrome, with dominant optic atrophy with hearing loss, or with autosomal dominant progressive low-frequency sensorineural hearing loss without any ophthalmological abnormalities.213,229,739 In several families with presumed autosomal dominant inheritance, Wolfram gene was localized to the short arm of chromosome 4 (4p16.1).684 However, this locus does not account for all Wolfram pedigrees. The gene at this locus has been designated WFS1, and multiple point mutations and deletions have been identified.354,891 Some of these mutations have been found to be a common cause of inherited isolated low-frequency hearing loss. In one report,53 the locus on chromosome 4p16 was proposed as a predisposing factor for the formation of multiple mitochondrial deletions. DIDMOAD patients were also found to exhibit a preponderance of two major mtDNA haplotypes that are also overrepresented among LHON patients.364 That many associated abnormalities in Wolfram syndrome are commonly encountered in patients with mitochondrial disease has led to speculation that the Wolfram phenotype may be nonspecific and reflect a wide array of underlying genetic defects in either the nuclear or mitochondrial genomes, with a unifying pathogenesis in mitochondrial dysfunction.618

Toxic/Nutritional Optic Neuropathy Symmetrical, usually insidious bilateral optic neuropathy may result from nutritional deficiency (e.g., thiamine, vitamin B12, pyridoxine, folic acid, cobalamin, riboflavin). Children with a history of malnutrition, on starvation diets (e.g., teenagers with anorexia) or other unusually restrictive diets, or gastrointestinal malabsorption disorders should be particularly suspected of harboring this diagnosis (Fig. 4.13). The diagnosis of vitamin B12 deficiency should be considered in the child with “sporadic” dominant optic atrophy (R. Michael Siatkowski, verbal communication). Hoyt and Billson372 described two children who developed symmetrical, bilateral optic neuropathy while being treated with ketogenic diets for seizure control. Both patients recovered normal visual acuity following treatment with thiamine. The epidemic optic neuropathy afflicting Tanzanian schoolchildren in their second decade of life may be partly attributable to low serum levels of B group vitamins.91a Optic atrophy may arise from adverse metabolic effects of certain drugs (e.g., ethambutol, chloramphenicol, rifampin, Carmistine [BCNU], vincristine) and toxins (e.g., methanol, lead, cobalt). Numerous substances have been implicated in causing optic atrophy.313,355 Chloramphenicol can produce an optic neuropathy that is akin to Leber Hereditary optic neuropathy.789 Before its discontinuation, some patients with cystic fibrosis treated with chloramphenicol presented with sudden bilateral loss of vision, central scotomas, papilledema, engorgement of the retinal veins, and subsequent disc pallor.355 It was subsequently discovered that chloramphenicol acts as

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4 Optic Atrophy in Children

Fig. 4.13 Nutritional optic atrophy. This 9-year-old girl with a history of malnutrition in infancy had subtle temporal disc pallor and pigmentary maculopathy. Visual acuity was 20/30 OD and 20/40 OS

a specific inhibitor of mitochondrial protein synthesis in patients with cystic fibrosis.791 Alcohol ingestion and intake of recreational and other drugs should be thoroughly reviewed in the clinical history. Maternal ingestion of alcohol and fetal alcohol syndrome may cause optic nerve hypoplasia or congenital optic atrophy.141,831 In adults, some cases of the socalled cases tobacco-alcohol amblyopia have been shown to represent variants of Leber hereditary optic neuropathy,178 and whether tobacco-alcohol amblyopia can develop in the absence of a genetic predisposition is uncertain. Cecocentral scotomas are the typical visual field defects in toxic/nutritional optic neuropathies, but they may be difficult to elicit in the early stages of these disorders.

Neurodegenerative Disorders with Optic Atrophy There are a large and ever-expanding number of neurodegenerative disorders of the central and/or peripheral nervous system that can be associated with ophthalmologic disorders, including optic atrophy (Table 4.4). The distinction between neurodegenerative disorders and other genetic and neurometabolic disorders is becoming increasingly blurred as the responsible gene, its enzyme and protein products, and the specific metabolic defect are identified. Many neurodegenerative disorders show considerable overlap, demonstrating combinations of progressive degeneration of the cerebellum, pyramidal tract, polyneuropathies (sensory neuropathy, motor neuropathy, or both), deafness, and optic atrophy. In some instances, overlapping features preclude separate nosologic classification. Generally, these disorders are diagnosed

on the basis of associated clinical findings and other features rather than by the optic atrophy. In some sense, even isolated optic atrophies, such as dominant optic atrophy, may be thought of as limited neurodegenerative disorders that preferentially involve the optic nerve. Degenerative disorders affecting gray matter are less common than those affecting white matter, and generally the two are very difficult to differentiate on clinical grounds. Optic atrophy is common in children with neurodegenerative disease. Because it reflects irreversible injury to the pregeniculate pathways, optic atrophy occurs preferentially in neurodegenerative disorders that primarily affect the white matter. Children with white matter disease tend to present with corticospinal tract dysfunction, peripheral neuropathies, and optic atrophy. In contrast, gray matter disease tends to produce seizure disorders, movement disorders, and dementia. The child with purely gray matter disease (e.g., Tay– Sachs disease) will tend to have seizures without optic atrophy, whereas the child with purely white matter disease may present with optic atrophy without seizures. The development of optic atrophy in a child with seizures may signify a spread of the disease process from gray to white matter (as may occur in the later stages of Leigh disease). Although neurodegenerative and neurometabolic diseases are often classified as gray or white matter disorders, most eventually involve both gray and white matter to some degree. Neurodegenerative disorders that are commonly associated with optic atrophy are summarized in Table 4.4. Some of the neurodegenerative disorders present in infancy as infantile progressive encephalopathies, and these are exemplified by the first six disorders subsequently discussed. These represent a heterogeneous group of disorders that can be differentiated on the basis of metabolic abnor-

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Neurodegenerative Disorders with Optic Atrophy Table 4.4 Neurodegenerative disorders commonly associated with optic atrophy in children Pelizaeus–Merzbacher disease Canavan disease X-linked adrenoleukodystrophy Alexander disease Leigh disease Metachromatic leukodystrophy Krabbe disease Multiple sclerosis Spinocerebellar degeneration (Friedreich ataxia, olivopontocerebellar degeneration) Neuronal ceroid lipofuscinosis Hallervorden–Spatz disease MELAS Congenital lactic acidosis Vanishing white matter disease

malities (e.g., Krabbe disease, Menke syndrome), typical histopathological findings (e.g., neuronal ceroid lipofuscinosis), additional extra-cerebral findings (e.g., Aicardi syndrome), or dysmorphic features (e.g., PEHO syndrome).

Krabbe’s Infantile Leukodystrophy This is an autosomal recessive disorder of sphingolipid metabolism that is caused by mutations in the galactosylceramide gene on chromosome 14q31.44,918 Affected children are normal at birth, but begin to deteriorate within the first few months of life, developing irritability, restlessness, spasticity, convulsions, hyperacusis and, in the terminal stages, bulbar signs, deafness, and flaccidity. Optic atrophy and blindness are prominent features. MR imaging shows symmetrical white matter involvement with a predilection for the parietooccipital regions. Diagnosis is established by assay of galactocerebrosidase in leukocytes. Death usually occurs by the age of 2 years.905 Autopsy shows loss of myelin in the brain, with globoid cells in the area of demyelination. A rare, juvenile-onset form of Krabbe disease has also been reported in association with optic atrophy.44

Canavan Disease (Spongiform Leukodystrophy) This is an autosomal recessive disorder in which patients who are often asymptomatic in their early months show a wide spectrum of clinical presentation that includes macrocephaly without hydrocephalus, poor head control, seizures, hypotonia, lack of movements, optic atrophy, and significant developmental delay.13 This disorder occurs almost exclusively in Ashkenazi Jews. MR imaging reveals diffuse symmetric lesions of the cerebral white matter and, in the later stages, cortical atrophy. Death usually occurs between the ages of 1 and 3 years. Histopathology reveals demyelination and spongy degeneration

in the cortex. The disease is caused by deficiency of aspartoacylase, the enzyme responsible for the hydrolysis of N-acetylaspartic acid into acetate and l-aspartate.13 Deficiency of aspartoacylase in skin fibroblasts or N-acetylaspartic acid in the urine is diagnostic of the disease.13 The abnormal gene is localized to the short arm of chromosome 17.66,304

Subacute Necrotizing Encephalomyelopathy (Leigh Disease) Leigh disease is a neurodegenerative syndrome that can result from multiple different biochemical defects that all impair cerebral oxidative metabolism.64,150,200,206,589,704,761,798,885,890 Depending on the genetic defect, it may be inherited in an autosomal recessive, X-linked, or maternal pattern,573 and may present in an infantile, juvenile, and an adult form.468 It is caused by a deficiency of pyruvate carboxylase, with increased levels of lactate and pyruvate in the blood. The infantile form begins within the first 6 months of life. A positive family history is present in half of the infantile cases. In infants, the insidious course of the disease ranges from weeks to years, with patients developing somnolence, deafness, psychomotor regression, and spasticity, in addition to optic atrophy and blindness. Death occurs between 2 and 10 years of age. Autopsy findings show bilateral, multifocal, subacute necrotic lesions from the thalamus to the pons, and demyelination in the optic nerve. The clinical features of Leigh disease may be associated with several biochemical defects, which can arise from either nuclear or mitochondrial gene mutations.249 Childhood lactic acidosis comprises a number of clinically heterogeneous disorders that share increased levels of lactate and pyruvate in the blood.357 In addition to Leigh disease, disorders showing childhood lactic acidosis include MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), pyruvate decarboxylase deficiency, pyruvate dehydrogenase deficiency, pyruvate dehydrogenase phosphatase deficiency, cytochrome c oxidase deficiency, dietary ketoacidosis, or idiopathic.117,357 Optic atrophy is a common neuro-opthalmologic finding in children with lactic acidosis due to their propensity for CNS white matter involvement.357

Pelizaeus–Merzbacher Disease (Sudanophilic Leukodystrophy) This is an X-linked recessive disorder that differs from the other leukodystrophies by the presence of irregular pendular nystagmus and head shaking in the first few months of life. Poor head control, cerebellar dysfunction, choreiform movements of the arm, and spasticity develop later. The nystagmus may later disappear. Optic atrophy and retinal degeneration

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occur later. Intellectual function is generally preserved despite neurological deterioration. Death ensues between 5 and 7 years of age. Autopsy findings show patchy demyelination.

PEHO Syndrome PEHO syndrome denotes progressive encephalopathy, with edema, hypsarrhythmia, and optic atrophy.337,758,812,813 It is apparently transmitted as an autosomal recessive disorder, and most patients are of Finnish descent.259,460,895 Most patients are healthy or only slightly hypotonic at birth. The disorder becomes manifest at 2 weeks to 3 months of age, with progressive hypotonia, poor vision, and limb jerks. Affected patients also show infantile spasms, exaggerated deep tendon reflexes, and early arrest of psychomotor development. Subcutaneous edema in the limbs and blindness with optic atrophy and nystagmus are also present.812,813 Affected infants show typical dysmorphic facial features that include epicanthal folds, midfacial hypoplasia, promi-

nent ear lobes, gingival hypertrophy, small chin, and tapered fingers. The most typical physical finding is subcutaneous nonpitting edema of the limbs and face. A few patients have survived into the teens. MR imaging scans show cerebellar hypoplasia as the predominant finding.516 A progressive brain atrophy may involve the brain stem, cerebellum, and optic nerves, sometimes with abnormal myelination suggestive of periventricular leukomalacia.516,723,813,895 A metabolic defect has yet to be determined.573 One recent study found deficient production of IGF-1, which may permits elevated levels of nitrous oxide to damage the cerebellar granule cells, promote seizures, damage cerebellar granule cells, and permit the underlying neurodegeneration in PEHO syndrome.723

Neonatal Leukodystrophy This is one of the peroxisomal disorders that includes a wide array of disorders including Zellweger cerebrohepatorenal

Table 4.5 Clinical features of peroxisomal disorders Disorder

Age at onset

Ophthalmologic findings

Other clinical findings

Zellweger syndrome

Neonatal period

Craniofacial dysmorphism Seizures Hypotonia Psychomotor retardation Hepatomegaly, renal cysts

Neonatal adrenoleukodystrophy

Neonatal period

Infantile Refsum disease

First decade

Rhizomelic chondrodysplasia punctata

Neonatal period

Pigmentary retinopathy Attenuated retinal arterioles Optic atrophy Corneal clouding Glaucoma, cataract Extinguished ERG Pigmentary retinopathy Attenuated retinal arterioles Pigment epithelial clumping Optic atrophy Extinguished ERG Pigmentary retinopathy Attenuated retinal arterioles Optic atrophy Extinguished ERG Cataract Normal ERG

X-linked adrenoleukodystrophy

First decade

Optic atrophy Visual pathway demyelination Normal ERG

Primary hyperoxaluria type I

First through second decade

Parafoveal pigmentary changes Optic atrophy

Classical Refsum disease

First through fourth decade

Pigmentary retinopathy Attenuated retinal arterioles Night blindness Optic atrophy Attenuated ERG

Adrenal cortical atrophy Seizures Hypotonia Psychomotor retardation Deafness Psychomotor retardation

Short proximal extremities Dermatitis Psychomotor retardation Radiographic epiphyseal stippling Adrenal cortical atrophy Darkened skin Emotional lability Hearing loss Incoordination, spasticity Intellectual deterioration Renal failure Osteodystrophy Hydrocephalus Polyneuropathy Ataxia Hearing loss Anosmia Metatarsal/metacarpal abnormalities Ichthyosis-like skin

Neurodegenerative Disorders with Optic Atrophy

syndrome, infantile refsum disease, neonatal adrenoleukodystrophy, rhizomelic chondrodysplasia punctata, X-linked adrenoleukodystrophy, primary hyperoxaluria type I, and classical Refsum disease.265 The various clinical features of these disorders are summarized in Table 4.5. With the exception of X-linked adrenoleukodystrophy, the inheritance of these disorders is autosomal recessive. In patients suspected of harboring peroxisomal disorders, analysis of cultured fibroblasts for very long chain fatty acids (VLCFA), dihydroxyacetone-phosphate acyltransferase (DHAPAT), and/or plasmalogen are helpful.

Metachromatic Leukodystrophy Metachromatic leukodystrophy is an autosomal recessive disorder that is usually caused by mutations in the arylsulfatase A (ARSA) gene on chromosome 22q13.31. Several forms of this autosomal recessive disorder are recognized, including a late infantile and a juvenile form. The late infantile form presents at between 1 and 2 years of life, with gait disorder and strabismus. Speech impairment, spasticity, intellectual deterioration, and optic atrophy follow. Optic atrophy is found in about one-third of cases and is, along with cortical visual impairment, a cause of significant visual loss.269 Other, less common, ophthalmological features include retinal arteriolar attenuation, course granular macular pigmentary deposition, rippling of the internal limiting membrane (due to retinal atrophy), and a cherry red spot. The ERG is usually normal or mildly abnormal, in contrast with the various juvenile amaurotic idiocies. Deep tendon reflexes are reduced or absent in the lower extremities. Patients may suffer unexplained episodes of fever or abdominal cramps. The CSF protein is elevated. Neuroimaging demonstrates white matter disturbances, especially of the periventricular region. The diagnosis was formerly made by demonstration of intracellular metachromatic substances in the urine and assay of arylsulfatase A in leukocytes. When the disease begins before 30 months of age, death usually ensues between 5 and 10 years of age.918 No treatment has been shown to be effective.

X-Linked Adrenoleukodystrophy (Addison–Schilder Disease) Adrenoleukodystrophy is an X-linked recessive disorder that is caused by mutations in the ATP-binding cassette gene (ABCD1) on chromosome Xq28.918 It usually presents with visual defects and neurological disturbances at an average age of 7 years. Affected boys may display signs of attention deficit disorder, behavioral disturbance, visual loss, incoordination, and dementia.918 These bizarre visual symptoms

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and their associated behavioral disturbances may lead to the mistaken diagnosis of hysterical blindness, particularly in the early stages when the fundus findings are normal.847 Affected boys develop hormonal disturbances manifesting as Addison’s disease, with skin hyperpigmentation or hypogonadism. The early visual impairment early is cortical in origin. Neuroimaging demonstrates symmetric bilateral involvement of the periventricular white matter, especially posteriorly (hence, the cortical visual impairment). Optic atrophy develops later in the disease. The diagnosis can be confirmed by finding an excess of very long chain fatty acids in cultured skin fibroblasts, white cells, red blood phospholipids, or total plasma lipids.592 Carrier females occasionally develop a variable degree of neurological impairment and may have symptoms and MR lesions similar to those found in multiple sclerosis. Genetic counseling is therefore important for symptomatic females. The disease is characterized by inexorable neurological deterioration culminating in death within a few years. Bone marrow transplantation has stabilized or improved neurologic function in selected cases.918

Pantothenate Kinase-Associated Neurodegeneration Pantothenate kinase-associated neurodegeneration (formerly known as Hallervorden–Spatz syndrome) is a rare familial neurodegenerative disorder that presents in childhood or early adolescence with dystonia, parkinsonism, choreoathetosis, corticospinal tract involvement, optic atrophy, pigmentary retinopathy, and cognitive impairment.855 Dystonia is more frequent in early-onset patients, whereas parkinsonism is seen predominantly in adult-onset patients. It is also referred to as neurodegeneration with brain iron accumulation, with iron deposition in the globus pallidus producing the characteristic “eye-of-the-tiger” sign on MR imaging. Characteristic MR changes include decreased signal intensity in the globus pallidus and the substantia nigra on T2-weighted images compatible with iron deposition.29,837 Death occurs an average of 15 years after onset. There is no known biochemical basis or genetic marker for the disorder yet.8 Before the advent of MR imaging, confirmation of the diagnosis was done on autopsy. A mild degree of visual impairment is frequently described in Hallervorden–Spatz syndrome, typically attributed to optic atrophy, pigmentary retinopathy, or tapetoretinal degeneration. Rarely, visual loss due to optic atrophy is the presenting symptom.135 However, one recent ophthalmologic study of 16 patients found no patient with optic atrophy.228 Mutations in the PANK2 gene on chromosome 20p12.3-p13 are associated with a younger age at onset and a higher frequency of dystonia, dysarthria, intellectual impairment, and gait disturbance.433,855

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Neuronal Ceroid Lipofuscinoses (Batten Disease) The ceroid lipofuscinoses are autosomal recessive disorders that have been subdivided according to the age at which the neurologic symptoms first appear. The clinical features of these various types are detailed in Table 4.6. These disorders must be considered in the differential diagnosis in the infant or child who develops seizures, loss of acquired milestones, progressive intellectual deterioration, and progressive visual impairment. Confirmation of the diagnosis previously required electron microscopic examination of suitable specimens derived from skin, conjunctiva, muscle, or rectal biopsy that demonstrate characteristic storage materials. It is now more quickly and definitively established by genetic testing for mutations in the CLN3 genes.296,297 No enzymatic deficiency has been identified. Neuroimaging studies reveal nonspecific changes, but are helpful in distinguishing the lipofuscinoses from the various leukodystrophies in which there are striking abnormalities of the white matter. Juvenile Batten disease (Spielmeyer–Vogt disease) is of particular importance to the ophthalmologist because visual impairment is commonly the presenting symptom (Table 4.6).816 In contrast, the infantile and late infantile forms show a rapidly progressive downhill course and are rarely diagnosed by the ophthalmologist.

Familial Dysautonomia (Riley–Day Syndrome) This is an autosomal recessive disorder that is confined to Ashkenazi Jews. Although the name suggests that the disorder is strictly one of autonomic dysfunction, the peripheral sensory and motor nerves as well as other neuronal populations are affected. Children present with poor suck reflex, hypotonia, hypothermia, and nursing difficulties with frequent regurgitation, at birth. Patients with this syndrome also show poor

temperature control, motor incoordination, reduced deep tendon reflexes, postural hypotension, and emotional lability. The children lack the fungiform papillae on the tongue and have markedly diminished taste sensation. The most prominent ophthalmological findings are pronounced corneal hypesthesia and absent tears, which in combination lead to corneal ulcerations. Other findings include retinal vascular tortuosity, ptosis, anisocoria, exotropia, and increased incidence of myopia. Optic atrophy has been rarely reported.204 Rizzo et al727 reported three patients with the syndrome who showed visual impairment due to optic atrophy, initially diagnosed after the first decade. The authors suggested that the presence of an optic atrophy demonstrates that there is some degree of CNS involvement in familial dysautonomia.

Infantile Neuroaxonal Dystrophy Infantile neuroaxonal dystrophy is an autosomal recessive disorder that presents in infancy with psychomotor retardation, truncal hypotonia, peripheral spasticity, and areflexia.327,918 Optic atrophy develops in 40% of cases by 3 years of age.11,257 In one study,247 after 2 years of age, patients show characteristic electroencephalographic changes with fast phase activity superimposed upon a slow background.918 MR imaging showed cerebellar atrophy and mildly increased signal from the cerebellar cortex on T2-weighted images, and a few showed increased signal from the dentate nuclei and from the posterior periventricular white matter. Histopathologically, patients with this disorder have eosinophilic spheroids in the central, peripheral, and autonomic nervous systems; cerebellar degeneration and degeneration of various neuronal, myelin, and glial elements.913 Similar pathologic findings occur in pantothenate kinase-associated neurodegeneration, an autosomal-recessive disorder with a later onset that is more insidiously progressive.305 There is no effective treatment.

Table 4.6 Clinical features of the neuronal ceroid lipofuscinoses Eponym Age at onset Myoclonic seizures Ataxia Late features Ophthalmologic findings

Blindness Electron microscopy (lymphocytes)

Infantile

Late infantile

Juvenile

Variant

Santavuori 8–18 months Present Marked Microcephaly death by 4 years Macular pigmentary changes Attenuated retinal arterioles Optic atrophy Extinguished or attenuated ERG

Batten–Bielschowsky 2–4 years Present (presenting sign) Marked Death by 7 years

Spielmeyer–Vogt 4–10 years Occasional Mild and late Dementia Death 2nd to 3rd decade Bull’s eye maculopathy (early) Diffuse pigmentary changes (late) Attenuated arterioles Optic atrophy Extinguished ERG

Early Granular, amorphous inclusions

Late Curvilinear or fingerprint inclusions

Batten 5–7 years Present Marked Dementia Death 2nd decade Pigmentary changes, retinal pigment aggregation Attenuated retinal arterioles Optic atrophy Early Negative, fingerprint inclusions

Marked pigmentary changs Attenuated retinal arterioles Optic atrophy Extinguished ERG

Early (presenting symptom) Fingerprint inclusions

Neurodegenerative Disorders with Optic Atrophy

Organic Acidurias Biotinidase Deficiency Biotinidase Deficiency, also known as late-onset multiple carboxylase deficiency, is an autosomal recessive disorder of the BTD (biotinidase) gene.388 Biotinidase recycles biotin, which is a water-soluble vitamin and necessary coenzyme for multiple carboxylase enzymes involved in amino acid, fatty acid, and glucose metabolism. The incidence of this disorder is especially high in Brazil. Biotinidase deficiency can be detected with newborn screening and treated with biotin supplementation.920 Multiple case reports and series describe presentation at a young age, with developmental delay, seizures, sensorineural hearing loss, spastic paraparesis, skin rash, infections, acute intermittent ataxia, lactic acidosis, alopecia, and stridor. The main ophthalmologic finding is optic atrophy. The diagnosis is confirmed by a low serum biotinidase level.388 The critical importance of diagnosing biotinidase deficiency lies in the efficacy of treatment, which simply involves oral biotin supplementation. Symptomatic children often have developmental delay and are at risk of irreversible damage to auditory, visual, or central nervous functions. In one study,920 no child with profound biotinidase deficiency detected by newborn screening had auditory or visual loss, and milestones of speech development and motor skills were reached at an appropriate age, emphasizing the need for newborn screening.

Propionic Acidemia Propionic acidemia is a rare autosomal recessive disorder that leads to chronic metabolic compensation with paroxysmal ketoacidosis, failure to thrive, and mild developmental delay.389 It is characterized by the accumulation of propionyl-CoA inside the mitochondria, secondary to a deficiency of propionyl-CoA carboxylase, a biotin-dependent mitochondrial enzyme involved in the catabolism of long-chain fatty acids and amino acids.746,839,936 Clinical manifestations include episodic acidosis and hyperammonemia, leading to irritability, lethargy, tachypnea, vomiting, shock, and death.282,636 Males with propionic acidemia have moderate-to-severe bilateral optic atrophy.389 Rarely, females can develop it too.932

Cobalamin C Deficiency with Methylmalonic Acidemia Cobalamin C methylmalonic acidemia with homocystinuria is an autosomal recessive inborn error of metabolism that results in the combined dysfunction of two essential coenzymes, adenosylcobalamin and methylcobalamin.736 It

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is characterized by progressive maculopathy, failure to thrive, megaloblastic anemia, and neurologic dysfunction.770 Two distinct phenotypes have been described: early and late onset, with early onset carrying a more severe prognosis.736 The associated retinopathy is both developmental and degenerative. Patients present either at birth or later with metabolic decompensation in response to illness and are found to have high methylmalonic acid in the urine. Cobalamin C methylmalonic acidemia is one of the few causes of infantile maculopathy.874 Affected patients have a dramatic disturbance of the retinal pigment epithelium in the macula (sometimes consisting of large areas of macular hypopigmentation with course clumps of pigment), nystagmus, and epileptiform eye movements.162,728 The ERG becomes progressively attenuated.770 Some children develop macular coloboma-like changes. Optic atrophy can sometimes accompany these findings.666 Other forms of methylmalonic acidemia without cobalamin C deficiency can also be associated with optic atrophy.932 Treatment with methionine does not rescue the macula or postreceptoral retinal responses represented by the b wave, but has recently been reported to restore normal rod photoreceptor sensitivity in one patient.874

Spinocerebellar Degenerations Prior to genetic analysis, Harding categorized the autosomal dominant cerebellar ataxias (ADCA) into four types.352,573 Only ADCAI had optic atrophy, which was seen in about 30% of cases. Other neurologic symptoms included supranuclear ophthalmoplegia, basal ganglia dysfunction, amyotrophy, and dementia113,352,513,653,735 Harding’s classification,352 which separated the hereditary ataxias into early onset (predominantly autosomal recessive) and late onset (autosomal dominant), as been further refined by genetic discoveries over the past two decades, leading to a more definitive genomic classification and the possibility of molecular diagnosis. The current classification of hereditary ataxias supplants earlier pathological descriptions of the olivopontocerebellar degenerations.342 ADCA1 is now known to encompass multiple genetic loci, including pedigrees that are now classified as SCA1, SCA2, and SCA3, and SCA4.222,361,423,573 Optic atrophy is seen more commonly in SCA1, but has been found in SCA2 and SCA3 as well.113 Patients previously diagnosed as having olivopontocerebellar atrophy are now known to carry mutations for SCA1, SCA2, and SCA3.116 These patients show progressive cerebellar ataxia, tremor, spasticity, and speech impairment, which are detailed in chapter 7.113,116,645 Molecular testing of DNA from whole blood is now available to detect the spinocerebellar degenerations.651

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Rarely, spinocerebellar ataxias can present in infancy.314 When the SCA2 alleles contain more than 200 repeats, for example, SCA2 can present in infancy with hypotonia, developmental delay, dysphagia, and retinitis pigmentosa.42 Earlyonset is associated with a shorter survival, while the prognosis is relatively good with later onset, after age 20.343 Involvement of the inferior olivary nuclei is present.342 Intellectual deterioration and dementia may occur later in the course of the disease. Both autosomal dominant cerebellar ataxia types I and II are associated with optic atrophy and ophthalmoplegia.349,352 However, type II is distinguished by the presence of pigmentation macular dystrophy; this dystrophy includes early granularity and mottling that is later associated with pigmentary changes that gradually spread to the periphery, with late optic atrophy and attenuation of retinal vessels.238,308,405,745,866 Most cases become evident in adulthood, but a dominantly inherited form that is associated with retinal degeneration can present as early as the first year of life. The optic atrophy seen in some patients may be secondary to associated retinal degeneration or may occur primarily as part of the multisystem CNS atrophy seen on MR imaging in this condition.216,345,492,531,767 Unfortunately, detailed analysis of the prevalence of optic atrophy among the different genetic subtypes has not been performed,573 and the distinction between primary optic atrophy and optic atrophy secondary to retinal disease has not been analyzed.2,351,832 Autosomal dominant cerebellar ataxia type 2 (now termed SCA7) is the only type associated with pigmentary degeneration.67,309,692 The ADCA type II locus has been mapped to chromosome 3p12-p21, suggesting that this phenotype corresponds to a homogeneous genotype.309,365 The responsible gene for this new subtype of ADCA, termed SCA7, has been cloned.187 SCA7 (or ADCA type II) is caused by an unstable CAG repeat in the SCA gene. Larger expansions are associated with earlier onset, a more severe and rapid clinical course, and a higher frequency of decreased vision, ophthalmoplegia, extensor plantar responses, and scoliosis. The mutation is highly unstable, with an increase in repeats with paternal transmission, correlating with marked anticipation. This instability of transmission is more marked than with other SCA subtypes. Friedreich ataxia is the most common genetic ataxia and the first known example of a trinucleotide repeat resulting in autosomal recessive disease.342 It is an autosomal recessive disorder characterized by the onset of progressive cerebellar ataxia, dorsal root ganglion degeneration, and corticospinal tract involvement, generally associated with muscular wasting. Most patients with Friedreich ataxia present with symptoms prior to age 25, with an average age at onset of 12.342 Key diagnostic features include progressive ataxia of the limbs and gait, extensor plantar responses, dysarthria, abnormal position and vibration sense and absent deep tendon reflexes in lower extremities, progressive scoliosis and pes

4 Optic Atrophy in Children

cavus, and hypertrophic progressive cardiomyopathy.513,840 MR imaging reveals a normal cerebellum with variable atrophy of the cervical spinal cord. Friedreich ataxia results from defects on the frataxin gene on chromosome 9q13, resulting in an expansion of the GAA repeat in the first intron in over 90% of cases.918 Because of the clinical resemblance to ataxia with Vitamin E deficiency (which responds to vitamin E supplementation), it is important to confirm this condition genetically.918 Unlike in Charcot–Marie–Tooth syndrome, the motor nerve conduction is normal, and the sensory nerve conduction is abnormal, especially in the lower extremities. Neuroophthalmologic manifestations include mild-to-severe optic atrophy in up to 25% of patients. While visual acuity may be affected, patients are frequently asymptomatic. In one study, 131 64% had abnormal visual evoked potentials. Using quantitative eye movement recordings, Moschner et al591 found frequent saccadic intrusions (especially square wave jerks and ocular flutter), low vestibuloocular reflex (VOR) gain, a prolonged low-frequency VOR phase in association with preserved pursuit, and optokinetic nystagmus (OKN) and VOR suppression with fixation. A Freidreich ataxia DNA test is now available to confirm the clinical diagnosis by identification of excessive trinucleotide repeats. Other than physiotherapy, no effective treatment is currently available.

Hereditary Polyneuropathies The Charcot–Marie–Tooth diseases, also known as hereditary motor and sensory neuropathies, are a heterogenous group of disorders affecting primarily the peripheral nerves.918 Most are autosomal dominant disorder, but some are autosomal recessive. The autosomal dominant CMT1 presents in the first decade of life with a slowly progressive motor neuropathy affecting the lower more than the upper extremities. Affected children show distal wasting of the legs, impaired sensation, and reduced or absent reflexes, and foot drop or foot deformity (pes cavus). Optic atrophy rarely complicates the syndrome and is typically detected during the teenage years. The associated occurrence of Leber hereditary optic neuropathy in patients with Charcot–Marie–Tooth disease has been reported.552 CMT1 accounts for half of cases of Charcot–Marie–Tooth disease while CMT2 accounts for another 30–40%. CMT1A is usually caused by duplications or mutations in 17p11.22.12 (PMP-22).918 Another autosomal form of Charcot– Marie–Tooth disease, CMT2A, is caused by mutations in the mitofusin 2 gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot–Marie–Tooth disease and hereditary motor and sensory neuropathy VI.157,897 It is interesting that the mitofuscin

Optic Atrophy due to Hypoxia-Ischemia

2 shows significant functional overlap with OPA1, the protein underlying dominant optic atrophy, and with the mitochondrial encoded oxidative phosphorylation components as seen in Leber hereditary optic atrophy.961 The Rosenberg–Chutorian syndrome, a variant of Charcot–Marie–Tooth syndrome, comprises the triad of deafness, sensorimotor polyneuropathy, and visual loss.734 In most pedigrees, the visual loss has been attributed to optic neuropathy on the basis of normal full-field electroretinogram and funduscopic findings.366,667 In a recent case,691 electrophysiologic testing suggested visual loss at the level of amacrine cells, suggesting that more than one mechanism can contribute to the visual loss.691 It is unclear whether mitochondrial dysfunction underlies this condition.

Mucopolysaccharidoses The mucopolysaccharidoses (MPS) are storage diseases caused by a deficiency of certain lysosomal enzymes, leading to abnormal degradation of one or several mucopolysaccharides (e.g., dermatan, heparan, keratan sulfate). These materials then accumulate in multiple organ systems, leading to progressive clinical disorders.612 The ophthalmologic findings in MPS include corneal clouding, retinal pigmentary dystrophy, glaucoma, optic nerve head swelling, or optic atrophy. Collins et al167 reviewed the ocular findings in 108 patients with MPS, with attention to optic disc appearance. They concluded that patients with Hurler, Hurler–Scheie, Maroteaux–Lamy, and Sly syndromes showed a greater than 40% chance of developing optic nerve head swelling, whereas the chance in those with Hunter's and Sanfilippo's syndromes was 19.7% and 4.6%, respectively. Some patients showed optic nerve head swelling in one eye and optic atrophy in the other. In others, the optic atrophy was documented to follow disc swelling. The authors concluded that optic nerve head swelling precedes the development of optic atrophy in patients with systemic MPS. The cause of disc swelling is not always obvious, but hydrocephalus plays a role at least in some cases.435

Optic Atrophy due to Hypoxia-Ischemia One of the most difficult aspects of pediatric neuro-ophthalmology involves the diagnostic evaluation of optic atrophy in the child with perinatal hypoxic-ischemic injury to the visual system, because a significant percentage show some degree of pallor or hypoplasia.97,302 Associated neurologic handicaps often preclude sensory visual tests such as color vision testing,

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stereopsis, and visual fields. In this setting, neuroimaging has often been obtained at some remote point prior to the consultation. Because some degree of optic disc pallor so frequently accompanies cortical visual insufficiency (CVI), neuroimaging is not necessarily warranted for the evaluation of optic atrophy unless symptoms of progressive visual dysfunction or other progressive neurologic symptoms are elicited. When visual acuity is good, the finding of normal color vision using HRR plates provides corroborative evidence of a noncompressive lesion. In a retrospective study, Brodsky and Fray97 found normal optic discs in 56% of children with term injury producing CVI, with isolated optic atrophy in 24% and combined hypoplasia and atrophy in 20%. In children with preterm injury and periventricular leukomalacia, 24% had normal optic discs, 50% had optic nerve hypoplasia with some degree of atrophy, and 26% had isolated optic atrophy. Another quantitative study740 found that patients with cortical visual impairment have, on average, smaller optic nerve heads, with increased excavation and increased temporal pallor. Optic atrophy is also common in premature children with a history of high-grade intraventricular hemorrhage.152,640 Because optic atrophy is so commonly seen in children with a history of hypoxic ischemic injury, it is not routine to obtain neuroimaging in this setting. The parents should be questioned thoroughly about the perinatal and neonatal period of their child and, if available, the related medical records should be reviewed. Only when the clinical history suggests acquired or progressive visual loss is diagnostic neuroimaging obtained to rule out an unrelated compressive lesion. The optic atrophy in the setting of prematurity879 may take the form of large optic cups.97,402 Cicatricial retinopathy of prematurity, cortical visual impairment, and optic atrophy are the major causes of significant visual loss in patients with a history of premature birth.451,551 One Danish study675 found that perinatal stress factors (e.g., prematurity, low birth weight, perinatal asphyxia) accounted for a significant percentage of cases of optic atrophy in children reported to the Danish National Register. Significantly, they found that all children with optic atrophy attributed to perinatal difficulties showed one or more additional handicaps (e.g., cerebral palsy, epilepsy, psychomotor retardation). This is supported by other studies551 and may attest to the relative resilience of the anterior as compared with the posterior visual pathways to hypoxia. It also argues against attributing perinatal hypoxic damage to solitary cases of optic atrophy in otherwise healthy children.302 Despite the frequency of hypoxia-ischemia in the perinatal period, damage to the anterior visual pathway with optic atrophy appears to occur less frequently than damage to the posterior visual pathway. Six of 30 children with hypoxic cortical blindness described by Lambert et al481 showed mild optic atrophy. In a retrospective study,302 28% of all infants

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4 Optic Atrophy in Children

who had documented hypoxic encephalopathy showed optic atrophy and, essentially, all of these showed significant neurological dysfunction. The authors considered these findings to indicate a relative resilience of the optic nerve to hypoxia. Besides the possibility that the concurrent optic atrophy described in such cases may represent primary damage to the retinogeniculate pathway, some cases may represent transsynaptic degeneration. Therefore, it has been concluded that in the presence of normal neurologic findings and neuroimaging results, optic atrophy should not be attributed to perinatal hypoxia.302 Patients in cardiovascular shock with hypotension due to acute blood loss are at risk of ischemic damage to the optic nerves. Shock patients who are on positive pressure ventilation may be at an increased risk for such damage. The increased intraocular pressure associated with positive pressure ventilation along with the low systemic perfusion pressure may compromise the perfusion of the optic discs.144 Posterior ischemic optic neuropathy (PION) following spine surgery has been reported in both adults and children.112a,446a,665a As detailed in chapter 3, primary nonarteritic optic neuropathy is rare in children and usually occurs under pathological circumstances,158 as in diabetic papillopathy. Children with vigorous treatment of accelerated hypertension and children with migraines and prothrombotic disorders have also developed AION.89 Secondary nonarteritic ischemic optic neuropathy is a rare event in childhood, occurring mostly in the setting of spinal surgery or peritoneal dialysis, and hypovolemia was postulated to be the major etiology.82a,322,473a Diagnosis may be delayed in this age group because visual loss may not be noticed in a timely manner.82a Treatment of pulmonary hypertension with sildenafil may have led to the development of ischemic optic neuropathy in one 5-year-old child.473a A rare idiopathic disorder, termed anterior ischemic optic neuropathy of the young, has been reported to affect teenagers and young adults.224,340 It is included in this section because of its designation as ischemic, which is adopted due to certain resemblance to the adult variety of ischemic optic neuropathy. Differentiation from optic neuritis, however, cannot be made with certainty. Unlike the variety affecting older patients, the disorder displays a propensity for recurrence in the same eye, which may lead to significant visual impairment. Affected patients are otherwise healthy.

ophthalmoscopic evidence of injury to the eye and related structures (e.g., shaken baby syndrome). The possible pathophysiologic mechanisms of traumatic optic neuropathy of childhood are not different from the adult variety and include tears or avulsion of the optic nerve; laceration of the nerve substance by bone fragments; hemorrhage into the optic nerve sheath spaces or into the dura itself; and contusion, necrosis, or edema of the optic nerve tissue.534 Traumatic chiasmal syndromes may also occur. The optic disc appears normal in typical traumatic cases involving the intracanalicular or intracranial portion of the nerve. Optic atrophy eventually ensues. A 4- to 6-week latent period has been demonstrated in primates between optic nerve disruption and subsequent development of optic atrophy, regardless of the site of damage.701 Although visual recovery is sometimes seen, the prognosis for recovery of vision is poor. Cases due to remote trauma that the patient does not specifically recollect may pose a diagnostic quandary. If such trauma had been associated with blunt injury to the globe itself, as well as to the head or orbit, ophthalmologic signs such as iris sphincter tears, angle recession, lens subluxation, corneal scarring, chorioretinal scarring, and bony defects of the cranium may provide valuable clues to the traumatic etiology. Traumatic optic neuropathy in children is caused by mechanisms similar to those that cause it in adults. The severity of visual loss as well as the rate and degree of improvement are also similar.301 Although there is anecdotal evidence of the efficacy of high-dose corticosteroids in this condition, there are no prospective, randomized trials to attest to its benefits.822 The largest retrospective study499 showed no benefit from high-dose corticosteroids in the treatment of traumatic optic neuropathy. There is some evidence that this treatment is actually harmful if administered more than 8 hours after injury.93 A recently reported placebocontrolled randomized clinical trial of high-dose corticosteroids in head injury729 was stopped prematurely because of a significantly greater mortality in the corticosteroid-treated patients. Other experimental studies also suggest that methylprednisolone may be harmful to the optic nerve. Although surgical decompression of the optic canal may be helpful in selected cases,781 it showed no clear indication of benefit in a larger multicenter trial.500

Traumatic Optic Atrophy

Miscellaneous Causes

Trauma is a significant cause of optic nerve damage in children.534 Damage to one or both optic nerves may result from direct or indirect trauma. Direct trauma is commonly associated with penetrating injuries or severe blunt trauma to the globes and orbit. Indirect trauma occurs without external or

Vigabatrin Vigabatrin (Sabril, Avenbtis Pharma, Laval, Canada) is an effective and popular GABA-ergic anticonvulsant used in the management of infantile spasm (West syndrome), in seizures

Summary of the General Approach to the Child with Optic Atrophy

associated with tuberous sclerosis, and in partial seizures of adults as adjunctive therapy. It acts through the irreversible inhibition of GABA transaminase, with the resultant accumulation of the inhibitory neurotransmitter GABA in the brain and even higher concentrations in the retina. Thirty percent to 40% of treated patients develop peripheral visual field constriction that is usually asymptomatic.230,426,486,929 Vigabatrin visual field loss has been associated with evidence of reduced cone b-wave response, decreased amplitude of the 30-Hz flicker response, abnormalities in photopic and scotopic oscillatory potentials,169,186,353,470 and reduced visualevoked responses.467 Buncic et al112correlated this visual field loss with a characteristic “inverse” form of secondary optic atrophy with nasal optic atrophy and relative sparing of the macular nerve fiber layer and temporal aspect of the disc. OCT is useful in monitoring patients taking vigabatrin. Visual field loss in vigabatrin is associated with selective thinning of the nasal retinal nerve fiber layer, with sparing of the temporal nerve fiber layer, and variable involvement of the superior and inferior nerve fiber layer. This pattern of nerve fiber layer loss can precede the visual field loss.487 Because most children with epileptic syndromes taking vigabatrin cannot complain about their eye symptoms, regular ophthalmologic and electrophysiologic follow-up is necessary to elicit these changes.467

Carboplatin Periocular carboplatin injection to avoid systemic complications in patients with advanced retinoblastoma has recently been reported to cause ischemic necrosis and atrophy of the optic nerve.771

Summary of the General Approach to the Child with Optic Atrophy Important clues to the etiology, nature, and location of the lesion underlying optic atrophy are often provided by the age of the patient, best corrected visual acuity, laterality of optic atrophy, funduscopic appearance of the disc and retina, color vision anomalies, the natural history (onset and rate of progression), visual field defects, and other associated ophthalmologic, neurologic, and systemic findings. The combination of a thorough, tailored medical and family history with physical, neurological, and ophthalmologic examination should pinpoint at least the general category of optic atrophy in most cases. The medical history is of paramount importance. In infants and children with optic atrophy and poor vision, the answers to certain questions can be very important diagnostically.

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Are there any identifiable factors in the medical and family history that can help in the diagnosis, specifically, perinatal hypoxia, prematurity, intracranial hemorrhages, meningitis, encephalitis, hypoxia-ischemia, trauma, poisoning, maternal toxin intake, etc. (e.g., optic atrophy due to hypoxia-ischemia, transsynaptic degeneration, maternal alcohol intake, traumatic optic neuropathy)? Again, optic atrophy due to hypoxia-ischemia is commonly associated with brain damage and generally indicates that the insult was severe. Is there a family history of blindness or consanguinity (e.g., inherited optic atrophy, neurodegenerative disorders)? Was the child normally sighted at some point before losing vision (e.g., Leber hereditary optic atrophy, neuronal ceroid lipofuscinosis), or was the vision always impaired (congenital optic atrophy)? Aside from the visual impairment, is the child otherwise neurologically and systemically normal in all respects? If neurologic or systemic disease exists, are there known causes for these findings, such as perinatal hypoxia, intracranial hemorrhages, trauma, or a family history of similar affliction? This history helps differentiate these disorders from metabolic, neoplastic, and neurodegenerative disorders. If no known cause for the neurologic or systemic disease exists, at what age did these findings present; specifically, was the child normal initially before developing these disorders (e.g., Batten disease, X-linked adrenoleukodystrophy), or had these disorders been present in the neonatal period? Has the visual impairment been stable since onset, or has the visual impairment progressed (e.g., compressive intracranial lesions, neurodegenerative disorders)? Has there been any progression in the neurologic and/or systemic disease (neurodegenerative or metabolic disorders), or have these been stationary since onset (static encephalopathy, mental retardation, hydrocephalus)? We recognize that exceptions to these generalizations exist, but believe that the general framework is helpful. The clinical examination can further narrow down the diagnostic possibilities raised by the medical and family history. The presence of nystagmus probably excludes all disorders with onset after 2 years of age. The presence of deafness suggests one of the disorders associated with optic atrophy and deafness. Cerebellar signs suggest one of the cerebellar ataxias or spinocerebellar degeneration associated with optic atrophy. Static encephalopathy, most commonly encountered in the setting of prematurity, suggests that the optic atrophy is either due to primary damage to the anterior visual pathways due to hypoxia-ischemia or associated hydrocephalus or due to secondary transsynaptic degeneration following perinatal brain damage. The presence of café au lait spots, emaciation, spasmus nutans, or unilateral proptosis or a family history of neurofibromatosis suggests optic pathway glioma. Ancillary testing (e.g., neuroimaging, metabolic workup) is not necessary to arrive at the diagnosis in most children with optic atrophy. Any associated ocular abnormalities must

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be detected and, in infants, it is advisable to consider performing an ERG to rule out retinal disease. Visual evoked potentials may be helpful to assess the integrity of the visual pathways, but are generally not helpful in determining a specific diagnosis. Neuroimaging is helpful when neurological signs indicative of intracranial dysfunction are present. Metabolic workup is indicated in selected cases. Ancillary testing is most clearly indicated in a previously healthy child who develops progressive visual loss and optic atrophy, with or without associated neurologic and systemic signs and symptoms, to rule out underlying neurologic, metabolic, and neoplastic disorders.

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211 958. Zervos A, Hunt KE, Tong HQ, et al. Clinical, genetic and histopathologic findings in two siblings with muscle-eye-brain disease. Eur J Ophthalmol. 2002;12:253–261. 959. Zhou X, Wei Q, Yang L, et al. Leber’s hereditary optic neuropathy is associated with the mitochondrial ND4 G11696A mutation in five Chinese families. Biochem Biophys Res Commun. 2006;340:69-75. 960. Zimmerman CF, Schatz NJ, Glaser JS. Magnetic resonance imaging of optic nerve meningiomas. Ophthalmology. 1990;97:585–591. 961. Züchner S, De Jonghe P, Jordanova A, et al. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol. 2006;59:276–281. 962. Zumrová A, Krepelová A, Kyncl M, et al. First cases in the Czech Republic of the Hallevorden-Spatz disease resulting from mutation in the pantothenate kinase 2 gene. Neuro Endocrinol Lett. 2005;26:213–218.

Chapter 5

Transient, Unexplained, and Psychogenic Visual Loss in Children

Introduction Some children have visual disturbances that occur in the absence of, or are out of proportion to, their objective ophthalmological findings. These symptoms reflect a wide range of processes that may be benign or a sign of neurological, systemic, or psychiatric disease. This chapter deals with the neuro-ophthalmologic detection of organic and psychogenic disorders that may manifest as transient or unexplained visual loss of the same episodic visual disturbances that occur in childhood, but several formidable problems confront the physician who is trying to reach the correct diagnosis. The descriptions of episodic visual disturbances and hallucinations in children are less complex in detail than those of the adult population because children have limited vocabulary and limited experiential basis of sensory phenomenon to draw upon. Children share with adults a difficulty in distinguishing homonymous from monocular defects and may insist that a homonymous defect affects only one eye. Children are also less likely than adults to draw a distinction between a positive and a negative visual disturbance. They may simply maintain that something is blocking their vision and may be unable to describe it further. If pressured by the examiner to be more descriptive, a child or even a teenager may attempt to give the examiner what they think is being asked for, even if it does not accurately depict their symptoms. Children with refractive errors or other organic visual problems may describe visual symptoms only in terms of their effect upon a specific activity (such as difficulty reading the blackboard at school or reading textbooks), making it difficult to determine from the history whether the disturbance is indeed episodic. Visual hallucinations have been described in a variety of conditions, including epilepsy, migraine, infarction, drugs, degenerative disease, and mass lesions of the visual pathways.254 Simple or elementary hallucinations involve perception of colored or colorless shapes, lines, or flashes that may be stationary, moving, or enlarging.34,183,254 Complex visual hallucinations take the form of people, objects, animals, or scenes that may or may not be familiar to the patient.34,183,254

The most common cause of episodic visual loss disturbances in childhood is migraine.288 The visual disturbance of mig raine is characterized by episodic visual hallucinations and visual loss as well as other neurological disturbances, with headache being the most common. However, the characteristic hemicranial throbbing headache is often absent in the pediatric age group, and the diagnosis is based on a compilation of circumstantial evidence. A personal profile of the child should be explored, with specific attention to eliciting a history of extreme fussiness or colic as a baby, night terrors, recurrent abdominal pains, or motion sickness.65 A family history of migraine must be sought because family members with migraine may never have been diagnosed or may have been misdiagnosed as having tension or sinus headaches. The diagnosis of migraine for the child’s visual disturbances and the parent’s headaches can often be established in the same interview. Careful questioning may determine that the child is describing a visual hallucination rather than a visual obscuration. As in adults, visual hallucinations in children may be formed or unformed, simple or complex. Unformed hallucinations typically consist of lights, heat wave sensations, or simple geometric patterns that may be spatially stable or move. Formed hallucinations consist of recognizable objects or people. These may be simple, such as visualizing a single animal or an object, such as a table or chair, or they may demonstrate varying degrees of complexity involving the purposeful movement of several people in a scene with appropriate colored backgrounds and facial expressions. If the attacks are repetitive, the hallucination may be stereotyped, or a new scene or object may be visualized with each recurrence. Visual hallucinations are generally divided into irritative and release hallucinations.126,254 Irritative hallucinations emanating from the temporal lobes tend to be complex and stereotyped, while those arising in the occipital lobes tend to be simple and unformed. Complex visual hallucinations are sometimes accompanied by intense fear or panic attacks.177 Other aspects of the seizure disorder are often more prominent, including changes in consciousness and sensory or motor abnormalities due to the spread of the epileptic activity;

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however, isolated and localized occipital or temporal lobe seizures may produce visual hallucinations as their only manifestation. Release hallucinations often occur in patients with decreased vision or visual field defects.254 They may also occur in the setting of monocular or binocular visual loss or homonymous hemianopia and may manifest in patients with relatively mild visual loss.60,254 These hallucinations range from unformed phosphenes to formed hallucinations with complex patterns. Release hallucinations presumably occur when normal visual impulses are removed, releasing indigenous cerebral activity within the visual system.60 They tend to be continuous and can last from minutes to days, in contradistinction to irritative hallucinations, which last from seconds to a few minutes.60 Release hallucinations are neither associated with electroencephalographic abnormalities nor altered by anticonvulsant therapy. The failure to clearly distinguish the irritative from the release type of hallucination has led to considerable confusion regarding their localizing value. The concept that hallucinations of occipital origin comprise unformed phosphenes applies only to the irritative variety. Unlike irritative hallucinations, which vary in character depending on their site of origin, release hallucinations have no localizing value and can follow injury to the visual system anywhere from the eye to the occipital cortex.60,225,412 For example, formed release hallucinations occasionally occur in adults with dense cataracts or macular degeneration.244 Children can experience “phantom vision” following enucleation of one or both eyes.61 Patients with visual loss frequently acknowledge experiencing both formed and unformed visual hallucinations when specifically asked.

The aura may occur prior to, concurrently, or even after the onset of the headache. The diagnosis of pediatric migraine is established on the basis of the personal profile, attack profile, and family history, as well as the absence of physical findings. In the child with transient visual disturbances or unexplained headache, the personal history provides important clues to the diagnosis of migraine.65 Pediatric migraineurs often have a history of migraine equivalents, including colic, recurrent abdominal pain, cyclic vomiting, pavor nocturnus (night terrors), paroxysmal vertigo, and paroxysmal torticollis in the first few years of life.26,27,49,125 Some children stop playing with their friends, watching television, or using the computer. Even between attacks, migraineurs often describe themselves as very reactive to extraneous visual, auditory, olfactory, gustatory, and thermal stimuli.14,86–88,137 Bright lights (sunlight reflecting from snow or water) or strong smells (e.g., perfume, gasoline) can precipitate a migraine.80,85,87 A history of motion sickness is also strongly associated with migraine and considered to be an associated feature of the migraine diathesis.14,24,86–88 In attempting to elicit a family history of migraine, it is useful to ask whether any of the first- degree relatives have “sick headaches” or have ever had to go into a dark room, put a damp rag on their head, and go to sleep because of a severe headache. Features of the attack history include the presence or absence of an aura, the characteristics of the headache, and the presence or absence of additional neurological impairment. The prevalence of migraine is approximately equal in boys and girls younger than 7 years of age. A female predominance of 3:2 is present from 7 years of age until puberty. After puberty, the relative prevalence becomes further skewed toward girls.36

Transient Visual Loss

Migraine Aura

Migraine Migraine is not just a headache49 but an episodic brain disorder that affects approximately 15% of the population.240 Migraine can cause transient sensory, autonomic, motor, visual, and cognitive impairment. Although headache is a prominent feature of migraine, it is not invariably present.49 Many migraine attacks begin slowly and evolve through sequential stages of neurological dysfunction. Selby357 described migraine as a “drama in three acts,” comprising premonitory symptoms (frequently not recognized) and aura, a headache phase, and a post-headache phase. Premonitory symptoms, which precede the aura, include mood changes, irritability, fluid retention, increased thirst, and frequent urination, food cravings, and increases or decreases in energy levels.11

Although migraine headache is less prevalent in children than in adults, the presenting complaint of transient visual disturbances results in the diagnosis of migraine with considerable frequency in the pediatric age group.36,58,100 The stereotypical visual migraine aura lasts 25–30 min but occasionally may subside in a few minutes or last several hours. The variability in the characteristics and the frequency of migraine aura so common in adults is even greater in children. The examiner must be aware not only of the classic adult migraine aura but also of the variations on this theme that are presented in the pediatric age group.10,108,176 Some children are able to describe the classical form of scintillating scotoma with expansion or buildup of the fortification figure (Fig. 5.1). The visual disturbance typically begins as a fog, loss of illumination, central flashbulb, or brightness pericentrally in one hemifield, progressing in a

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few seconds or minutes to a few degrees of central scotoma lined on the temporal side by a luminous zigzag line, or teichopsia (Greek word meaning fortification-seeing). The jagged lines of the fortification specter may be colored or gray and appear to vary in brightness in a way that is often described as flashing, jabbing, boiling, or rolling217 (Figs. 5.1 and 5.2). The visual disturbance expands in the shape of a horseshoe with a centrally directed open end encompassing a negative scotoma.176

Fig. 5.1 Fortified Italian City of Palmanova, Italy. Courtesy of James J. Corbett, M.D.

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This sensation usually begins as a small pericentral disturbance encompassing only a few degrees, and gradually expands toward the temporal periphery over 20–30 min to involve a large portion of the hemifield of both eyes (although patients frequently interpret the visual disturbance as monocular). As the fortification scotoma expands peripherally, it erases the visual field to produce a transient homonymous scotoma. Fortification scotomas are seen with the eyes open or closed and are even perceived in patients with no eyes. This hemifield scotoma frequently precedes the characteristic headache of migraine, but it may also occur alone in the absence of a headache, in which case it is termed an acephalgic migraine.290 In addition to the typical fortification scotoma, the range of visual disturbances in adult migraine is quite broad and includes positive and negative scotomas,108 blurred vision, foggy vision, flickering lights, colored lights, zigzag lines, and a heat wave sensation, all presumably of occipital origin. Children with migraines are more likely than adults to describe a variety of visual disturbances other than the classic fortification scotoma.65 The descriptions provided by children tend to be more picturesque, such as “a star breaking into a million pieces,” “heat waves,” “water coming down a window,” “lines coming down from the sky like it’s raining,” “like looking through cellophane,” “sparkles,” “dancing lights,” or “dots and blobs” that gradually enlarge to obliterate the visual field.152,299 Migraine with aura (classic migraine) is preceded by or accompanied by a focal disturbance of cerebral or brainstem function.49 The migraine aura may also be nonvisual. Some patients experience a sensory aura consisting of migratory paresthesias of the tongue, lips, and hand (cheiro-oral

Fig. 5.2 Drawing from patient with migraine showing temp oral progression of fortification scotoma. Courtesy of James J. Corbett, M.D.

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migraine). Transient language disturbance, including mild aphasia, may occur as part of the aura phenomenon. Common migraine may not have a clearly defined visual or sensory prodrome, but autonomic premonitory symptoms may occur, including yawning, hunger, thirst, irritability, edema, euphoria, or depression. The premonitory mood changes and skin pallor, which are often noted by parents prior to the onset of childhood migraine, may be manifestations of the same autonomic symptomatology.280 Benign paroxysmal childhood vertigo can precede by months or years migrainous vertigo symptoms in affected patients.305 Mothers learn to recognize their child’s migraine attack prior to the onset of headache by observing skin pallor and “goose bumps,” with cold, clammy perspiration, and cold extremities.49 Some children develop periorbital discoloration during or just before a migraine.365

tic studies are unwarranted in young patients with transient visual loss and who are otherwise healthy because significant and/or systemic diseases are rarely discovered. O’Sullivan et al299 found a personal or family history of migraine in 8 of 9 children and young adults with transient monocular visual loss. They noted that, as with migraines, the episodes of visual loss tended to occur in clusters. Investigation revealed no embolic or atheromatous etiology. Appleton et al16 also attributed atypical forms of transient visual loss in children with acephalgic migraine and found that it carries a benign prognosis in young patients. While the term migraine is reassuring to parents and useful to clinicians in connoting a benign prognosis in children with transient monocular visual loss, little is known about the underlying pathophysiology or the site (retinal neurons, retinal vessels, optic disc) of dysfunction.

Amaurosis Fugax as a Migraine Equivalent Migraine Versus Retinal Vasospasm The old term amaurosis fugax is somewhat arbitrarily applied to transient monocular visual loss of relatively rapid onset and fairly rapid resolution. The episodes characteristically last 2–10 min and are unaccompanied by significant pain. In adults older than 50 years of age, the term amaurosis fugax has come to signify transient visual loss associated with ipsilateral carotid atherosclerosis. The characteristics and duration of transient visual loss have therefore become the critical historical determinants in distinguishing retinal embolization from migrainous visual loss in older adults. In young adults or children, however, migraine is a common association with amaurosis fugax. Tomsak and Jergens388 described 24 adults with benign recurrent transient monocular blindness that was presumed to be migrainous in etiology. The visual loss was predominantly one-sided and stereotyped in character, although symptoms varied greatly from patient to patient. Postural change or exercise was a provocative factor in half of the cases. Other neurological symptoms were not present, and only one patient developed permanent visual loss during an attack. Evaluation by computed tomography (CT) scanning, cerebral angiography, echocardiography, and ophthalmodynamometry, when performed, were uniformly normal. Tippin et al386 reported similar findings in a group of adolescents and young adults with amaurosis fugax. They found that headache or orbital pain accompanied the amaurotic spells in 41% of cases and that an additional 25.3% had severe headaches independent of the visual loss. None of the 11 patients who had angiography had an atherosclerotic lesion of the carotid artery. None of the patients who were reexamined after an average follow-up of 5.8 years have had a stroke. The authors concluded that amaurosis fugax is associated with a more benign clinical course in young patients and that migraine is a likely cause for the visual episodes. They advised that carotid angiography and invasive diagnos-

The term vasospasm is often postulated as the mechanism of migrainous transient monocular visual disturbances in both children and adults.185 The notion that retinal vasospasm can be ascribed to migraine derives from the long-supplanted concept of migraine as a vasospastic process.220 However, retinal vasospasm may occur as an independent event or as a component of migraine. As discussed below, the hemodynamic changes that occur with migraine are not due to vasospasm but rather due to changes in neuronal activity with vasoneural coupling.128 While retinal vasospasm may occur idiopathically, affected individuals often have medical histories that are significant for Raynaud’s phenomenon, systemic lupus erythematosus, hypercoagulability, autoimmune diseases, and atherosclerosis. Retinal vasospasm may therefore be precipitated by a number of factors, including migraine headache or its pharmacological treatment with vasoconstrictors. Isolated retinal vasospasm has been described, visualized, and photographed in fewer than ten adult patients.31,45, 83,198,313,428,429 During these attacks, the retina appears pale, the arterioles are narrowed, there are focal arteriolar constrictions, the veins are narrowed, and fluorescein angiography shows delayed filling. The retinal veins appear to dilate dramatically as the attack abates. Similar arterial vasospasm may affect other tissues in the same patients (e.g., Raynaud’s phenomenon, Prinzmetal angina). The clinical course is generally benign, but optic nerve or retinal infarction has been documented as an uncommon consequence of retinal vasospasm.176 It has recently been argued that retinal vasoconstriction is a more likely mechanism than retinal migraine for transient monocular visual loss.167,426 A large review of previously reported cases found definite migraine, as defined by

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International Headache Society (IHS) criteria, to be an exceedingly rare cause of transient monocular visual loss. With one possible exception, there have been no convincing reports of permanent monocular visual loss associated with migraine. Thus, the diagnosis of retinal migraine remains one of exclusion. Spreading depression has been observed in vitro in the avascular retinas of frogs and chicks,398,399 but has never been seen in vascularized mammalian retinas.167,261 Moreover, no clinical correlation has been made between retinal spreading depression and monocular visual loss.167,426 However, it remains entirely possible that these cases may result from transient neuronal inhibition or depression at the retinal level rather than focal ischemia related to vasoconstriction, and that such cases will eventually be classified as migraine equivalents.

Migraine Headache Migraine headache in adults may be hemicranial or holocranial, bifrontal, or frontal in distribution. Unilateral headache is seen in both common and classic migraine. Migraine headache has a gradual onset and builds in intensity over minutes or hours. It can last a few hours to several days.49 It is described as a dull headache if the pain is not severe, but it becomes throbbing or pulsatile as the pain increases, although the character of the headache in children differs somewhat from that in adults, so that a minority of children describe their headache as throbbing.280 Even in the absence of the classic visual aura, some adults report short-lived phosphenes.62 The duration of migraine headache is shorter in children, typically lasting 1–2 h, compared with a 4-h minimum for adults.2,3 Complaints of bifrontal or bitemporal headaches or central forehead pain are more common in children, and unilaterality is uncommon.280 Head trauma may be a significant triggering factor. Migraine headache is often associated with nausea, vomiting, or diarrhea, and children are often photophobic and phonophobic during the attack.18,280 The pain is relieved by vomiting or sleep. In attempting to determine whether headaches are migrainous, we ask the patient what they do when they get an attack. They often give a stereotypical reply such as “I go in my room, close the door, turn off the lights, pull down the shades, pull the covers over my head, and go to sleep.” Migraineurs may also describe jabs of pain in the scalp or eye when they are not having headaches, as well as during a migraine attack.49 These have been termed “ice-pick headaches” or “the syndrome of jabs and stabs.”329 They may be isolated or occur repetitively over a day or two. Those involving the eye are known as ophthalmodynia fugax.47 The diagnosis of migraine in an infant or toddler is often made only in retrospect, when the child is older and clear symptoms of pediatric migraine become evident. Barlow

found the most common migraine manifestations in the first years of life to be repeated vomiting followed by a behavioral change (i.e., irritability or lethargy), vertigo, ataxia, or pallor, and sleep relief.26,63 Many of these children were also able to communicate that they had a headache either verbally or by holding their head. Headaches that interrupt play are also an important clue to the diagnosis of migraine. Contrary to the notion that migraine aura activates trigeminal afferents, thus causing the pain and cascade of events that we recognize as migraine, Goadsby and colleagues have argued that migraine aura is a parallel process to the pain.128,133 According to this hypothesis, the aura is triggered or facilitated by the same hyperexcitability that is responsible for the pain, and other symptoms and process that resides in, and is governed by the brain. These investigators believe that migraine pain may have more to do with abnormal perception of the normal sensory input than activation in the nociceptive pathways in the classical way that pain is generated. About two-thirds of patients with migraine complain of allodynia (pain from nonnoxious stimuli).357 In this context, the characteristic photophobia and phonophobia are normal light and sound sensation that become exaggerated or amplified by the migrainous brain.133

Complicated Migraine Complicated migraine syndromes are more common in children and adolescents than in adults. Many systemic diseases including episodic ataxia type 2, MELAS, and ornithine transcarbamylase (OTC) deficiency may present with complicated migraines. For example, the finding of a micronystagmus with upbeat or downbeat nystagmus during a migraine, which is brought on by hunger, alcohol, anxiety, or fatigue, should suggest the diagnosis of episodic ataxia type 2.374 The MELAS syndrome may underlie the “malignant migraine syndrome,” in which children with complicated migraine headaches develop intractable seizures and large alternating occipital infarcts.58 OTC deficiency is a urea-cycle disorder caused by a mutation in the enzyme that converts ornithine to citrulline.374 This x-linked mutation decreases the efficiency of the urea cycle, causing an accumulation of ammonia. Affected males present as newborns and heterozygous females present later in life. The presenting signs of OTC deficiency are largely due to cerebral edema caused by elevated levels of ammonia. They include seizures, chronic vomiting, developmental delay, ataxia, headache, lethargy and cortical visual loss.434 Children with this disorder often have a history of protein aversion and frequent migraines.355 Acute confusional migraine was first reported by Gascon and Barlow116 in four children ages 8–16. It resembles acute toxic psychosis and usually presents as one of the first episodes of migraine in a child.116 During an attack, the

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child may display confusion, agitation, an altered sensorium, or withdrawn, noncommunicative behavior. The attack usually ends with a period of prolonged sleep. Recurrent 30- to 60-min episodes of confusion or even psychotic behavior in children should lead one to consider the diagnosis of migraine. These attacks eventually evolve into more typical migraine episodes.98 Acute hemiplegic migraine may occur as a manifestation of complicated migraine as a familial or sporadic disorder.57,127,129,385 Familial hemiplegic migraine is characterized by attacks of hemiplegia and hemianesthesia that begin in childhood and may last several days.57 Recurrent episodes may vary from side to side and may be associated with hallucinations, aphasia, or confusion. The gene for familial hemiplegic migraine has been mapped to chromosome 19.184 Triptans are contraindicated in the treatment of this form of migraine. Alternating hemiplegia of childhood is a rare disorder characterized by paroxysmal spastic or dystonic attacks affecting one side of the body, with onset prior to 4 months of age.7,97,333 It is associated with tonic or dystonic attacks, abnormal ocular movements (monocular pendular nystagmus, episodic deviations of the ipsilateral eye),97 and autonomic abnormalities (focal blanching of a limb or whole side of the body), which may usher in an attack.97,333 Its onset is usually before 18 months of age, and its clinical course is progressive, with patients developing fixed neurologic deficits including choreoathetosis, dystonia, ataxia, and neurodevelopmental disturbances.333 Many patients have associated motion sickness.68 Seizures are reported in a subset of patients.7,97,112,330 Although familial cases have been reported,187,272 the disorder is usually isolated. Benign paroxysmal vertigo of childhood is the most common cause of vertigo in children without any detectable ear disease or hearing loss.393 This condition was originally described as a typical vestibular attack including nystagmus, nausea, vomiting, and diaphoresis.27 The only objective evidence of vestibular system dysfunction is the presence of nystagmus during the attack.271 The age of occurrence is usually 1–5 years.6 Many patients have associated motion sickness and go on to have other migraine symptoms,393 suggesting that benign paroxysmal vertigo of childhood is a precursor of migrainous vertigo (alias, basilar artery migraine. See below).49 Benign paroxysmal childhood vertigo often precedes the onset of migrainous vertigo symptoms by months or years.305 Most patients show mild central ocular motor signs such as saccadic pursuit, spontaneous or gaze-evoked nystagmus, and positional nystagmus in the symptom-free interval, suggesting migraine. Benign paroxysmal torticollis of infancy may be another forerunner to migrainous vertigo,271,347 as its benign course and close association with migraine resembles benign paroxysmal vertigo of childhood.125

Bickerstaff33 first described symptoms of basilar artery migraine as referable to the very diffuse circulation territory of the basilar artery involving virtually all structures in the posterior fossa and brainstem. Because basilar migraine has symptoms that are neither limited to the basilar artery territory nor with evidence that the basilar artery is involved in its pathophysiology, it is now termed basilar type migraine, emphasizing that is it not a primary vascular event.129 Rather, it probably results from a regional hyperexcitability, with a similar vasoneural coupling to that seen in cortical sprea ding depression. This type of migraine is more common in adolescents. In one study,249 5% of children with migraine in an outpatient clinic were diagnosed with this form of complicated migraine. Symptomatology is progressive during an attack, with each attack lasting 2–45 min. Visual loss is often the initial event, with a disturbance of central vision, which is often described as resembling a bright sun or flashbulb.49 This visual disturbance may evolve into a total loss of vision or large blotches of positive visual scotomas obscuring both hemifields. The visual loss is then followed by some combination of vertigo, ataxia, dysarthria, tinnitus and, occasionally, tingling of the hands and feet. Other symptoms of basilar type migraine include alteration or loss of consciousness, and hyperacuisis. Headache may be absent, but when it occurs, it is frequently occipital and throbbing. Abrupt loss of consciousness, lasting for a few minutes, can also occur.171,216 Most children also have common or classic migraine attacks, and symptoms of basilar type migraine gradually become less frequent and eventually stop altogether. Basilar type migraine must be distinguished from benign childhood epilepsy with occipital paroxysms (discussed later). Triptans are contraindicated in the treatment of basilar type migraine (IHS criteria). Acute migrainous vertigo is an important cause of episodic dizziness in children.41,78,286 The topic of migrainous vertigo encompasses an evolving classification system in which the terms paroxysmal torticollis of infancy, benign paroxysmal vertigo of childhood, migrainous vertigo, and basilar artery migraine are used to describe what are probably different expressions of the same disease as a function of age.68 Its pathophysiology can involve both central and peripheral vestibular dysfunction,406 which has shown to be linked to CACNA1A mutation.125 The differential diagnosis of migrainous vertigo includes the channelopathy episodic ataxia type 2,374 which also exhibits interictal nystagmus and saccadic pursuit,113 as well as neurometabolic disorders such as MELAS and OTC deficiency, and temporal lobe epilepsy. Disturbances of higher cortical function have also been described with pediatric migraine.65,208,290 In older children, these disorders include disturbances of color vision (central achromatopsia), abnormal facial recognition (prosopagnosia),

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Fig. 5.3 11-year-old girl’s drawing of an episode of higher cortical dysfunction she experienced on her way to school one morning. Her perception of scene before (left) and after (right) “She stood at a crosswalk facing her school. In front of her was a friend who was wearing a stocking cap with a pompom and writing on the cp the spelled ‘M-M good.’ Suddenly, she felt ill and everything looked funny. The writing disappeared from the stocking (right); the school and schoolyard became a jumble of colorless, disorganized figures and windows. Colors were desaturated; Everything looked gray. She felt disoriented and became pale.” This description depicts development of migranious central achromatopsia and word anomia. Courtesy of James J. Corbett, M.D.

difficulty reading (alexia with or without agraphia), and transient global amnesia35,101,107,116,152,176,288 (Fig. 5.3). The Alice in Wonderland syndrome, characterized by distortions of time, sense, and body image, has also been described as a manifestation of pediatric migraine.136,387 Although the term migraine connotes a benign and fundamentally reversible condition, a subgroup of patients develops infarction following a severe episode. Rossi et al338 described seven children who had at least one episode of CT-documented infarct, possibly during an attack of migraine. Although a causal relationship could not be assured, the epidemiological data suggest that childhood migraine can be a contributing risk factor for childhood stroke.253 Whether reports of optic nerve and retinal infarction in patients with retinal vasoconstriction (which have been traditionally designated as migraine) are related to underlying migraine diathesis (such as that seen with anticardiolipin syndrome) is unknown. Ophthalmoplegic migraine usually manifests as a unilateral third nerve palsy in the wake of a migraine headache.404 It has a predilection for young children, and the first episode may occur in infancy.335,408 Even in children, ophthalmoplegic migraine is rare and has always been considered a diagnosis of exclusion. Numerous reports of magnetic resonance (MR) imaging in ophthalmoplegic migraine have described focal gadolinium enhancement of the oculomotor nerve in the perimesencephalic cistern,371 providing neuroimaging confirmation of this condition92,249 (Fig. 5.4). In the second edition of the International Classification of Headache Disorders (ICHD II), the entity of ophthalmoplegic

Fig. 5.4 Axial and coronal MR images showing nodular enhancement of right cisternal nerve in child with opthalmoplegic migraine. Courtesy of Thomas Carlow, M.D.

migraine is no longer classified with migraine but as a neuralgia, because in many cases of this rare condition, signs of inflammation of the affected nerve have been found on gadolinium-enhanced MR imaging.179,291 It is now believed that repeated inflammation (rather than vasoconstriction) could lead to a demyelination/remyelination process with Schwann cell proliferation and “onion bulb” formation.53,256 The clinical features of ophthalmoplegic migraine are detailed in Chap. 6. Carlow53 has proposed that inflammation of the oculomotor nerve, which is the only cranial nerve adjacent to the circle of Willis at its exit, can still be initiated by a migraine stimulus affecting the trigeminovascular system.53 Neuro peptides are secreted at the level of the circle of Willis and adjacent vessels that cross a relatively open blood-nerve barrier junction at the oculomotor nerve exit. A sterile inflammation is induced that further opens the blood-brain barrier. Demyelination results in Schwann cell proliferation and edema in the ocular motor nerve as it emerges from the brainstem. Subsequent third nerve compression from nerve hypertrophy and scar formation, after repeated episodes of demyelination and remyelination, could result in permanent oculomotor nerve paralysis or aberrant regeneration.53

Pathophysiology Numerous theories have been advanced to provide a unified theory for migraine phenomenology and the associated headache. Most agree that migraine represents a complex system malfunction and that the system can malfunction in many different ways. The centerpiece involves a susceptibility to recurrent headaches that are initiated by inappropriate environmental triggers. Affected patients have probably inherited one or more polymorphisms that, somewhere along the cascade of migraine events, cause instability. One susceptibility is to

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cortical aura, but whether the aura is causal to the headache or simply another manifestation of the same genetic/environmental susceptibility that causes the headache is hotly disputed. Understanding migraine pathogenesis is further complicated by the dynamic nature of the system. A repeatedly activated biologic system changes over time so that a dynamic system malfunction that has most of its roots in genetic susceptibility can evolve new characteristics. The original vasogenic theory,432 which viewed migraine as a form of vascular dysregulation, assumed that the aura was due to a transiently induced ischemia, and the headache due to a rebound vasodilatation that caused a mechanical depolarization of primary nociceptive neurons within the walls of engorged intracerebral and extracerebral vessels.71 This theory has been largely supplanted by the neurogenic theory, which views migraine as a disorder of the brain in which vascular changes follow neuronal dysfunction.71,218,295 However, neither theory can fully account for all of the clinical and treatment responses of migraine, alone.71 Olesen et al294 have used serial cerebral blood-flow measurement by the intracarotid xenon-133 technique to show that patients with classic migraine have localized decreases in blood flow beginning in the occipital lobes that spread continuously along the cerebral cortex and do not follow a vascular pattern. Bilateral cerebral hypoperfusion beginning in the occipital lobes and spreading anteriorly into the temporal and parietal lobes was also recently documented by positron emission tomography (PET) scanning during a classic migraine attack.433 The region of decrease in cerebral blood flow expands at a rate of 2.2 mm/min, which is similar to the rate of spread of experimentally produced spreading depression through the occipital lobe, as well as the involvement of the visual scotoma reported by many patients with classic migraine.209,218 The concept of spreading depression was introduced on the basis of experimental data in which changes in intracellular/extracellular potassium ion concentrations were induced to spread across the cortex after a central depolarization.222 It was surmised that the reductions in cerebral blood flow, and the spread of the reduction in cerebral blood flow, at a rate similar to spreading depression, could occur because the blood flow to the area decreases in response to the metabolic abnormality.218 Critics of the vasogenic theory contend that the migraine aura is often accompanied by multiple neurological symptoms that are difficult to localize within one neurovascular territory. They also point out that neuroimaging studies conducted during spontaneous, classical visual auras indicate that the decreases in cortical blood flow observed during aura are not sufficient to cause ischemia and that the subsequent vasodilatation does not take place until well after the onset of headache.73 In humans, spontaneous spreading depression is difficult to record because the slowly varying phenomena of spreading depression cannot be observed in surface electro-

encephalography (EEG), but a similar phenomenon has been observed with PET scanning, and it has been demonstrated by magnetic encephalography.414 Whether cortical spreading depression, as it occurs in animals, occurs in the human cortex is unknown, but a related spreading wave of hyperexcitation followed by suppression has been demonstrated using PET scanning to occur in the occipital cortex during visual aura.153 The role of cortical spreading depression in producing migraine is now thought to reflect vasoneural coupling, with the resulting hyperemia followed by oligemia representing a neurometabolic rather than a blood flow phenomenon. Patients complain of throbbing pain in the head, but there is no reliable relationship between vessel diameter and the pain207 or its treatment.237 According to Goadsby, migraine aura cannot be the solitary trigger for pain because the aura occurs in less than 30% of migraine patients. Conversely, the aura can be experienced without any pain at all. These findings indicate that cortical spreading depression does not cause migraine pain but that the aura and the trigeminovascular activation are manifestations of the same neuronal hyperexcitability.133 In addition to examining cortical spreading depression and its relationship to visual migraine symptomatology, the study of migraine pain has elucidated mechanisms of trigeminal nerve activation.130,219,282 According to the trigeminovascular theory of Moskowitz,282 migraine headache involves dysfunction of brainstem pathways that normally modulate sensory input. The key pathways for pain are the trigeminovascular input for the meningeal vessels, which passes through the trigeminal ganglion and synapses on secondorder neurons in the trigeminovascular complex. The dura mater is innervated by branches of the trigeminal nerve.128 Stimulation of the trigeminal ganglion results in plasma protein extravasation,257 cerebral vasodilatation,130 and local nerve stimulation in dural vasodilatation.424 Neurogenic inflammation is associated with release of neuropeptides and cytokines (e.g., substance P, CGRP, neurokinin A), dilatation of vessels, leakage of plasma and plasma proteins into surrounding tissue, and a mast cell response with release of histamine.133 Stimulation of the superior sagittal sinus activates neurons in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C 2192 levels in the cat and monkey (the trigeminocervical complex).128,131 This trigeminocervical system permits convergent sensory input from the head and neck to the trigeminal nucleus caudalis and C1, C2, and C3 to refer head pain to the back of the neck. Knight and Goadsby201 postulated that the role of the periaqueductal gray is to inhibit afferent trigeminal nociceptive traffic and that brainstem dysfunction might lead to disinhibition of trigeminal afferents and be important in the process of migraines.

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During a migraine attack, patients show increases in regional blood flow in the anterior cingulate cortex (which modulates emotional response to pain) and in the auditory and visual association cortex. Contralateral increases in brainstem blood flow involving the dorsal midbrain to regions including the periaqueductal gray (PAG), the dorsolateral pontine tegmentum,411 and the periaqueductal gray area may be a major trigger for migraine pain. Functional brain imaging with PET has shown activation of the dorsal midbrain, including the PAG and the dorsal pons close to the locus coeruleus, in studies during migraine without aura.411 Dorsolateral pontine activation is observed with PET in spontaneous, episodic, and chronic migraine263 and with nitroglycerintriggered attacks.4,22 Goadsby133 has proposed that migraine aura (a cortical process) and pain (a brain stem process) probably involving the PAG are not causally related but represent dual manifestations of central hyperexcitability. According to Goadsby, either cortical spreading depression or local factors (e.g., substance P, Nitrous oxide (NO), vasoactive intestinal neuropeptide) can trigger activation of the trigeminal autonomic reflex. These abnormal pathways may become entrained by whatever pathophysiology causes overexpression of neuronal activity in different modules of the brain. Migraine has also been attributed to excessive sympathetic nervous system stimulation and its effects on the trigeminovascular system,312 but it remains to be established whether increased sympathetic activity is the cause, rather than the effect, of migraine. At a molecular level, there is evidence for increased extracellular potassium and glutamate and reduced intracellular magnesium levels in the brains of migraine patients.413,414 Stimulation of the serotonergic pathways from the brainstem to the cortex and cerebral arteries may initiate the migraine. Large quantities of serotonin from neurons and platelets are released during the aura, with subsequent depletion of serotonin in the headache stage to follow. The other major physiologic abnormalities described in migraine pathogenesis relate to platelet function. Elevation of the serum content of the platelet factors has been documented during migraine attacks, including beta-thromboglobulin and platelet factor IV.74,157 Patients experiencing a migraine attack have been documented to show a decrease in serotonin and a rise in urinary 5-hydroxyindoleacetic acid (5-HIAA).74 It had been postulated that spontaneous platelet aggregation and release of platelet contents in the occipital cortex could trigger spreading depression, with a subsequent drop in regional cerebral blood flow following the migration of spreading depression.176 However, it now appears that platelet activation represents an epiphenomenon, possibly of an underlying endothelial dysfunction in migraineurs.385,401 As stated previously, the known pathophysiology, clinical manifestations, and treatment of migraine bear little resem-

blance to those of isolated vasospasm, with secondary constriction and dilation of intracranial and extracranial arteries. Migraine seems to be a common inherited diathesis, probably dominantly involving central nervous system (CNS) neuronal excitability,413 with vascular epiphenomena involving primarily large and medium-sized vessels. The visual aura in migraine may be related to cerebral ion flux and the headache to edema. It is usually treated with vasoconstriction and anti-inflammatory drugs.428 In contrast, vasospasm denotes a temporary reduction in arterial caliber that is grossly discernible on angiography or retinal examination. It is usually demonstrated in the anterior circulation and best studied at the microvascular level. Vasospasm is rarely accompanied by headache and can be successfully treated with vasodilating agents.427 Therefore, intracranial vasoconstriction is now considered to be an epiphenomenon of vasoneural coupling rather than a cause of migraine.

Genetics Hereditary factors are important in the individual susceptibility to migraine attacks.71,151 These factors may operate either by inappropriately activating a normal trigeminocervical pain system or by appropriate stimulation of trigeminovascular pain systems with relatively low activation thresholds or in which there are defects in inhibitory modulation.71 The genes for several hereditary migraine syndromes have been discovered.151 There is a clear familial tendency to migraine, which has been well defined in the autosomal dominant form of familial hemiplegic migraine (FHM). In patients with FHM, missense mutations in the alpha1 subunit of the voltage-gated P/Q-type calcium channel have been identified. FHM mutations so far identified include those in CACNA1A (P/Q voltage-gated Ca2+ channel, ATP1A2 [N+-K+-ATPase] and SCN1A [Na+ channel]) genes. In the early 1990s, FHM became the first migraine syndrome to be linked to a gene defect. The syndrome was later found to be associated with point mutations in the gene CACNL1A4 located on chromosome 19p13 in 50% of affected families.297 Another genetic mutation in a group of families with FHM has been assigned to chromosome 1q31, implying genetic heterogeneity.90 Attempts to link chromosome 19 with the common form of migraine have heretofore been unsuccessful.381 More recently, linkage analysis has been used to identify novel migraine susceptibility genes for the migraine with and without aura in several families on chromosomes 4q24, 6p12.2-21.1, and X(Xq24-2).54,289,421 It is possible that other ion-channel mutations contribute to migraine without aura, because it is primarily cases of migraine with aura that have been linked to the FHM locus.381

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It is doubtful that all patients with migraine with aura share the same genetic or pathophysiologic underpinnings.70 Whether migraine aura and its sensory accompaniments are necessarily based on a single proximate pathophysiologic event is also doubtful.70,72 Given that cortical spreading depression can occur without migraine, and vice versa, it seems likely that many factors can trigger the migraine circuit, and spreading depression is just one of them. Migraineurs have a genetically determined reduced threshold for migraine triggers.396 It now seems likely that numerous modules in the brain can be independently affected, and identifying threshold genes and deciphering their function will help unravel the triggering mechanisms for migraine attacks.396

of a normal neurologic examination.230 Once the diagnosis is established, reassurance that the migraine symptoms are benign is the mainstay of initial therapy. Most practitioners treating children with migraine have noted that there is a significant reduction in the frequency and intensity of migraine in children once the anxiety is relieved.318 Over the long term, most children do well, and many outgrow their migraines. Parents are understandably concerned that their child may have a brain tumor or some other neurological disorder. The parents are often migraine sufferers who have adapted to the condition and are familiar with the fundamentally benign nature of the diagnosis. On occasion, it is possible to introduce the parents to a therapeutic program for their own migraine headaches at the same time the child’s headaches are diagnosed and managed. Symptomatic relief of pain and nausea is the second order of treatment. Because there is a disappointing lack of evidence from controlled, masked, clinical trials, there are conflicting and insufficient data to make any other recommendations for the preventive therapy of migraine in children and adolescents.231 For children older than 6 years of age, ibuprofen is effective and can be considered for the acute treatment of migraine.155,233 Acetaminophen is superior to placebo in the treatment of migraine.154,164,200,308,366,382,415 However, many children who seek medical attention for their headaches either have tried over-the-counter analgesics with minimal relief from pain, or there has been a change in the frequency, or intensity of their headaches has changed. The avoidance of medications with addictive potential should be encouraged in any treatment plan. Pharmacological treatment for pediatric headache can be divided into abortive and prophylactic therapy. A few clinical studies have evaluated the use of either abortive or prophylactic medications in the pediatric population. Although most migraine medications do not have pediatric indications for treating headache, many have been used extensively in children and are considered safe and effective. Abortive therapy should be considered for children who experience infrequent headaches (less than two per month), especially if the headaches are preceded by a visual, sensory, or motor aura. Abortive medications are most effective in the preheadache phase. In children under 10 years of age, Imitrex (sumatriptan) nasal spray is effective if administered before central allodynia sets in.46 These medications are less attractive to use in children who are less likely to ask for medication until they have significant head pain or are experiencing other symptoms of migraine, such as vomiting. Abortive medications include Fioricet (acetaminophen, caffeine, and butalbital), taken 1 or 2 given every 6 h for headache; and Imitrex, 6 mg given subcutaneously at onset of headache.250 Ergotamines are rarely used in children due to their propensity to cause vomiting. Compazine and DHE-

Sequelae Although migraine is considered to be a largely benign disorder, cortical spreading depression may produce a hypoxic state in the absence of a reduction in cerebral blood flow under conditions of high energy demand.380 Lewis et al234 analyzed the Humphrey 30-2 threshold test results in 60 migraine patients and found visual field abnormalities in 35%. The prevalence of visual field loss was greater with increasing age and duration of disease. More recently, McKendrick et al found long-lasting dysfunction in contrast discrimination, color perception, prolonged visual evoked potentials (VEPs), and decreased visual field sensitivity in people with migraine.8,266,361,438 Some children with migraine develop persistent visual phenomena lasting months to years. Visual symptoms involve the entire visual field and consist of diffuse small particles such as TV static, snow, lines of ants, dots, and rain.243 These patients have normal neurological examinations, neuroimaging, and EEGs, and the persistent symptoms seem refractory to treatment. These persistent positive visual phenomena do not appear to be related to a prolonged migraine aura181 but may be akin to allodynia (pain evoked by nonnoxious stimuli) and to the hyperesthesia that reflects generalized CNS hyperexcitability in these patients. Although we assure patients that the condition is benign, migraineurs in general have an elevated risk of asymptomatic white matter lesions and stroke compared with nonmigraineurs,82,206,239,403 suggesting that, in some patients, migraine behaves as a chronic, progressive disorder.

Treatment Before predicating treatment, migraines must be distinguished from the recurrent headaches in children and adolescents in the absence of a family history of migraine and the presence

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45 have been used in an emergency department setting for the treatment of acute headache. For adolescents older than 12 years of age, sumatriptan nasal spray is effective and should be considered for the acute treatment of migraine.231 For preventative therapy, flunarizine is probably effective and can be considered, but it is not available in the United States.231 Migraine headaches that are frequent or severe enough to require prophylactic therapy are relatively uncommon in childhood.281 Only 18% of children younger than 8 years of age with migraine have more than one attack per month.281 Prophylactic therapy is warranted when the child has frequent headaches (more than four per month) or if the headaches are infrequent but severe, or if the child fails to respond to abortive therapy. Most medications used for adult migraine prophylaxis have been used in pediatrics; some have clinical studies to support their use, while others are used on the basis of clinical experience. Some studies have shown propranolol and anticonvulsants to be effective in the treatment of migraine in children;18,117,247 however, other studies have questioned these results.111,296 In our experience, these medications frequently have side effects (e.g., lethargy, tiredness, apathy, memory problems), and we use them infrequently. Periactin (cyproheptadine) is an effective prophylactic medication, but it causes drowsiness and weight gain. In our experience, the most effective prophylactic medications are the tricyclic antidepressants or beta blockers as first-line treatments, calcium channel blockers as second-line treatment, and the anticonvulsant topiramate as a thirdline treatment.231 Amitriptyline appears to be a safe and effective prophylactic medication. It has been proven effective in the treatment of both migraine and tension-type headaches in adults66,443 and appears to be equally safe and effective in children when used at lower doses than those used to treat depression. For this reason, the prophylactic effect of amitriptyline against migraine is believed to be independent of its antidepressant effect. Once-a-day dosing (bedtime), relatively infrequent side effects (transient daytime sedation), and improvement in sleep patterns make it attractive to use in children. Children younger than 5 years of age are usually given 10 mg as a starting dose, while older children are started at 25 mg. This dose can be gradually increased at 3- to 4-week intervals, with a maximum dose that rarely exceeds 75 mg a day. A baseline electrocardiogram (EKG) should be obtained prior to starting any tricyclic antidepressant to look for a prolonged PR interval (greater than 0.20 ms) or a corrected QT interval (greater than 0.45 ms). A follow-up EKG should be obtained once a therapeutic level has been reached. Beta blockers can be prescribed as propanolol, 1 mg/kg/day, or atenolol, 25 mg/day. If the headache is exclusively migrainous, with no other headache (e.g., tension headache) occurring at regular inter-

vals, we also consider verapamil a safe and effective prophylactic medication.15 The starting dose is generally 20 mg three times a day in younger children and 40 mg three times a day in older children. This dosage can gradually be increased, with the final daily dosage rarely exceeding 240 mg. Side effects are few, with constipation being the most common. Treatment for 2–6 months is usually recommended before the child is weaned from the medication. Topiramate (76 mg/ day) has found application in pediatric migraine prophylaxis, but some patients report side effects including sedation, cognitive slowing, loss of appetite, and weight loss.105,232,439 Pediatric dosing starts at 25 mg at bedtime and increases to 50–100 mg at bedtime. Many children, at some point, require reinstitution of a prophylactic medication if the headaches become frequent again. Nonpharmacologic therapy, including sleep regulation, avoidance of dietary triggers, and stress management, can be incorporated into the treatment plan.89,232 Relaxation techniques and biofeedback have been found to have both shortand long-term benefits in migraine.89 The concentration and effort required to learn these techniques limit their usefulness in children, but these techniques should be considered in children who seem intractable to other therapy. In our experience, some children with migraine and moderate amounts of hyperopia show a dimunition of frequency with glasses to correct most of their hyperopic refraction. In this setting, the work of constant focusing may precipitate migraines in the child who has an inherent predisposition. Tinted lenses can be prescribed when photophobia is problematic. In adults, botulinum toxin injected into the frontal region works by being a synaptic poison for cGRP, which may be a local mediator for pain in the trigeminal system. In the future, cGRP antagonists will undoubtedly find application in the treatment of migraine. MR stimulation has been reported to prevent headaches when administered during the aura.

Epilepsy Epileptiform Visual Symptoms with Seizure Aura In 1879, Gowers140 described a patient with epilepsy who had “epileptoid attacks with visual aura.” The patient described episodes of having a very brilliant image before him “as if he had a polished plate on his breast” or “a flickering light, like a gold serpent.” Gowers then examined the records of a thousand of his personal patients with epilepsy and found 84 who exhibited a visual aura.140 Holmes172 expanded on the findings of Gowers in his classic studies of gunshot wounds to the occipital region and elaborated on elementary visual hallucinations and temporary blindness as features of epilepsy in these patients. Penfield and Erickson309 reported the ability to

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reproduce the visual aura by cortical stimulation of the occipital lobe at the time of surgery. Since that time, elementary visual hallucinations have been reported as the most common symptom of occipital lobe epilepsy.248,345,424,425 Children with a seizure focus may have irritative visual hallucinations associated with a purely focal seizure in which the visual hallucinations are associated with only minimal alterations in consciousness or with a more dramatic seizure with secondary generalization. The degree of organization of the visual hallucinations or images reflects the anatomical area of the visual sensory system that is involved in the abnormal discharge. The most complex visual scenes are produced by seizure discharge in the temporal lobe, which may take the form of vivid and detailed scenes containing recognizable human and animal forms that move and interact. Some children report autoscopic phenomena (visual reproductions of the self or parts of the body in external space) as part of a temporal lobe aura.419 Focal seizures in visual association areas may also produce complex imagery, including geometric shapes, such as squares and triangles, or simple animal forms. Occipital lobe seizure foci are more common in children than in adults.402 Generalized seizures may or may not emanate from an occipital focus. When they do, epileptic photopsias last only seconds or, rarely, minutes before the onset of a seizure.212 Patients with photosensitive epilepsy are reported to have deficient cortical mechanisms for contrast gain control for pattern stimuli of low temporal frequency and high luminance, which may explain why television and video games can be powerful triggers of visually induced epileptic seizures.317 Seizures in area 17 (occipital pole) are elementary, lacking form, depth, movement, whereas those originating more anteriorly, in visual association areas (areas 18 and 19) are more elaborate, with form, color, depth, movement. A focal seizure in the occipital cortex produces the simplest form of epileptic visual image, consisting of multicolored hallucinations with circular or spherical patterns contralateral to the focus.303 Seizures that also affect the posterior temporal neocortex are the most complex, representing people and formed objects in the environment. The laterality of the seizure focus can often be inferred from the clinical signs and symptoms. Conjugate eye deviation that occurs at the onset of a clinical seizure is highly suggestive of an occipital focus contralateral to the direction of eye deviation, especially if visual auras are also present. The hallucination also tends to occupy the visual hemifield contralateral to the seizure focus. Some patients also report an unusual sensation that their eyes are moving.173 In a review of 42 patients with medically refractory occipital lobe epilepsy, 29% of the patients described blacking out of the vision, sometimes lasting for several minutes. In many of these patients, no other manifestation of seizure activity

occurred.345 Visual hallucinations, usually described as flashing, colored lights, stars, wheels, or triangles, were commonly reported. Only a small number of patients had formed visual hallucinations and, of these patients, all had right-sided occipital lesions. In this series, 46% became seizure-free, and 21% had a significant reduction in seizure frequency following surgical excision of the epileptic focus. Ludwig and Marsan248 found simple visual aura to be the most prevalent subjective sensory experience (47%) among 55 epileptic patients with EEG evidence of exclusively or predominantly occipital involvement.444 Visual field defects are found in 20% of epileptic patients with EEG evidence of occipital foci.248 Other estimates of the overall incidence of visual disturbances in epilepsy have ranged from 4% to 10%.124,310 Visual aura was most common when patients were selected according to the criterion of occipital epileptiform involvement.444 Hallucinations associated with seizures can be either ictal or part of a postictal cortical release phenomenon, and their clinical features may help distinguish their etiology.183 Occipital lobe epilepsy has been divided into benign and symptomatic categories.122,284,302 Benign occipital epilepsy (BOE) in childhood is further subdivided into two disorders. The first is early-onset Panayiotopoulos syndrome, which presents in early childhood with predominantly nocturnal spells of tonic eye deviation, nausea, vomiting, clonic activity, and possibly other autonomic manifestations.67,259 Ictal visual symptoms occur in only 10% of patients and consist of elementary or complex visual hallucinations, illusions, blurring, or blindness. Long-term outcome is excellent, and seizures remit with age. The second is Gastaut syndrome, which presents in later childhood with diurnal, brief visual seizures consisting of elementary visual hallucinations and, possibly, sensory illusions of ocular movement and tonic eye deviation.120,302,306 Postictal headache is common. This form can be mimicked by other symptomatic etiologies of occipital lobe epilepsy. Common causes of symptomatic occipital epilepsy in children include Sturge-Weber syndrome, cortical dysplasia, neonatal hypoglycemia, celiac disease, MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes), traumatic brain injury, gliotic or inflammatory scarring of brain tissue, porencephalic cysts, glial tumors, and angiomatous lesions). It tends to be more refractory to medical treatment, and the prognosis is less clear than with Panayiotopoulos syndrome.248 Mitochondrial disease due to mutations in the POLG1 gene can cause an epileptoic syndrome with initial features of occipital lobe epilepsy.102,211 Occipital seizure phenomena include flickering colored light (sometimes persisting for weeks, months, or even years), ictal visual loss, horizontal or vertical nystagmus, dysmorphopsia, micropsia, macropsia, and palinopsia. In one study,102 age at presentation ranged

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from 6 to 58 years, with a mean age at presentation of 18.4 years (6–58 years). Most patients develop simple partial seizure phenomena with motor symptoms, suggesting frontal lobe seizure initiation or spread. All patients develop status epilepticus, often leading to death.102 In other familial types of epilepsy, mutations may be found, and epilepsy susceptibility genes continue to be identified.211 Celiac disease is increasingly recognized as a multisystem disorder that can cause visual disturbances secondary to occipital lobe epilepsy in both children and adults. CT scanning shows bilateral cortical calcification of the occipitoparietal regions, while MR imaging shows low-signal areas on axial T2-weighted sequences corresponding to these calcifications. Seizure types include simple partial, complexpartial, and secondarily generalized seizures. The seizure semiology may include blurred vision, loss of focus, seeing colored dots, and brief stereotyped complex visual hallucinations, such as seeing unfamiliar faces or scenes.314

weakness of Todd’s paralysis, postictal blindness is usually temporary, but cases of permanent visual loss have been described.9,203,340 These episodes of permanent visual loss have occurred in patients with preexisting visual abnormalities.307 Harris160 reported several cases of hemianopia following unilateral convulsions. Postictal blindness may range in duration from minutes to days, and in rare cases, it may last several weeks.204 The mechanisms of postictal visual loss are poorly understood. Permanent neurological damage following seizures has usually been attributed to the effects of hypotension, ischemia, acidosis, and hypoxia. Permanent blindness following generalized seizures has been likewise attributed to the effects of poor oxygenation.342 However, primate studies have demonstrated that prolonged seizure activity can produce neuronal damage without hypotension, acidosis, or hypoxia.268 It may be that prolonged seizure activity can directly injure the visual cortex and thereby lead to permanent visual loss.

Ictal Cortical Blindness Distinguishing Epilepsy from Migraine Because occipital epileptiform activity is most common in children, ictal cortical blindness should be considered in the differential diagnosis of intermittent cortical blindness in children.444 Children with epilepsy limited to the occipital lobe may have acute cortical blindness as the major manifestation of the seizure.444 Most reports describe cases in which amaurosis was the sole presentation of epileptic activity (i.e., an “ictal equivalent”) or cases in which epileptiform activity was documented by EEG during the amaurotic episode. Due to the inherent difficulty involved in obtaining an EEG during these brief attacks (unless they occur frequently), the diagnosis is often made presumptively on the basis of the presence of interictal occipital epileptiform activity. Strauss373 described an 11-year-old boy who suffered from attacks of complete blindness lasting 2–10 min, with preservation of consciousness. The postictal EEG showed bioccipital epileptic activity, with similar and often simultaneous activity in the temporal lobes. Zung and Margalith444 described a 7-year-old boy who experienced several episodes of complete visual loss, accompanied by gastrointestinal symptoms and a sensation of fright, but with preservation of consciousness. These episodes ended abruptly with visual recovery and no postictal phenomena. CT scanning was normal, and interictal EEG showed bioccipital epileptiform activity.

Postictal Blindness Cortical blindness is a rare but well-recognized manifestation of epilepsy. Children seem to have transient visual loss following seizures more often than adults.204,342 Similar to the

There is considerable overlap in the symptoms produced by epilepsy and migraine in children.25 Both disorders are episodic, with sudden onset and recovery. Both may have visual loss or hallucinations, are frequently associated with headache and behavioral changes, and are associated with neuronal hyperexcitability. There is an increased incidence of epilepsy among migraineurs and of migraine among epileptics.28,77,195,241 Although headaches associated with seizures are usually postictal, ictal headaches may, occasionally, be the sole expression of a seizure in the limbic system and/or other parts of the cortex.253,375 The utility of EEG in distinguishing epilepsy from migraine is unfortunately limited, because EEG abnormalities, including focal epileptiform changes, have been reported in up to 74% of children with migraine who never develop clinical epilepsy.25 The neurological features that can be used to differentiate migraine from epilepsy are summarized in Table 5.1. The major differentiating feature is that consciousness may be lost or substantially altered during a seizure, and the transition is relatively abrupt. The most common phenomenon in a complex partial seizure is progression to a state of altered consciousness, with an appearance of confusion and bewilderment accompanied by unresponsiveness. This is frequently the result of spread of the ictal discharge into the temporal lobe following occipital origination. Progression to loss of consciousness or secondary generalization with the production of a convulsive seizure may also occur. Loss of consciousness does not occur in most forms of migraine, but it may occur in basilar type migraine.33

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Table 5.1 Clinical features useful in differentiating migraine from epilepsy Migraine Onset Duration Termination

Rapid (minutes) Longer (minutes to hours) Gradual

Family history of migraine Consciousness Other symptoms of seizures Quality of symptoms

Positive (+++) Usually normal Usually absent Pain

EEG Response to treatment

Variable, usually not epileptiform Responds to migraine medications or antiepileptic drugs

Seizure Acute (seconds) Brief (minutes) Sudden (but may be followed by a more gradual postictal recovery) Negative (+/−) Commonly impaired Usually present Ill-defined, not similar to any previous experience (if recurrent, then stereotypical) Usually frankly epileptiform No response to migraine medications, response to antiepileptic drugs

EEG, electroencephalogram Adapted, with permission, from Hanson158

The characteristics of the visual hallucinations and their temporal relationship to other symptoms are also useful in distinguishing epilepsy from migraine. The visual hallucinations of migraine are usually present longer (20–30 min) than the visual aura of a seizure (seconds to a few minutes). Occipital lobe seizures tend to occur daily, whereas migraine-associated hallucinations tend to occur with longer time intervals (weeks to months).288 However, occipital lobe seizures can be followed by a headache that is indistinguishable from migraine.288 Panayiotopoulos303 compared elementary visual hallucinations in 50 patients with migraine and 20 patients with occipital epileptic seizures. He found that epileptic seizures are predominantly multicolored, with circular or spherical patterns, as opposed to the predominantly black and white linear patterns of migraine. Elementary visual hallucinations, particularly when combined with headache, vomiting, or blindness, are more likely to be diagnosed as characteristic of migraine despite the fact that they are also common ictal manifestations of occipital lobe seizures.303 Other major points of differentiation between epilepsy and migraine are summarized in Table 5.2. The distinction between migraine and epilepsy becomes critical in the child with photopsias and headaches who harbors an occipital arteriovenous malformation (AVM). In the absence of other clinical evidence of seizure activity, the character of the photopsias and their temporal relationship to the headache can often provide a historical clue to the presence of an occipital seizure focus. A history of flickering photopsias that begin and terminate abruptly and remain stationary rather than enlarging in a crescendolike fashion suggests the possibility of an occipital AVM or other seizure focus, as opposed to migrainous cortical phenomena; it also indicates the need for neuroimaging and EEG.390 Darkening or dimming of the homonymous visual field is also suggestive of seizure activity.390 In patients with an AVM, the visual disturbances start and almost always remain on the same side of the visual field (contralateral to the lesion), and headaches

Table 5.2 Causes of unexplained visual loss in children Refractive abnormalities Bilateral high hyperopia Bilateral meridional amblyopia Cornea Early keratoconus Mucolipidosis IV Retina Stargardt disease Cone dystrophies (congenital cone dystrophy, early progressive cone dystrophy, blue-cone monochromatism) AIBSE, MEWDS, and related disorders Oligocone trichromacy Isolated foveal hypoplasia Bradyopsia Old ROP Optic nerve Early bilateral optic neuritis Mild or segmental optic nerve hypoplasia Mild optic atrophy Central Nervous System Structural Suprasellar tumors (craniopharyngioma, chiasmal glioma) Cortical visual loss PVL Alexia without agraphia Congenital prosopagnosia Nonstructural Amblyopia (due to transient amblyogenic factors) Monofixation syndrome Posttraumatic blindness

are usually localized to the side of the lesion and often lack the typical pulsatile quality of migraine.390 There is some evidence to suggest that occipital mass lesions may also predispose patients to developing classic migraine headaches.279 Troost et al390 reported a patient with an occipital AVM who described typical fortification scintillating scotomas lasting less than 30 min, with “buildup” that preceded a pulsatile headache with nausea. After removal of the AVM, the migrainous attacks resolved. Riaz et al331 described a similar patient

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whose typical migraine headaches resolved following resection of a meningioma. The authors speculated that activation of intradural and extradural arteriovenous shunts, by a vascular meningioma, could effectively create a migraine diathesis.

Vigabitrin-Associated Visual Field Loss Vigabitrin is an excellent antiepileptic drug that has found application in children with otherwise intractable epilepsy. Vigabitrin is an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase, which is used in the treatment of epilepsy. One of the side effects associated with vigabitrin is persistent visual field constriction, which electrophysiologic studies suggest may be due to the toxic effects of vigabitrin on the retina. The visual field constrictions are often localized binasally, and mfERG has been used to evaluate topographical retinal dysfunction.32,159,221,251,316,341 mfERG demonstrates reduced generalized or peripheral mfERG response amplitudes. In some cases, these abnormalities correlate with the visual field defects, while in others, they are more diffuse than the visual field abnormalities. One limitation of this technique has been the restriction of mfERG responses to the central 50–60 degrees of retina, so that more peripheral retinal dysfunction may go undetected.

Posttraumatic Transient Cerebral Blindness Occipital head trauma in children may produce a syndrome of transient cerebral blindness. This condition occurs preferentially following occipital head trauma, and there may be a delay of minutes to hours between the trauma and the onset of the blindness. The blindness is often accompanied by other symptoms, including somnolence, confusion, agitation, and vomiting. The duration of blindness may range from several hours to a day, and the prognosis for return to normal vision is excellent. Electroconvulsive discharges are sometimes recorded from the occipital head regions during the first day following the injury. Greenblatt143 has called attention to the strong migraine and seizure diathesis in children who develop this syndrome, and suggested that vasomotor and neuronal instability may be important factors in its pathogenesis. The “ding” injury in football may produce a transient confusional state indistinguishable from transient global amnesia. These patients may have migraine features, and it has been suggested that most cases of transient global amnesia are migrainous. The possibility of arterial dissection should be considered in children who present with transient visual loss following head or neck trauma.165,326 Carotid artery dissection presents with a nonthrobbing headache ipsilateral to the dissection.

The pain may be retro-orbital and extend to the face and neck. It is often accompanied by a bad taste in the mouth. The telltale neuro-ophthalmologic sign in carotid dissection is an ipsilateral postganglionic Horner’s syndrome. Carotid artery dissection may produce transient monocular visual loss or scintillating scotomata with headache, which simulates a migraine headache.327 Vertebral artery dissection is characterized by posterior headache or neck pain, which may be accompanied by other brainstem signs of vertebrobasilar ischemia. The most common visual symptoms include transient visual symptoms and diplopia. Treatment of arterial dissection usually consists of followed by administration of an antiplatelet agent.165 Surgical intervention is an option in patients with progressive neurological deficits.

Cardiogenic Embolism Heart disease is considered to be the most common cause of stroke in children.332 Cerebrovascular emboli from the heart have been associated with a number of congenital and acquired disorders. Potential sources of cardiac emboli include left atrial myxoma, vegetative valvular lesions associated with bacterial endocarditis or old rheumatic heart disease, mitral valve prolapse, and atrial septal defects (including patent foramen ovale), which may be associated with rightto-left shunting of “paradoxical emboli.”431 Heart defects with a right-to-left intracardiac shunt can also cause polycythemia, with potential for thrombosis.332 Most of these conditions can be identified by echocardiography. However, the demonstration of a cardiac abnormality in a child with a previous stroke or with transient neurological disturbances does not constitute proof that the cardiac lesion is causative. Emboli from the venous circulation are ordinarily unable to enter the systemic arterial circulation because they are filtered by the lungs. A patent foramen ovale provides venous emboli direct access to the systemic circulation and may be a source of “paradoxical” embolism that can cause cerebral and retinal dysfunction in patients of all ages.431 As with mitral valve prolapse, the subject of patent foramen ovale has generated considerable interest as more sensitive echocardiographic techniques have revealed a higher prevalence of anatomical defects than was previously recognized. Specifically, a number of recent studies have attempted to define the risk of developing neurological dysfunction when a patent foramen ovale is present. Several studies have found a significantly higher prevalence of patent foramen ovale in patients with stroke (40% vs. 10%) and transient cerebral ischemic events than in control patients.224,431 One recent study224 found that the association of mitral valve prolapse with stroke is not significant when controlled for the presence of a patent foramen ovale.224

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Transesophageal echocardiography has proven to be more sensitive than routine transthoracic echocardiography for detecting patency of the foramen ovale in older patients.84,431 In infants and young children, transesophageal echocardiography requires general anesthesia. Many pediatric cardiologists reserve transesophageal echocardiography for cases in which there is a high index of suspicion for intrinsic cardiac disease. More recently, contrast transcranial Doppler imaging with Valsalva maneuver has been used to noninvasively diagnose patent foramen ovale in children.29a The diagnosis of paradoxical embolism associated with a patent foramen ovale should be considered in children with cerebral or retinal ischemic events who (1) have been at prolonged bedrest, (2) have a history of lower extremity or pelvic fracture (producing the potential for venous stasis), and (3) have symptoms brought on by a Valsalva maneuver (which can reverse the normal intracardiac left-to-right pressure gradient).38 Associated venous thrombosis may be clinically occult, with no detectable signs of thrombophlebitis.224 Treatments for patent foramen ovale with paradoxical emboli include anticoagulation, interruption of the vena cava, or surgical closure of the foramen ovale.224 Many cardiologists are unenthusiastic about closing a patent foramen ovale surgically, even in children who have had cerebral ischemic events.

with transient visual loss in early childhood.103 These children have episodes of vomiting, migrainelike headaches, seizures, and stroke-like events. Initially, there may be surprising improvement with partial recovery, but recurrent stroke-like episodes leave these children with mental deterioration, hemiparesis, hemianopsia, or blindness. Additional neuro-ophthalmologic findings include chronic progressive external ophthalmoplegia, optic atrophy, and atypical pigmentary retinopathy with macular involvement.339 Other systemic abnormalities may include short stature, sensorineural deafness, and muscle weakness.139 Ragged-red fibers and complex I deficiency is usually seen in their muscle biopsies, and serum lactate levels are elevated.139 Similar features may be found in family members. MR imaging shows multifocal areas of hyperintense signal confined to the cortex of the cerebrum, cerebellum, and immediately adjacent white matter, with relative sparing of deep white matter.264 Several mitochondrial DNA mutations have been associated with MELAS syndrome.170

Nonmigrainous Cerebrovascular Disease An exhaustive list of systemic vasculopathies and coagulopathies has been associated with stroke in children.332 Many of these conditions also produce retinal vascular occlusions. These include systemic vascular disease (e.g., hypertension), hemoglobinopathies (e.g., sickle cell disease), coagulopathies (e.g., antiphospholipid antibody syndrome, protein C deficiency, protein S deficiency), collagen vascular diseases (e.g., systemic lupus erythematosus), and structural vasculopathies (e.g., Moyamoya disease).332 Nantowicz and Kelley285 have summarized the many hereditary disorders that predispose to embolic, thrombotic, or hemorrhagic stroke. Certain rare conditions, especially Moyamoya disease, can present with transient visual loss or scintillating scotoma.277 Whether all of these conditions can produce transient visual loss in children is unclear, because children with known cerebrovascular disease are rarely asked about previous visual symptoms. Statistically, children with transient visual loss rarely turn out to have cerebrovascular disease as the underlying cause. Furthermore, a positive laboratory study does not necessarily establish a cause for the visual symptoms. Investigative studies are generally reserved for children who display other systemic signs of vascular disease, or who have had a previous stroke or retinal vascular occlusion. The MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) can frequently present

Miscellaneous Transient Visual Disturbances in Children Transient Visual Obscurations Associated with Papilledema Transient visual obscurations associated with increased intracranial pressure may be monocular or binocular. They may be described by the child as a graying out or a blurring out of the vision and usually last only a few seconds at a time. There is usually a buildup in the frequency of the obscurations over time until a diagnosis is made. The child may describe dozens of these episodes over the course of a day. Precipitating factors may include rapid changes in position or Valsalva maneuvers; however, the obscurations may occur with no precipitating event. These transient visual obscurations can be distinguished from migraine by their frequency, lack of any positive visual scotoma, and the rapidity with which they come and go. In our experience, most children with elevated intracranial pressure present initially with complaints of headache, nausea, and vomiting and acknowledge transient visual disturbances only when asked. Transient visual disturbances are rare as a presenting symptom. Headaches associated with elevated intracranial pressure share a number of similarities with migraine headaches. Like migraine headaches, these headaches are made worse by coughing, sneezing, or changes in posture, and they are not relieved by mild analgesics, such as acetaminophen. Headaches associated with increased intracranial pressure tend to be worse in the reclined position, causing some patients to prop themselves up to sleep in a position that reduces venous pressure. Unlike migraine headaches, they are rarely of sufficient severity to necessitate an emergency

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department visit (excruciating headaches are rarely caused by brain tumors). They are frequently present on awakening, in contradistinction to migraine headaches, which are usually relieved by sleep. In a comparison study of headache characteristics in patients with migraine versus brain tumors, Rossi and Vassella337 found nocturnal headache, headache present on arising, and increased frequency of headache, to be most predictive of brain tumor. The authors noted that progressive neurological symptoms or signs appeared within 4 months of the headache onset in 94% of cases with tumors. However, elevated intracranial pressure headaches cannot always be clinically distinguished from migraine, because vascular symptomatology may also accompany the headache of elevated intracranial pressure. Children with preexisting migraine headaches can also develop brain tumors.

Anomalous Optic Discs Transient visual loss has been documented in eyes with anomalous elevated optic discs, including pseudopapilledema with and without visible drusen, and congenitally tilted discs. Most reported cases are in adults, suggesting that the disc elevation may have to reach some critical degree before visual symptoms develop. Lorentzen245 reported an 8.6% incidence of visual obscurations (and, in some cases, amaurosis) in patients with disc drusen. Sadun et al343 proposed a vascular hypothesis by which both papilledema and anomalous elevation of the optic discs lead to increased interstitial pressure and decreased perfusion pressure in the intraocular portion of the optic nerve. Thus, minor fluctuations in arterial, venous, or cerebrospinal fluid pressure would result in brief but critical decrements in perfusion, leading to transient

Fig. 5.5 Contractile morning glory disc anomaly associated with transient blindness in left eye. These spells occurred numerous times daily and were associated with afferent pupillary defect. (a) denotes noncon-

obscurations of vision. Katz and Hoyt191 recently described an uncommon disorder associated with anomalous optic discs and posterior vitreous detachment.191 They described a group of young myopic Asians (ages, 11–42 years) whose optic discs were mildly dysplastic and slightly elevated. These patients manifested intrapapillary and subretinal peripapillary hemorrhages with incomplete posterior vitreous detachment. Visual symptoms were mild (blur, spot, smudge) or absent, but abnormalities were detected on visual field testing in most cases. They suggested that elevated anomalous optic discs may have abnormal vitreopapillary adhesions and may be unusually susceptible to vitreous traction. Transient visual loss can also occur in patients with excavated optic disc anomalies.141,359 Graether141 described a young adult who had episodes of amaurosis accompanied by transient dilation of the retinal veins in an eye with a morning glory disc anomaly. Brodsky42 reported an almost identical case in a 10-year-old boy (Fig. 5.5). Seybold359 described a young adult who had transient visual obscurations in an eye with a peripapillary staphyloma. In both cases, the amaurosis could be induced by light stimulation. Entoptic Images Entoptic images are formed by the reproducible perception of objects in the eye, the anatomical structures of the eye, or the perception of the consequences of nonphotic stimulation of the visual sensory apparatus of the eye. Under normal circumstances, these stimuli are either not perceived or ignored; however, under special viewing circumstances, they may become manifest. Although children are less likely than adults to report them, there is no reason to believe that they are less able to perceive them.

tractile state; (b) denotes contractile state. Note reduced optic disc diameter, increased hyperemia of the disc, and dilatation of the peripapillary retinal veins. From Brodsky, MC, with permission36b

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Media Opacities The common entopic phenomenon of the perception of vitreous floaters seen in adults occurs by a similar mechanism in children. Posterior vitreous detachment is only rarely seen in children, but children with vitreous hemorrhages may report the characteristic movement of shadows as the blood clears. Perceptive and articulate children with corneal or lenticular opacities are sometimes able to see the opacity and describe the circumstances in which they become most apparent to them, such as with variability in illumination.

Lepore226 found Uhthoff symptom in 18 of 100 patients with pregeniculate visual loss; ten had multiple sclerosis, four had compressive lesions, and four had other lesions. Neither the extent of visual field loss, decreased acuity, or binocular deficits correlated significantly with Uhthoff symptom. Thus, Uhthoff symptom is strongly but not invariably associated with multiple sclerosis. It has been suggested that hyperthermia is not the exclusive cause of Uhthoff symptom and that changes in metabolic status and ionic channel kinetics that alter the conduction properties of demyelinated fibers can cause this phenomenon.226,358,410

Retinal Circulation

Alice in Wonderland Syndrome

Children may independently report the flying capillary phenomenon that consists of bright dots of light moving away from the blind spot area when looking at a Ganzfeld-like background (e.g., the sky), or a large, uniform surface (e.g., ceiling or light-colored painted wall).

In 1952, Lippman238 used the term Alice in Wonderland syndrome to describe the impairment of time sense and body image in a patient with migraine. Todd387 later used the term to describe the strange distortions of body size and distance from their surroundings perceived by patients with migraine, epilepsy, hypnotic states, drug intoxication with lysergic acid diethylamide (LSD) or marijuana, fever, cerebral lesions, and schizophrenia. Copperman64 reported the association between infectious mononucleosis and Alice in Wonderland syndrome in three children whose symptoms included macropsia, micropsia, metamorphopsia, teleopsia, xanthopsia, and a detached feeling. Numerous children have since been noted to develop these acute perceptual disturbances, usually during the acute phase of infectious mononucleosis64,144,235,346 and as an accompaniment of juvenile migraine.136 The condition is self-limited and requires no specific treatment.

Phosphenes The production of phosphenes by pressing on the eye is a particularly important phenomenon when dealing with children with low vision, especially of retinal origin. The repetitive finger poking in the eye in order to produce these sensations by the otherwise blind child may result in atrophy of orbital fat and discoloration of the lids and periorbital tissues. Strategies to keep the child otherwise occupied may prevent these disfiguring consequences. However, the determined child will be very difficult to dissuade from this activity. Phosphenes on eye movement and with sudden loud noises have been reported in young adults with optic neuritis, and this has been likened to the Lhermitte sign.76,228

Uhthoff Symptom In patients with multiple sclerosis, minor elevation of body temperature by external causes or physical activity increases neural transmission but rapidly leads to electrophysiological blockage through areas of demyelination. This phenomenon, termed Uhthoff symptom, commonly affects the optic nerve, causing visual blurring or amaurosis lasting minutes to an hour. It is less common in children than adults, presumably due to the lower incidence of multiple sclerosis in children. Transient monocular diminution in vision can be brought on by bathing in hot water, hot weather, exercise, consuming hot food or drink, and less frequently, by emotional disturbances, fatigue, menstruation, increased lighting, smoking, or cooking.226

Charles Bonnet Syndrome Healthy elderly patients with bilaterally decreased vision may experience vivid, formed hallucinations in the absence of a psychiatric disorder (termed the Charles Bonnet syndrome).135 The type of hallucinations in Charles Bonnet syndrome may reflect segregation of hierarchical visual pathways into streams.348 These vivid images are believed to represent release hallucinations because they occur in the absence of CNS pathology and may cease following improvement in vision.293 These hallucinations have the following general features: (1) They are exclusively visual, complex, well formed, and often lifelike in their actions, frequently involving people and places. (2) They occur with insight and an otherwise clear consciousness; affected patients know they are hallucinating. (3) The hallucinations are devoid of emotional content (unlike those of peduncular hallucinosis, which is associated with a pleasurable affective reaction). (4) They are superimposed on, or occur in combination with normal perceptions. (5) They are brief, lasting a few minutes at most.

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(6) They are much more common in the elderly, and (7) they generally occur in the setting of visual loss, which has been gradual (most commonly, cataract formation).336 The Charles Bonnet syndrome is benign and usually self-limited; however, some patients may continue to hallucinate for years with little response to anticonvulsants or other medications. Although this condition is classically seen in elderly patients, an increasing number of reports indicate that it may also occur in children with bilateral anterior visual pathway disease.269,353,422 Because children are often reluctant to report visual hallucinations, this condition is probably frequently overlooked. Medical treatment is rarely effective, but children with this disorder benefit from simple reassurance. The formed and unformed visual hallucinations that occur in the hemianopic field of adults with occipitovascular disease may be of the irritative or release variety.60 Children with congenital hemianopic defects do not complain of similar hallucinations, probably because they have never experienced vision in the affected hemifield and therefore do not have the visual association area connections that become deafferented in adults.

Lilliputian Hallucinations Lilliputian hallucinations refers to the perception of very small, perfectly formed figures, usually active and mobile, gaily colored, and pleasant to look upon.351 Despite their unique character, they seem to be a nonspecific symptom, because they have been reported in various forms of intoxication, visual deprivation, acute infection, epilepsy, and CNS tumor and infarction. Lilliputian hallucinations have been reported in children with scarlet fever and measles.351

have been advanced to explain the existence of palinopsia (enhancement of the normal physiological afterimage, release hallucination, sensory seizure, involuntary visual memory), its neuropharmacological basis remains unclear.

Peduncular Hallucinosis Peduncular hallucinosis is a rare phenomenon in which vascular disease of the cerebral peduncles or associated midbrain structures is associated with moving, intensely colorful visual imagery that changes in a kaleidoscopic fashion, is nonthreatening, and is often pleasurable to the patient.123,419 The hallucinations may consist of geometric patterns and designs or as more elaborate pictures, such as landscapes, country and mountain scenes, flowers, birds, animals, or human beings.287 Although formed visual hallucinations do not generally have strong localizing value, peduncular hallucinosis is usually associated with other neuro-ophthalmologic signs of midbrain dysfunction, allowing clinical localization of the lesion.123 Autopsy studies and neuroimaging have confirmed lesions intrinsic to or compressing the mid-brain.50,91,104,123,283,395 Peduncular hallucinosis is believed to be a special form of release hallucination caused by diminished activity in the reticular activating system and other ascending brainstem pathways, leading to abnormal activity in the temporal lobes. Sleep disturbances often coexist, and it has been suggested that peduncular hallucinosis may be due to a dissociation of the sleep mechanism, causing dream activity to be released while consciousness remains normal or nearly so.287

Hypnagogic Hallucinations Palinopsia Palinopsia is a rare symptom in which there is visual perseveration beyond the physiological afterimage.69,175,227 It is experienced as a persistence or reappearance of portions of a recently viewed scene. Some cases consist of freeze-frame or stroboscopic images of a moving stimulus.175 Palinopsia is usually accompanied by other visual hallucinations or a hemianopia. When a visual field defect is present, symptoms usually involve the hemianopic field.274 It is rare for palinopsia to occur as an isolated visual phenomenon. Palinopsia has been noted predominantly with vascular or neoplastic lesions of the posterior portions of the cerebral hemispheres, most of which have been right-sided.29 Less commonly, it has been reported in association with seizures, hallucinogenic drug use, antidepressant therapy (Trazadone), encephalopathy, and migraine.175 Palinopsia occasionally responds to anticonvulsant therapy.43 Although a number of elaborate theories

Hypnagogic hallucinations are fragments of rapid eye movement (REM) sleep that occur during entry into sleep. They may be visual or auditory. The visual ones consist of vivid scenes, objects, animals, or people that may be frightening to the child or elementary hallucinations, such as flashes or patterns.149,150 Hypnagogic visual hallucinations may occur in normal children,419 but the child should be evaluated for narcolepsy if there is also a history of sleep attacks, cataplexy, or sleep paralysis.149,150

Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) is becoming an increasingly recognized etiology of transient visual symptoms and seizures of occipital onset in children. Characteristic symptoms include visual disturbances, altered mentation, seizures, headache, and vomiting, transient cortical

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blindness, and complex visual hallucinations during the recovery period.430 T2-weighted MR imaging demonstrates focal, symmetrical areas of increased signal intensity involving both gray and white matter, with no significant mass effect or cortical effacement. Vision normalizes and the associated MR abnormalities resolve following successful lowering of blood pressure, suggesting that the MR abnormalities are caused by extravasation of fluid and protein across the blood-brain barrier rather than infarction. These signal abnormalities reflect the presence of vasogenic edema that predominantly affects the posterior cerebral hemispheres. Most reported pediatric cases have occurred in the presence of known hypertension, renal disease, or use of immunosuppressive agents, when the suspicion for this diagnosis may be high.162,258 When symptoms of PRES occur de novo in an otherwise well child, diagnosis may be more difficult. The diagnosis of PRES should be considered in any child presenting with new-onset seizures, encephalopathy, and visual symptoms.168 Visual symptoms include blurred vision and hallucinatory activity related to occipital seizures.430 The pathophysiology of PRES involves vasogenic rather than cytotoxic edema. Cerebral autoregulation maintains a relatively constant cerebral blood flow over a range of mean arterial blood pressure, thus protecting the brain from acute changes in blood pressure. However, at high mean arterial pressures, autoregulation fails, leading to arteriolar vasodilation and endothelial dysfunction; this, in turn, results in disruption of the blood-brain barrier and capillary leakage. The white matter is predominantly affected, because as it is less tightly packed than the cortex. The posterior brain appears to be preferentially affected because of diminished sympathetic innervation. Children with acute onset of hypertension are probably more at risk than those with chronic hypertension, because they have not yet developed adaptive vascular changes. PRES can also be seen with use of immunosuppressive drugs. The pathophysiology in this setting is less clear, but may involve damage to the vascular endothelium, resulting in vasospasm, reduced tissue perfusion, activation of the coagulation cascade, and extravasation of fluid. Although abnormalities may be seen on CT scanning, fluid-attenuated inversion recovery (FLAIR) MR sequences are much better at showing the extent of the hyperintense lesions and the degree of cortical involvement. The calcarine and paramedian part of the occipital lobe are classically spared, helping to distinguish PRES from bilateral posterior cerebral artery infarction.

rodegenerative diseases that eventually involve the optic nerves or higher cortical centers. Examples include episodic visual loss in the early stages of ornithine decarboxylase deficiency (a hyperammonemia syndrome),364 transient homonymous hemianopia in subacute sclerosing panencephalitis,194 and formed visual hallucinations in juvenile ceroid lipofuscinosis.215,367,440

Neurodegenerative Disease As in adults with Alzheimer’s disease, transient visual disturbances may occur as early symptoms in a variety of neu-

Multiple Sclerosis Transient visual disturbances may occur in children with multiple sclerosis. Recognized causes of transient visual disturbances include mild or subclinical episodes of optic neuritis, Uhthoff symptom, phosphenes induced by ocular motion, and the Pulfrich phenomenon. (The Pulfrich effect is a well-known visual illusion in which a pendulum swinging in a frontal plane in front of a subject is perceived as moving in an oval trajectory, with the plane of the oval being parallel to the floor. It is noted most commonly in patients who have recovered from optic neuritis in one eye.)420

Schizophrenia Schizophrenic hallucinations are most often auditory in nature, but they may also be visual.419 The visual hallucinations are usually of frightening objects, such as skeletons or ghosts, or may represent a recently deceased relative or friend.114 Schizophrenic hallucinations are not influenced by eye closure or opening, as opposed to drug-induced visual disturbances that tend to exacerbate with the eyes closed.419 Visual hallucinations have also been described in children with reactive psychosis, depressive syndromes, and organic brain syndromes114 and are reported most frequently in psychoses of late childhood.96 Differential diagnosis from temporal lobe epilepsy is sometimes difficult due to overlap in symptomatology. Children with less severe psychiatric disorders, such as emotional and behavior problems, also experience hallucinations in the form of fantasies and “pretend companions” that may possibly aid them in coping with their situational disturbances.96 Such children do not appear to be at increased risk for psychosis, depressive illness, organic brain damage, or other psychiatric disorders.115

Hallucinogenic Drug Use While LSD, mescaline, and psilocybin ingestion can all produce visual hallucinations, the hallucinatory phenomena associated with LSD have been studied most extensively. Ingestion of LSD can produce several organic mental disorders, causing hallucinations. The first is an acute dose-related

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reaction involving complex formed and unformed visual hallucinations, often with auditory-visual synesthesia (the transformation of a sound stimulus into a visual experience).419 Individuals ingesting LSD often report that they can see music or that they can hear pictures translated into sound. In some individuals, sounds of different frequencies evoke different visual hallucinations.228,405 A second perceptual abnormality is a delayed phenomenon involving visual flashbacks. Visual flashbacks have been estimated to occur in 5% of hallucinogenic drug users.229 Symptoms include alterations of color perception, positive and negative afterimages, illusions of movement, halos around objects, shimmering of images, micropsia, macropsia, teleopsia, and palinopsia.322 These phenomena are not dose-related. They may occur after only one exposure to LSD or may begin long after cessation of the drug. Flashbacks are usually episodic but, in some cases, persist indefinitely.1,13,186,229

of intravascular venous thrombosis rather than direct neural toxicity or arterial disease. It is well known that coagulation abnormalities are a complication of cancer, including the commonly encountered myeloproliferative disorders of childhood.275,315 It has also been postulated that there may be direct myelin toxicity in patients whose neuroimaging shows mainly white matter abnormalities.362 A confusing syndrome of delayed visual loss with neurological decline may be seen in leukemic patients following bone marrow transplantation with fludaribine immunosuppression. Fludaribine neurotoxicity, which is seen 18–60 days after exposure, can produce a progressive syndrome of visual loss, encephalopathy, paraparesis, coma, and death. This devastating complication is reported in 18% of treated patients. MR imaging shows hyperintensity in the periventricular and periatrial white matter that does not enhance and shows restricted diffusion.59,408 The mass effect and the periventricular location on MR imaging and restricted diffusion help distinguish this condition from progressive multifocal leukoencephalopathy which is subcortical in location.223

Cannabinoid Use Abnormal visual perceptions may be described by patients who use marijuana or hashish or who have recently discontinued their use. Symptoms include the following: (1) black and white spots flickering at high frequency, similar to interference on a television screen, (2) a perceived reduction in depth perception, (3) visual perseveration after looking at bright objects, and (4) the perception of moving objects as a series of still pictures.210,229 These symptoms are made worse by physical exertion or staring at bright objects. Because chronic marijuana and hashish consumption is widespread in our society and common in teenagers, a history of illicit drug use should be suspected in teenagers with these symptoms.

Digitalis Digitalis has been known for many years to cause xanthopsia (yellow vision) in toxic dosages. Other visual abnormalities associated with digitalis toxicity include scintillating scotomas, defects in the yellow/blue color vision, and paracentral scotomas. Electroretinograms (ERGs) obtained in patients with digitalis toxicity have shown decreased cone-mediated wave forms and increased photopic b-wave implicit times. Symptoms of digitalis toxicity may be the result of abnormalities of sodium and potassium metabolism of the cellular membrane, leading to abnormal photoreceptor polarization.416 Erythropoietin

Toxic and Nontoxic Drug Effects Antimetabolites and Cancer Therapy Seizure activity, complex visual hallucinations, and cortical blindness have all been described in patients with cyclosporin neurotoxicity.166,362,397 Transient or permanent visual loss has been reported among other neurological complications in patients receiving a variety of anticancer agents, including l-asparaginase and vinca alkaloids, methotrexate, FK506, methylprednisolone, and tiazofurin.47,319–321,328,334,362 The mechanisms for these neurological complications are multiple. The vinca alkaloids may cause direct damage to neuronal cells by interfering with microtubule function.440 Alternatively, arterial spasm in arteritis has been postulated as a cause in some patients.334 Some authors have noted a pattern of lesions demonstrated by CT and MR imaging that is more characteristic

Recombinant human erythropoietin is widely used in patients on dialysis to treat the anemia of chronic renal failure. Steinberg369 described moving formed visual hallucinations without delirium or psychosis, in patients who were being treated with erythropoietin. Atropine (Anticholinergic Drugs) Atropine can serve as a model drug for the toxicity of all anticholinergics. Visual system toxicity may be produced by overadministration of these drugs therapeutically or by encountering these in the form of belladonna, jimson weed, and stramonium. The neuropsychiatric features specifically include agitated behavior with formed visual hallucinations that frequently involve seeing insects and small animals on clothing or blankets, as well as disorientation to person, time,

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and place. Treatment is usually supportive, but cholinergic agonist therapy that penetrates the blood- brain barrier, such as physostigmine, may hasten recovery.142

Summary of Clinical Approach to the Child with Transient Visual Disturbances

Carbon Monoxide Carbon monoxide poisoning causes hypoxia of neural tissue due to the reduced oxygen- carrying capacity of blood that has had a portion of its hemoglobin converted to carboxyhemoglobin. The principle complication is CNS dysfunction. Transient visual loss of cortical origin is frequently encountered, and vision may wax and wane for several days during recovery. Visual hallucinations and agnosia have also been reported. Optic nerve damage has also been reported, but the retina is unaffected.142

Our approach to the child with transient visual disturbances is summarized in Fig. 5.6. It includes: 1. Obtaining a detailed attack history, personal profile, and family history to determine the likelihood of migrainous phenomena and to rule out other readily identifiable causes, such as drug ingestion, entoptic phenomena, transient visual obscurations, or Uhthoff phenomenon. Inquire about congenital heart disease, rheumatic fever, and cardiac symptoms (e.g., palpitations or shortness of breath unrelated to vigorous activity). Ask whether the child has had previous epileptic events and specifically inquire about contraversive eye movements, blinking, automa-

Fig. 5.6 Clinical algorithm summarizing the causes of transient visual loss in children 57

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tisms, or other evidence of seizure activity coincident with the visual disturbance. Has there been recent head trauma to suggest the possibility of transient posttraumatic cerebral blindness or arterial dissection? Inquire about a personal or family history of thromboembolic events and look for nail bed splinter hemorrhages, which would suggest the rare possibility of antiphospholipid antibody syndrome or a protein S or C deficiency.79 2. Performing a complete neuro-ophthalmologic examination to look for papilledema, pseudopapilledema or other optic disc anomalies, optic disc pallor (possibly suggesting old optic neuritis), homonymous hemianopia, or other neurological deficits. If a child is examined during an episode of monocular visual loss, look for retinal vasospasm. Carefully examine the retina for detachments, tears, signs of vitreous traction (which are easily overlooked when they overlie the disc), and retinal whitening to suggest recent infarction. When transient visual disturbances are unilateral, look for an ipsilateral Horner’s syndrome, which would suggest carotid artery dissection. 3. Obtaining a pediatric examination to rule out clinical signs or symptoms of cardiac disease, collagen vascular disease, hypertensive encephalopathy, and other systemic disease.

The diagnostic yield for these tests is low, but they are more likely to be abnormal when they are applied only in suspicious cases.

Laboratory Evaluation of Transient Visual Disturbances in Children

Occasionally, a child is found consistently to have decreased vision in an eye that is otherwise normal. In such cases, it is assumed that transient amblyogenic factors must have led to amblyopia and subsequently resolved.407 Such factors may include neonatal lid swelling, early anisometropia, transient strabismus, macular hemorrhage, and vitreous hemorrhage. Monocular suppression on sensory testing (Bagolini striated lens, Worth 4-Four Dot) of an eye with no structural abnormality is suggestive of amblyopia. There is a unique disorder that may present as a deficit of stereopsis, despite relatively normal monocular visual acuity in either eye. This disorder, labeled the monofixation syndrome, is characterized by the presence of a facultative central scotoma in one eye under binocular viewing conditions, which is absent under monocular conditions. As a result, central fusion and fine stereopsis are lacking, but peripheral fusion (which provides fusional vergence amplitudes and gross stereopsis) is retained. While the presence of strabismus is not a prerequisite for this condition, it is common for affected children to have an esotropia of 8–10 prism diopters or less on simultaneous prism cover testing and a larger esotropia (16–25 prism diopters) on alternate prism cover testing. The smaller deviation on simultaneous prism cover testing reflects the preservation of peripheral fusion. Children with monofixation syndrome may appear to have straight eyes and be found to have a surprisingly large deviation on prism alternate cover testing. Children with monofixation syndrome often show some degree of superimposed amblyopia. The diagnosis is estab-

The laboratory investigations ordered depend on the examiner’s clinical impressions that are based on the history and physical findings (Fig. 5.6). If a clear-cut clinical picture of migraine is obtained, then no investigations are indicated. If the description of the visual disturbance is reminiscent of a seizure disorder or there are other abnormalities suggestive of a CNS disorder, MR imaging and EEG should be undertaken. Children in whom the pathophysiology of the transient visual disturbance is not clearly migrainous or epileptic pose the greatest diagnostic dilemma. Cardiac disease is more frequently recognized as a cause of permanent neurologic impairment in children, now that advanced noninvasive cardiac imaging techniques, such as transesophageal echography, are available.332,441 Children with a history suggestive of intrinsic cardiac disease should be referred to a pediatric cardiologist for clinical and echocardiographic evaluation. A serum hemoglobin electrophoresis is indicated in black children to rule out sickle cell disease. A complete hemogram, erythrocyte sedimentation rate, platelet count, antinuclear antibody, and partial thromboplastin time (to screen for antiphospholipid antibodies) should be obtained when there are other systemic signs to suggest a vasculopathy. In the rare cases that are particularly suspicious for thromboembolic disease, anticardiolipin antibodies, antithrombin III, and protein C and S levels can be obtained to rule out a coagulopathy.

Unexplained Visual Loss in Children Many children who have decreased vision are referred for neuro-ophthalmologic evaluation after ocular abnormalities have been ruled out. The subspecialist must be familiar with common as well as rare causes of unexplained visual loss in childhood so that the neuro-ophthalmologic examination and ancillary workup can be directed in an expedient fashion (Table 5.2). Underlying conditions can range from refractive errors to retinal or intracranial disorders that can reduce vision before visible signs of disease become evident.

Causes of Unexplained Visual Loss in Childhood Transient Amblyogenic Factors

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lished by placing a four-prism diopter base-out prism sequentially in front of one eye, then the other eye, while the child fixates a distant target binocularly. A rapid horizontal refixation movement is observed in one eye but not in the opposite eye with the central scotoma. The absence of central fusion with preservation of peripheral fusion is also confirmed by performing the Worth 4-Four Dot test using the handheld flashlight at near and at a distance. In the monofixation syndrome, this test reveals the presence of fusion for near targets (which subtend a large angle and thereby stimulate peripheral fusion) and suppression of the involved eye for small, distant targets (for which images fall within the scotoma).

In children with unexplained visual loss, retinoscopy through an undilated pupil is a sensitive office screening test, because the earliest changes may be confined to the central cornea, and the bright reflex obtained from dilated retinoscopy may obscure these changes. The diagnosis of early keratoconus can be confirmed by keratoscopy.17 Slit lamp biomicroscopic signs may be absent early in the disorder. Corneal topography is a sensitive means of diagnosing keratoconus, although expense and availability limits its general application. Mucolipidosis IV is a rare autosomal recessive disorder that is more common in Ashkenazi Jews than in other ethnic groups. Mothers may note decreased intrauterine motility. There is delayed psychomotor development from birth, corneal clouding, and some coarseness of facial features (not as striking as that seen in the mucolipidoses). The corneal clouding is epithelial in origin and can easily be mistaken for congenital cataracts, leading to unnecessary cataract surgery.329a These patients develop a retinal dystrophy, go blind, and die in their teens and twenties. Although the enzymatic defect has been identified, known, no treatment is currently available. Diagnosis is especially important for future genetic counseling, because the risk of this disease in subsequent children is 25%.

Refractive Abnormalities Children with bilateral hyperopia of 6 diopters or more can present with bilaterally decreased vision in the range of 20/100. When given their full cycloplegic refraction, their vision initially improves to 20/40–20/70 and, in some cases, may approach normal. The subnormal vision is presumed to represent a bilateral form of ametropic (form deprivation) amblyopia. Because the optic discs appear small in high hyperopes, the diagnosis of optic nerve hypoplasia may be entertained, but close examination reveals a normal peripapillary nerve fiber layer. Children with corrected bilateral meridional amblyopia may present with unexplained visual loss when the increased visual demands of school work brings attention to their visual difficulty. One should inquire about recent ingestion of medications with anticholinergic side effects in any child who complains of blurred vision that is worse for near tasks. If accommodative amplitudes are found to be decreased, other systemic disorders associated with hypoaccommodation, such as botulism, dorsal midbrain syndrome, diabetes, head and neck trauma, diphtheria, and familial forms of hypoaccommodation, must be considered in the differential diagnosis.380,389

Cornea Keratoconus in children can reduce vision in the absence of any biomicroscopic findings. Keratoconus is a progressive, noninflammatory ectasia, in which the cornea assumes a progressively conical shape secondary to central thinning and protrusion. Its incidence has been estimated at 50–230 per 100,000 people. It is usually bilateral, but may be unilateral or highly asymmetrical. Most patients have no family history of keratoconus, but a few autosomal dominant and recessive pedigrees have been described. Keratoconus is generally an isolated finding but is occasionally associated with systemic disease, most notably atopic disease and Down syndrome.17

Retina Stargardt macular dystrophy should be a major diagnostic consideration in the child who presents with unexplained or psychogenic visual loss in both eyes. Stargardt macular dystrophy is a hereditary condition (usually autosomal recessive but, rarely, autosomal dominant) in which central vision decreases in childhood. Occasionally, patients become symptomatic in adulthood.118 Over time, atrophic macular degeneration develops, surrounded by yellow pisciform flecks that increase in size and number and may subsequently disappear.39 A bull’s-eye maculopathy may be seen as an intermediate stage. Peripheral pigmentary clumping is also occasionally seen. Although children with Stargardt disease eventually develop distinct retinal abnormalities, the retina may appear normal until visual acuity approaches 20/200. Some children with Stargardt disease experience significant visual loss over the course of weeks to months.109 Once vision decreases to 20/40, it usually deteriorates rapidly to 20/200. The final visual acuity usually stabilizes in the range of 20/200–20/400.109,418 Despite their diffuse retinal involvement, children with Stargardt disease have mild dyschromatopsia, mildly constricted visual fields, and no symptoms of night blindness. The diagnosis of Stargardt disease should be suspected in a child whose “psychogenic” visual loss fails to improve with reassurance and whose color vision is relatively preserved despite poor acuity.236 ERGs and electro-oculograms are generally unhelpful in establishing the diagnosis, because they are

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normally early in the disease and become only mildly abnormal in advanced disease. Fluorescein angiography shows the characteristic absence of choroidal fluorescence (termed a silent choroid), in 65–85% of cases.109,338a,392 This angiographic finding correlates with the histopathological finding of increased retinal pigment epithelial lipofuscin content.35 Autofluorescence is also decreased in areas of lipofuscin deposition.136a Mutations in the ABCA4 gene, which encodes a photoreceptor-specific binding protein, are responsible for almost all cases of Stargardt disease.136a,338a,372,417,418,437a,442 Other retinal disorders can also manifest as unexplained visual loss in children. In the child with bilateral central visual loss, a normal retinal appearance, and a normal fluorescein angiogram, ERG may be useful to rule out a progressive cone dystrophy.236 In this condition, the attenuated photopic ERG may provide the only clue to the diagnosis. Other congenital retinal dystrophies, such as blue-cone monochromatism, can also present as acquired visual loss in the absence of visible retinal abnormalities. The diagnosis of blue-cone monochromatism must be established by ERG. Teenagers and adults may develop acute idiopathic blind spot enlargement (AIBSE) without optic disc edema or retinal abnormalities.110 In some cases, this disorder appears to be a variant of several inflammatory retinal disorders, including multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis, and acute macular neuroretinopathy.48,156 In other cases, however, the retina appears normal. AIBSE is usually unilateral and characterized symptomatically by a paracentral dark spot near fixation that may enlarge to eclipse fixation. The patient may report swirling photopsias within the confines of the spot. Although MEWDS may produce the same constellation of symptoms, a subgroup of patients has no visible retinal abnormalities, and it is unclear whether these patients had retinal lesions early in their course of disease. The diagnosis of AIBSE relies upon the ability to use kinetic perimetry to demonstrate a discoriented, steep enlargement of the blind spot with geographic borders but no other visual field abnormalities. The young child’s inability to maintain fixation and to provide accurate and consistent responses may make it impossible to establish the diagnosis. These perimetric findings establish that the blind spot enlargement is due to a circumscribed dysfunction of the peripapillary retina rather than an optic neuropathy (which would have smooth borders and a sloping margin). AIBSE is now believed to be a postviral retinopathy. In some cases, the scotoma resolves, while in others, it persists or improves only minimally. Oligocone trichromacy is a rare cone dysfunction syndrome characterized by reduced visual acuity, mild photophobia, normal fundi, and reduced amplitude of the cone ERG, but with color vision within normal limits.270,400 It has been proposed that affected patients might have a reduced number of normal functioning cones (oligocone syndrome),

with preservation of the three cone types in normal proportions, thereby permitting trichromacy. These patients generally have a history of reduced visual acuity from infancy (20/40–20/80), mild photophobia, good color vision, no nystagmus, and normal fundi. Cone ERG findings are absent or markedly reduced (in some cases, predominantly affecting the B waves). This disorder is likely inherited as an autosomal recessive trait.270 Other retinal disorders are increasingly recognized as causes of unexplained visual loss. Isolated foveal hypoplasia does rarely produce mildly decreased acuity in children with no visible nystagmus. In this setting, the diagnosis can be confirmed by optical coherence tomography (OCT) and multifocal ERG.193 Occult macular dystrophy can produce bilaterally visual central acuity without visible fundus abnormalities.202,265,278 Fluorescein angiograms and full-field ERGs are normal, but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly abnormal. Rare visual disorders such as bradyopsia (slow vision), are increasingly recognized and characterized. Affected children have subnormal visual acuity and complain of photophobia, difficulties adjusting to changes in illumination, and problems seeing objects at ball games. Pinhole vision (which omits surrounding light) is often better than the best corrected vision with glasses. It is caused by a mutation in the RGS9 (regulator of G-protein signaling 9) gene, which is involved in the deactivation of photoreceptor responses. Color and dark adaptation tests are normal, and visual field testing shows no defects, except for a generally reduced central sensitivity. The diagnosis of bradyopsia can usually be made on the basis of ERG measurements and confirmed by the detection of a mutation in either the RGS9 or R9AP gene.161 Averaged single-flash scotopic ERG measurements typically show reduced amplitudes with higher flash intensities, whereas single-flash responses to dim light (rod response) are normal in amplitude. The time to generate a fully recovered response to the second strong flash after a normal response to the first strong flash is severely prolonged when paired flash tests are used.161 Finally, a rare syndrome of acquired visual loss in adults with old retinopathy of prematurity can cause unexplained visual loss.379 OCT should be performed, as previous reports suggest that this form of visual loss may be attributable to subclinical tractional retinal detachment.360 Plasmin-assisted vitrectomy successfully restored baseline visual acuity in one patient.

Optic Nerve Optic neuritis in children is usually associated with acute bilateral visual loss and bilateral optic disc swelling. In some

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children, however, the visual loss may precede the development of optic disc swelling by several days. We have examined children who were initially thought to be feigning blindness, only to develop bilateral optic disc edema over several days. In this context, the dilated, poorly reactive pupils may be falsely attributed to the effects of recent mydriatic administration. Dominant optic atrophy may also present with unexplained visual loss in the pediatric population. Dominant optic atrophy is a disorder in which segmental optic disc pallor is associated with decreased visual acuity in both eyes. Many children are unaware of any visual disability until they undergo routine visual screening. They typically complain of difficulty seeing the blackboard, but do well when placed at the front of the class. They are often mildly photophobic but do not have nystagmus. Visual acuity is usually in the 20/70–20/80 range but may vary from 20/25 to 20/400.199 Asymmetry in vision between the two eyes is not unusual. The temporal optic discs show marked focal pallor that may appear triangular, wedge-shaped, or excavated, with absence of the corresponding nerve fiber layer.199 The severity of visual loss can vary considerably between family members, and it is common to find affected siblings who are visually asymptomatic. Affected patients are systemically normal, although sensorineural hearing loss may occasionally coexist.174 Patients with dominant optic atrophy display a psychophysical profile that differs from other forms of optic atrophy. Goldmann or tangent screen perimetry demonstrates a central or centrocecal scotoma that may require considerable effort to identify. Patients with dominant optic atrophy are usually tritanopic when tested with Farnsworth-Munsell hue 100 but show diffuse dyschromatopsia when tested with color plates. This finding distinguishes them from patients with compressive, inflammatory, ischemic, or other forms of acquired optic atrophy, which are preferentially associated with red-green or global color deficits. Color perimetry in dominant optic atrophy demonstrates a characteristic inversion of color isopters, with the yellow or blue isopters smaller than the red and green isopters. The major differential diagnostic consideration in dominant optic atrophy is a cone dystrophy, which may also be associated with temporal pallor of the disc and which may show minimal macular changes. Although most children with congenital cone dystrophies have nystagmus and photophobia, exceptions exist. In some cases, ERG may be necessary to distinguish these two conditions. Bilateral temporal disc pallor may also be seen as a familial condition in Leber optic neuropathy. These patients initially have normal acuity, but experience severe consecutive visual loss over weeks to months. In contrast, visual acuity in dominant optic atrophy remains stable or gradually diminishes by only a few lines over years of observation.99

Mild optic atrophy or hypoplasia of any cause can elude detection when close examination of the peripapillary nerve fiber layer is not possible. Segmental optic nerve hypoplasia involving the papillomacular bundle may cause sensory esotropia in the preschool population and present as strabismic amblyopia that is refractory to treatment. Leber optic atrophy can also cause unexplained visual loss before optic disc pallor becomes evident.

Central Nervous System A child who seems to have psychogenic visual loss rarely has a suprasellar tumor infiltrating or compressing the visual pathways. The early diagnosis of functional visual loss is common in children who harbor a craniopharyngioma.274 Compressive or infiltrative suprasellar lesions often produce bitemporal hemianopia; however, reliable visual fields may be unobtainable in young children, and early visual symptoms may precede optic atrophy or other objective signs of anterior visual pathway dysfunction. It is inevitable that the diagnosis of craniopharyngioma or other suprasellar tumors are delayed in children who present with early isolated visual symptoms with no objective neuro-ophthalmologic findings to support an organic basis for their complaints. Close followup, neurologic consultation, and neuroimaging are all viable options in suspicious cases. Neuroimaging is obtained when (1) the pupils are abnormally large or poorly reactive with light-near dissociation, (2) confrontation visual fields show a bitemporal or homonymous hemianopia, (3) examination of the peripapillary nerve fiber layer shows dropout of the nasal nerve fiber layer consistent with band atrophy, and (4) neurologic or systemic signs are found (severe headaches, macrocephaly, café au lait spots, diabetes insipidus, short stature), which suggest that the child may harbor a suprasellar tumor. These cases remind us of the need for caution and humility when diagnosing psychogenic visual loss in a child. Cortical visual loss is rarely present in children who have no overt neurological problems.246 A history of seizures, developmental delay, or perinatal hypoxia suggests that the child may have unrecognized cortical visual loss. Neuroimaging should therefore be obtained in the child with bilaterally symmetrical visual field defects. Rarely, occipital dysfunction that is long-standing or recently acquired can present as unexplained visual loss when a child confronts the increased visual demands of the school setting. Finally, children with selective dorsal stream injury involving the visual association areas can present with unexplained visual loss, because they can still navigate and pick up things without being able to consciously identify their features or orientation.138 A history of antecedent trauma to the occiput suggests the possibility of transient posttraumatic cerebral

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blindness. This condition usually resolves within 24 h but occasionally lasts for weeks. The diagnosis of alexia without agraphia should be considered in the child with an acute isolated inability to read, even in the absence of homonymous hemianopia.242 The most common etiology of this disorder of higher cortical function is an infarction in the territory of the left posterior cerebral artery (hemianopia).242 In children, alexia without agraphia has been reported in the setting of bilateral occipital infarction,292 ruptured AVM,304 and following biopsy of a thalamic tumor,378 or acute disseminated encephalomyelitis hemianopia.242. Congenital prosopagnosia can also simulate psychogenic visual loss. This newly recognized disorder has a prevalence of 2.5% in the general population and is inherited with an autosomal dominant transmission. A point mutation in a single gene may be responsible for the condition.146 The cardinal symptom is an inability to recognize familiar faces. Prosopagnosic children often overlook familiar people and confuse strangers with familiar persons.147 People with congenital prosopagnosia have no mental images of faces, not even of their nearest relatives.145 Interestingly, they recognize emotions on faces as easily as other people do. Their difficulties with facial recognition produce a special problem in crowded places. The underlying brain defect has not been localized. Anatomic MRI scans show normal cerebral structures, except for a slight gray matter deficit in parts of the anterior temporal lobe. As detailed in Chap. 1, premature children with periventricular leukomalacia may also display striking prosopagnosia.93,180,267,344

Psychogenic Visual Loss in Children Psychogenic, or “functional,” visual loss is surprisingly common in children. Eames95 found that 9% of 193 unselected school children exhibit tubular visual fields. Bahn21 stated that “functional nervous disorders … are more frequently manifested in the visual mechanism than in any other of the special senses.” Psychogenic or functional visual loss in children has a clinical profile that differs from nonorganic visual loss in adults. It should be suspected when a discrepancy exists between the purported visual deficit and the objective findings or when a review of records shows that the level of acuity has varied considerably from one examination to the next. Psychogenic visual loss in children remains a diagnosis of exclusion, and some children who exhibit signs of psychogenic visual loss are later found to have an underlying organic disease.324 For example, the diagnosis of X-linked adrenoleukodystrophy should always be considered in boys who present with psychogenic visual loss in the first decade of life, who may display bizarre behavior and poor vision before optic atrophy or other neurologic signs develop.

Although the natural history is one of the spontaneous resolutions, long-term follow-up is important to rule out coexistent organic disease and to adequately treat children in whom psychogenic symptoms persist.324 Children and adults are differentially sensitive to their vision, as they are to health in general. Some tolerate substantial alterations in function without noticing them. Others are so sensitive that any floater or discomfort is perceived as disabling. Children who tend to dwell on their health, or whose parents closely monitor their physical well-being, are more apt to become concerned about subtle visual variations. Children can be viewed as existing along a spectrum with regard to their threshold for feeling visually intact. At one extreme is the intelligent child who needs glasses and is unaware that he or she cannot see well. The child with psychogenic visual loss represents the opposite extreme.

Clinical Profile Psychogenic visual loss is most commonly seen in prepubescent girls in the 9- to 11-year age range.255 Mantyjärvi255 estimated the incidence at 1.4/1,000 per year. Psychogenic visual loss is often said to preferentially affect children who are of above average intelligence and who are high achievers at school,323 but this information is largely anecdotal and has never been verified by careful studies. When true, it is unclear whether such children have unusually high self-expectations of themselves or whether psychogenic visual loss occurs when the child’s psyche eventually “yields” in some way to the high expectations imposed on them by others. Systematic psychological evaluation data of children with psychogenic visual loss are generally lacking, and many published opinions represent impressions of ophthalmologists. Mantyjärvi255 referred to psychogenic visual loss as the “amblyopic schoolgirl syndrome,” which he attributed to the stress of puberty and prepuberty. Rabinowicz323 believed that psychogenic visual loss usually represents a cry for help and, particularly, for parental attention. Rada,324 a psychiatrist, observed that inadequately understood feelings of being threatened, usually because of strife within the family, tend to predominate in young children with psychogenic visual loss. He concluded that information obtained from psychological tests and parental interviews suggests a neurotic conflict between the wish to express feelings of hostility and the wish not to lose the love of their parents.324 Psychological testing of affected children usually shows a significantly high “neurosomatic” score.394 In another psychiatric study, adolescents who had previously presented with psychogenic disorders of vision were more likely to report having experienced school difficulties and the loss of a significant figure at the time of presentation, to rate their mothers as overly

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involved, and to report adjustment difficulties and obsessive personality traits in adolescence. Bullying and loss of an important figure seemed to be important concomitants.436 Many afflicted children report that school is the source of their stress. However, these school anxieties sometimes represent a displacement from the real source of the problem, which is often the home,323,325 as evidenced by the fact that the temporal distribution of psychogenic visual loss in children is virtually even throughout the school year rather than skewed toward the beginning.255 Decreased acuity is often noted initially when teachers report that the child complains of difficulty seeing the blackboard and doing schoolwork, while parents note that there seems to be no difficulty watching television or playing games.325 The child is moved closer to the blackboard with little symptomatic improvement. Vision testing at school reveals bilaterally decreased acuity, and the child is referred for ophthalmologic examination. The child’s affliction may result in considerable secondary gain. According to Rabinowicz,323 “the deterioration of grades when an ‘A’ student begins to perform at a ‘B’ or ‘C’ level is certainly something that will immediately focus parental and school attention on the child, and the deteriorated vision brings forth sympathy, of which many of these children feel deprived. The child’s visual symptoms may bring about a temporary cease-fire in an ongoing interparental war.” While such explanations sound plausible and may indeed be applicable in some cases, it is reasonable to assume that the intricate psychological details of each case are difficult to uncover. Bizzare forms of psychogenic visual loss referable to specific behaviors are occasionally described.252 (The complaint of eyestrain in children may have a strong psychogenic component, as evidenced by a recent study that found that most children with eyestrain have normal eye examinations, while most patients with refractive error, amblyopia, or strabismus were free of eyestrain).178

Table 5.3 Different clinical profiles of psychogenic visual loss in children versus adults Children Adults

Neuro-Ophthalmologic Findings The primary goal of the neuro-ophthalmologic examination is to rule out organic causes of unexplained visual loss. This process requires the examiner to be familiar with organic conditions that may masquerade as psychogenic visual loss in children and to have the necessary clinical and ancillary tests to diagnose them. Major inconsistencies between the current test results and those of previous examinations often provide an early clue to the psychogenic nature of the child’s symptoms. The next goal is to determine whether the child’s vision is better than he or she reports. Unlike adults, children with nonorganic visual loss are rarely malingering (i.e., deliberately feigning a visual prob-

Malingering uncommon Strong predilection toward girls Clusters around puberty Visual loss usually bilateral Normal confrontation visual fields, except in older teenagers Usually resolves with reassurance Recurrences rare

Malingering common Affects both men and women Occurs at any age Visual loss unilateral or bilateral Tubular visual field constriction Variable response to reassurance Recurrences common

lem in order to obtain some desired goal) (Table 5.3). When they complain of visual difficulties, they generally believe they are afflicted. They often display genuine bafflement regarding the nature of their visual problems, and they try very hard to cooperate and please the examiner.255,323 Ophthalmologic examination usually reveals defective distance acuity in the range of 20/30–20/100.323 The Snellen chart is often read in a hesitant manner, with wrinkling of the forehead and facial grimacing, even when the line falls well within the range of the child’s purported acuity.352 Some letters are read quickly, while similar-sized letters seem to present insurmountable difficulty.323 Attempts to guess the letters are often inappropriate (the child will call an 0 an E rather than a D). Some children complain of headaches prior to or during the examination.323 Both children and adults with nonorganic visual loss display visual field constriction when tested with Goldmann or automated perimetry.30,363 Goldmann or tangent screen testing may show the characteristic spiraling of isopters. However, it has been our experience that, with encouragement, most prepubescent children with psychogenic visual loss demonstrate normal confrontation visual fields. Older teenagers, like adults, may display functional visual field constriction when tested with confrontation techniques.30,298,363 Even when kinetic visual fields are normalized, static visual fields may remain abnormal, showing false-negative errors and short-term fluctuations.298 Bourke and Gole40 have noted that children with psychogenic visual loss are unable to see the Ishihara numbers while maintaining perfect color vision to shapes (which subtend the same visual angle). Unlike malingering adults, who may have to be tricked into seeing using a variety of tests,56 one can often persuade the suggestible child with psychogenic visual loss to improve his or her performance on a visual test. Titmus stereoacuity is often initially poor, but many children can be persuaded to identify all Titmus circles with encouragement. Normal Titmus stereoacuity is a valuable finding, as it demonstrates that visual acuity is at least 20/30 in each eye, and it demonstrates that the child’s visual loss, at least in part, is psychogenic.

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In attempting to determine the child’s actual visual acuity, it is helpful to place a negligible corrective lens in the phoropter (plano + 0.50 × 90°) and urge the child to read an isolated 20/10 letter on the Snellen line. When the child is unable to read the letter, the examiner can make use of suggestion by offering an isolated 20/15 letter as a major concession, thereby implying that the child’s failure to read the letter represents a major visual loss.383 When an “enormous” letter from the 20/25 line appears on the screen, the child often readily identifies it. In performing this exercise, it is important to use a single letter viewed through a phoropter in a dark room, which removes external cues as to the size of the letter. If the vision fails to improve, it is helpful to repeat the process after dilation, with the suggestion that the pupils are “huge” so that “extra light” can enter the eyes. The ability of the examiner to use negligible refractive lenses to improve acuity is further evidence of psychogenic visual loss. The visuscope is a valuable and underutilized diagnostic tool in the evaluation of psychogenic visual loss in children. In this test, the child is instructed to follow the star from the visuoscope as the examiner observes the position of the star on the macula. Children with early Stargardt disease display eccentric (nonfoveal) fixation on the star, while those with psychogenic visual loss “lock on” to the star and maintain foveal fixation as the star is moved. In a child with monocular visual loss that is suspected to be nonorganic, a useful test for nonorganic monocular visual loss is to place red-green glasses on the child, with the green filter over the eye with decreased vision. The red-green colored filter bar in the projector is placed over the Snellen line with the red filter over the first three letters, and the green filter over the last three. The glasses allow the child to see only the red letters through the red filter, while all letters are visible through the green filter. The child with psychogenic monocular visual loss may demonstrate the nonorganic nature of his or her visual loss by reading the entire line. As an optional second test, the examiner can place the green filter in front of the normal eye. Some children read only half the letters, despite the fact that all letters can be seen through the green filter. Scott and Egan354 found a high frequency of organic visual disorders in children who manifest with psychogenic visual loss. Early-onset macular dystrophies (cone dystrophy, Stargardt’s disease), and Leber hereditary optic neuropathies are easily misdiagnosed as psychogenic visual loss.236 As mentioned above, children with craniopharyngiomas that compress the optic nerve but have not yet produced visible optic atrophy can behave functionally, as can children with cortical visual loss that selectively involves the dorsal streams in the visual association areas.138 In the child whose vision fails to normalize over time, the possibility of organic underlay necessitates periodic reevaluation. Although the psychiat-

ric underpinnings are difficult to elucidate, functional imaging studies have shown a positive pathophysiologic substrate in patients with “hysterical” disorders, suggesting that any true distinction between “organic” and psychogenic remains tenuous. For all these reasons, the clinician should never become cavalier about the diagnosis of psychogenic visual loss.

Categories of Psychogenic Visual Loss in Children We have found it useful to conceptualize children with psychogenic visual loss as falling into one of the four groups:

Group 1: The Visually Preoccupied Child Most children with psychogenic visual loss have, for unknown reasons, become preoccupied with their vision and concerned about their visual health. They start to believe their visual function has changed for the worse. These children can be compared with adults who become concerned about their cardiac function and find that their pulse rate is high whenever they measure it. Aside from their concern about their vision and the anxiety it engenders, these children seem to have no serious personality disorder that interferes with their day-to-day functioning. Simple reassurance leads to gradual resolution of their symptoms and normalization of their acuity. One might speculate that such cases represent a physiological adjustment period (reminiscent of the general physical awkwardness one sees during puberty) during which hormonal/physiological alterations somehow under lies this phenomenon in predisposed individuals. It is likely that the psychodynamics differ in these children from those whose visual symptomatology lingers for years despite reassurance.189,190 Occasionally, we examine children who are concerned about their ability to function visually and have become convinced that glasses are the solution. These are usually younger children with friends who have recently received glasses. If asked, these children volunteer that they would like to wear glasses. (Although such children may have negligible refractive errors, we sometimes prescribe glasses for them after a frank discussion with the parents and after reaffirming for the child that he or she seems to see normally without glasses). It is difficult to know what symbolic value wearing glasses may have for a given child. If one assumes that this child is expressing some kind of need and that glasses will not harm the child, then one may decide to give glasses and reevaluate the situation after several months.

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Group 2: Conversion Disorder

Group 4: Psychogenic Visual Loss Superimposed on True Organic Disease

Conversion disorder is a psychiatric term that indicates an unconscious loss of neurologic function (e.g., visual loss) for secondary gain, which is also unconscious. For example, a child may believe that he or she cannot see. The gain is that the child no longer has to go to school, where he or she may be experiencing intolerable conflict with the teacher or harassment by students. Children with conversion reactions are more likely to be girls. A conversion symptom manifests as a disturbance of bodily functioning that does not correspond to concepts of the anatomy of the pathways of the central or peripheral nervous system.148 Generally, it occurs in the setting of psychological stress and produces considerable impairment. Although conversion reactions may simulate neurological disease, they are not associated with the usual pathological neurodiagnostic signs, but instead, the signs and symptoms correspond to the child’s concept of the medical condition. A conversion reaction transforms psychic energy from the turmoil of an acute conflict into somatic symptoms and sometimes leaves the child calm (la belle indifference). Some forms of psychogenic visual loss may represent a conversion reaction to a previous experience of sexual abuse, in which the visual loss may a signal that the child has seen something inadmissible or unacceptable.30 Sexual abuse as a cause of psychogenic visual loss is uncommon but well recognized;30,236 the prevalence of sexual abuse as a precipitant of psychogenic visual loss has not been studied. If a history of sexual abuse is elicited, psychiatric evaluation is warranted.

Group 3: Possible Factitious Disorder Parents of children with psychogenic visual loss occasionally display behavior that is reminiscent of a factitious disorder by proxy. This disorder (sometimes called Munchausen syndrome by proxy) refers to the intentional production or feigning of physical or psychiatric signs or symptoms in another person who is under the individual’s care for the purpose of indirectly assuming the sick role.13 This possibility should be considered when one or both parents seem overly invested in the child’s disability and appear to be actively driving the symptom. At an unconscious level, the child cooperates with the parents and may come to share the belief.352 The parents may become hostile and sometimes violent when the physician suggests that the visual loss is nonorganic, and “sabotage” the physician’s reassurances by telling the child that the doctor does not believe the symptoms are real. These parents often refuse psychiatric consultation and fail to return for follow-up appointments.

Several studies have noted that approximately one-fourth of children with conversion symptoms have true organic disease.189,236,324,354 In these children, the psychogenic component can conceal or distract from a true organic visual loss. Such children have organically decreased vision as the cause of their symptoms, and in trying to bring attention to the problem, they exaggerate it to the point at which the symptoms appear nonorganic. Visual symptoms that are long-standing, progressive, and relatively nonfluctuating should arouse suspicion of organicity.324 An organic etiology is also suggested if the child complains of symptoms while engaged in activities he particularly enjoys (e.g., sports). Long-term follow-up of children with psychogenic visual loss is important to detect the subgroup with true organic disorders.189,236,324,354

Management of Psychogenic Visual Loss in Children Interview with the Parents Many children with psychogenic visual loss see several ophthalmologists and/or neurologists before the psychogenic nature of the symptoms becomes evident. The parents have frequently consulted numerous health care professionals and incurred a large medical bill. Parental anxiety induced by the child, whose vision seems to be declining, intensifies with successive consultations and tests.323 In this context, the process of informing the parents that there is no organic basis for the symptoms becomes a delicate matter. Prior to discussing the psychogenic nature of the visual symptoms with the parents, we read the hospital chart for social work notes pertaining to previous psychologically traumatic events, such as sexual abuse. The child is then asked to sit outside, and the parents are invited into the examining room. The parents are informed that the eyes are physically normal and that we believe the child’s vision is decreased on a psychological rather than a physical basis. The parents are reassured that psychogenic visual loss is common in children who have high expectations of themselves. We emphasize that the child is concerned about his or her vision, and that this concern is interfering with the child’s ability to see normally. We explain that the child’s vision is truly impaired on a psychological basis. In explaining this, it is helpful to draw an analogy to the adult who develops real headaches or muscle tension from stress. One should inquire about the child’s previous school performance and whether it has deteriorated since the symptoms began. One should also inquire about

Psychogenic Visual Loss in Children

possible stressors, such as family discord, divorce, or a death in the family, and attempt to determine whether other psychologically traumatic events have taken place. Parents can be told that their child’s visual impairment can be expected to resolve with time. We generally advise parents to de-emphasize the symptomatology by not discussing the child’s visual difficulties and by urging the child’s relatives and teachers to do the same, although some have questioned the efficacy of this approach.55

Interview with the Child It is counterproductive to tell a child with psychogenic visual loss that his or her vision is normal. The child has teachers, relatives, and friends, who are concerned about his or her visual difficulties. If one “confronts” the child about the absence of evidence of a visual disorder, he or she has little choice but to claim that the symptoms are real. Notwithstanding whatever secondary gains are present, the child may be searching unconsciously for a path to recovery. According to Rabinowicz,323 “the purpose of the apparent visual loss may have already been served, and the child is often more than ready for recovery. However, a rapid and ‘miraculous’ cure in the physician’s office is likely to provoke rage from the parents, dismay from the school authorities, and sadness, disappointment, and resentment, together with a feeling of having been deceived from the child’s own teacher and friends,” thus stigmatizing the child. Because children are suggestible, psychogenic visual loss in children is usually a “curable” condition.262 Because these children rarely have serious psychopathology, some authorities feel justified in using placebo therapy to take advantage of the child’s suggestibility.323 This approach may be efficacious, but we believe it is possible to achieve equally good results with patience and reassurance. In most cases, the child is well-oriented, has normal thought processes (i.e., no hallucinations or delusions), and has a normal affective state. One can then reassure the child that he or she is having a minor visual disturbance but that the eyes are healthy.23 One can state that visual disturbances are common in children but that the vision will recover over several weeks. This reassurance permits the child to gradually experience improved vision while maintaining esteem with parents, teachers, and friends. A return appointment is scheduled for 2 months (which underscores the notion that there is no urgent physical disorder). On follow-up examination, the child usually claims to be relieved of symptoms and cheerfully demonstrates normal acuity.236 The issue of pediatric placebo treatment is highly controversial, with placebos recently marketed specifically for children.19 We dislike the use of placebo therapy for the treatment of psychogenic visual loss in children because it reinforces the notion that

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a physical illness is the cause, and most mental health professionals oppose reinforcing the patient’s misperceptions.44

When to Refer Children with Psychogenic Visual Loss for Psychiatric Treatment The issue of when to obtain psychiatric consultation for the child with psychogenic visual loss is controversial. Because psychiatric disturbances (anxiety, depression, attention-deficit hyperactivity disorder (ADHD)) and home and school stress occur commonly in children with psychogenic visual loss; an underlying psychiatric or psychosocial disturbance should be ruled out in children who present with psychogenic visual loss.376 Advocates for early psychiatric intervention believe that psychogenic visual loss should be viewed as a cry for help or a signal that indicates the child has seen or has experienced something disturbing or unacceptable,437 and that there is a possibility of sexual abuse.30 Other stressful events (e.g., marital discord, divorce, illness, death in the family, a poorly kept parental secret that allows the child to sense that something is terribly wrong) may also produce this reaction and be detrimental to the general well-being of the child. They stress that the child may be coping with a deep-rooted emotional conflict and may benefit from professional assistance. Given lack of formal psychiatric training and the time constraints of most ophthalmologists and neurologists, it may be difficult for such physicians to accurately determine which children need psychiatric counseling. Proponents of limiting initial intervention to reassurance23,55,189,255,325 argue that it is counterproductive to react to psychogenic visual loss in children and point to the consistent efficacy of reassurance, the natural history of resolution, and the infrequent recurrence of such symptoms in children. Others stress that psychiatric intervention could stigmatize the child at school, and make it difficult for the child to face friends and teachers.323 Kathol et al189 point out that there is no hard evidence that a psychiatric referral would substantially hasten the child’s visual (or psychological) recovery. In our experience, most children with psychogenic visual loss do not require psychiatric consultation because most fall into the benign group of visually preoccupied children that respond well to reassurance. Those who desire but do not need glasses and those who are found to have organically decreased vision with a psychogenic overlay do not generally require additional psychiatric intervention. We reserve psychiatric consultation for children who have (1) a history of previous psychogenic disturbances, (2) signs of a frank mental disorder, (3) significant impairment in daily functioning at school or at home, (4) a history of psychic trauma (e.g., sexual abuse or otherwise), (5) a grossly dysfunctional family, (6) signs of factitious disorder by proxy (Munchausen syndrome by proxy), or (7) a history of

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chronic visual loss (i.e., longer than 3 months, with no evidence of organic disease). In such cases, a child psychiatrist can determine the nature of any specific traumatic experience that may have preceded the symptoms and define any ongoing sources of psychological conflict. The psychiatrist will also interview the parents to determine the stresses to which the child is currently subjected. In some cases, the psychiatrist may uncover a previous episode of sexual abuse or other psychic trauma and determine that the child needs more extensive counseling and social intervention.

References

Horizons Although the literature describes a basic clinical profile, the problem of psychogenic visual loss in children continues to be a scantily explored condition. Numerous basic questions have yet to be addressed in controlled studies. These questions include the following: What are the “risk factors” for developing psychogenic visual loss in children? Why is it more prevalent in prepubescent girls? What is the prevalence of sexual abuse in this disorder? Can psychogenic visual loss be a sign of depression in children? Are the symptoms confined strictly to the visual system, or do they affect other aspects of the child’s life (e.g., school performance, social interactions)? What is the long-term psychological prognosis (i.e., do these children go on to develop other symptoms of somatoform disease in adulthood)? Systematic studies to address these controversies will hopefully provide a more integrated understanding of the psychodynamics of this disorder and enable us to treat children with psychogenic visual loss more effectively. Functional neuroimaging technologies such as single photon emission computerized tomography (SPECT), and positron emission tomography (PET) bolster the notion that parts of the brain normally involved in emotion may be activated inappropriately in patients with conversion disorder, and may inhibit the normal functioning of brain circuitry responsible for movement, sensation, and sight. Future functional imaging studies may identify similar metabolic alterations, allowing us to attach a positive pathophysiologic substrate to the psychogenic visual loss that we have come to dismiss in the absence of organic (i.e., structural) disease.196 OCT can demonstrate subtle structural abnormalities involving the fovea that are not visible clinically and may not be detectable electrophysiologically. These recent technological advances underscore the fact that the diagnosis of psychogenic visual loss remains one of exclusion.

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396. van de Ven RCG, Kaja S, Plomp JJ, et al. Genetic models of migraine. Arch Neurol. 2007;64:643–646. 397. van Gelder P, Geurs Ph, Kho GS, et al. Cortical blindness and seizures following cisplatin treatment: both of epileptic origin? Eur J Cancer. 1993;29:1497–1498. 398. van Harreveld A. Two mechanisms for spreading depression in the chick retina. J Neurobiol. 1978;6:419–431. 399. van Harreveld A. The nature of chick’s magnesium sensitive retinal spreading depression. J Neurobiol. 1984;15:333–344. 400. Van Lith GH. General cone dysfunction without achromatopsia. In: Pearlman JT, ed. 10th ISCERG Symposium-Color Vision Deficiencies. XII. Amsterdam: Kluver Academic Publishers; 1995:203–210. 401. Vanmolkot FH, Van Bortel LM, de Hoon JN. Altered arterial function in migraine of recent onset. Neurology. 2007;68:1563–1570. 402. Vega-Talbot ML, Duchowny M, Jayakar P. Orbitofrontal seizures presenting with ictal visual hallucinations and interictal psychosis. Pediatr Neurol. 2006;35:78–81. 403. Velentgas P, Cole A, Mo J, et al. Severe vascular events in migraine patients. Headache. 2004;44:642–651. 404. Vijayan N. Ophthalmoplegic migraine: ischemic or compressive neuropathy? Headache. 1980;20:300–304. 405. Vike J, Jabbari B, Maitland CG. Auditory-visual synesthesia: report of a case with intact visual pathways. Arch Neurol. 1984;41:680–681. 406. von Brevern M, Zeise D, Neuheuser H, et al. Acute migrainous vertigo: clinical and oculographic findings. Brain. 2005;128: 365–374. 407. von Noorden GK. Idiopathic amblyopia. Am J Ophthalmol. 1985;100:214–217. 408. Walsh JP, O’Doherty DS. A possible explanation of the mechanism of ophthalmoplegic migraine. Neurology. 1960;10:1079–1084. 409. Warrell RP, Berman E. Phase I and II study of fludarabine phosphate in leukemia: therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol. 1986;4:76–79. 410. Waxman SG. Clinical course and electrophysiology of multiple sclerosis. In: Waxman SG, ed. Functional Recovery in Neurological Disease. New York: Raven Press; 1988:157–184. 411. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1:658–660. 412. Weinberger LM, Grant FC. Visual hallucinations and their neurooptical correlates. Arch Ophthalmol. 1940;23:166–199. 413. Welch KM, D’Andrea G, Tepley N, et al. The concept of migraine as a state of central neuronal hyperexcitability. Neurol Clin. 1990;8:817–828. 414. Welch KM, Barkley GL, Tepley N, et al. Central neurogenic mechanisms of migraine. Neurology. 1993;43(Suppl 3):S21–S25. 415. Welch KM. Drug therapy of migraine. N Engl J Med. 1993;329:1476–1483. 416. Weleber RG, Shults WT. Digoxin retinal toxicity. Clinical and electrophysiological evaluation of a cone dysfunction syndrome. Arch Ophthalmol. 1981;99:1568–1572. 417. Weleber RG, Carr RE, Murphey WH, et al. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch Ophthalmol. 1993;11:1531–1542. 418. Weleber RG. Stargardt’s macular dystrophy. Arch Ophthalmol. 1994;112:752–753. 419. Weller M, Wiedemann P. Visual hallucinations. An outline of etiological and pathogenetic concepts. Int Ophthalmol Clin. 1989;13:193–199. 420. Wertenbaker C, Gutman I. Unusual visual symptoms. Surv Ophthalmol. 1985;29:297–299. 421. Wessman M, Kallela M, Kaunisto MA, et al. A susceptibility locus for migraine with aura, on chromosome 4q24. Am J Hum Genet. 2002;70:652–662.

422. White CP, Jan JE. Visual hallucinations after acute visual loss in a young child. Dev Med Child Neurol. 1992;34:252–265. 423. Williamson DJ, Hargreaves RJ, Hill RG, et al. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural blood vessel diameter in the anaesthetized rat. Cephalalgia. 1997;17:518–524. 424. Williamson PD, Boone PA, Spencer DD, et al. Occipital and parietal epilepsy. Epilepsy. 1988;29:682. 425. Williamson PD, Thadani VM, Darcy TM, et al. Occipital lobe epilepsy: clinical characteristics, seizure spread patterns, and results of surgery. Ann Neurol. 1992;31:3–13. 426. Winterkorn JM. “Retinal Migraine” is an oxymoron. J Neuroophthalmol. 2007;27:1–2. 427. Winterkorn JM, Kupersmith MJ, Wirtschafter JD, et al. Treatment of vasospastic amaurosis fugax with calcium channel blockers. N Engl J Med. 1993;329:396–398. 428. Winterkorn JM. Vasospasm or migraine? Presented at the American Academy of Ophthalmology. San Francisco; November 1994 429. Winterkorn JM, Burde RM. Vasospasm-not migraine-in the anterior visual pathway. Ophthalmol Clin North Am. 1996;9:393–405. 430. Wirrell EC, Hamiwka LD, Hamiwka LA, et al. Acute glomerulonephritis presenting with PRES: a report of 4 cases. Can J Neurol Sci. 2007;34:316–321. 431. Wisotsky BJ, Engel HM. Transesophageal echocardiography in the diagnosis of branch retinal artery obstruction. Am J Ophthalmol. 1993;115:653–656. 432. Wolff HG. Headache and Other Head Pain. 2nd ed. New York: Oxford University Press; 1963. 433. Woods RP, Iacoboni M, Mazziotta JC. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med. 1994;331:1689–1692. 434. Wraith E. Ornithine carbamoyltransferase deficiency. Arch Dis Child. 2001;84:84–89. 435. Wunderlich G, Suchan B, Volkmann J, et al. Visual hallucinations in recovery from cortical blindness. Arch Neurol. 2000;57:561–565. 436. Wynick S, Hobson RP, Jones RB. Psychogenic disorders of vision in childhood (“visual conversion reactions”): perspectives from adolescence: a research note. J Child Psychol Psychiatry. 1997;38:375–379. 437. Yasuna ER. Hysterical amblyopia in children. Am J Dis Child. 1963;106:505. 437a. Xi Q, Li L, Traboulsi EI, et al. Novel ABCA4 compound heterozygous mutations cause severe progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease. Mol Vis. 2009;15:638–645. 438. Yenice O, Onal S, Incili B, et al. Assessment of spatial-contrast function and short-wavelength sensitivity deficits in patients with migraine. Eye. 2007;21:218–223. 439. Younkin D. Topirate in the treatment of pediatric migraine. Headache. 2002;42:456. Abstract. 440. Zemen W, Donahue S, Dyken P, et al. The neuronal ceroid lipofuscinosis (Batten-Vogt syndrome). In: Vinken PJ, Bruyn GW, eds. Leukodystrophies and Polio Dystrophies. Handbook of Clinical Neurology, X. New York: American Elsevier; 1970:588–679. 441. Zenker G, Erbel R, Kramer G, et al. Transesophageal two-dimensional echocardiography in young patients with cerebral ischemic events. Stroke. 1988;19:345–348. 442. Zhang K, Bither PP, Park R, et al. A dominant Stargardt’s macular dystrophy locus maps to chromosome 13q34. Arch Ophthalmol. 1994;112:759–764. 443. Ziegler DK, Hurwitz A, Hassanein RS, et al. Migraine prophylaxis: a comparison of propranolol and amitriptyline. Arch Neurol. 1987;44:486–489. 444. Zung A, Margalith D. Ictal cortical blindness: a case report and review of the literature. Dev Med Child Neurol. 1993;35:917–926.

Chapter 6

Ocular Motor Nerve Palsies in Children

Introduction Ocular motor nerve palsies in children pose a different clinical paradigm than those in adults and require a specialized knowledge base for proper evaluation and treatment. Children with acute ocular motor nerve palsies come to medical attention because of diplopia, abnormal head posture, ptosis, ocular misalignment, or systemic disease. Those with chronic ocular motor nerve palsies are often referred because of strabismic amblyopia. Neurologically-impaired children have a predilection for developing comitant as well as incomitant forms of strabismus. In strabismic children with a history of neurological disease (e.g., brain tumors, congenital hydrocephalus, and meningitis), signs of ocular motor nerve palsy (e.g., incomitance, pupillary abnormalities, and torticollis) should be carefully sought. Conversely, in children with diagnosed cranial nerve palsies, other signs of neurological disease should be ruled out with a thorough neurological evaluation. Assessing objective torsion is now an integral part of the strabismus examination.207 Coexistent neurological signs frequently assist the examiner in clinically localizing the lesion and determining its pathophysiology. For example, signs of fever and nuchal rigidity raise the possibility of meningitis, while coexistent signs of dorsal midbrain syndrome suggest tumor, hydrocephalus, or shunt failure. As with other neuro-ophthalmologic disorders, there is little overlap in the differential diagnosis of ocular motor nerve palsies in children versus adults.234 This disparity reflects the relative preponderance of congenital ocular motor nerve palsies in children and the unique predisposition of children to develop certain disorders (e.g., benign recurrent sixth nerve palsy, ophthalmoplegic migraine, bacterial meningitis), as well as the comparative rarity of aneurysms and vasculopathic palsies in children.287 An initial impression can be gained by observing a child’s head posture prior to formal evaluation. A large head turn in an esotropic child suggests an acute sixth nerve palsy, while a head tilt in the absence of obvious strabismus suggests trochlear nerve palsy. Although the abrupt, recent onset of

torticollis associated with acquired cranial nerve palsy is rarely overlooked by parents, it is not uncommon for torticollis associated with congenital palsies to go unnoticed. When a cranial nerve palsy is suspected, one must rule out masquerading restrictive disorders and neuromuscular disease. This process begins with a carefully taken history, which includes the following questions: 1. Is there a history of antecedent head trauma? Traumatic cranial nerve palsies may be single or multiple and may involve any of the ocular motor nerves.583 Usually, a history of recent head trauma is well established, and there is little question as to the traumatic nature of the palsy. However, cranial nerve palsies due to parasellar tumors may occasionally be precipitated by mild head trauma. In a child with a cranial nerve palsy, the coexistence of a blowout fracture or a skew deviation can complicate the diagnostic task.19,136,418 Perinatal cranial trauma should also be considered with inquiry about difficult forceps delivery, breech presentation, cephalohematoma, and cranial molding in the perinatal period. Photographs taken in the perinatal period may be informative in this regard. In patients with a severe head trauma, the response to surgical treatment may be inexorably compromised by disruption of sensory or motor fusion.440,441,463 Those with loss of motor fusion from a vergence system disorder can often superimpose images momentarily, but cannot maintain fusion through a head movement, or a small proximal or distal shift in the fixation target.462,463 2. Is there a history of variability throughout the day? Diplopia or ptosis that is minimal on awakening and becomes worse as the day progresses suggests myasthenia gravis. 3. Is there a history of headache? A history of headache suggests the possibilities of elevated intracranial pressure, meningitis, and ophthalmoplegic migraine. 4. Is the child otherwise neurologically normal (by history)? Coexistent neurological signs often suggest a specific mechanism or site of ocular motor nerve injury. 5. Are the symptoms relating to the condition old or of recent onset? The diagnosis of a congenital ocular motor nerve

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palsy should be considered in any child with long-standing signs and no diplopia. The ocular motility deficits associated with congenital third nerve palsy or Duane syndrome are often noticed by the parents, in contrast to congenital trochlear nerve palsy, which may escape detection because of the absence of obvious strabismus. However, observing old family photographs confirms the presence of a longstanding head tilt. It is not unusual for a congenital trochlear nerve palsy to first become symptomatic during the teenage years due to a gradual increase in the size of the deviation or a decompensation in fusional control. The facial asymmetry associated with congenital trochlear nerve palsy is frequently overlooked by inexperienced observers. This finding also takes time to develop and may not be sufficiently advanced to be diagnostically helpful in early childhood. 6. If a head tilt is present, at what age is it first noted? Does it normalize when the child reclines? A head tilt associated with congenital trochlear nerve palsy is first noted around 6 months of age, when the child acquires head and neck control, while a head tilt due to congenital muscular torticollis is noted within the first few months of life. A head tilt associated with trochlear nerve palsy resolves when the child reclines,540 while one associated with congenital muscular torticollis persists. Resolution of torticollis in a child with an ocular motor palsy may signal either recovery of the palsy or development of amblyopia and suppression. We reassure the parents that the anomalous head position is (paradoxically) a positive prognostic sign for binocular vision, and advise them to call immediately if the child stops maintaining it. It is not established how much stereopsis or binocularity is lost prior to the disappearance of an abnormal head posture. Therefore, the finding of an abnormal head posture in a young child is no guarantee that the child is maintaining normal binocularity and stereopsis. Close monitoring of vision and early institution of amblyopia therapy is recommended in such children. While trochlear nerve palsy is the major cause of vertical diplopia in children, other causes must also be considered. The physical examination of the child with incomitant strabismus consists of gross inspection, examination of versions, ductions, field measurements, sensory and acuity testing, and ancillary testing (Double Maddox Rod, Lancaster red–green, Lees screen, forced duction test, active force generation test), as indicated.573 A head tilt toward the side of the lower eye that persists despite a manifest vertical deviation suggests the diagnosis of skew deviation.74,146 Donahue146 have documented that a skew deviation arising from selective unilateral injury to the anterior or posterior canal otolithic pathways on the side of the lower eye can produce ocular motility that is indistinguishable from isolated superior or inferior oblique muscle palsy, respectively.146,147

6 Ocular Motor Nerve Palsies in Children

Following complete resolution of cranial nerve palsies, patients may be left with a comitant strabismus from longstanding disruption of fusion or from secondary extraocular muscle contracture.65 The term muscle contracture refers to a muscle that has been structurally altered by remaining in a shortened position for a prolonged period. This results in an increased, nonlinear resistance to stretch that is greater at longer muscle lengths. Early investigations attributed muscle contracture to fiber atrophy and hyalinization, but it is now known that the number of muscle fiber sarcomeres actually decreases.501 In a long-standing sixth nerve palsy, a medial rectus contracture may develop. To some degree, the clinician can distinguish residual lateral rectus weakness from medial rectus contracture by observing the saccadic velocity during attempted abduction of the eye and by performing active force generation and forced duction testing. In the case of true lateral rectus weakness, the saccadic velocity is slow throughout the refixation movement, whereas with medial rectus contracture, the saccadic velocity is normal until the abduction saccade is abruptly terminated by the tight medial rectus muscle. A medial rectus contracture with no residual lateral rectus weakness produces some degree of forced duction limitation, but if the eye is grasped with forceps and the patient is instructed to look away from the contractured muscle, a normal “pull” on the forceps is felt by the examiner. The phenomenon of muscle contracture renders a trochlear nerve palsy more horizontally comitant over time. Children with long-standing superior oblique palsies may develop a contracture of the superior rectus muscle in the hypertropic eye if they chronically fixate with their nonparetic eye, or a contralateral inferior rectus contracture if they habitually fixate with the paretic eye. These secondary contractures may confound the diagnosis and alter the surgical strategies to restore normal ocular alignment. For example, the development of a contralateral inferior rectus contracture in a patient with trochlear nerve palsy may cause the hyperdeviation to secondarily become larger in upgaze than in downgaze. The role of medial rectus contracture in the development of horizontal spread of comitance in patients with long-standing sixth nerve palsy, if any, has not been established. The forced duction test and force generation test play an important role in the neuro-ophthalmologic evaluation of incomitant strabismus in children and in the differentiation of muscle paresis from restrictive strabismus. These tests are most important in the setting of (1) previous orbital trauma, when there is a question of muscle entrapment (as in a blowout fracture); (2) previous ocular surgery, when there is a possibility of iatrogenic peribulbar scarring (as may occur following a scleral buckling procedure); (3) incomitant congenital strabismus with ptosis, when congenital fibrosis syndrome remains a diagnostic consideration;

Introduction

(4) coexistent signs of orbital inflammation or muscle enlargement on neuroimaging studies, when the diagnosis of rectus muscle inflammation with secondary restriction must be ruled out257,259; and (5) longstanding muscle paresis, when the antagonist of a paretic muscle may have undergone contracture secondary to long-term malpositioning of the eye (as in a contracture of the medial rectus muscle following lateral rectus muscle palsy). In young children, the forced duction test must be performed in the operating room under general anesthesia, whereas teenagers may tolerate the necessary manipulation with topical anesthesia. When general anesthesia is used, it is important to avoid succinylcholine or other depolarizing agents that produce prolonged extraocular muscle contracture for up to 20 min.172 In an outpatient setting, anesthesia should be carefully obtained by using topical anesthetic drops combined with placement of an anesthetic-soaked cotton swab over the area of perilimbal sclera to be grasped by the forceps. Attention should be paid to maintaining the eye in its usual arc of rotation. If the eye is pushed into the orbit (as inevitably occurs when a Q-tip is used to rotate the eye), tension is relieved from the rectus muscle, and the examiner may erroneously conclude that the muscle in question is not tight. Conversely, a tight oblique muscle may become slack when the eye is proptosed during rotation. The forced duction test is considered positive when an abnormal limitation of movement is demonstrated and negative when the examiner is able to fully rotate the eye. In the case of an orbital floor fracture, the location of the fracture is an important determinant of the degree of restriction and paresis that develop. When an orbital floor fracture is posteriorly located, then the main contractile portion of the muscle (the midbelly) may be entrapped, but enough elastic muscle exists anterior to the entrapment site to allow ocular rotation. A posterior orbital floor fracture may result in a combination of mechanical paresis from muscle injury and/or adhesions and neurogenic paresis from damage to its neural input as it enters the muscle in the posterior orbit.261,487 In contrast, anterior entrapment may severely restrict elevation of the globe, while the contractility of the muscle is preserved. A positive forced duction test can also result from anterior scarring of periocular tissue to the globe. In children, who have sustained orbital trauma or had previous ophthalmic surgery, it is important to determine whether a positive forced duction test represents a “leash” or a “reverse leash.” Jampolsky250 has described the technique of retropulsing or proptosing the globe during forced duction testing, to gain additional information regarding the nature of the restriction. In the case of a leash caused by a tight rectus muscle, the rotational excursion of the globe increases as the globe is retroplaced during rotation with the forceps and decreases as it is proptosed. In the case of a reverse leash caused by scarring

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of conjunctiva or peribulbar tissue to the anterior aspect of the globe, the opposite occurs. In Brown syndrome, a congenitally restricted superior oblique tendon also produces a reverse leash that becomes more restricted as the globe is manually retroplaced. The active force generation test is used to estimate contractile power in the setting of entrapment or recovering muscle paresis. This is an important determination, as the antagonist of an entrapped muscle (the superior rectus muscle in the case of a blowout fracture) may appear paretic, or the entrapped muscle itself (the inferior rectus muscle) may be restricted. The eye is grasped with forceps near the limbus and held in a direction opposite the deficient movement, while the child attempts to look in the direction of limitation. Forces developed by the contracting muscle can be felt. While attempts have also been made to quantify the force generation test,498 valuable clinical information can be obtained from the examiner’s subjective assessment. A saccade produced by a paretic muscle is visibly slower than a normal saccade, causing the eye to appear to drift toward the premature termination of its rotation. Although decreased saccadic velocity is usually seen in the setting of isolated ocular motor paresis, it is not specific to this condition and may also be seen in disease that primarily involves the extraocular muscles (e.g., orbital pseudotumor), the neuromuscular junction (e.g., myasthenia gravis), and the central nervous system (CNS) (e.g., olivopontocerebellar degeneration, chronic progressive external ophthalmoplegia). Nevertheless, the clinical finding of slowed saccadic velocities allows the examiner to quickly tease out the abovementioned paretic disorders from a mixed bag of conditions, including contracture, restriction, and comitant strabismus. Modern neuroimaging adds increasing information to the diagnostic evaluation of oculomotor nerve palsies. The neuroimaging evaluation of patients with ocular motor nerve palsies have been transformed from a primitive search for causative mass lesions in the brain to a sophisticated set of techniques to directly visualize the intracranial ocular motor nerves and blood vessels, the orbital ocular motor nerves, and the extraocular muscles, both statically and dynamically.139 High-resolution MR imaging can directly demonstrate pathology of the oculomotor and abducens nerves and atrophy of their corresponding extraocular muscles.139 Attention to the orbital extraocular muscles reveals obvious signs of atrophy, hypoplasia, or heterotopia of extraocular muscles that are easily missed by the neuroradiologist, who is necessarily focused on the search for a causative intracranial lesion. High-resolution MR imaging of the head can be combined with quasicoronal orbital MR images in multiple gaze positions to yield enormous information. In cases of traumatic head injury, quasicoronal orbital images can show associated superior oblique muscle atrophy (suggestive of trochlear nerve palsy) or blowout

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fractures that are clinically unsuspected.267 In cases diagnosed as idiopathic, high-resolution orbital images can identify a neurinoma involving the oculomotor nerve. Although orbital images usually show reduced extraocular muscle volume in affected muscles, cases with aberrant regeneration may show preserved extraocular muscle volume but decreased contractility. In some cases, reduced size of the motor nerve to extraocular muscles innervated by the paretic oculomotor nerve has been identified.

6 Ocular Motor Nerve Palsies in Children

one muscle innervated by the oculomotor nerve (except the levator muscle).135 A complete unilateral third nerve palsy with no involvement of the other eye cannot be nuclear, nor can an isolated unilateral levator weakness. Because medial rectus neurons are distributed in multiple areas in the nucleus, some believe that isolated medial rectus paresis is incompatible with a nuclear lesion.135

Fascicle

Oculomotor Nerve Palsy In a study of 30 children with isolated oculomotor palsy, Miller368 found the differential diagnosis to include congenital palsy (43%), trauma (20%), infection and inflammation (13%), tumor (10%), aneurysm (7%), and ophthalmoplegic migraine (7%). Other series reflect a similar distribution,222,271,399 although a series by Ing et al243 included a higher percentage with traumatic cases.

Clinical Anatomy Nucleus The oculomotor nerves arise from nuclei in the tectum of the midbrain just anterior to the cerebral aqueduct. The nucleus has a midline opthalmologic paired portion and lateral paired portions. The currently accepted anatomic scheme was described by Warwick587 in rhesus monkeys and is supported by neuroimaging correlations in humans.83 The paired superior rectus subnuclei are unique in providing innervation to the contralateral superior rectus muscles. The cells that supply the levator palpebrae superioris muscle of both eyes lie in a single midline structure located dorsally in the caudal portion of the nucleus. Medial rectus neurons are distributed in multiple areas in the nucleus, making an isolated nuclear medial rectus palsy unlikely.135 However, isolated paresis of convergence (with normal adduction) has been attributed to selective involvement of a subgroup of neurons within the medial rectus subnucleus.555 Pupillary involvement in nuclear third nerve palsy indicates dorsal, rostral damage that is usually bilateral and is generally associated with additional infranuclear or supranuclear vertical gaze palsies.369 Nuclear third nerve palsies are rare. A nuclear lesion is certain in the presence of (1) a unilateral third nerve palsy with contralateral superior rectus palsy and bilateral ptosis or (2) a bilateral third nerve palsy with normal levator function.135 A nuclear lesion is possible if there is complete bilateral third nerve palsy, bilateral ptosis, or a selective deficit of

As the fascicular oculomotor fibers exit from the nucleus, they are separated in both a mediolateral and a rostrocaudal fashion.305 Fascicular fibers designed for the superior rectus and inferior oblique muscles lie in the lateral fascicle, while those corresponding to the inferior rectus, medial rectus, and pupil are segregated medially, with pupillary fibers taking the most rostral course.478 Consequently, brainstem lesions involving the lateral oculomotor fascicle produce a monocular elevation deficit and ptosis,236 while those involving the medial fascicle produce an inferior divisional oculomotor palsy.305 The inferior oblique fascicles are situated most laterally, while pupillary fibers are situated most medially.95 The presence of coexistent neurological signs may enable the examiner to specifically localize the site of a fascicular oculomotor injury. A midbrain lesion in the region of the brachium conjunctivum may produce an oculomotor palsy and cerebellar ataxia (Nothnagel syndrome). A dorsal fascicular lesion involving the red nucleus may produce oculomotor palsy combined with contralateral hemidyskinesia (Benedikt syndrome). A ventral fascicular lesion involving the oculomotor nerve may also damage the cerebral peduncle, producing contralateral hemiplegia (Weber syndrome).369 As it exits the midbrain in the interpeduncular cistern, the oculomotor nerve passes between the posterior cerebral and superior cerebellar arteries. An extra-axial lesion in this location can compress, infarct, inflame, or infiltrate the adjacent cerebral peduncle and produce a Weber syndrome,117,369 while an intra-axial lesion is usually necessary to produce a Benedikt syndrome. The nerve then traverses the subarachnoid space in a long course between the midbrain and the posterior aspect of the cavernous sinus. Here, it is vulnerable to compression by an internal carotid-posterior communicating artery aneurysm and to injury from basilar skull fracture or contiguous arachnoiditis. The oculomotor nerve passes medial to and slightly inferior to the ridge of the free edge of the tentorium. The tentorial edge may form a deep groove in the oculomotor nerve, indicating the susceptibility of the nerve to pressure with transtentorial herniation at this site. In the subarachnoid space, the pupilloconstrictor fibers are located superficially in the superior portion of the nerve.

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In the cavernous sinus, the oculomotor nerve is located dorsal to the trochlear nerve, and both nerves lie in the deep layer of the lateral wall of the sinus. In the anterior cavernous sinus, the nerve divides into superior and inferior trunks, which become distinct near the orbital apex. The superior division is smaller and supplies the superior rectus and the levator palpebrae superioris. The inferior division sends branches to the medial rectus, inferior rectus, inferior oblique, and ciliary ganglion. Although divisional palsies are usually caused by superior orbital fissure or orbital lesions, it is now well established that more proximal fascicular lesions can also produce divisional paralysis, because the segregation of oculomotor fibers is maintained at the fascicular level.204,370 The only location in which a divisional palsy cannot occur is in the nucleus.369

Clinical Features Injury to the oculomotor nerve may result in complete or partial weakness of any or all of the muscles it innervates. In complete oculomotor palsy, the eye is markedly exotropic and mildly hypotropic with complete ptosis and pupillary dilation. There is no elevation, depression, or adduction, and a characteristic intorsion on attempted downgaze reveals the residual presence of superior oblique function. Ptosis is often the most prominent clinical sign and the first to resolve. Contrary to earlier beliefs and anecdotal observations,274,584 a dedicated study found that relaxation of the rectus muscles in oculomotor and abducens palsies does not produce measurable proptosis.246 Nevertheless, we have seen patients in whom unilateral oculomotor palsy produced a slight proptosis, thereby simulating an orbital lesion. The vertical rectus muscles are the primary elevators and depressors and remain so even in adduction. A pathological process that is uniformly distributed across the fibers of the oculomotor nerve causes little vertical deviation of the affected eye in its exotropic position because the superior oblique muscle has a primarily torsional action in this position. Therefore, a significant hypotropia in this position suggests that the inferior divisional fibers are preferentially affected. As the eye moves into adduction, the depression vector of the superior oblique muscle becomes more prominent, and the eye may become increasingly hypotropic. When the inferior division of the third nerve is primarily affected, the eye lies in an exotropic position due to involvement of the medial rectus muscle and be hypertropic due to inferior rectus paresis (Fig. 6.1). If the superior division is injured, the eye is hypotropic in any position of gaze. Injury to the inferior oblique muscle causes intorsion of the globe, which may produce torsional diplopia and disrupt fusion once ocular alignment is re-established.53

Unilateral oculomotor palsy also leads to central adaptations in the vestibulo-ocular reflex, such as reduced abduction and incyclotorsional gains. These secondary adaptations function to reduce asymmetrical movement of the retinal images during head motion, reduce retinal image disparity, and prevent nystagmus.602

Partial Forms of Oculomotor Palsy Isolated Inferior Rectus Muscle Palsy Isolated inferior rectus palsy is a well recognized condition that has a surprisingly broad differential diagnosis443,464,526,558,575 (Table 6.1). The child with inferior rectus palsy usually complains of vertical diplopia that increases in downgaze. On examination, the child manifests an incomitant hypertropia that increases in downgaze. Although some children show a classic three-step test (Fig. 6.2), von Noorden and Hansell575 have stressed that the three-step test should not be relied upon to confirm the diagnosis of inferior rectus palsy. Children with acquired inferior rectus palsy may show either incyclotropia of the involved eye or excyclotropia of the opposite eye when tested with the Double Maddox Rod, while children with congenital inferior rectus palsy may have an absence of subjective cyclotropia.575 The infrequent occurrence of isolated inferior rectus palsy reflects the complex neuroanatomy of the oculomotor nerve.464 Most compressive, ischemic, and inflammatory third nerve lesions affect the portion of the nerve located between the oculomotor nucleus in the dorsal midbrain and its bifurcation into superior and inferior divisions in the anterior cavernous sinus, where axons destined to innervate all extraocular muscles served by the oculomotor nerve are closely bundled. Such injuries generally produce divisional or incomplete palsies. Neuroanatomically, there are two sites in which a third nerve injury can produce an isolated paralysis of the inferior rectus muscle.523 One site is the oculomotor nucleus, where cell bodies of neurons for each muscle are segregated into distinct subnuclei. A focal vascular, demyelinating, or metastatic lesion involving the inferior rectus subnucleus can result in isolated inferior rectus palsy. The orbit is the second site, where an injury or disease process involving either the branch of the inferior oculomotor division destined for the inferior rectus muscle, the myoneural junction, or the muscle itself could produce an isolated inferior rectus palsy.523 Myasthenia gravis is the primary diagnostic consideration in a child with unilateral inferior rectus palsy and no history of orbital trauma. With the use of orbital MR imaging, cases of unilateral inferior rectus aplasia are increasingly recognized.23a,182

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Fig. 6.1 Inferior divisional paresis of right oculomotor nerve

Table 6.1 Differential diagnostic considerations of unilateral inferior rectus palsy in childhood

Isolated Inferior Oblique Muscle Palsy

Myasthenia gravis Orbital disease (blowout fracture, orbital inflammation, or tumor) Iatrogenic (following retrobulbar injection, inferior oblique myectomy, blepharoplasty) Nuclear third nerve palsy Congenital Idiopathic

Isolated inferior oblique palsy is rare. Most children who present with a limitation of elevation in adduction have a congenital restriction involving the superior oblique tendon (Brown syndrome). The distinction between inferior oblique palsy and Brown syndrome is primarily based on three features: (1) In inferior oblique palsy, there is marked overaction

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Fig. 6.2 Child with right inferior rectus palsy and positive three-step test. Used with permission from Brodsky et al78

of the antagonist superior oblique muscle with correllary intorsion of the affected eye; while in Brown syndrome, there is little, if any, superior oblique muscle overaction or associated torsion. (2) In inferior oblique palsy, there is a large A pattern; while in Brown syndrome, the eyes remain horizontally aligned until the patient looks into far upgaze, where a large exotropia develops (Y pattern). (3) Inferior oblique palsy is usually associated with a negative forced duction test, whereas a positive forced duction test is considered the sine qua non of Brown syndrome. The three-step test in a right inferior oblique palsy would show a right hypotropia that is worse in left gaze and when the head is tilted to the left. Jampolsky252 has found a tight superior rectus muscle to be a common cause of a positive forced head tilt test. An isolated tight left superior rectus muscle produces a pattern on the three-step test that is indistinguishable from a right inferior oblique palsy. However, it may be impossible to determine whether the tight contralateral superior rectus muscle is the primary problem or a secondary consequence of inferior oblique palsy. Inferior adhesions following trauma or surgery can also produce restrictive changes that simulate inferior oblique palsy.249 A report of a transient isolated inferior oblique paresis accompanied by mydriasis and accommodative palsy in a 15-yearold boy after sinus surgery was probably attributable to damage to the inferior division of the oculomotor nerve.43 Pollard437 reported a series of 25 cases of presumed inferior oblique palsy seen over a 17-year period. No systemic

cause was identified, and most underwent successful surgery. Most patients with inferior oblique palsy can be successfully treated with a weakening procedure (spacer, tenotomy or recession) of the antagonist superior oblique muscle, with a low risk of postoperative trochlear nerve palsy.22,448 If intraoperative forced duction testing reveals a tight contralateral superior rectus muscle, consideration should be given to recessing this tight muscle instead of superior oblique weakening. Khawam et al279 have used ipsilateral superior oblique tenotomy or tenectomy in combination with recession of the contralateral superior rectus muscle. Since pupillary fibers are known to travel with the nerve to the inferior oblique muscle, how can an isolated inferior oblique palsy occur in the absence of pupillary involvement? Within the oculomotor nucleus and fascicle, neurons and corresponding axons destined for the inferior oblique muscle are situated most laterally, while those destined for the pupil are situated medially.95 Isolated inferior oblique paresis has been documented to arise from lateral fascicular injury to the oculomotor nerve.95 Selective involvement could of the inferior oblique fibers occur in the region of the nucleus or fascicle, or in the orbit after the pupillary fibers branch off to the ciliary ganglion. Despite prevailing doubts and the existence of simulating conditions, the recent finding of reduced inferior oblique muscle diameter on MR imaging suggests that isolated inferior oblique palsy (or hypoplasia) is indeed a distinct entity.154

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Isolated Internal Ophthalmoplegia Intermittent unilateral pupillary mydriasis can occur in the absence of other motility deficits in the setting of an otherwise uncomplicated migraine headache.369 However, when headache and mydriasis are accompanied by extraocular muscle paresis or ptosis, an intracranial aneurysm must be ruled out.77 Compressive lesions of the oculomotor nerve occasionally produce unilaterally impaired accommodation as the initial symptom. The finding of intermittent exotropia in the child with isolated internal ophthalmoplegia should lead to suspicion of early oculomotor palsy.21 Cholinergic supersensitivity of the iris sphincter may develop in any oculomotor palsy with pupillary involvement.245 Other clinical signs usually attributed to postganglionic damage (light-near dissociation, segmental sphincter palsy) may also be seen;245,247 however, these signs arise too quickly to be explained by transsynaptic degeneration and are now believed to be a direct consequence of sphincter denervation.247 The presence of supersensitivity is not related to the severity of the third cranial nerve dysfunction or to the time between onset and testing, but to the extent of the associated iris sphincter palsy and to the extent of anisocoria.247 Isolated internal ophthalmoplegia has many causes.21 In one patient who sustained head trauma, biopsy demonstrated selective tearing of the medial aspect of the third cranial nerve.342 Wilhelm et al590 described a 19-year-old woman with isolated internal ophthalmoplegia, diagnosed as Adie’s pupil, who was found 14 years later to have an oculomotor neurinoma. Werner et al590 described a 10-month-old infant with internal ophthalmoplegia and cholinergic supersensitivity as the only sign of third cranial nerve compression by a cisternal endodermal cyst.

Isolated Divisional Oculomotor Palsy Most cases of superior branch oculomotor palsy have been reported in adults.67,141,159,204,266,304,350 Isolated superior division oculomotor palsy is extremely rare in children. Saeki et al479 described a 10-year-old boy who developed a superior division oculomotor palsy 1 week after a flu-like illness. The palsy spontaneously resolved over 2 months. Isolated inferior divisional oculomotor nerve palsy is usually reported in adults as a posttraumatic or idiopathic phenomenon.130,486,538

Oculomotor Synkinesis Oculomotor synkinesis, or aberrant reinnervation, can arise a few weeks to months following an oculomotor nerve injury.

6 Ocular Motor Nerve Palsies in Children

Oculomotor synkinesis most frequently results from trauma, tumors, and aneurysms, which involve the physical disruption of axons; however, it also accompanies some congenital cases.589 It is not a feature of ischemic oculomotor palsy. The major signs of aberrant regeneration of the oculomotor nerve169 include: • Pseudo-von Graefe sign: retraction of the eyelid on attempted downgaze; • Horizontal gaze eyelid synkinesis: elevation of the eyelid on attempted adduction of the affected eye; • Limitation of elevation and depression of the eye, with occasional retraction of the globe on attempted vertical movements; • Adduction of the affected eye on attempted elevation or depression; • Pseudo-Argyll Robertson pupil: the affected pupil reacts poorly and irregularly to light stimulation but will constrict on adduction; • Monocular vertical optokinetic responses: the normal eye responds normally, but the involved eye shows poor vertical responses. Three mechanisms have been proposed to explain abnormal muscular synkinesis.37,327 These include peripheral misdirection at the site of injury, ephaptic transmission, and central reorganization of motoneurons and their inputs. In peripheral misdirection, neuronal sprouts grow indiscriminately from the motor nucleus or proximal portion of the nerve following an acute injury. These nerve fibers make erroneous alignments in peripheral nerve sheaths and, thereby, arrive at a muscle that does not correspond to the musculotopic localization of their cell bodies. Bielschowsky52 suggested that peripheral misdirection may cause oculomotor synkinesis, and contemporary investigators continue to consider it the most common mechanism. Neuroanatomical tracer studies have been conducted in an experimental model of oculomotor nerve injury, which documents anomalous connections between the somatic motoneurons of the oculomotor nucleus and the ipsilateral superior rectus muscle.515 The superior rectus muscle in this model (cat) is normally 98% innervated by the contralateral nucleus, as is the case in primates. These studies show that after oculomotor injury and partial recovery, neurons terminating in the superior rectus muscle originate from regions of the ipsilateral oculomotor nucleus that previously innervated the inferior rectus, medial rectus, and inferior oblique muscles, thus supporting the peripheral misdirection hypothesis. Similar studies have been conducted on skeletal muscle and in facial synkinesis with similar conclusions.33,82 Naturally occurring facial nerve injury with motor synkinesis in a primate has also been shown to be due to peripheral misdirection by tracer studies.33 Ephaptic transmissions denote a propagation of neural impulses between adjacent cells by an electrotonic mechanism,

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thereby resulting in “cross talk” between adjacent axons that is not dependent on actual synaptic transmission. Lepore and Glaser327 cited a case of ophthalmoplegic migraine in which signs of aberrant regeneration occurred as a transient phenomenon and argued that ephaptic transmission may offer a possible explanation for such cases, because rewiring of the peripheral nerve would not be compatible with the evanescence of synkinetic movements.37 Ephaptic transmission has also been implicated in disorders involving the fifth nerve nucleus.199 However, the potential role of ephaptic transmission in synkinesis is controversial. This phenomenon is seen only as a transient event in the dystrophic mouse model447 and is not considered likely in the clinical situation, where stereotyped and reproducible movements occur over a period of decades following neuronal recovery. The final potential mechanism for oculomotor synkinesis is that of central reorganization. After motoneuron transection, dendrites acquire the ability to produce autonomous spike potentials.198 The rearrangement of synaptic input to the motoneuron may unmask existing inputs that usually are weak or suppressed. Such changes in the efficacy of normally weak pathways could theoretically participate in the development of synkinetic movements. In this scheme, ipsilateral monosynaptic input to motoneurons is lost and not re-established, and preexisting but normally-suppressed projections become functionally significant with synaptic reorganization after nerve damage. Histologic studies have documented such alterations in synaptic contacts on motoneuron cell bodies.58 However, these changes are present only transiently after injury, and a more normal appearance to the synaptic contacts reappears with time. When Lyle337 sectioned the right oculomotor nerve in eight monkeys, he observed that bilateral pseudo-Graefe’s sign occurred 21 days postoperatively. It is difficult to explain the bilaterality of these synkinetic movements resulting from a peripheral nerve injury without invoking at least one central mechanism.37 Although neuroanatomical studies provide more direct evidence for peripheral misdirection, the potential for the participation of synaptic reorganization in development of synkinesis cannot be dismissed.225,557 Rather than serving a maladaptive role that contributes to synkinesis, central reorganization might well be expected to function in the suppression of abnormal motor movements generated by aberrant axonal regrowth and reinnervation. A panoply of congenital and traumatic synkinetic eye movements continue to be described.174 Congenital ptosis and congenital ocular fibrosis syndromes may be associated with ocular motor synkinesis as part of the congenital cranial dysinnervation syndromes.73,408,553 Cases of abducens to oculomotor misdirection after trauma have been attributed to peripheral nerve misdirection.84 Khan et al276 described a large family in which two siblings exhibited ptosis with abnormal synkinetic elevation on ipsilateral abduction. One

was bilaterally affected, while the other had unilateral findings. A third demonstrated classic bilateral congenital ptosis, while a fourth demonstrated Duane syndrome. Teratogens such as isoretinoin A can produce disturbed ocular motility with congenital ocular motor synkinesis.388 Because the synkinetic lid elevation with depression that follows injury to the oculomotor nerve (pseudo-Graefe’s sign) is often greater in adduction than in abduction, it has been speculated that it may occasionally arise from the trochlear nerve.163,347,348 Rarely, cascade-like forms of ocular motor synkinesis are present at birth. Pieh et al433 described a 6-month-old boy with lack of innervation to a lateral rectus muscle, causing misrouting from the ipsilateral medial rectus muscle; this possibly induced secondary misrouting of trigeminal motor nerve fibers to the medial rectus muscle (manifesting as convergence during sucking).

Etiology The clinical algorithm in Fig. 6.3 is useful in facilitating the diagnostic workup of third nerve palsy in childhood.

Congenital Third Nerve Palsy Congenital third nerve palsies account for a sizable portion of patients in all reported series of childhood ocular motor nerve palsies.390 These children very frequently exhibit aberrant innervation, indicating that the mechanism probably involves an interruption and regrowth of axons (Fig. 6.4). In congenital third nerve palsy with aberrant regeneration, the involved pupil may be miotic compared with the normal pupil.210 In a retrospective review of 41 cases of pediatric oculomotor palsy, Mudgil and Repka390 found the most common causes to be congenital (39%), traumatic (37%), and neoplastic (17%). Oculomotor palsy was associated with a poor sensorimotor outcome in children younger than 8 years of age. In children who are otherwise normal, birth trauma, either with prolonged labor and molding of the skull or with a difficult forceps delivery, has been considered the most likely etiology.210,243 The presumed mechanism of third nerve damage in this circumstance is compression of the nerve as it crosses the tentorial edge while passing from the posterior to the middle cranial fossa. This compression is probably due to either diffusely increased intracranial pressure or compression of the temporal lobe uncus over the tentorial edge and into the posterior cranial fossa. However, Norman et al403 found nodular enlargement of the cisternal segment of the involved oculomotor nerve on MR imaging, in several cases of third nerve palsy in infancy, suggesting that neurinoma

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6 Ocular Motor Nerve Palsies in Children

Fig. 6.3 Clinical algorithm for evaluation of third nerve palsy in childhood

Fig. 6.4 Unusual facial–oculomotor synkinesis in child with congenital oculomotor nerve palsy. From Brodsky71, with permission

can be a causative lesion in this age range. Direct injury to the oculomotor nerve during amniocentesis has also been implicated as a cause of third nerve palsy.428 Neonates with congenital third nerve palsy may recover some degree of function over weeks to months. Although congenital third nerve palsy is frequently an isolated event,368,567 it may also be accompanied by neurological deficits.37,210 Some congenital third nerve palsies may be due to a congenital absence of the

nerve and/or nucleus.111 Contralateral hemiplegia accompanies congenital third nerve palsy in some cases, suggesting a ventral mesencephalic injury.37,243 Midbrain hypoplasia of the ventral portion of the midbrain has been associated with bilateral complete third nerve paresis without aberrant regeneration.168,537 MR imaging demonstrates hypoplasia of the involved extraocular muscles (Fig. 6.5) and, in some cases, intracranial absence of the affected oculomotor nerve.262

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Congenital third nerve palsy has also been associated with septo-optic dysplasia.318 The syndrome of congenital third nerve palsy, cerebellar hypoplasia, and facial capillary hemangioma592 probably represents the PHACE syndrome.361,362,592

Fig. 6.5 Congenital left oculomotor nerve palsy. Coronal orbital MR image shows selective hypoplasia of superior, medial, and inferior rectus muscles

Amblyopia is common in congenital third nerve palsy.243,567 Occasionally, preferential fixation with the paretic eye may lead to the development of amblyopia in the nonparetic eye. This finding has been noted in patients with nystagmus and probably relates to preferential dampening of the nystagmus on the side with oculomotor palsy.210,243,268 Although the potential for restoration of binocularity is poor, patients with congenital third nerve palsy often achieve reasonable cosmesis with strabismus and ptosis surgery.322

Congenital Third Nerve Palsy with Cyclic Spasm A unique form of oculomotor nerve palsy is associated with cyclic spasm of the affected muscles. This condition is usually noticed during the first year of life and consists of partial or complete third nerve palsy, with a dramatic additional feature. Every 1½ to 2 min, the paretic upper lid elevates, the pupil constricts, the eye adducts, and a myopic shift may

occur in the refraction (Fig. 6.6). The spastic phase usually lasts less than a minute, giving way to another paretic phase. The cycles continue throughout life and persist during sleep, although they become slower and less extensive than when the patient is awake. A review of all published cases41 suggests that the condition is frequently seen in the absence of other neurological abnormalities. A history of birth trauma or a significant intracranial infection may be seen in as many as half of the cases.166,335 Near fixational effort is noted to increase the extent and duration of the spastic phase in many cases. Abduction efforts shorten and reduce the spasms and accentuate or prolong the paretic phase. The condition is usually fully developed when first noted, but progression to cyclic spasm has been reported in a patient with a partial third nerve palsy.177 Cases in which the pupil is the only structure to cycle are probably underrecognized.177 Determining the site of the lesion in this condition is an intriguing neurophysiologic problem. The movements resemble oculomotor synkinesis, which is known to be caused primarily by misdirected regrowth of peripheral axons. However, in oculomotor synkinesis, the abnormal involuntary movements are always associated with attempted voluntary movements, whereas in oculomotor paresis with cyclic spasm, the involuntary movements are not reproducible by a particular voluntary effort, although they are influenced by these efforts. The weight of evidence suggests that the primary injury involves the peripheral nerve. However, indirect evidence suggests that reorganization of the central neurons also occurs subsequent to this damage, causing increased susceptibility to supranuclear influences or recurrent discharges of the neurons themselves due to abnormal supranuclear input. It is known that axotomy leads to changes in central nuclei, predominantly a decrease in synapses on the dendritic tree followed by a hypersensitivity to depolarization when exposed to neurotransmitters from other sources. The observation that the cyclic spasm almost always appears in infancy may reflect a particular sensitivity or predilection of the infant brain to develop the aforementioned central reorganization.37,210

Traumatic Third Nerve Palsy Head trauma may cause injury to the third cranial nerve anywhere from the nucleus to the orbit. The intra-axial fascicles of the nerve or the nucleus itself may be damaged as part of a diffuse axonal and neuronal injury pattern in severe head trauma or as part of an ischemic syndrome from temporary occlusion of the perforating branches of the basilar artery, as a result of the brainstem movement during rapid acceleration and deceleration of the head. Outside the brainstem, the nerve may be torn at its exit from the midbrain in the interpeduncular fossa, or it may be damaged at the tentorium from

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6 Ocular Motor Nerve Palsies in Children

Fig. 6.6 Cyclic oculomotor palsy: (a) paretic phase and (b) spastic phase (1 min later)

elevated intracranial pressure and uncal herniation. A basilar skull fracture may damage the nerve as it courses along the base of the middle cranial fossa and enters the cavernous sinus. Traumatic cavernous sinus thrombosis can cause third nerve palsy alone or in combination with a palsy of cranial nerves IV and VI. The orbital apex and superior orbital fissures syndromes can be the result of penetrating trauma to the orbit or diffuse orbital fractures. The nature of traumatic injury assures that most, but not all, cases have pupillary involvement.260 Patients with cranial nerve deficits and a history of trauma usually have had neuroimaging by the time they arrive for neuro-ophthalmologic consultation. Neuroimaging is usually warranted in traumatic third nerve palsy to rule out the possibility of a subdural hemorrhage87,598 or an occult intracranial tumor that can compress the oculomotor nerve, predisposing it to injury following relatively minor head trauma.561,586

thies in acute bacterial meningitis are often multiple372 and can sometimes involve all ocular motor nerves bilaterally.40 Oculomotor palsy is much less common than abducens palsy, but both occur with sufficient frequency to warrant vigilance.214 The ocular motor nerve palsies that occur in children with acute bacterial meningitis usually result from encasement of the nerves by purulent exudate in the subarachnoid space.339 Rarely, ocular motor nerve injury in meningitis can result from elevated intracranial pressure or septic cavernous sinus thrombosis.372 Acute bacterial meningitis in young children produces nonspecific symptoms and signs, including fever, irritability, drowsiness, failure to feed, and vomiting. Older children present with fever, severe headache, and nuchal rigidity. Other neuro-ophthalmologic complications include cortical blindness and optic atrophy (from the direct effects of the inflammatory process on the optic nerves and chiasm.)369

Meningitis

Ophthalmoplegic Migraine

Cranial nerve palsies are more likely to develop in forms of purulent meningitis and in forms that involve the skull base. Due to their basilar involvement, tuberculous, sarcoid, carcinomatous, and fungal meningitis are most likely to injure the cranial nerves, but these are uncommon. Due to its common occurrence, acute bacterial meningitis accounts for most cases of postinflammatory ocular motor nerve palsy. The possibility of acute bacterial meningitis should be considered when the child with one or more acute ocular motor nerve palsies is febrile or lethargic. Cranial neuropa-

The recent revision of the International Headache Classi fication has reclassified ophthalmoplegic migraine from a subtype of migraine to the category of neuralgia.223 Oculomotor palsy associated with migraine headache was the least common of the migraine syndromes (0.3% of children attending an outpatient neurology practice).338 The current definition of ophthalmoplegic migraine requires that at least two attacks fulfill the criterion for migraine headache, migraine-like headaches are accompanied or followed within 4 days of onset by paresis of one or more of the third, fourth, or sixth cranial

Oculomotor Nerve Palsy

nerves and parasellar, orbital fissure, and posterior fossa lesions have been ruled out by appropriate investigation.224 Most migraine patients with this finding are in the pediatric age group.176 Unlike other forms of migraine, ophthalmoplegic migraine shows no female predominance (probably because it is primarily a disorder of childhood, and the incidence of migraine is about the same in both sexes prior to puberty).122 Most children with ophthalmoplegic migraine experience their first attack in the first decade of life, and several reports have documented its occurrence in infancy.372 It is rare for ophthalmoplegic migraine to recur after age 30. A severe ipsilateral hemicranial headache of the crescendo type usually precedes the attack. The headache may abate hours or days before the onset of ophthalmoplegia. The third nerve is the most frequently involved ocular motor nerve, followed in frequency by the sixth nerve and the fourth nerve.240 Ophthalmoplegic migraine usually involves all branches of the oculomotor nerve, although a case with involvement confined to the superior division has recently been documented.266 The pupil is usually involved to some degree.176 The ophthalmoplegia usually lasts 3 or 4 days and resolves without any permanent extraocular muscle paralysis.240 However, repeated or prolonged episodes may last as long as 1 month and, eventually, some degree of permanent ophthalmoplegia and/or pupillary mydriasis may develop.92 Some patients develop transient or permanent oculomotor synkinesis.25,327 Nigerians with hemoglobin AS, seem to have an especially high incidence of ophthalmoplegic migraine, suggesting that a serum hemoglobin electrophoresis should be obtained in black children, who are suspected to have ophthalmoplegic migraine.419 Ophthalmoplegic migraine remains a diagnosis of exclusion. Other life-threatening causes of acute painful third nerve

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palsy must be ruled out by neuroimaging, arteriography, or both.585 The differential diagnosis of ophthalmoplegic migraine includes aneurysm, pituitary apoplexy, diabetic ophthalmoplegia, and Tolosa–Hunt syndrome.240 Findings that should call the diagnosis of ophthalmoplegic migraine into question include alteration of consciousness, absence of a history typical for migraine, onset after age 20, signs and symptoms of subarachnoid hemorrhage, and severe or persistent headache with total ophthalmoplegia.240 Older theories regarding etiology of ophthalmoplegic migraine invoked either (1) compression of the oculomotor nerve by a dilated intracavernous portion of the carotid artery585,600 or (2) an ischemic mechanism involving the artery supplying the vasonervosum of the ocular motor nerve. Walsh and O’Doherty585 suggested that the wall of the intracavernous carotid artery becomes thickened and edematous, causing compression of one or more of the adjacent ocular motor nerves. This mechanism is consistent with the finding that intravenous norepinephrine, which has the capacity to constrict large and small arteries and to reduce edema, has produced resolution of the palsy in several patients. When angiography has been performed during an attack of ophthalmoplegic migraine, changes in the caliber of the intracavernous carotid artery have been observed only occasionally.568 Some have argued that the partial pupillary sparing in many children with ophthalmoplegic migraine is more consistent with an ischemic than a compressive mechanism.568 Numerous neuroimaging studies have now demonstrated gadolinium enhancement of the perimesencephalic oculomotor nerve during an attack of ophthalmoplegic migraine support an ischemic mechanism (Fig. 6.7).2,329,345,405,439,532,605 Some investigators believe MRI findings should be required

Fig. 6.7 Ophthalmoplegic migraine causing right oculomotor nerve palsy. (a) Axial and (b) coronal MR imaging shows selective enhancement of proximal cisternal portion of right oculomotor nerve (courtesy of Kathleen Digre, M.D.)

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for diagnosis.429 In one study,345 contrast-enhanced MR imaging demonstrated focal thickening at the exit of the nerve in the interpeduncular cistern in five of six patients. The enhancement and thickening of the cisternal segment of the oculomotor nerve decreases as the episode resolves.48,405,439 Of cases demonstrating abnormal MR imaging, most show improved but persistent changes on repeat imaging.48 Mark et al345 hypothesized that ophthalmoplegic migraine may result from a benign viral infection (similar to Bell’s palsy), while others attribute it to a recurrent demyelinating neuropathy.316 Nazir et al395 reported a 11-month-old infant with recurrent parainfectious oculomotor palsy and enhancement of the proximal cisternal portion of the oculomotor nerve. The enhancing, thickened lesion may represent an inflammatory process similar to Tolosa–Hunt syndrome, occurring in the interpeduncular segment of the oculomotor nerve.406 The long potential duration of MRI changes and the scarcity of clinical episodes make feasible its incident discovery once the migraine attack has become a remote memory.439 In this context, however, it should be remembered that ocular motor schwannoma can rarely mimic ophthalmoplegic migraine with MR imaging showing an enhancing nodular lesion of the cisternal oculomotor nerve, but with persistence after resolution of the episode.54,403 Murakami et al392 described an 11-year-old girl with pathologically confirmed oculomotor schwannoma who had been suffering from symptoms that mimicked ophthalmoplegic migraines, and whose “migraine” attacks decreased following surgical excision of the tumor. Enhanced MR imaging is also useful in distinguishing ophthalmoplegic migraine from Tolosa–Hunt syndrome in children.340 While persistent thickening of the oculomotor nerve on MR imaging supports the notion of an inflammatory mechanism with headache as a secondary and later feature of the condition,356 it is difficult to see how an inflammatory or demyelinating lesion restricted to oculomotor or abducens nerve could cause coincident severe headache, photophobia, nausea, and other visual disturbances.356 Despite its reclassification, migraine prophylactic medications such as beta blockers and calcium channel blockers continue to be used.329 Systemic steroids are also used with mixed results.329,406

Recurrent Isolated Third Nerve Palsy Recurrent isolated third cranial nerve palsy has been described as a rare phenomenon in children.88,153,166 In such cases, the third nerve palsy resolves without deficit followed by an interval of normal ocular motility and one or more sub-

6 Ocular Motor Nerve Palsies in Children

sequent recurrences. It has been suggested that this condition represents a variant of ophthalmoplegic migraine because symptoms of migraine become apparent later on in some affected children.153,419

Cryptogenic Third Nerve Palsy in Children A number of children have been reported with acquired oculomotor palsies without evident cause, despite multiple neuroradiologic studies.481 Some children may develop an isolated, unremitting, painless, oculomotor palsy with pupillary involvement in the absence of any demonstrable systemic, neurologic, or neuroimaging abnormalities. Mizen et al380 described two such children who had normal cerebral arteriography and developed no additional signs or symptoms over more than 2 years of followup. We have managed similar children. In such cases, neuroimaging studies should be repeated at appropriate intervals before the designation of cryptogenic is applied, because some children may harbor intracranial tumors too small to detect on initial imaging studies.1 Nevertheless, it is important to recognize that acquired isolated oculomotor palsies in children are not always a harbinger of serious disease.

Vascular Third Nerve Palsy in Children Cerebral aneurysms are rare but well recognized in children, and posterior communicating artery aneurysms are particularly rare.64,181 When they do occur, they almost always present with subarachnoid hemorrhage. Gabianelli et al181 have recommended that arteriography, not be obtained routinely in children under 10 years of age with acquired oculomotor palsies unless signs and symptoms of subarachnoid hemorrhage are present. There have now been several documented cases of acquired oculomotor palsy in children with posterior communicating artery aneurysms.64,181,334,357,368,543,601 Even in infants, acquired isolated third nerve palsies can be the initial manifestation of an intracranial cerebrovascular malformation.543 Tamhankar et al543 described one infant with an acquired isolated third nerve palsies that were attributable to a partially thrombosed fusiform aneurysm of the internal carotid artery in one case, and another attributable to an arteriovenous fistula arising from the middle cerebral artery. DiMario and Rorke145 reported a 10-month-old child, who developed an isolated adduction deficit as a manifestation of transient third nerve palsy 7 days before fatal rupture of a congenital distal basilar artery aneurysm.

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Inflammatory Causes of Third Nerve Palsies in Children

Other Rare Causes of Third Nerve Palsy in Children

The association of pediatric third nerve palsy with inflammatory disease is now well established. It may occur as a painless autoimmune mononeuropathy,189 as part of the spectrum of ophthalmoplegic migraine, or following antecedent viral infection in the evolution to diffuse ophthalmoplegia in the setting of Miller Fisher syndrome.616 Some of these cases may represent postviral oculomotor palsy (see below).

Oculomotor palsy occasionally develops in children with collagen vascular diseases. Kirkali et al282 described oculomotor palsies in two children with polyarteritis nodosa that resolved following treatment with cyclophosphamide. Transient unilateral oculomotor nerve palsy has been reported following endoscopic third ventriculostomy,430 and transient unilateral and bilateral oculomotor palsy has been reported in a child with pseudotumor cerebri.98,547 Third and sixth nerve palsies have been reported in patients with pediatric tubercular meningitis.13 One transient oculomotor palsy developed in conjunction with benign recurrent sixth nerve palsy.226

Neoplastic Causes of Third Nerve Palsy in Children A variety of neoplasms have been reported to cause childhood oculomotor palsy, involving the nerve along its subarachnoid, intracavernous, or orbital portion.21,38,264,271,324,325, 360,404,471,496,542,607

Causative tumors have included astrocytoma, sarcoma, lymphoma, meningioma, schwannoma, neuroepithelial cyst, pituitary adenoma, craniopharyngioma, epidermoid, dermoid cyst, arachnoid cyst, endodermal cyst, malignant peripheral nerve sheath tumor, teratoid tumor, and cavernous hemangioma.481 Among acquired pupil-involving oculomotor nerve palsies in children, 10% are estimated to be due to neoplasm.368,398 Schwannomas are now detected more commonly using high-resolution MR imaging in children with oculomotor nerve palsies using serial gadolinium-enhanced 1–2 mm thin-section MR imaging with coronal views.398,403 Norman et al described five children with isolated monocular oculomotor palsy originally believed to be idiopathic but subsequently documented to be secondary to a presumed neuroma (schwannoma) of the intracranial oculomotor nerve distal to the mesencephalon.403 In these patients, the oculomotor findings progressed, and no signs of aberrant regeneration were noted. Less commonly, neurofibromas in the cavernous sinus,97 and malignant peripheral nerve sheath tumors of the oculomotor nerve have been found.297 Neural grafting procedures have been used to partially restore oculomotor function.178,344

Differential Diagnosis The differential diagnosis of third nerve palsy in childhood is summarized in Table 6.2. MR imaging has become an informative part of the routine diagnostic evaluation in pediatric oculomotor palsy. High-resolution intracranial and orbital MR imaging can demonstrate absence or hypoplasia of the involved oculomotor nerve, as well as hypoplasia of the extraocular muscles and correlative torsion causing a change in orbital extraocular muscle position in the coronal plane.136,606 In many cases, high-resolution MR imaging shows a reduction of volume and contractility of the involved extraocular muscles.262 The diagnosis of myasthenia gravis should be considered in the child with a painless, pupil-sparing third nerve palsy and no aberrant regeneration (especially when there is prominent inferior rectus or medial rectus weakness).47 Aberrant regeneration is commonly seen in congenital or acquired third nerve palsies but is never a feature of myasthenia gravis. The improvement of ptosis immediately upon awakening and a history of fluctuating or ophthalmologic or systemic symptoms (breathing difficulty, choking, drooling, facial palsy) warrant a prostigmine test and an antiacetylcholine receptor antibody test. Congenital fibrosis of the extraocular muscles (CFEOM) is an autosomal dominant disorder characterized by diffuse Table 6.2 Differential diagnostic considerations of third nerve palsy in childhood

Postviral Third Nerve Palsy Postviral oculomotor palsy have been reported in children following measles90 and norovirus infection.307

Myasthenia gravis Blowout fracture Congenital fibrosis syndrome Internuclear ophthalmoplegia Duane syndrome (Type II)

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replacement of orbital striated muscle by fibrous tissue. Affected children classically present with bilateral upper eyelid ptosis, diffuse ophthalmoplegia, and fixed downgaze with esotropia or exotropia. In some children, the ocular abnormalities are unilateral. The levator is the most common extraocular muscle involved, followed by the inferior rectus and the lateral rectus muscles. Children with CFEOM3 may therefore present with ptosis, exotropia, and a hypotropia from birth that may simulate pupil-sparing congenital third nerve palsy. Aberrant regeneration is now recognized to be a common feature in children with congenital fibrosis syndrome.80 The diagnosis of congenital fibrosis syndrome is suspected by its hereditary character and confirmed by a markedly positive forced duction test and often with genetic testing. As this condition is now classified as a congenital cranial dysinnervation syndrome,553 its nosological distinction with congenital third nerve palsy has blurred. The distinction between a third nerve palsy and an orbital blowout fracture in the child with head and/or orbital trauma is especially challenging.599 A blowout fracture may produce limited supraduction, infraduction, ptosis, and pupillary dilation (resulting from paralysis of the parasympathetic pupillomotor fibers from injury to the nerve to the inferior oblique muscle or from traumatic mydriasis). In the acute stage of injury, a forced duction test may not reliably distinguish blowout fracture from third nerve palsy, because a positive forced duction test can result from hemorrhage or edema in and around the fibrous septae that connect the inferior rectus and inferior oblique muscle to the periorbita. Furthermore, it is not uncommon for a blowout fracture and a third nerve palsy to coexist.599 Coexistent hemorrhage, edema, soft tissue entrapment, and surgical intervention may mask these associated palsies.418 Occasionally, orbital imaging demonstrates clinically unsuspected blowout fractures in patients with other forms of complicated strabismus. Because the orbital bones are more flexible in children, pediatric orbital fractures are often of the trapdoor type, (a fracture in which the orbital bones “snap back” causing entrapment of orbital tissues), which requires earlier surgical intervention. In these smaller fractures, soft tissue entrapment is easily overlooked on computed tomography (CT) and is better judged clinically.4 These linear nondisplaced blowout fractures may cause restriction without producing visible signs of entrapment on CT scanning, so it is important to suspect orbital fracture with muscle entrapment in any child with a history of even minor trauma and vertical gaze restriction, regardless of the radiologist’s interpretation of the CT scan. In this setting, careful review of the CT images with direct coronal (not coronal reconstructions from direct axial images) is warranted.124 Neuroimaging studies suggest that the inferior oblique muscle branch of the oculomotor nerve can become incarcerated in a trapdoor fracture causing an inferior oblique muscle paresis.261

6 Ocular Motor Nerve Palsies in Children

One special caveat applies to the debate about whether and when to treat children with this condition. Orbital blowout fractures in children can occasionally stimulate the oculodigital reflex. A patient experiencing the triad of bradycardia, nausea, and syncope following orbital injury should immediately undergo CT with coronal sections. If a trapdoor fracture with incarceration of soft tissue is identified, the fracture should be repaired the same day.519 Internuclear ophthalmoplegia is rare in children.282 It may be unilateral or bilateral and is characterized by an isolated adduction deficit with abducting nystagmus in the contralateral eye. The absence of strabismus in primary gaze distinguishes internuclear ophthalmoplegia from isolated medial rectus involvement secondary to partial third nerve palsy. Patients with type II Duane syndrome can have an isolated adduction deficit that may mimic a third nerve palsy. Duane syndrome can usually be distinguished from third nerve palsy by its normal vertical ductions and by the retraction of the globe during attempted adduction (although rare cases of electromyographically documented type II Duane syndrome show no retraction).201 Graves orbitopathy has been reported in children but is exceedingly rare.571

Management Amblyopia The ability of children to avoid diplopia and blurred visual images by suppressing one eye renders them prone to develop amblyopia from a third nerve palsy. The main mechanism of amblyopia is ocular misalignment, but occlusion by the ptotic lid and defocusing of the image by loss of accommodative tone also contribute.14,15 Elston and Timms158 have shown that children who recover from a third nerve palsy prior to the age of 6 weeks do not develop amblyopia, indicating that there may be a latent period of visual development prior to the onset of the sensitive period. Children beyond the age of 4 years are more likely to experience diplopia and less likely to develop amblyopia. In the remaining sensitive period, the risk of amblyopia must be borne in mind by the physician. Because these children have a period of normal visual experience, their response to amblyopia therapy, both in the recovery of vision and the redevelopment of stereopsis, is usually good. Ing et al243 found that amblyopia, although common in children with oculomotor palsy, usually responds readily to treatment. Part-time patching is recommended while conducting clinical investigations or awaiting spontaneous recovery, provided the lid is at a position or level that allows the child to use the eye. If recovery is incomplete, then amblyopia therapy must be continued while awaiting surgical correction.

Oculomotor Nerve Palsy

Ocular Alignment Of the three ocular motor nerve palsies, the treatment of third nerve palsy presents the most challenging problem to the strabismus surgeon. Oculomotor palsy is associated with poor visual and sensorimotor outcomes in children younger than 8 years of age.390 Young children with posttraumatic and postneoplastic oculomotor nerve injuries demonstrated the worst ophthalmologic outcomes.390 The only thoroughly satisfactory outcome occurs in children who have enough spontaneous recovery of neural function to regain sensory and motor fusion in all fields of gaze. Those who do not recover spontaneously are left with a complex disorder of static and dynamic ocular motor disturbances in both the horizontal and vertical planes. Multiple strabismus procedures are often necessary to achieve ocular alignment. Surgery rarely results in establishment or restoration of measurable binocular function.497 It is usually impossible to align the eyes in all positions of gaze. The range of outcomes includes diplopia in all gaze positions; single vision with a compensatory head posture but not with a primary head posture; single binocular vision in primary gaze with a normal head posture but diplopia outside relatively narrow range of eye movements; and a more extensive range of single binocular vision with a normal head position but diplopia on extremes of gaze.195 The goals of surgery in treating a third nerve palsy should be (a) to allow single binocular vision in the primary position, (2) to extend single binocular vision into reading position, (3) to maximize the number of degrees around a primary position in which single binocular vision can be maintained, and (4) to normalize the appearance of the affected eye. To achieve these goals in children with third nerve palsy, attention has to be given to both horizontal and vertical misalignment and to the lid position. In addition to the risk of creating new ductional deficits with large recess–resect techniques, the surgery may cause anterior segment ischemia that can occur when simultaneously operating on more than two rectus muscles.488,490 In some patients, postoperative intorsion (resulting from associated paresis of the inferior oblique muscle) may hinder fusion and necessitate superior oblique weakening.53 If there is some residual medial rectus function and only moderate horizontal misalignment (15–30 diopters), a recession of the lateral rectus muscle and a resection of the medial rectus muscle may be the simplest and most effective procedure. Alternatively, a very large recession of the contralateral rectus muscle will symmetrize ductions and improve postoperative alignment in some cases. If there is no power of adduction remaining in a patient with a third nerve palsy, a maximum recess–resect procedure may initially bring the eye to primary position, but the eye will gradually become exotropic as the lateral rectus muscle undergoes chronic contraction and the resected medial rectus muscle

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elongates.195 In this setting, the superior oblique tendon can be severed nasally and its proximal portion transposed to the insertion of medial rectus muscle to provide a tonic elevation and adduction force that mechanically holds the eye in primary position.195,499 This and other similar fixation procedures527 are performed in combination with a large lateral rectus recession.610 This procedure does little to restore adduction but simply provides an effective mechanical force to prevent recurrent exotropia.364 Some have achieved satisfactory results with primary extirpation of the lateral rectus muscle alone in children who have third nerve palsies and no medial rectus function. Similar success has been reported with lateral rectus muscle disinsertion and reattachment to the lateral orbital wall.383,564 The latter procedure has the advantage of being potentially reversible. If exotropia is accompanied by a mild (10 diopter or less) vertical misalignment in primary position, the recess–resect procedure can be combined with a vertical transposition of the horizontal rectus muscles in the direction that one wishes to move the eye.85 For example, in a patient with a third nerve palsy with partial recovery resulting in a 20 diopter exotropia and an 8 diopter hypertropia, the lateral rectus muscle could be recessed and the medial rectus muscle resected and both transposed a full tendon width inferiorly in an attempt to correct both the vertical and horizontal misalignment. It may ultimately be necessary to do further surgery on the vertical rectus muscles in this situation, as would certainly be necessary with larger vertical deviations; however, this should be delayed to allow time for anterior segment circulation to be reestablished. Vertical rectus muscle transposition procedures can also be employed in patients with third nerve palsy and minimal adduction; however, they are less predictable because the vertical rectus muscles are usually weak, limiting their usefulness as candidates for transposition to the medial rectus site. If the lateral rectus muscle has been weakened and transposition of the inferior and superior rectus muscles is contemplated, then it may more safely be done by the technique described by McKeown et al353 to maintain anterior segment perfusion. The use of botulinum in the treatment of third nerve palsy is limited to weakening the lateral or inferior rectus muscle. As in the treatment of sixth nerve palsy (discussed later), oculinum injection may be used in an acute setting to prevent antagonist contracture, or in the setting of a residual postoperative deviation, to try to produce a compensatory contracture of the paretic muscle. In comparing the efficacy of surgical strategies to treat strabismus resulting from ocular motor palsies, it is important to examine all available objective criteria, including (1) residual deviation in primary position, (2) residual face turn, (3) postoperative ductions, and (4) field of single binocular vision (which allows for quantitative comparison of surgical outcomes).470

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Ptosis In planning the restoration of function in a patient with an oculomotor palsy, treatment of ptosis is often particularly problematic. A ptotic lid prevents the patient from having diplopia, and raising it may cause symptoms. However, if any degree of normal binocular vision is to be attained in an affected child, a severe ptosis must be corrected. It is generally preferred to defer ptosis correction until after the eye has been maximally realigned. The degree of residual levator function largely dictates the ptosis procedure of choice. Patients with minimal or no levator function require a frontalis suspension procedure. Before a frontalis suspension is performed, the patient should be examined for the presence of Bell’s phenomenon and for a normal corneal reflex. If either of these is absent, ptosis surgery may be complicated by postoperative corneal drying and subsequent ulceration. The use of a Silastic sling (which is elastic and allows the lids to close) to produce mild lid elevation, together with frequently applied topical lubricant, minimizes this risk. Treating ptosis surgically in a child with horizontal-gaze lid dyskinesis presents a unique opportunity to surgically correct ptosis by exploiting the process of aberrant regeneration. If the lid of the affected eye elevates during attempted adduction of that eye, then a recess–resect procedure moving the contralateral (unaffected eye) into adduction will create a fixation duress. This, in turn, will necessitate increased innervational tone to maintain fixation with the nonparetic eye in

6 Ocular Motor Nerve Palsies in Children

primary gaze, which will recruit the paretic medial rectus muscle and thereby elevate the ptotic eyelid.195

Trochlear Nerve Palsy Trochlear nerve palsy is the most common isolated cranial nerve palsy and the most common cause of acquired vertical diplopia (Fig. 6.8).369 The great majority of superior oblique palsies are traumatic or congenital in origin.229,576 A vas cular, neoplastic, or neurologic etiology is rarely found.572 Amblyopia is rare in isolated acquired trochlear nerve palsy because children can fuse with a compensatory head tilt. The finding of associated amblyopia suggests a congenital origin.

Clinical Anatomy The trochlear nerve is the smallest and longest of the ocular motor nerves.554 It is the only cranial nerve to emerge on the dorsal surface of the brainstem and the only one to cross entirely. The trochlear nucleus lies caudal to the oculomotor nuclear complex, dorsal to the medial longitudinal fasciculus, and just ventrolateral to the cerebral aqueduct at the level of the inferior colliculus.66 The nucleus gives rise to the nerve fascicle that courses posteroinferiorly around the aqueduct to

Fig. 6.8 Clinical algorithm for evaluation of vertical diplopia in childhood

Trochlear Nerve Palsy

decussate in the anterior medullary velum (the roof of the aqueduct) just caudal to the inferior colliculus. It emerges for the dorsal surface of the lower midbrain as one or more rootlets that leave the midbrain contralateral to their nucleus of origin.66 The cisternal segment of the trochlear nerve extends anteriorly over the lateral surface of the brainstem. It lies adjacent to the free edge of the tentorium cerebellum and passes between the posterior cerebral and the superior cerebellar arteries. Because of its small caliber and hidden location under the tentorial edge, the cisternal portion of the nerve can be easily injured during neurosurgical procedures to treat tumors or aneurysms when the surgery involves manipulation of the tentorial edge.554 It then travels along the free edge of the tentorium to pierce the dura along the lateral aspect of the clivus to enter the cavernous sinus. The trochlear nerve lies just inferior to the oculomotor nerve in the lateral wall of the cavernous sinus. It enters the orbit through the superior orbital fissure but remains outside the annulus of Zinn along with the lacrimal and frontal nerves. In the orbit, it runs anteriorly and medially beneath the superior periorbita to cross over the superior rectus muscle as a single fascicle just before it enters into the superior nasal portion of the superior oblique muscle.138

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test shows an increase in the vertical deviation on head tilt toward the side of the affected superior oblique muscle and a decrease in the vertical deviation when tilting away from the affected side. Orbital MR imaging may show the superior oblique tendon to be present, hypoplastic (in congenital cases), atrophic (in acquired cases), or absent. MR imaging and tendon anomaly associated with congenital trochlear nerve palsy (Fig. 6.9).96,482,484 Sato et al found a greater reduction in superior oblique muscle volume in congenital (65.8% reduction) than in acquired cases (45.3% reduction),484 and found an absence of the superior oblique tendon on MR imaging to be predictive of a larger primary position vertical deviation.482 However, Chan and Demer96 found the clinical findings to be indistinguishable in children with present and absent tendons. Kono and Demer295 found the superior oblique muscle contralateral to the palsied eye to be hypertrophied relative to normal controls. Kushner313 has attributed this phenomenon to the innervational effects of a chronic head tilt toward the side of the normal eye, which provides tonic innervation to the normal superior oblique muscle. Enlargement and increased contractility of the contralateral inferior rectus muscle have also been described.255 However, MR imaging shows no evidence of inferior oblique muscle hypertrophy.295 Even in acute cases of trochlear nerve palsy, when there has been insufficient time for an inferior oblique contracture

Head Posture Ambulatory children who develop acute fourth nerve palsies are frequently noted by their parents or teachers to have adopted a head tilt (which is almost always to the side opposite the palsied eye). Kraft et al299 found an incidence of compensatory head posture in 71.2% of 139 patients with superior oblique paresis. Similarly, children with congenital trochlear nerve palsy often tilt their heads, but because they do it from infancy, it is more readily overlooked. In some infants, the head tilt is heralded by a body tilt that begins within the first month of life, indicating that the baby learns to use gravity to passively tilt the head in a compensatory fashion.79 Some turn their heads away from the side of the palsied muscle to eliminate an incomitant hypertropia, while others maintain a combined head tilt and head turn. Some children with congenital or acquired trochlear nerve palsy are brought to medical attention because of vertical diplopia associated with a hypertropia of the affected eye. On testing of versions, the hypertropia is found to decrease in horizontal gaze toward the affected eye and to increase in horizontal gaze away from the affected eye due to the increasing vertical action of the oblique muscles in adduction. The primary position hypertropia is often greater at distance than near and increases more at near when a prism adaptation test is performed to correct the vertical deviation.411 The three-step

Fig. 6.9 Congenital left superior oblique palsy. Coronal MR image shows selective hypoplasia of left superior oblique muscle. With permission from Brodsky and Karlsson79

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to develop, version testing often shows overaction of the antagonist inferior oblique muscle with little or no underaction of the paretic superior oblique muscle. Kushner313 has attributed the inferior oblique overaction associated with unilateral trochlear nerve palsy to a combination of strengthening and contracture. As the trochlear nerve palsy becomes chronic, spread of comitance develops, which leads to vertical measurements that are similar in abduction and adduction. Spread of comitance in long-standing trochlear nerve palsy can result from contracture of the superior rectus on the affected side (secondary to a chronic hyperdeviation) or from a contracture of the contralateral inferior rectus muscle (secondary to a contralateral hypotropia in a patient who habitually fixates with the paretic eye). In children who prefer fixation with the paretic eye, overaction of the antagonist inferior oblique muscle initially produces a “fixation duress” in gaze opposite the palsy, requiring excess downward innervation to fixate in horizontal gaze. This excess innervation may produce the appearance of a paretic superior rectus muscle on the contralateral side when versions are tested. When ductions are tested, however, movement of the eye in the field of action of the underacting superior rectus muscle is found to be normal. The appearance of superior rectus paresis contralateral to a trochlear nerve palsy when the paretic eye is used for fixation has been termed inhibitional palsy of the contralateral antagonist.572 Over time, the fixation duress produced by fixation with the paretic eye results in an inferior rectus contracture in the opposite eye, causing hypotropia with restricted elevation, and sometimes enophthalmos (the fallen eye syndrome).143 Such patients may be mistakenly thought to have a blowout fracture or a double elevator palsy in the contralateral eye. However, neuroimaging shows atrophy or hypoplasia of the paretic superior oblique muscle. These patients present a confusing diagnostic picture because the inferior rectus contracture may cause a hyperdeviation that is greater in upgaze than downgaze. For reasons that are poorly understood, subjective and objective fundus torsion may be localized to the nonparetic eye (perhaps attributable in part to the inferior rectus contracture). Once the appropriate ductions and versions are measured and the three-step test performed, the correct paretic muscles can usually be identified. Patients with acquired trochlear nerve palsy who habitually fixate with the paretic eye often report subjective excyclotropia of the nonparetic eye.414 This phenomenon results from a sensory adaptation to the cyclodeviation by means of a reordering of the spatial response of retinal elements along new meridians.414

Three-Step Test The three-step test is a diagnostic protocol originating from the work of Bielschowsky and popularized by Parks.426 The technique has several variations,217,228,232 but all address the

6 Ocular Motor Nerve Palsies in Children

same three questions: (1) Is there a right or left hypertropia in primary position? (2) Does the deviation increase in right gaze or left gaze? (3) Does it increase with head tilt to the right or to the left? With this test, an isolated paretic cyclovertical muscle can be identified in most cases. Analysis of the three-step test involves sequential elimination of possible weak muscles responsible for the vertical misalignment until only one choice remains. For example, a patient with a right hypertropia could have weakness of the depressors of the right eye (right inferior rectus or superior oblique muscles) or the elevators of the left eye (left superior rectus or inferior oblique muscles). If the deviation is greater in left gaze and less in right gaze, then the right superior oblique and left superior rectus muscles are the possible paretic muscles because these muscles are responsible for depressing the right eye in left gaze and elevating the left eye in left gaze. If, on head tilt testing, the deviation increases in right head tilt and decreases in left tilt, then the right superior oblique is implicated since the right superior oblique and superior rectus muscles work in concert to incycloduct the right eye during right head tilting. The depression and elevation action of these two muscles is normally offsetting, maintaining the vertical position of the eye. When the superior oblique is weak, the elevating action of the superior rectus muscle is unopposed, and the eye further elevates when the incycloduction is stimulated by right head tilting. The left superior rectus muscle is not innervated in excycloduction of the left eye (the torsional movement stimulated by right head tilt) and, therefore, is eliminated from consideration in the situation of increased vertical deviation during right head tilting. On the basis of the work of Wong and Sharpe602 Gamio has proposed that some patients with paretic strabismus can show changes in horizontal alignment with head tilt to either side.182 The general mechanism that underlies the Bielschowsky Head Tilt test, first proposed by Nagel394 in 1871, and later by Hofmann and Bielschowsky233 in 1900, is still generally accepted.489,577 Reports of central vestibular dysfunction as a putative cause of head tilt514 probably represent patients with skew deviations and ocular tilt reactions who were thought to have unilateral trochlear nerve palsy. However, Wong et al have demonstrated both deficits and compensatory adaptations in the vestibulo-ocular reflex in patients with trochlear nerve palsy.603 Kolling et al292 investigated the effects of Marlow occlusion in patients with unilateral trochlear nerve palsy. They found a shift to horizontal incomitance in their group who started out with horizontally-comitant deviations but little change after prolonged occlusion of the involved eye in their group of 18 patients who started with horizontally incomitant hyperdeviations. They concluded that Marlow occlusion may be necessary to uncover the real vertical deviations that characterize unilateral trochlear nerve palsy and that the post-occlusion pattern of hyperdeviation in different fields of gaze should be used to direct surgical management.

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A positive three-step test does not necessarily implicate an isolated vertical muscle palsy as the causative factor. Kushner309 reviewed a group of patients with positive threestep tests who had multiple muscle paresis, dissociated vertical deviation, previous vertical muscle surgery, skew deviation, myasthenia gravis, and small nonparalytic vertical deviations associated with horizontal strabismus. He cautioned that the results of the three-step test must be interpreted in the context of the clinical history and associated neuro-ophthalmologic findings. Absence of tone in the superior oblique muscle, allows an eye to rotate into an extorted position. Because the amount of torsion in unilateral trochlear nerve palsy (about 5°) falls within a child’s sensory cyclofusional range, most (77%) of the patients with acquired trochlear nerve palsy do not complain of image tilt under normal seeing conditions.576 Furthermore, such children can fuse when a vertical prism is placed before one eye to neutralize the deviation. Subjective torsion is usually measured with the Double Maddox Rod test. Objective torsion is generally evaluated by observing the horizontal position of the optic disc relative to the macula, using indirect ophthalmoscopy (in the absence of torsion, the macula should be aligned horizontally with the lower third of the optic disc). In addition to isolated oblique muscle paresis, objective torsion may also be seen in children with primary oblique muscle overaction. The commonly used term “macular torsion” is incorrect, because rotation of the globe in primary gaze occurs around a sagittal axis that goes through the macula. Confirmation of objective torsion is especially important in preverbal children.56 Patients with trochlear nerve palsy show persistent extorsion in the paretic eye on head tilt to either side,209,314 indicating that the compensatory head tilt serves to neutralize the vertical and not the torsional deviation.314 Discrepancies between subjective and objective tests are common in children with congenital superior oblique palsies (who may deny subjective torsion despite objective torsion)206,415 and in children who habitually fixate with the paretic eye (who may have objective torsion in the fixating eye but subjective torsion in the opposite eye).415 Although most unilateral superior oblique palsies are isolated lesions, a careful search should be made for localizing signs.66 For example, a lesion that affects the dorsal midbrain might cause upward gaze palsy and other signs of dorsal midbrain syndrome.66 An intramedullary lesion involving the fascicular portion of the fourth nerve may also involve the descending sympathetic tract to produce a contralateral Horner syndrome or the medial longitudinal fasciculus to produce an internuclear ophthalmoplegia.66,270 A lesion that affects the trochlear nucleus or fascicle (most commonly a trochlear nerve schwannoma) or the adjacent brachium of the superior colliculus produces a trochlear nerve palsy with a contralateral afferent pupillary defect but no associated visual field defect.156 Associated ocular motor nerve palsies suggest an intracavernous or orbital apical lesion. Kushner has noted that the results

of Bielschowsky Head Tilt testing in trochlear nerve palsy cannot be explained simply by the classic model of altered otolithic input to the four vertical rectus muscles. For example, the Bielschowsky Head Tilt test difference typically decreases in patients with unilateral superior oblique muscle palsy after inferior oblique muscle weakening. Also, inferior oblique overaction increases gradually over months to years, and the size of the Bielschowsky Head Tilt test difference gradually increases.197 Gräf et al197 speculated that there may be an adaptive mechanism that causes the size of the head tilt to gradually increase over time by amplification of the otolith reflex in response to vertical fusional vergence.412 Eye movement recordings during dynamic tilt, show a circular rotational trajectory in the affected eye, corresponding to a nasal deviation of the rotation axis toward the line of sight.588 In long-lasting trochlear nerve palsy, the extorsion decreases while the hypertropia and head tilt phenomenon increase,291 possibly reflecting a superimposed ipsilateral superior rectus contracture. Kommerell and Klein294 proposed that gain modulation of the otolith reflex could be caused by the chronic head tilt. Trochlear nerve palsy leads to kinematic aberrations of both the paretic and the unaffected eye. During dynamic head roll, the rotation axis of the covered paretic or unaffected eye deviates inward, while the rotation axis of the viewing paretic or unaffected eye aligns with the line of sight.588 During downward saccades, the trajectories of both eyes curve towards the unaffected side529; these curvatures increase when the head is rolled to the affected side and the gaze directed to the unaffected side.533 Hence, during both vestibular evoked and saccadic ocular movements, the unaffected eye shows similar kinematic aberrations as the paretic eye. While aberrations of the paretic eye can be explained by decreased force of the superior oblique muscle, aberrations of the unaffected eye may be due to increased force parallel to the paretic superior oblique muscle in the unaffected eye, in accordance with Hering’s law. Three-dimensional eye positions expressed as rotation vectors normally lie in a plane, called Listing’s plane. Listing’s plane in eyes with acquired trochlear nerve palsy is rotated temporally, which reflects the fact that vertical eye movements are associated with true torsion (up-extorsion, down-intorsion).534 The orientation of Listing’s plane in the presence of “congenital trochlear nerve palsy,” however, is not different from normal eyes. Hence, similar to anatomical studies, kinematical analyses of 3D eye positions suggest that congenital trochlear nerve palsy eventuates in a different set of ocular rotations.

Bilateral Trochlear Nerve Palsy The incidence of bilateral paresis in a series of trochlear nerve palsies has been estimated at 8%.301,308 While most cases are traumatic in origin, bilateral trochlear nerve palsy

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secondary to hydrocephalus, tumors, arteriovenous malformation, and multiple sclerosis have been reported.39,410 Clinical conjecture, supported by limited pathologic evidence and recent imaging studies suggest that the trochlear nerve decussation is the usual site of bilateral fourth nerve injuries.270 In such cases, neuroimaging may reveal ambient cistern hemorrhage, which serves as a useful marker for a dorsal midbrain injury.270 In contrast to patients with unilateral trochlear nerve palsy and a head tilt to the side opposite the paretic eye, patients with bilateral trochlear nerve palsy usually present with a chin-down head position.308 They typically display a right hypertropia in left gaze and a left hypertropia in right gaze. The hypertropia increases with head tilt to the same side as the hypertropic eye, and there is a V-pattern esotropia caused by the decreased abducting force of both superior oblique muscles in downgaze. Even when measured to be orthotropic in primary position, a chin-down position is often maintained, presumably to minimize the effects of bilateral extorsion and to maximize the operative field of single binocular vision. Difficulties in diagnosis arise when one nerve is damaged more extensively than the other.94,161,465 The child with asymmetrical fourth nerve palsies may display a head tilt rather than a chin-down position, and signs of bilaterality must be carefully sought524 (Table 6.3). In the child with a severe right trochlear nerve palsy and a mild left trochlear nerve palsy, a left hypertropia may be present only on left head tilt or on gaze right and up, corresponding to the overacting left inferior oblique muscle. Kushner308 has termed such cases “almost masked” bilateral superior oblique palsies. To further complicate the issue, there are occasionally children in whom the asymmetry of involvement is sufficient to prevent a reversal of the hypertropia in any position of gaze. These have been termed “true masked” bilateral fourth nerve palsies. Such cases are recognized to be bilateral only after operating on one eye allows the contralateral trochlear nerve palsy to become clinically manifest.232 Saunders and Roberts 489 have cautioned that some cases of so-called masked bilateral trochlear nerve palsy may, in fact, be surgical overcorrections in which the initial incomitance is maintained. For example, a child with an overcorrected right trochlear nerve palsy will have a left hypertropia, which is worse in right gaze and worse in left head tilt, simulating an unmasked left trochlear nerve palsy.

Table 6.3 Neuro-ophthalmologic signs of bilaterality in traumatic trochlear nerve palsy Excyclotropia greater than 10° Alternating hyperdeviations in lateral gaze or with forced head-tilt testing V pattern with esotropia in downgaze and minimal horizontal deviation in primary and upgaze Bilateral inferior oblique muscle overaction

6 Ocular Motor Nerve Palsies in Children

Patients with bilateral superior oblique palsies typically show a much smaller Bielschowsky Head Tilt test difference than those with unilateral superior oblique muscle palsy. One would expect that a bilateral trochlear nerve palsy would result in a larger Bielschowsky Head Tilt difference because the forces that cause it for each eye should be additive. Several innervational factors may contribute to this seemingly paradoxical observation. Kushner308 has pointed out that a patient with a unilateral palsy will habitually fixate with the normal eye so that there is no alteration in the resting tone to the antagonistically acting vertical muscles in that eye. In contrast, a patient with bilateral trochlear nerve palsy is, by definition, fixating with a paretic eye, which would have a tendency toward hypertropia. Therefore, the innervation to the inferior rectus muscle would be increased in the fixating eye, and this would be accompanied by a relative inhibitory signal to the superior rectus muscle of the same eye. This inhibitory signal would be presumed to interact with the stimulation of the superior rectus muscle on ipsilateral head tilt, resulting in a smaller deviation than normal. More recently, Kushner312 has invoked the effects of dynamic torsion, which recruit oblique muscle innervation to produce “anticompensatory saccades during a head tilt, to explain these aberrations.” Torsion can be measured by the Double Maddox Rod test 99,301,308,378,503,504,540,576 or by using Bagolini lenses.358,476,507,571,572 Excyclodeviation of more than 10° should raise the suspicion of bilateral fourth nerve pareses, and excyclodeviation over 15° is highly suggestive of bilaterality. Kraft et al300 have found that, when the Double Maddox Rod test is performed in 20° of downgaze, the presence of 20° of excyclodeviation has a 90% association with bilateral trochlear nerve palsy. Recently, Simons et al518 have cautioned that same color Maddox rods should be placed before both eyes to avoid artifactual localization of the torsion to the eye with the red lens placed before it. If bilateral trochlear nerve palsy can be diagnosed preoperatively, then the surgical procedure is usually directed at correcting both palsies simultaneously.524

Etiology In a retrospective study of 92 children with trochlear nerve palsy, Tarczy–Hornoch and Repka544 found the etiologies to be congenital in 56, craniofacial anomalies in 12, head trauma in 5, postresection of brain tumors in 3, orbital inflammation in 1, prenatal stroke in 1, and idiopathic in 14. They noted that strabismus surgery improved motor status but not sensory status, and those sensory outcomes were generally worse in children who presented at younger ages.

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Trochlear Nerve Palsy

Traumatic Trochlear Nerve Palsy

Congenital Trochlear Nerve Palsy

Trauma is the most common cause of acquired unilateral or bilateral trochlear nerve paresis.86,121,187,218,280,472–475,613 All traumatic fourth nerve pareses should be assumed to be bilateral until examination proves otherwise. The trochlear nerve may be damaged anywhere along its course by direct orbital trauma, frontal trauma, or an oblique blow to the head. In severe brainstem damage, trochlear nerve paresis may be obscured by horizontal gaze abnormalities, and become apparent only when horizontal gaze begins to recover. As the trochlear nerves emerge from the dorsal surface of the midbrain, they are susceptible to damage from closed head trauma. The neurosurgical trauma involved in resecting a posterior fossa tumor can similarly injure one or both trochlear nerves.320 More anteriorly, the proximity of the trochlear nerve to the tentorial edge also makes it susceptible to injury in closed head trauma. A blow to the forehead may cause a contrecoup contusion of one or both nerves by impingement against the rigid tentorium.29 Traumatic avulsion here has also been described.227 Damage at this location is often bilateral, and trauma patients must be carefully examined for this possibility.540 Lindenberg333 has described a contrecoup contusion of the midbrain tectum at the caudal edge of the tentorial notch, when the forehead or skull vertex strikes a stationary object. Blows to the occiput or even falls on the buttocks may transmit forces that cause the cerebellum to be thrust against the tentorium from below, injuring the trochlear nerve.333 The fourth cranial nerve may also be injured by contusion or hemorrhage within the substance of the midbrain.333 Because the fourth nerve may be injured by remote trauma, reports of coexisting orbital floor fracture and trochlear nerve palsy are not surprising.91,99,269,284 The susceptibility of the fourth nerve to trauma that is not severe enough to produce either skull fracture or loss of consciousness may lead one to miss other underlying disease. Neetens396 has described three cases of basal intracranial tumors associated with trochlear nerve paresis following minor head trauma. It is unusual for the trochlear nerve to be the sole nerve damaged by cavernous sinus lesions, but it can be damaged in combination with other cranial nerves from lesions in the cavernous sinus. When orbital trauma causes superior oblique weakness, it may be impossible to know whether the injury involved the fourth nerve, the trochlea, or the superior oblique tendon. Direct trauma to the superior-medial orbit can also produce a trochlear nerve palsy by laceration of the tendon, muscle, or by damage to the trochlea.25 Knapp285 coined the term “canine tooth syndrome” to describe the association of a mild Brown syndrome and trochlear nerve palsy caused by orbital trauma (Knapp type VII trochlear nerve palsy). Blunt trauma to the superior-medial orbit may also produce a Brown syndrome with no superior oblique weakness.28,35

Congenital trochlear nerve palsy is underdiagnosed, because many children are asymptomatic, and some affected infants may be thought to have congenital muscular torticollis.219 The vast majority of cases are nonfamilial, but several families with more than one affected member have been documented.219 Numerous cases of familial congenital trochlear nerve palsy have now been reported.23,49,62,256 Children with congenital trochlear nerve palsy typically come to medical attention because of a hypertropia in side gaze or an unexplained head tilt. In older children, congenital trochlear nerve palsy may present as acquired vertical diplopia. The diagnosis is based upon a history of head tilt beginning in infancy (as demonstrated by examination of family photographs) in a child with no specific inciting event, together with the following findings on examination, orbital MR imaging, and results of traction testing at the time of surgery. The following clinical findings are considered to be predictive of congenital trochlear nerve palsy:

Large Vertical Fusional Vergence Amplitudes Normal vertical fusional vergence amplitudes are 2–3 prism diopters. Mottier and Mets389 studied 14 patients with congenital trochlear nerve palsy and found average vertical vergence amplitudes to be 16 prism diopters. We have seen adults with congenital trochlear nerve palsy who fuse up to 30 prism diopters of hyperdeviation. On examination, such a patient will initially seem to be orthotropic, but with prolonged occlusion, the measured vertical deviation will slowly increase as the examiner “chases it” with the prism bar. Symptomatically, older children note that, once they begin to see double, the images gradually spread apart. It is not unusual for patients with congenital trochlear nerve palsy to become symptomatic for the first time in their teenage or adult years. Whether such cases result from a gradual increase in the size of the deviation (perhaps related to ipsilateral superior rectus contracture) or from an age-related reduction in fusional vergence amplitudes is unknown.

Facial Asymmetry Facial asymmetry is present in most cases of congenital trochlear nerve palsy, but it may also be seen in acquired cases that are longstanding.595 Wilson and Hoxie595 found facial asymmetry to be present in seven of nine patients with congenital trochlear nerve palsy. This facial asymmetry is thought to be secondary to chronic tilting of the head.595 Patients with facial asymmetry secondary to congenital trochlear nerve palsy have hemifacial retrusion with an upward

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Fig. 6.10 Facial asymmetry in left superior oblique palsy. Note retrusion of the right side of the face with interpupillary axis downslanting to the right and mouth upslanting to the right

slanting of the mouth on the side of the head tilt (Fig. 6.10). The recognition of facial asymmetry associated with congenital trochlear nerve palsy can be facilitated by drawing one line through the center of both pupils and another line through the closed lips. In children with facial asymmetry, these lines converge and intersect toward the side of the shallow, more retruded side of the face (Fig. 6.10).595 In our experience, children with congenital trochlear nerve palsy characteristically have a detectable enophthalmos in the paretic eye due to absence of the translational force exerted by the normal superior oblique tendon. This form of facial asymmetry must be distinguished from that associated with synostotic plagiocephaly, congenital muscular torticollis, and the nonspecific facial asymmetry that is common in normal individuals. Unlike synostotic plagiocephaly, which also involves the forehead, the facial asymmetry in the latter two conditions is confined to the midface. Because facial asymmetry in congenital muscular torticollis has been reported to resolve with continued facial growth, a similar regression is assumed, albeit unproven, to be possible following early treatment for congenital trochlear nerve palsy. The age of onset of facial asymmetry in congenital trochlear nerve palsy and the degree of potential resolution relative to the age at corrective surgery are as yet unknown. Its gradual development with a chronic head tilt suggests that strabismus surgery should not be unduly postponed when a congenital superior oblique muscle palsy is diagnosed in a young child. Patients with vertical diplopia associated with congenital trochlear nerve palsy do not complain of associated image tilt, whereas image tilt is noted in about 23% of patients with vertical diplopia from acquired trochlear nerve palsy.576 The absence of subjective torsion in congenital fourth nerve palsies presumably reflects the gradual development of complex pathophysiological and/or psychological adaptive mechanisms.122,576

6 Ocular Motor Nerve Palsies in Children

The exaggerated superior oblique traction test, as described by Guyton,122 is more likely to show tendon laxity in congenital versus acquired cases.377 Plager436 used forced duction testing to demonstrate decreased superior oblique muscle resistance to rotation in 14 patients who carried the clinical diagnosis of congenital trochlear nerve palsy, while all ten patients with acquired trochlear nerve palsy had normal resistance to rotation. Helveston et al229 examined the superior tendon of 89 eyes of patients undergoing surgery for trochlear nerve palsy and found congenital trochlear nerve palsy to be associated with an abnormality of the superior oblique tendon in 87% of cases, as compared with 8% of cases with acquired trochlear nerve palsy. Abnormalities of the superior oblique tendon include absence, redundance, misdirection, and insertion into posterior Tenon’s capsule.482 Sato et al found that the amount of vertical deviation does not seem to correlate with the type of tendon abnormality found at surgery.482 An inherited anomaly confined to the superior oblique tendon could account for reports of familial congenital trochlear nerve palsy.219 MR imaging has shown that the anatomical abnormality is not limited to the tendon. The ipsilateral superior oblique tendon is often found to be small or absent on coronal orbital MR imaging in children with congenital trochlear nerve palsy.96,421,482 One study found an absence of the superior oblique tendon on MR imaging to be predictive of a larger primary position vertical deviation,482 while another found the clinical findings to be indistinguishable in children with present and absent tendons.513 Shokida et al513 found enlargement of the contralateral trochlear nerve palsy in some congenital cases. Because hypoplasia (in congenital cases) and atrophy (in acquired cases) are indistinguishable on MR imaging, the finding of a small superior oblique muscle cannot be used to classify the etiology of the palsy.421 There is suspicion that the structural abnormalities of the superior oblique tendon that characterize congenital trochlear nerve palsy could result from lack of innervation. Several studies have found polymorphisms in the ARIX gene in patients with congenital trochlear nerve palsy (some with an absent superior oblique muscle) that may be a genetic risk factor.242,256 They suggested that polymorphisms, in this homeobox-containing gene, may be responsible for some cases of congenital trochlear nerve palsy. The ARIX gene is known to be expressed in the brainstem nuclei for oculomotor and trochlear nerves387,617 and is the same gene that is responsible for affected families with CFEOM2.256 Wallace and von Noorden582 found the following examination findings in the patient with trochlear nerve palsy to be predictive of a congenitally absent tendon: 1 . An associated horizontal deviation 2. Amblyopia 3. A large hypertropia in primary position (averaging 20.8 prism diopters)

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Trochlear Nerve Palsy

4 . Spread of comitance 5. Pseudo-overaction of the contralateral superior oblique muscle (due to ipsilateral superior rectus contracture resulting from a longstanding hyperdeviation) In patients with intermittent exotropia and some degree of comitant hypertropia, examination of versions, forced head tilt testing, Double Maddox Rod testing, and fundus examination for torsion should be performed to look for signs of underlying trochlear nerve palsy alone.104 Cho and Kim104 found that small amounts of hypertropia can disappear with horizontal surgery alone. The issue of whether the ocular motor synkinesis can contribute to the positive Bielschowsky Head tilt test, especially in congenital cases, requires further examination. Ohtsuki et al412 reported a case of trochlear nerve palsy with an unusually large Bielschowsky head tilt phenomenon and disproportionately small vertical deviation. Because the tilt improved after a small (3 mm) superior rectus recession, they attributed this phenomenon to a gain in the otolith ocular reflex affecting the vertical rectus muscles. It remains possible, however, that synkinetic innervation of the superior oblique muscle could explain this observation. While reported cases of ocular motor synkinesis generally tend to spare the trochlear nerve,174 Kothari et al296 reported primary superior oblique muscle levator synkinesis in a 7-year-old boy in whom gaze into the field of action of the superior oblique muscle caused the ptotic upper eyelid to retract. Other patients with congenital and acquired synkinesis involving the trochlear nerve have been reported.163,332,348,516

of the suprapineal recess is assumed to compress the trochlear nerves at their point of decussation.203 The association of bilateral trochlear nerve paresis with hydrocephalus is easily overlooked when signs of dorsal midbrain syndrome coexist.203 Idiopathic The diagnosis of idiopathic trochlear nerve palsy is assigned to children who develop acute vertical diplopia with signs and symptoms of isolated trochlear nerve palsy, no history of recent head trauma, no signs of congenital trochlear nerve palsy, and no associated neurological abnormalities.455 Adults with idiopathic trochlear nerve palsies generally show spontaneous recovery over 4 months.121 This scenario in older adults is often attributed to microvascular infarction of the trochlear nerve.270 As discussed below, many patients who would previously have been classified as idiopathic, are now found to have schwannomas of the trochlear nerve on highresolution MR imaging. The natural history (persistence versus resolution) of idiopathic trochlear nerve palsy in children is unknown. In our experience, the rarity of compressive lesions as a cause of isolated trochlear nerve palsy in children suggests that clinical observation of persistent trochlear nerve palsy may be appropriate, and that neuroimaging need only be performed if additional neurological signs develop.

Compressive Lesions Synostotic Plagiocephaly Synostotic plagiocephaly caused by stenosis of the ipsilateral coronal suture with subsequent deformation of the orbit has been shown to have a high association of vertical strabismus that mimics a trochlear nerve palsy corresponding to the side of the coronal synostosis.454 These patients have apparent overaction of the inferior oblique muscle, and an anatomical deformation of the position of the trochlea has been hypothesized as the cause.25 In contrast, children with congenital muscular torticollis and deformational plagiocephaly have an associated torticollis that is not ocular in nature.173

Hydrocephalus Unilateral and bilateral trochlear nerve palsies are not uncommon in children with noncompressive hydrocephalus.113,123,203,257,550 Because the finding of bilateral trochlear nerve palsy localizes to the superior medullary velum, the associated dilation

Because of the rarity of compressive trochlear nerve palsies in children, routine intracranial MR imaging is not indicated in uncomplicated pediatric superior oblique palsies.86 However, neuroimaging of the brain often ends up being performed when orbital MR imaging is obtained to look for diminution in the size of the superior oblique muscle. Over the past decade, trochlear nerve schwannoma, a slow-growing benign tumor that is increasingly detected on high-resolution MR imaging, has been detected with greater frequency in children and adults with unilateral trochlear nerve palsy (Fig. 6.11).75,165,183,541 In the child with trochlear nerve palsy and clinical signs of neurofibromatosis 2, the possibility of trochlear nerve schwannoma warrants high-resolution MR imaging.75 In some patients, these tumors and their associated symptoms have been observed to resolve spontaneously, as these tumors are slowgrowing, and their associated symptoms occasionally resolve spontaneously.612 Other compressive causes of trochlear nerve palsy are rare. Krohel et al303 described a 9-year-old child who developed an isolated trochlear nerve palsy as the initial sign of

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a posterior fossa astrocytoma. Atilla et al24 described trochlear nerve palsy in a child secondary to an orbital dermoid cyst in the region of the trochlea. Tumor surgery is more likely to cause an isolated trochlear nerve deficit

6 Ocular Motor Nerve Palsies in Children

than the tumor itself.270,544 The few reports of large aneurysms causing isolated trochlear nerve palsies have been in adults.5,119,354 Figure 6.12 is a clinical algorithm to facilitate the diagnostic workup in the child with a trochlear nerve palsy.

Rare Causes of Trochlear Nerve Palsy Rarely, trochlear nerve palsy can occur in patients who have elevated intracranial pressure without ventriculomegaly (pseudotumor cerebri).27 In this context, trochlear nerve palsy must be distinguished from skew deviation, which can also rarely accompany pseudotumor cerebri.27 These vertical deviations are usually seen in conjunction with sixth nerve palsy and resolve with normalization of intracranial pressure.

Differential Diagnosis

Fig. 6.11 Axial MR scan demonstrating a trochlear neurinoma in child with right superior oblique palsy and NF2. Used with permission from Brodsky and Boop75

The differential diagnostic considerations of trochlear nerve palsy in childhood are listed in Table 6.4. Isolated superior oblique palsies are generally straightforward in older children. In children who have sustained head trauma, however, careful attention should be paid to ruling out skew deviation.213

Fig. 6.12 Clinical algorithm for evaluation of fourth nerve palsy in childhood

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Trochlear Nerve Palsy Table 6.4 Differential diagnostic considerations of trochlear nerve palsy in childhood Dissociated vertical divergence Congenital muscular torticollis Synostotic plagiocephaly Double elevator palsy Ocular tilt reaction Incomitant skew deviation

The major differential diagnostic considerations in infants with a head tilt are dissociated strabismus and congenital muscular torticollis. Dissociated vertical divergence may present with a hyperdeviation and a contralateral head tilt, which simulates trochlear nerve palsy, but is not associated with diplopia.115 Congenital muscular torticollis can be distinguished from congenital trochlear nerve palsy by (1) the examiner’s inability to passively tilt the head in the opposite direction, (2) the palpation of a tight sternocleidomastoid muscle on the side of the tilt, (3) the persistence of the tilt when the infant is reclined, and (4) the persistence of the tilt when either eye is patched. Synostotic plagiocephaly can also present with a hypertropia, contralateral head tilt, and facial asymmetry that can resemble a congenital trochlear nerve palsy. The diagnosis of trochlear nerve palsy must also be considered in older children who appear to have a monocular elevation deficiency (“double elevator palsy”). This situation arises in children who habitually fixate with the paretic, hypertropic eye and develop a contracture in the contralateral inferior rectus muscle (fallen eye syndrome). The ocular tilt reaction is a rare ocular motility disturbance of central vestibular origin characterized by vertical divergence of the eyes (skew deviation), a head tilt toward the side of the lower eye, and bilateral torsion of the eyes with the superior poles directed toward the side of the lower eye. The combination of vertical strabismus and a head tilt may initially suggest the diagnosis of trochlear nerve palsy, however, the finding of subjective and objective intorsion of the higher eye and extorsion of the lower eye establishes the diagnosis.147 The hypertropia is usually comitant, but cases of incomitant hypertropia with a Bielschowsky Three Step test corresponding to that seen in trochlear nerve palsy have been described.147 Heterotopic positioning of the extraocular muscles can simulate trochlear nerve palsy when the lateral rectus muscle in the contralateral eye is inferiorly positioned, causing it to descend in abduction to a greater degree than the adducting eye descends (Fig. 6.13).562 The finding of facial asymmetry is not useful in distinguishing these two conditions.562 Finally, trochlear nerve palsy can evolve to simulate an idiopathic hypertropia when the superior rectus muscle of the chronically hyperdeviating eye develops a secondary contracture. This contracture can erase the preexisting torsion and enhance the Bielschowsky Head Tilt difference.278

Fig. 6.13 Coronal MR image demonstrating excyclorotation of extraocular muscles within left orbit. Inferior displacement of left lateral rectus caused overdepression of left eye during abduction and simulated right superior oblique palsy. Courtesy of Joseph Demer, M.D.

Treatment Traumatic or other forms of acquired trochlear nerve palsy should be observed for a minimum of 6 months before considering surgical correction. During this period, occlusion therapy is often unnecessary for unilateral cases, because most children can fuse with a compensatory head tilt. The development of amblyopia in this setting suggests a coexistent motility disorder, an associated traumatic disruption of the fusional mechanism, or the inability to obtain fusion by adopting an anomalous head position. The surgical treatment of unilateral trochlear nerve palsy should be individualized, but some general guidelines will be summarized. The goal of surgery is to obtain single binocular vision within a functional field of gaze and to normalize the head position. Kraft and Clarke298 found that patients with trochlear nerve palsy who underwent surgery to eliminate a compensatory head posture had a 75.6% incidence of successful restoration of normal head posture. However, the Bielschowsky head tilt test difference usually persists after successful surgery, at least in congenital cases.400 The measured postoperative improvement in saccadic conjugacy is greater in patients with congenital trochlear nerve palsy and correlates with preoperative vertical vergence.331 Using the example of a right trochlear nerve palsy, the important fields of gaze to consider in planning surgical strategy are primary gaze, right gaze, and downgaze. Because there is always a hyperdeviation in left gaze, this finding does not enter into the surgical decision. The following list is a general guideline to surgical strategy:

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Most cases of trochlear nerve palsy manifest with isolated overaction of the ipsilateral inferior oblique muscle, with little or no underaction of the superior oblique muscle. These cases can be managed by weakening the antagonist inferior oblique muscle surgically (i.e., recession or myectomy). Inferior oblique surgery can neutralize up to 15 prism diopters of hypertropia in primary gaze and has the advantage of being self-titrating.220,238,351,385,409 Numerous inferior oblique weakening procedures have been used to treat unilateral trochlear nerve palsy, but properly performed recession or myectomy seem to work equally well.154,157,241,391 However, it is important to remember the caveat that inferior oblique anteriorization192,382 runs the risk of inducing diplopia in upgaze, secondary to limitation to elevation of the affected eye. Anterior and nasal transposition of the inferior oblique muscle has been advocated for treatment of severe or recurrent trochlear nerve palsy to convert the inferior oblique muscle into an intorter or a depressor.528 A significant (>10 diopter) right hypertropia in right gaze suggests a secondary right superior rectus contracture, which does not respond to inferior oblique weakening alone. In this setting, the ipsilateral superior rectus muscle must also be recessed (usually 3 mm or less) to eliminate the hyperdeviation in right gaze.278 Pseudo-overaction of the contralateral superior oblique muscle serves as a useful clinical clue to the presence of a superior rectus contracture.582,596 Superior rectus contracture can be confirmed by forced duction testing at surgery, and small (3 mm) recessions can eliminate them. A significant (>10 diopter) right hyperdeviation in downgaze suggests a contralateral inferior rectus contracture, as occurs in children who habitually fixate with the paretic eye. Because inferior oblique surgery does not produce a significant effect in downgaze, a small (3 mm or less) recession of the contralateral inferior rectus muscle (with or without a posterior fixation suture) should be considered. In our hands, combined inferior oblique and contralateral inferior rectus weakening produce a high incidence of surgical overcorrection. Contrary to the recommendation of combined surgery, we and others now treat such cases with isolated inferior oblique recession220,238,351,385,409 and add small inferior rectus recessions (no more than 3 mm) only in the most severe cases. Numerous inferior oblique weakening procedures, ranging from recession, resection, disinsertion, and anteroplacement, and orbital wall fixation have been used to treat unilateral trochlear nerve palsy successfully. Except for the aforementioned problems with inferior oblique muscle anteroplacement, all of these procedures seem to work equally well. We reserve superior oblique tucks for cases in which there is superior oblique underaction, symptomatic torsion, and minimal ipsilateral inferior oblique overaction.50 Unlike the inferior oblique weakening procedure, a superior oblique tuck must be carefully titrated.488 A tuck that is too small

6 Ocular Motor Nerve Palsies in Children

produces a negligible treatment effect, while one that is too large produces a problematic Brown syndrome. Parents must be warned preoperatively that even a successful tuck will produce a mild iatrogenic Brown syndrome that may be associated with vertical diplopia in gaze up and to the opposite side. Some authors recommend that this surgical strategy be modified for cases of congenital trochlear nerve palsy, which are often associated with a lax or anomalous superior oblique tendon.229,436 The absence of normal superior oblique tendon tension can be demonstrated prior to surgical exploration by one of several exaggerated forced duction tests.206,436 von Noorden573 has outlined a surgical strategy for treatment of congenital absence of the superior oblique tendon that relies on inferior oblique weakening as the central procedure, with other muscles added with minor modifications to the general rules previously stated. Plager has argued that decreased superior oblique tendon tension suggests a lax or absent tendon that should be explored and tucked if present, while a child with normal tendon tension is at high risk of iatrogenic Brown syndrome if the superior oblique tendon is tucked, but responds favorably to inferior oblique recession with recession of additional muscles as indicated.436 Bilateral trochlear nerve palsy is more difficult to treat, and parents should be warned preoperatively that comfortable binocular vision in all fields of gaze may not be possible.216,285,378 In children with alternating hyperdeviations in side gaze and a large esotropia in downgaze, bilateral superior oblique tucks can often restore single binocular vision in primary gaze, but diplopia near the downgaze position usually persists due to esotropia and residual torsion in this position of gaze. Kushner311 has utilized a procedure described by Forrest Ellis, MD, and Carlos Souza-Dias, MD, consisting of bilateral inferior rectus recession (5 mm OU) to successfully restore single binocular vision in downgaze. This procedure produces a “fixation duress,” requiring excess downgaze innervation that recruits the paretic superior oblique muscles, thereby enhancing abduction and intorsion of the eyes in downgaze. It, therefore, requires that some residual superior oblique function be present. Jampolsky has advocated bilateral superior rectus and inferior oblique weakening to “scroll down” the field of single binocular vision from upgaze to primary position. This procedure carries the relative disadvantage of crippling upgaze. Children with bilateral superior oblique palsies may have complaints that are predominantly torsional in nature with minimal alternating hyperdeviations in sidegaze or V-pattern in downgaze. In such cases, an alternative to a superior oblique tuck is the dissection and anterior–inferior transposition of the anterior portion of the superior oblique tendon that is primarily involved in torsional movements (Harada–Ito procedure).216,365 In addition to decreasing or eliminating the excyclodeviation, this procedure augments abduction in downgaze, thereby reducing the associated V-pattern esotropia.

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Abducens Nerve Palsy

Abducens Nerve Palsy Clinical Anatomy The abducens nucleus lies just lateral to the midline of the pons at its junction with the medulla. The genu of the facial nerve passes close to its dorsal and lateral surface. The medial longitudinal fasciculus is just medial to the nucleus. There are two cell populations in the abducens nucleus: Motor neurons of the abducens nerve and interneurons of the contralateral medial longitudinal fasciculus that pass to the medial rectus subnucleus of the contralateral third nerve nucleus. The fascicular portion of the abducens nerve courses ventrally through the pons. Structures near the fascicle include the motor nucleus and fascicle of the facial nerve, the motor nucleus of the trigeminal nerve, the spinal tract and nucleus of the trigeminal nerve, the superior olivary nucleus, the central tegmental tract, and the corticospinal tract. The extra-axial portion of the sixth nerve turns rostral along the base of the pons lateral to the basilar artery. The nerve ascends through the subarachnoid space along the clivus and penetrates the dura about 1 cm below the crest of the petrous bone. It then passes under the petroclinoid ligament to enter the cavernous sinus. Within the cavernous sinus, the abducens nerve is not situated within the lateral wall, as are the oculomotor and trochlear nerves, but it lies in the body of the sinus close to the carotid artery. The sixth nerve enters the orbit through the superior orbital fissure within the annulus of Zinn, adjacent to the lateral rectus muscle. The nerve ramifies in the posterior orbit, and its branches enter the lateral rectus muscle diffusely. The classic notion is that the vulnerability of the abducens nerve is attributable to its long intracranial course.215 Because the abducens nerve is about one third the length of the trochlear nerve, however, its vulnerability probably results from other structural and vascular relationships.215 A sixth nerve nuclear lesion paralyze ipsilateral horizontal gaze, because cell bodies of lateral rectus motoneurons and medial longitudinal fasciculus (MLF) interneurons are juxtaposed in the nucleus.373 Because these lesions usually have some spillover to involve the adjacent abducens nerve, these patients often have concurrent esotropia. Brainstem lesions involving the sixth nerve frequently damage nearby structures, and some localizing syndromes have been named. A large dorsal pontine lesion can produce a horizontal gaze palsy with a variable combination of other signs, including ipsilateral facial palsy, analgesia of the face, peripheral deafness, and loss of taste from the anterior two thirds of the tongue (Foville syndrome). A ventral pontine lesion involving the pyramidal bundles and tegmentum can produce lateral rectus weakness with or without ipsilateral facial paralysis, and contralateral hemiplegia (Millard–Gubler syndrome).369

The sixth nerve is particularly vulnerable to traumatic, inflammatory, or compressive injury as it leaves the pons and passes vertically through the subarachnoid space to enter the dura overlying the clivus. Blunt trauma may injure the sixth nerve at this point, as may a clivus chordoma or petrous ridge tumor.127,227,466,494,536,560,613 Basilar meningitis preferentially affects the subarachnoid portion of the abducens nerve. After entering the cavernous sinus, the abducens nerve is especially prone to damage from intracavernous lesions because of its location in the body of the sinus next to the carotid artery, although intracavernous tumors and aneurysms are more rare in children than in adults.281,404 Abducens palsies from cavernous sinus lesions may not be distinguishable from those caused by superior orbital fissure lesions, as associated cranial neuropathies are similar in both cases. Sympathetic fibers have been demonstrated to leave the carotid plexus and join the abducens nerve in the posterior cavernous sinus.425 The coexistence of a sixth nerve palsy and an ipsilateral Horner syndrome localizes a lesion to the cavernous sinus.202

Clinical Features Because the sixth nerve innervates only the lateral rectus muscle, the sole action of which is to abduct the eye, the clinical features of a sixth nerve palsy are more straightforward than those of oculomotor or trochlear nerve palsies. Children with an acute sixth nerve palsy present either with a head turn toward the side of the lesion or with a horizontally noncomitant esotropia that increases in gaze toward the affected eye and decreases or disappears in gaze away from the affected eye. The esodeviation is usually greater at distance than at near fixation. It is also greater when the child fixates with the paretic eye. Infants and children with sixth nerve palsy who avoid looking into their diplopic field of gaze may appear to have a gaze palsy.28 Examining versions with the child’s head in its neutral position or spinning an infant to stimulate the vestibulo-ocular reflex should reveal the noncomitancy of the deviation. A child with an acute complete sixth nerve palsy has about 35 prism diopters of esotropia when fixating with the nonparetic eye at near. In the recovery phase, a significant esotropia may persist despite almost full recovery of abduction. This could result from a residual imbalance in the ratio of phasic to tonic lateral rectus innervation from secondary medial rectus contracture, or from decompensation of a preexisting esophoria. Small sixth nerve palsies can unleash small physiologic hyperphorias, which persist with head tilt to either side in patients with peripheral lesions, and switch sides with head tilt to either side in central lesions.604

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Causes of Sixth Nerve Palsy There are numerous causes of acquired sixth nerve palsy in childhood.4,182 Robertson et al458 reviewed 133 cases of isolated acquired sixth nerve palsy in children and found the major diagnostic categories to include neoplasm (39%), trauma (20%), inflammation (17%), and idiopathic conditions (9%), which included cases of benign recurrent sixth nerve palsy. Martonyi349 reviewed the cases of 16 children with sixth nerve palsies and found that eight had benign recurrent sixth nerve palsy, four had elevated intracranial pressure, one had meningitis, one had meningomyelocele, one had ependymoma, one had an idiopathic condition, and one also had a transient palsy in infancy. More recently, Lee et al323 reviewed the charts of 75 children with sixth nerve palsies who had undergone modern neuroimaging. Neoplasms or their neurosurgical removal were the most common cause (45%), followed by elevated intracranial pressure without tumor (15%), trauma (12%), congenital (11%), inflammatory (7%), miscellaneous (5%), and idiopathic conditions (5%). These authors and others have recommended neuroimaging due to the high risk of neoplasm in pediatric sixth nerve palsies.191 In general, the relative prevalence of tumor versus benign recurrent sixth nerve palsy probably reflects the proximity of the investigators to a neurosurgical referral center. In one

6 Ocular Motor Nerve Palsies in Children

retrospective review of 64 children with sixth nerve palsy,20 an underlying etiology could be identified in all but three. The most common cause was tumor (335), followed by hydrocephalus (23%) and trauma (19%). These figures undoubtedly reflect the study center’s proximity to a large neurosurgical center. In our experience, the most readily identifiable causes of nontraumatic sixth nerve palsy in childhood are benign recurrent sixth nerve palsy, elevated intracranial pressure, and pontine glioma. When we examine the child with a nontraumatic acquired sixth nerve palsy, our examination is directed toward obtaining historical information and looking for clinical signs that would suggest one of these conditions. We inquire about recent head trauma, antecedent viral illnesses or immunizations, a history of previous episodes, time of onset, symptoms of increased intracranial pressure, and other neurological symptoms. Our initial neuro-ophthalmologic examination is primarily directed toward looking for ipsilateral facial weakness (which would suggest a pontine glioma) and signs of papilledema. We obtain a complete neurological examination and MR imaging in all children with an initial episode of sixth nerve palsy, including cases that are clearly traumatic in origin. The decision whether to perform a lumbar puncture is then predicated on the results of these studies (Fig. 6.14). We classify the major causes of pediatric sixth nerve palsy as follows:

Fig. 6.14 Clinical algorithm for evaluation of sixth nerve palsy in childhood

Abducens Nerve Palsy

Congenital Sixth Nerve Palsy Congenital sixth nerve palsy is rare. However, it may also be underdiagnosed due to inherent difficulties in identifying abduction deficits in neonates. Such cases are almost always identified in the neonatal nursery and not in the eye clinic. Congenital esotropia has been reported to occur after 6–8 weeks of life, because occurrence in the neonatal period has not been documented.18,401 Therefore, the observation of an esotropia shortly after birth should lead one to consider the possibility of a congenital sixth nerve palsy. Most congenital sixth nerve palsies without peripheral misdirection are transient, probably arising as sequelae to perinatal cranial trauma. Two forms of transient congenital sixth nerve palsy can be identified. The first presents as a neonatal esotropia with an obvious unilateral abduction deficit that generally improves or resolves over the first month of life.46,132,450 The incidence has been variously estimated to occur in 1 in 124450 and 1 in 182132 neonates. Such cases may be due to perinatal trauma. The second form presents with neonatal esotropia with no obvious abduction deficit.18 The presence of subtle abduction weakness is, however, very difficult to exclude in such neonates.

Traumatic Sixth Nerve Palsy Sixth nerve palsies occur frequently in head trauma patients. Blunt trauma is believed to damage the sixth nerve where it is tethered beneath the petroclinoid ligament at its entrance to the dura overlying the clivus.29 Closed head trauma may also elevate intracranial pressure and secondarily produce unilateral or bilateral sixth nerve paresis. Basilar skull fractures may damage the petrous segment of the abducens nerve after the nerve has penetrated the dura and passed beneath the petroclinoid ligament.29,68,133,326,457,560 Posttraumatic carotid cavernous fistulas can also be associated with sixth nerve palsy. Clinical signs of traumatic sixth nerve injury are more readily recognizable than those of fourth nerve injury because the resultant ocular deviation is usually larger in the primary gaze position. The occurrence of sixth nerve palsy after apparently trivial head trauma should raise suspicion of an underlying intracranial tumor.107 In one retrospective series of all traumatic sixth nerve palsies,393 the spontaneous recovery rate was found to be 27% for traumatic unilateral sixth nerve palsy and 12% for traumatic bilateral sixth nerve palsy.

Benign Recurrent Sixth Nerve Palsy In 1967, Knox et al286 described 12 children ranging in age from 18 months to 15 years who developed an acute unilateral sixth nerve palsy after an apparently benign viral illness.

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Reinecke and Thompson449 reported five recurrent cases of a similar nature. Werner et al591 reported several cases of benign recurrent sixth nerve palsy that followed viral illness or immunization (with measles, mumps, and rubella in one child and diphtheria, pertussis, and tetanus [DPT] in another). Other reports have mentioned the association with DPT vaccination.60,116 Sternberg et al531 described recurrent attacks of sixth nerve palsy after febrile illness. Afifi et al3 reviewed the literature and found that this condition had a female and leftsided preponderance. Benign transient sixth nerve palsy may also follow varicella infection.16,190,231,286,397,458 They speculated that possible etiologies could include viral infection, neurovascular compression by an aberrant artery, and migraine. Isolated reports implicate Epstein–Barr virus infection as the causative agent in some cases105,535 and impetigo in others.57 Other reported antecedent infections include cytomegalovirus,184 Q fever, and Lyme disease.60,116 The pathophysiological mechanism and location of injury to the sixth nerve are unclear. It is not known whether the much less common recurrent form of third nerve palsy in childhood represents a variant of the same disorder. Unlike sixth nerve palsies associated with compression or elevated intracranial pressure, benign recurrent sixth nerve palsies are usually sudden in onset and associated with a severe abduction deficit in the involved eye (Fig. 6.15). Affected children are normal between attacks and have no other intracranial or metabolic abnormalities.55,60,449,591 Recurrences typically involve the same eye.349 In most cases, complete resolution occurs over 8–12 weeks, however, some children retain a residual esotropia after numerous recurrences and require surgical correction.55,449,565 Because strabismic amblyopia may develop prior to resolution,349 we generally institute part-time occlusion therapy for children in the amblyogenic age range at the initial office visit. The diagnosis of benign recurrent sixth nerve palsy can be suspected on the initial visit on the basis of the following information: (1) acute onset, (2) complete absence of abduction, (3) antecedent febrile viral illness, (4) absence of other cranial nerve dysfunction, and (5) absence of signs and symptoms of elevated intracranial pressure. Because there are numerous causes of sixth nerve palsy in children (Fig. 6.8), we obtain neuroimaging for all initial episodes of sixth nerve palsy in children, although we rarely repeat these studies for recurrent episodes. However, if an apparently benign sixth nerve palsy in a child with negative neuroimaging studies improves but fails to completely resolve, neuroimaging should be repeated, because this scenario has been noted in children who are ultimately found to have a pontine glioma on repeat neuroimaging.597 When an otherwise normal child presents with idiopathic sixth nerve paresis, clinical features suggestive of later recurrence include female sex, left eye involvement, younger age, and recent vaccination.614 Recurrence is less likely if it has not occurred within 1 year of the initial event.614

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Pontine Glioma Brainstem gliomas are particularly common in children. More than 80% appear to arise from the pons. The peak age of onset is between 5 and 8 years.341 They characteristically present with an insidious onset of symptoms and signs, including disturbances of gait, sixth and seventh nerve palsies, headaches, nausea, and vomiting. Neuroradiologically, they produce a diffuse, relatively symmetrical expansion of the pons.341 Larger tumors may elevate the floor of the fourth ventricle to produce obstructive hydrocephalus. Presenting symptoms include ataxia, gait disturbance, and unilateral or bilateral abducens palsy. Esotropia greater at a distance than near may be the presenting abnormality in some children.81 The presence of intact sensory and motor fusion does not preclude the diagnosis of pontine glioma.81 Facial palsies, trigeminal deficits, and palsies of cranial nerves IX and X can also develop. Headache, nausea, and vomiting in the absence of hydrocephalus may develop from irritation of the posterior fossa structures. Open biopsy is generally avoided, as it commonly worsens the neurological picture and may not result in a positive biopsy due to tissue sampling.341 Stereotactic biopsy guided by CT scanning or MR imaging is generally reserved for cases in which there is a major question as to the clinical diagnosis. The prognosis for pontine glioma remains poor, although it has improved with radiation therapy. Favorable prognostic features include neurofibromatosis, duration of symptoms of 1 year or more before diagnosis, calcification present on neuroimaging studies, focal (versus diffuse infiltrating) tumors, exophytic growth, and histopathological features of a low-grade tumor.341,369 Chemotherapeutic regimens have not increased survival. Although the clinical presentation and neuroimaging findings are highly specific for this entity, other conditions rarely produce similar findings. The differential diagnosis of sixth nerve palsies with a thickened pons on MR imaging includes multiple sclerosis, brainstem vascular malformation, Bickerstaff’s brainstem encephalitis, tuberculoma, cysticercosis, and AIDS.341 Because many authors advocate radiotherapy without biopsy, it is important to always consider the possibility of multiple sclerosis (which may improve spontaneously) and to search carefully for other white matter lesions before committing a child with diffuse pontine enlargement to irradiation.188 A compressive etiology should always be ruled out by neuroimaging in the child with unilateral sixth nerve palsy. Skull base tumors (chordoma, meningioma, nasopharyngeal carcinoma, metastasis) predominate in adults, while posterior fossa tumors (pontine glioma, medulloblastoma, ependymoma, cystic cerebellar astrocytoma) can produce unilateral or bilateral sixth nerve palsies in children. The tempo of onset, associated neurological signs, and the pres-

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ence or absence of papilledema provide the most important diagnostic clues, but the possibility should be more definitively evaluated with MR imaging. Mechanism of abducens nerve injury include direct infiltration of the pons and elevation of intracranial pressure (with or without hydrocephalus). Sixth nerve palsy is also a common postoperative complication following neurosurgical resection of posterior fossa tumors in children. Schwannomas and, less commonly, malignant peripheral nerve sheath tumors originating from the trigeminal nerve, rarely present with sixth nerve palsy.461 Associated trigeminal dysfunction should suggest a spaceoccupying lesion.461 Medulloblastoma93 and clival tumors compressing the pons, 321,359 are particularly prone to present with unilateral or bilateral sixth nerve palsies in children. Salvin et al480 described a child who had abducens palsy consequent to a large middle cranial fossa arachnoid cyst that required cystoperitoneal shunting. Chemotherapeutic agents can cause sixth nerve palsy.319 Unilateral sixth nerve palsy in children can also be caused by the acute neurotoxic effects of vincristine therapy for leukemia. Although intracranial aneurysms are rare in children, intracavernous aneurysms rarely cause isolated sixth nerve palsies.180,281

Elevated Intracranial Pressure Elevated intracranial pressure can result in downward displacement of the brainstem, thereby stretching the sixth nerves, which are tethered in Dorello’s canal. In children, an elevation of intracranial pressure may occur in the setting of posterior fossa tumors, neurosurgical trauma, shunt failure, pseudotumor cerebri, venous sinus thrombosis, meningitis, Lyme disease, or hemolytic uremic syndrome.114,152,328 In this context, the sixth nerve palsy may be unilateral or bilateral, and it is almost always partial rather than complete. Sixth nerve palsy due to elevated intracranial pressure summarily resolves when the intracranial pressure is normalized. However, Chiari 1 malformation has been reported to cause bilateral sixth nerve palsy in children367 and adults.434 Because Chiari malformation may be associated with pseudotumor cerebri, it is important to rule out an associated Chiari malformation, especially when the sixth nerve palsy fails to resolve with otherwise successful treatment of the condition.

Infectious Sixth Nerve Palsy Hanna et al214 found abducens palsy in 16.5% of patients with acute bacterial meningitis, compared with 3% for ocul-

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omotor nerve involvement and 3% for facial nerve involvement. The predominance of sixth nerve injury could not be attributed to elevated intracranial pressure, given the low incidence of associated papilledema (3%) in this series. As previously mentioned, cranial neuropathies in the setting of acute bacterial meningitis tend to be multiple and are often bilateral.108 Transient sixth nerve palsy has been reported as a possible meningitic complication in children with chicken pox.397,467

Inflammatory Sixth Nerve Palsy Children with antecedent viral infections may develop limitations of ocular movement characterized initially by bilateral sixth nerve palsies and, subsequently, by impaired adduction and vertical movement, resulting in a diffuse ophthalmoplegia. These neuro-ophthalmologic symptoms, when associated with areflexia, distal paresthesias, and cerebrospinal fluid (CSF) albuminocytologic dissociation, are clinical markers for anti-GQ1b IgG-antibody associated with ophthalmoplegia, which is considered a mild form of Miller Fisher syndrome or a regional variant of Guillain– Barré syndrome.616 The compilation of reported cases suggests that the abducens nerve is more vulnerable to the anti-GQ1b IgG antibody than the other cranial nerves, and that bilateral abducens palsy is a characteristic sign of the pathologic state.485 Sato and Yoshikawa485 described two boys, aged 10 and 12 years, who developed bilateral sixth nerve palsies with increased titers of serum anti-GQ1b IgG antibodies. The anti-GQ1b antibody is more often detected in the sera from patients during the acute phases of Miller–Fisher syndrome, Bickerstaff’s brainstem encephalitis, and Guillain– Barré syndrome with ophthalmoparesis.615 These cases seem to demonstrate a close relationship between ophthalmoparesis and serum anti-GQ1b antibody.103 Cases of external ophthalmoplegia without other neurologic symptoms associated with the anti-GQ1b antibody have also been reported.615 Patients with bilateral sixth nerve palsy and mild neurologic symptoms are sometimes classified as having atypical Miller Fisher syndrome.103 Conversely, this syndrome can produce ataxia in the absence of ophthalmoplegia.315 Many patients with atypical Miller Fisher syndrome improve spontaneously, even without plasmapheresis or intravenous immunoglobulin therapy.485 Although the abducens nerve appears more susceptible to the anti-GQ1b IgG antibody in young people, an immunohistochemical study showed that the GQ1b epitope was expressed mainly in the paranodal regions of the oculomotor, trochlear, and abducens nerves, and that the oculomotor nerve had the highest content.103,485

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Rare Causes of Sixth Nerve Palsy Sixth nerve palsy is occasionally seen in children with otherwise typical features of ophthalmoplegic migraine.340 In this setting, lateral rectus muscle function can be expected to be recovered. In infantile botulism, total ophthalmoplegia has been reported to evolve into bilateral sixth nerve palsies and then into comitant esotropia with bilateral inferior oblique overaction.127 Schroeder and Brieden reported on a 17-year-old girl who developed a transient bilateral sixth nerve palsy associated with Ecstasy abuse.495 Children with elevated intracranial pressure or hydrocephalus occasionally develop a sixth nerve palsy following lumbar puncture or shunting procedures.162 Children without elevated intracranial pressure can also develop a sixth nerve palsy following diagnostic lumbar puncture or myelography.150,431 The mechanism of injury is thought to involve caudal displacement of the brain after loss of CSF support in the basal cisterns.549 The abducens nerve may be most susceptible to traction, as it changes direction at the petrous ridge to pass forward under the petroclinoid ligament. Gradenigo syndrome is a vanishingly rare condition in which severe mastoiditis extends from the mastoid air cells to the tip of the petrous bone, producing localized inflammation of the meninges in the epidural space and paresis of the ipsilateral sixth nerve with very intense pain localized to the temporal and parietal regions.196,442 Ipsilateral facial weakness may also develop. More commonly, the association of sixth nerve palsy with mastoiditis in children results from contiguous inflammatory venous sinus thrombosis with elevation of intracranial pressure114,317,569,618 The treatment of true Gradenigo syndrome usually consists of mastoidectomy and antibiotics, but rare cases can be managed medically (Fig. 3.4).343

Differential Diagnosis The differential diagnosis of sixth nerve palsy in childhood is summarized in Table 6.5.

Duane Retraction Syndrome Duane syndrome is probably the most common pediatric disorder associated with an isolated abduction deficit.151 Although Duane syndrome is simply a congenital sixth nerve palsy with peripheral misdirection, its clinical features and prognosis differ from other forms of sixth nerve palsy and warrant a more detailed discussion. Duane syndrome is a common disorder of unknown etiology in which decreased or absent lateral rectus innervation by the sixth nerve occurs in conjunction with misdirected innervation to the lateral rectus muscle from a branch of the third nerve. This neural misdirection leads to

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Table 6.5 Differential diagnostic considerations of sixth nerve palsy in childhood

Genetics

Duane syndrome Myasthenia gravis Spasm of the near reflex Medial orbital fracture with entrapment Longstanding esotropia with medial rectus muscle contracture Ocular neuromyotonia Graves’ ophthalmopathy

Some forms of familial Duane syndrome is caused by mutations in the gene CHN-1, on chromosome 2q31 that encodes alpha2-chimaerin, a signaling protein implicated in the pathfinding of corticospinal neurons in mice.378 However, the gene loci of Duane syndrome have been mapped on 8q, 2q,17,111,163 and 1q,265 indicating genetic heterogeneity. The transcription factors SALL4 and HOX1A have been iden tified as the genes mutated in Duane syndrome with radial anomalies, and in Duane syndrome with deafness, vascular anomalies, and cognitive deficits, respectively.160 SALL4 mutations on chromosome 20q13.13–13.2 have been found in patients with Okihiro syndrome, Holt–Oram syndrome, and acro-renal-ocular syndrome, explaining the considerable clinical overlap of these disorders.7,44,263,289 The distinction between Duane syndrome and sixth nerve palsy can readily be made in a cooperative child but may be difficult in an infant. Jampolsky251 has cautioned that one cannot rely on palpebral fissure changes during sidegaze to identify globe retraction, because the palpebral fissure may normally widen in abduction and narrow slightly in adduction. Rather, one must directly observe the globe from a lateral view as the eye is moved from its position of maximal abduction into a position of adduction. The discrepancy between the primary gaze deviation and the degree of abduction deficit often provides an additional clue to the presence of Duane syndrome in an infant. For instance, it is not uncommon for a patient with Duane syndrome to be orthotropic or almost orthotropic despite the complete absence of abduction in one eye. In contrast, a complete unilateral sixth nerve palsy produces about 35 diopters of esotropia at near fixation. The distinction between Duane syndrome and sixth nerve palsy in infancy is also aided by having the infant view a toy with the affected eye in adduction and performing a quick alternate cover test. The infant with Duane syndrome is exotropic in this position due to cocontraction of the lateral rectus muscle, whereas the infant with a sixth nerve palsy is orthotropic or esotropic.

cocontraction of the lateral rectus muscle and a characteristic retraction of the globe on attempted adduction. The anomalous recruitment of the paretic lateral rectus muscle in attempted adduction can lead to a variety of bizarre motility disturbances, some of which have only recently been recognized as epiphenomena of Duane syndrome. Clinically, most children with Duane syndrome exhibit the following common features: (1) Limited abduction, (2) widening of the palpebral fissure on attempted abduction, and (3) retraction of the globe with narrowing of the palpebral fissure on attempted adduction.512 Although adduction is always limited because of lateral rectus cocontraction, it often appears to be full because the globe retracts. About 22% of children with Duane syndrome have significant enophthalmos of the involved eye in the primary position, which occasionally is the most disfiguring aspect of the syndrome.512 Children with Duane syndrome rarely complain of diplopia, although they can recognize two images when forced to gaze in the direction of the paretic lateral rectus muscle. About 50% are orthotropic or esotropic in the primary gaze position, adopting a small face turn.9 For this reason, amblyopia is uncommon in Duane syndrome,512 but binocular sensory function and stereoacuity may be reduced.109,522,551 Unilateral Duane syndrome is more common in females and involves the left eye more often than the right.381 Duane syndrome is unilateral in about 86% of cases and bilateral in 14%.277 Bilateral Duane syndrome is associated with a higher prevalence of strabismus in the primary position and, unlike unilateral Duane syndrome, is more common in males.277 The types of Duane syndrome tend to be the same in the two eyes, esotropia appears to be more common than exotropia, and amblyopia is rare in bilateral cases,277 although one series244 found a higher incidence of exotropia. Bilateral Duane syndrome appears to be associated with a lower incidence of multisystem disorders.277 Duane syndrome occurs as a sporadic condition in about 90% of cases and is familial in about 10%,134 although the high rate of systemic malformations in first-degree relatives suggests that the inheritance of Duane syndrome may actually be higher.346 In hereditary cases, it is rare to find more than one other affected family member. Familial cases are commonly bilateral and have associated vertical eye movement abnormalities.392a Some reports of bilateral familial Duane retraction syndrome may represent congenital ocular fibrosis syndrome.621

Other Clinical Features of Duane Syndrome With rare exceptions,420,422 an innervational abnormality of the lateral rectus muscle is the underlying cause of all of the associated ocular motility disorders, which are summarized as follows:

Upshoots and Downshoots During adduction of the affected eye, the cocontracting lateral rectus muscle overlies the crest of the globe, and there is maximal retraction. When the eye elevates or depresses

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Fig. 6.15 Child with right Duane syndrome demonstrating: (1) upshoot in adduction and (2) recruitment of lateral rectus muscle in downgaze

in adduction, many children develop an upshoot or downshoot (or both), which may cause the eye to completely disappear under the upper or lower eyelid (Fig. 6.15). Upshoots or downshoots represent a “retraction escape” or “retraction substitute.” The finding that these movements in Duane syndrome are associated with electromyographic (EMG) activity in the superior and inferior rectus muscles initially led to the belief that they resulted from anomalous superior rectus recruitment. However, it has since been shown that increased EMG activity occurs with any retraction of the eye.250 Presumably, these muscles are “taking up the slack” caused by the origins and insertion of the muscle being brought closer together. Because surgically tenotomizing the superior rectus muscle under local anesthesia does not eliminate the upshoot, one must assume that the EMG activity seen in the vertically acting rectus muscles occurs as a result of (rather than causing) the upshoot or downshoot.251 This supposition is supported by the fact that surgically disinserting the lateral rectus muscle under local anesthesia almost completely eliminates the upshoot or downshoot. The longstanding notion that the cocontracting horizontal rectus muscles slip superiorly or inferiorly over the globe (the “bridal theory” or “leash effect”) to produce the upshoot or downshoot has been supported by improvement or resolution when the lateral rectus muscle is recessed by a large

amount, recessed and split, or fixated retroequatorially to the globe.446 However, recent cinematic MR imaging studies by Bloom et al59 show little, if any, vertical displacement of the horizontal rectus muscles. von Noorden575 has argued that these findings confirm (rather than refute) the bridal theory by providing indirect evidence that it is the center of rotation of the globe that slips beneath the muscles as the eye elevates or depresses, rather than vice versa.

Y or l Pattern Some children with Duane syndrome display an abrupt splaying of the eyes into exotropia in upgaze293 (Fig. 6.16). Kommerell and Bach293 described a rare form of Y-pattern Duane syndrome characterized by a unique twitch abduction of the involved eye that was accompanied by a mild retraction of the globe, producing an arc or diamond-shaped trajectory of its rotational path as the patient moves the eyes into upgaze. Abduction remains full in some patients, obscuring the diagnosis of Duane syndrome and simulating primary inferior oblique muscle overaction.310 However, fundus extorsion is absent, and inferior oblique weakening fails to improve the problem. Supraplacement and recession of the misinnervated lateral rectus muscles have been used successfully to normalize ocular rotations.310

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Fig. 6.16 Child with left Duane syndrome demonstrating Y pattern secondary to recruitment of lateral rectus muscles in upgaze. Note minimal abduction limitation despite retraction in adduction. Absence of

alternating hypertropia of adducting eye in sidegaze helps distinguish this condition from primary inferior oblique overaction

This phenomenon results from anomalous recruitment of the lateral rectus muscle in upgaze. A similar phenomenon with a l pattern is less commonly seen in downgaze (Fig. 6.17). The finding of horizontal splaying of the eyes in extreme vertical gaze may cause diagnostic confusion when it occurs in the absence of an abduction deficit (Fig. 6.10). Because abduction may be normal or decreased, Kushner311 has suggested that cases without abduction deficits still fall within the spectrum of Duane syndrome. This rare motility pattern can be distinguished from the more common V-pattern associated with inferior oblique muscle overaction by abrupt divergence of the eyes in far upgaze and the absence of alternating hyperdeviations on sidegaze.311 Kushner has treated this condition with recessions and superior transposition of the lateral rectus muscles.312 This variant of Duane syndrome shows that the aberrant innervation of lateral rectus muscle need not always arise from the medial rectus branch of the oculomotor nerve. Rarely, the vertical rectus muscle rarely cocontracts to produce upshoot or downshoot in Duane syndrome.420

affected eye (termed synergistic divergence)579,593 (Fig. 6.17). Most patients with this phenomenon have a large exotropia and simultaneous nystagmoid movements on attempted adduction of the affected eye.134 The condition is usually unilateral, but bilateral cases have been described.80,128,212,548,583,611 The occurrence of synergistic divergence in several patients with congenital fibrosis syndrome77,80,211 reflects the fact that a primary failure to establish normal neuronal-extraocular muscle connections may underlie this disorder (see Chap. 7). Lateral rectus muscle fibrosis in Duane syndrome is seen histopathologically only in areas of lateral rectus muscle lacking innervation.41,374 In congenital fibrosis syndrome, the paradoxically abducting eye simultaneously abducted and depressed, suggesting that this form of synergistic divergence is attributable to aberrant innervation of the superior oblique muscle.72 Synergistic divergence may occur as a surgical complication following medial rectus recession in patients with Duane syndrome who have marked lateral rectus cocontraction. The treatment of synergistic divergence is difficult, because crippling of the cocontracting lateral rectus muscle is usually necessary to abolish the phenomenon.212 Synergistic divergence poses a complex surgical dilemma that can be eliminated only by crippling the misinnervated lateral rectus muscle. To the extent that bilateral lateral rectus muscle recession is necessary to treat the associated exodeviation, recessing the contralateral lateral rectus muscle increases the adduction innervation in the misinnervated eye,

Synergistic Divergence Rarely, recruitment of the lateral rectus muscle in attempted adduction can exceed the force produced by the medial rectus muscle, resulting in a paradoxical abduction of the

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Fig. 6.17 Child with right Duane syndrome demonstrating synergistic divergence on attempted left gaze. Used with permission from Hamed et al212

which tends to augment its anomalous abduction. Thus, when bilateral lateral rectus muscle recession is necessary to treat the baseline exotropia, the misinnervated lateral rectus muscle must be weakened to the extent that it provides less force than the normal medial rectus muscle. Rarely, synergistic divergence accompanies other complex syndromic disorders.545

Rare Variants

Fig. 6.18 Axial MR scan demonstrating absence of abducens nerve in child with Duane syndrome. Courtesy of Joseph Demer, M.D.

Kesen et al273 described a 5-year-old girl with Duane syndrome who exhibited synergistic convergence with retraction of the globe in abduction and widening of the palpebral fissure in adduction. Cases of “inverse” Duane syndrome (widening of the palpebral fissure in adduction) may be attributable to excessive tightening of the medial rectus muscle due to excessive diversion of its innervation to the lateral rectus

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muscle.330 Khan275 described a patient with bilateral “inverse” globe retraction on abduction, and two siblings with ptosis and abnormal synkinetic lid elevation associated with ipsilateral abduction276 have been described. Other bizarre examples of ocular motor synkinesis in combination with insertional abnormalities of the extraocular muscles have also been described.416

Systemic Associations Duane syndrome may be associated with one or more additional systemic findings in about 33% of cases.72,217 Associated conditions most commonly involve the ears, spinal column, kidneys, heart, and upper limbs.578 High-tone hearing loss or sensorineural deafness is found in about 10% of patients with Duane syndrome.285,456,512,513 Conversely, Duane syndrome was found in seven of 500 deaf children, and a horizontally noncomitant strabismus was found in an additional four.6 Crocodile tears (gustatory tearing) can accompany unilateral or bilateral Duane syndrome and are often overlooked.51,520,619,620 Wildervanck syndrome (cervico-oculo-acoustic syndrome) comprises bilateral Duane syndrome, a cervical malformation known as the Klippel–Feil anomaly, and deafness.142 Female predominance is much more marked in Wildervanck syndrome than in Duane syndrome.86 Hypoplasia and other anomalies of the brainstem and cerebellum often accompany this condition.36,76 Other systemic associations include Okihiro syndrome (an autosomal dominant disorder consisting of Duane syndrome,44 radial ray anomaly [manifesting as congenital thenar hypoplasia], and variable sensorineural deafness),110 Holt–Oram syndrome (Duane syndrome with cardiac anomalies),134 acro-renalocular syndrome (radial ray defects, renal anomalies, and ophthalmological abnormalities such as coloboma, microphthalmia, and Duane syndrome,44,288,290,366,546 and branchio-oto-renal syndrome).453 Duane syndrome may also occur as part of the Goldenhar sequence,89 as well as in arthrogryposis multiplex congenita.352,375 The association of familial Duane syndrome and urogenital abnormalities with a defect in chromosome 22 was recently described.129 Numerous other ocular and systemic anomalies have been described with Duane syndrome, most notably Marcus Gunn jaw winking and iris heterochromia.134,512 A contiguous gene syndrome resulting from a de novo 8q12.2–21.2 deletion is characterized by branchiooto-renal syndrome, Duane syndrome, hydrocephalus, and aplasia of the trapezius muscle.453,570 The autosomal recessive HOXA1 variant of bilateral Duane syndrome may be accompanied by autism, carotid artery hypoplasia or agenesis, and deafness.61

6 Ocular Motor Nerve Palsies in Children

Etiology of Duane Syndrome For many years after its initial description, Duane syndrome was attributed to mechanical factors (a tight, paretic lateral rectus muscle that does not abduct and restricts adduction, producing retraction of the globe). Indeed, it is well recognized that contraction of a medial rectus muscle against a tight lateral rectus muscle can produce visible retraction of the globe and simulate Duane syndrome. It is also recognized clinically and histopathologically that the lateral rectus muscle in Duane syndrome tends to be tight and fibrotic. However, EMG studies237,477,506 have conclusively shown that the lateral rectus muscle shows minimal electrical activity in its normal field of action, but that it cocontracts with the medial rectus muscle on attempted adduction, thus explaining retraction of the globe and narrowing of the palpebral fissure. Autopsy studies of two patients with Duane syndrome have demonstrated a total absence of the sixth nerve on the involved side, with innervation of the lateral rectus muscle by an aberrant branch of the third cranial nerve.235,374 In both cases, the lateral rectus muscle was fibrotic in areas lacking innervation but appeared relatively normal where innervated. The portion of the sixth nerve nucleus corresponding to the abducens cell bodies was also deficient. High-resolution MR imaging can now confirm the absence or hypoplasia of the intracranial abducens nerve in vivo (Fig. 6.18).137,140,263,423,427 One study by Demer et al139 found that, in contrast to the severe lateral rectus atrophy that accompanies chronic sixth nerve palsy, aberrant innervation allows for sparing of the normal lateral rectus size in Duane syndrome.263 However, a subsequent study by the same authors137 found absence of the abducens nerves, hypoplasia of the oculomotor nerve, and hypoplasia of many of the involved extraocular muscles. Although the diagnosis of Duane syndrome does not warrant neuroimaging, exceptional reports of tumors with possible causal associations have been reported.75,517 The degree to which sporadic mutations in the signaling proteins such as SALL4,160 HOX1A,160 and CHN-1,378 which underlie many hereditary and syndromic forms of Duane syndrome, play a causal role in isolated cases is unknown.

Classification of Duane Syndrome on the Basis of Range of Movement Huber237 classified Duane syndrome into types I, II, and III, depending on the pattern of horizontal movement abnormality that accompanied the anomalous lateral rectus innervation. Type I Duane syndrome, which is by far the most common form, is characterized by severely limited abduction with

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mildly limited adduction with retraction of the globe and narrowing of the lid fissure on attempted adduction. Type II (the rarest) has limited or absent adduction, with relatively normal abduction and retraction of the globe, with narrowing of the lid fissure on attempted adduction. The adduction deficit in type II Duane syndrome can superficially resemble a partial third nerve palsy (Table 6.2). Patients with type III Duane syndrome demonstrate reduced abduction and adduction and have retraction of the globe and narrowing of the lid fissure on attempted adduction. These three types have recently been shown to have differing mean age at presentation, primary position horizontal deviation, upshoot and downshoot, and associated systemic abnormalities.381 Nevertheless, surgical management is predicted on para meters that generally fall outside the realm of this classification system.

Embryogenesis The embryogenesis of Duane syndrome is yet to be elucidated.552 It is not known (1) what circumstances unique to embryogenesis allow for axonal sprouting of the third nerve to innervate the lateral rectus muscle, (2) what is the critical time period in embryogenesis for this type of misinnervation to occur, (3) why neural misdirection occurs preferentially from the medial rectus branch of the third nerve, (4) where along the course of the sixth nerve the injury occurs, and (5) why decreased lateral rectus muscle innervation in utero leads to muscle fibrosis. There is strong circumstantial evidence to suggest that at least some cases of Duane syndrome are caused by a brainstem injury. Such an injury would have to involve the fascicular portion of the nerve, because affected patients have no evidence of a horizontal gaze palsy (i.e., normal adducting saccades in the opposite eye). Furthermore, autopsy studies have demonstrated the selective absence of the cell bodies corresponding to abducens motoneurons with selective preservation of rostral cell bodies believed to represent internuclear neurons.374 Jay and Hoyt253 found a high incidence of abnormal latencies of brainstem auditory evoked responses (BAER) in Duane syndrome. The hearing loss noted in a significant number of patients with Duane syndrome454,511 would seem to fit with the abnormalities in BAER. However, auditory function testing and otolaryngologic examination have also implicated associated middle ear disease and cochlear abnormalities in some patients, indicating that a thorough auditory evaluation should be undertaken in all children with Duane syndrome.454 Ramsay and Taylor445 found a high incidence of Duane syndrome in patients with crocodile tears (which is caused

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by seventh nerve misdirection). Miller371 found classic Duane syndrome in 31% of patients with thalidomide embryopathy, while other exposed patients had horizontal gaze palsies, facial weakness, and VIII nerve deficits. The clustering of these effects in patients with early thalidomide exposure suggests teratogenic injury involving the dorsal pons. However, experimental denervation of peripheral cranial nerves in the cavernous sinus of kittens has also led to peripheral misdirection with retraction movements,596 suggesting that an extra-axial sixth nerve fascicular injury can also eventuate in Duane syndrome. Two theories exist as to the early events in the ontogenesis of the extraocular muscles. One holds that the anlagen of each muscle condenses from one of three distinct myogenic precursors, separately and at different times.186 The alternative theory509,510 is that the extra-ocular muscles develop concurrently from a single mesenchymal condensation that subsequently divides into separate superior and inferior mesodermal complexes. According to this theory, individual extra-ocular muscles may receive contributions from both mesodermal complexes or may arise from only one complex. During organogenesis, the developing brainstem also is segmented into regions known as rhombomeres that give rise to the cranial nerves.336 Each of the ocular motor nerves arise from particular rhombomeres, thereby establishing the segmental nature of the cranial nerves. A caudal-to-rostral internuclear gradient for the genesis of oculomotor motoneurons has been described in rats.10,11 Most motoneurons in abducens, trochlear, and oculomotor nuclei are postmitotic by the time the eye muscles are forming. Recent studies suggest that aggregates of myoblasts may be contacted by oculomotor nerves prior to migration and carry their innervation with them into the developing orbit.30,32,580,581 Whether innervation first occurs in the orbit or while myoblasts are still adjacent to the neural tube, the close proximity of the anlagen of the extraocular muscles may actually facilitate development of anomalous innervation of eye muscles. Taken together, these developmental sequences set the stage for the pattern of malformation of which Duane syndrome is the prototype. Specifically, the muscle anlagen are very close to each other and to the nuclei of the brainstem at the time of their innervation, so an oculomotor neural growth cone would have a very short distance to travel to innervate the lateral rectus anlage. Furthermore, the lateral rectus may receive myoblasts from both an upper and a lower anlage, rendering at least partial innervation by the third nerve, which also supplies upper and lower anlagen, more likely. A similar outcome has been seen in a transgenic mouse model in which the oculomotor and trochlear nuclei are absent and the abducens nerve sprouts to innervate extraocular muscles other than the lateral rectus.438

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Surgical Treatment of Duane Syndrome The innervational anomalies in Duane syndrome produce a variety of ocular motility disturbances that dictate the proper surgical management. The fundamental abnormality in Duane syndrome remains the aberrant or inappropriate innervation of the lateral rectus muscle by a branch of the oculomotor nerve. The position of the eye at rest; positions of comfortable binocular vision; and relative amounts of abduction, adduction, and retraction depend upon a continuum of the power of cocontraction of the lateral rectus muscle and, to a lesser extent, the amount of contracture that has developed in the lateral rectus muscle.444 The general principles that guide the surgical approach to the child with Duane syndrome include the following:

Esotropia in Duane Syndrome 1. Most children with Duane syndrome who require surgical treatment have an esotropia with a compensatory face turn to fuse. In this setting, unilateral recession of the medial rectus muscle in the involved eye is often sufficient to restore ocular alignment in primary gaze.175 In Duane syndrome, however, the size of the necessary medial rectus recession varies for a given deviation, depending on the amount of cocontraction in primary gaze. Surgical treatment of esotropia in Duane syndrome is fraught with pitfalls because a given deviation may be associated with either mild or severe cocontraction of the lateral rectus muscle. From a surgical point of view, it is useful to view Duane syndrome with esotropia as existing on a continuum from congenital sixth nerve palsy (i.e., cases with only minimal lateral rectus cocontraction) to cases with severe cocontraction, which tend to manifest with upshoots and downshoots. The most important (and overlooked) step in the preoperative evaluation of Duane syndrome with esotropia is to attempt to assess the amount of cocontraction on the basis of clinical findings. In a child with minimal cocontraction, even a large medial rectus recession (e.g., 7 mm) may be insufficient to restore ocular alignment (as would be the case with a sixth nerve palsy). In a child with marked cocontraction, even a moderate medial rectus recession may unleash the cocontracting lateral rectus muscle and produce postoperative exotropia, limited adduction, and iatrogenic synergistic divergence. In addition to observing the degree of retraction of the globe in attempted adduction, the amount of lateral rectus cocontraction can be judged by observing the degree of

6 Ocular Motor Nerve Palsies in Children

face turn relative to the degree of esotropia. A large face turn relative to the degree of esotropia (as would be seen in a sixth nerve palsy), suggests that there is minimal lateral rectus cocontraction and that a large medial rectus recession is, therefore, required to realign the eyes.200 A smallerthan-expected face turn in the presence of a large esotropic deviation suggests the presence of marked lateral rectus cocontraction in primary position because even mild adduction produces sufficient cocontraction to realign the eyes. In this circumstance, a large medial rectus muscle recession to improve the primary position alignment of the eye leaves the strongly cocontracting lateral rectus muscle unopposed in primary position, resulting in a consecutive exotropia. In gaze away from the affected eye, the cocontracting lateral rectus muscle, which is now unopposed, may now abduct (rather than adduct) the affected eye, resulting in postoperative synergistic divergence. If this complication can be anticipated by preoperative examination, it can be avoided by performing only a small recession of the medial rectus of the affected eye (e.g., 3 mm) along with a large (e.g., 8 mm) recession of the medial rectus muscle in the unaffected eye.492 This leads to a mild limitation of adduction of that eye, but serves the purpose of aligning the eye in primary position without allowing the lateral muscle of the affected eye to overwhelm its antagonist when it cocontracts. It also minimizes the risk of postoperative synergistic divergence.195 Marked enophthalmos in the Duane eye also suggests that a large amount of cocontraction is present. The finding of normal saccadic velocities of adducting saccades in Duane syndrome also suggests minimal contraction, while a decreased adducting saccadic velocity suggests significant cocontraction.609 Although isolated medial rectus recession in the normal eye is also efficacious.492 This procedure can produce a prominence of the globe that contrasts sharply with the enophthalmos of the affected eye. 2. Although some have treated Duane syndrome with recess– resect procedures,384 lateral rectus muscle resections are generally to be avoided. The lateral rectus muscle is already short, tight, and innervationally abnormal in Duane syndrome. Resection of this muscle creates the risk of producing disfiguring enophthalmos, severely limiting adduction and producing iatrogenic synergistic divergence. 3. Although transposition procedures of the vertical rectus muscles can increase abduction, vertical rectus muscle transpositions have the benefit of increasing abduction.70,468,530,539,563 They have the potential to induce a vertical deviation and disrupt fusion, especially in patients with marked cocontraction. Many strabismus surgeons, therefore, favor the inherent simplicity of unilateral or bilateral medial rectus recessions.39,306

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Abducens Nerve Palsy

Duane Syndrome with Exotropia Primary gaze position exotropia is rare in children with Duane syndrome. It is a progressive condition that becomes symptomatic in older adults when the degree of exotropia cannot be comfortably compensated by a face turn. In the setting of a large-angle exotropia, Duane syndrome often goes unrecognized because the adduction limitation may be attributed to a secondary lateral rectus muscle contracture. The clue to the diagnosis lies in the seemingly paradoxical finding of limited abduction in a patient with large-angle exotropia. This scenario exemplifies the importance of distinguishing the position of the globe (which may merely reflect muscle tightness) from the contractility of the muscles. Surgery usually consists of large (as much as 15 mm from the insertion) unilateral or bilateral lateral rectus recessions.38 The usual dose–response curve of millimeters of surgery to diopters of correction does not apply to Duane syndrome due to the combination of contracture and cocontraction. Patients must be forewarned that, although the position of the eye will be transferred to primary gaze, the eye will be unable to move laterally following surgery. Due to the propensity of the lateral rectus muscle to undergo progressive contracture in all exotropic patients, recurrences and undercorrections are common. There are several options in the surgical management of upshoot or downshoot on adduction. The lateral and medial rectus muscles can both be recessed, decreasing the amount of force on the eye in adduction, allowing the muscle to stay on the main arc of the eye.574 The distal lateral rectus muscle can be longitudinally split, with the upper and lower segments reattached above and below the horizontal main arc of the eye, making it impossible for the globe to slip over or under the lateral muscle when it cocontracts.302 Alternatively, a posterior fixation suture of the lateral rectus muscle may be used to prevent the eye from slipping above or below the cocontracting horizontal rectus muscles.574 Lateral rectus muscle fixation to the orbital wall has been used to treat Duane syndrome with exotropia and effectively eliminates upshoots and downshoots.69,564

Bilateral Duane Syndrome Surgical repair of bilateral Duane syndrome with esotropia is especially problematic because of the presence of bilateral cocontraction. In this setting, even moderate (5 mm) bimedial recessions may produce a medial rectus “fixation duress” in the fixating eye while at the same time unleashing the cocontracting lateral rectus muscle in the nonfixating eye, leading to a large consecutive exotropia.251 It is usually necessary to

decrease the size of the medial rectus recession from those provided by standard dose–response formulas. Large lateral rectus recessions for Duane syndrome with exotropia can simultaneously treat upshoots and downshoots.

Management of Sixth Nerve Palsy Children with sixth nerve palsy from head trauma should be observed for 6 months prior to surgical intervention because most recover spontaneously. Sixth nerve palsy in children is associated with a high rate of permanent strabismus and amblyopia.20 For children in the amblyogenic age range, we utilize part-time occlusion of the fixating (usually nonparetic) eye to prevent amblyopia or treat it if it has already developed. This therapy also stimulates abduction of the paretic eye, thereby minimizing the chance of contracture formation. Patching the unaffected eye also stimulates maximal inhibition of the medial rectus muscle to establish the most appropriate head position possible, thus minimizing the potential for a secondary medial rectus contracture to develop.502 Prisms are rarely helpful in the recovery phase due to the horizontal incomitancy of the deviation. The indications for botulinum injection for acute sixth nerve palsy in children are controversial.363 We reserve medial rectus botulinum injection for children with a severe palsy who would have to assume an uncomfortably large face turn to fixate with the paretic eye. It has not been found to be efficacious in children with sixth nerve palsy secondary to brain tumors.272 Its long-term superiority over simple observation has not been documented. Residual esodeviations in children with sixth nerve palsy can result from incomplete neural recovery, from a medial rectus contracture, or both. Children who show incomplete recovery after 6 months with residual esodeviations in primary gaze are generally treated with strabismus surgery. Surgical treatment in sixth nerve palsy is predicated on the degree of lateral rectus function. Visible abduction past the midline demonstrates the presence of residual lateral rectus function and suggests that a recess–resect procedure will be sufficient to restore ocular alignment. As in Duane syndrome, it is often helpful to perform an additional medial rectus recession and/or a medial rectus posterior fixation suture of the contralateral medial rectus muscle to create a fixation duress to “drive the palsy.” This procedure improves abduction of the paretic eye and leads to a larger postoperative field of single binocular vision. Absence of abduction past midline indicates either a lateral rectus paralysis or severe medial rectus contracture with some lateral rectus function. In this circumstance, the surgical decision is predicated on the clinical estimation or

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measurement of saccadic velocity, the forced duction test, and the forced generation test. In the child with no abduction past midline, the finding of a “floating saccade” as the eye moves from a position of adduction toward primary gaze is a useful clue that the lateral rectus muscle is completely paralyzed.470 In contrast, a rapid saccade from adduction to midline is evidence that the lateral rectus muscle is functioning and that the abduction limitation results from a medial rectus contracture. In cooperative children, a forced generation test is also useful in clinically confirming the presence or absence of lateral rectus function, which can be estimated or felt as a “pull” on the forceps when the child attempts to abduct the paretic eye. These clinical tests can be supplemented by a forced duction test (performed either in clinic or under anesthesia prior to strabismus surgery) to further assess the degree of medial rectus contracture. Children with little or no recovery of sixth nerve function require a transposition procedure of the vertical rectus muscles to the lateral rectus muscle to create a new abduction force.179,254,508 A large resection of a completely paralytic rectus muscle accomplishes little and sacrifices a portion of the anterior ciliary circulation. Vertical rectus muscle transposition can be performed in conjunction with a recession of the antagonist medial rectus muscle469; however, this procedure creates a risk of anterior segment ischemia in adults. A large recession (>7 mm) of the contralateral medial rectus muscle also works well and does not risk anterior segment ischemia. In this setting, most surgeons now utilize augmented vertical rectus muscle transposition.170,171 Because this procedure can induce complicated vertical deviations, however, we have continued to utilize transposition in conjunction with preoperative or intraoperative injection of botulinum toxin into the ipsilateral medial rectus muscle. Botulinum functions as a “chemical traction suture” by creating a temporary medial rectus paralysis, thereby positioning the eye in abduction for several months.167,355,500 Parents must be warned that this procedure creates an initial postoperative exotropia and that continued part-time occlusion therapy will be necessary until the paretic medial rectus recovers. Kraft and Clarke298 found that patients with isolated lateral rectus palsy with a compensatory head posture undergoing surgery to eliminate the head position had a 75.6% incidence of success from the surgery. A therapeutic dilemma arises in the child who is undercorrected after a recess–resect procedure for a complete sixth nerve palsy. In such a case, vertical rectus muscle transposition would disrupt the remaining anterior ciliary circulation, raising the risk of anterior segment ischemia.470,488,490 In this setting, microdissection of the anterior ciliary vessels of the vertical recti prior to transposition reduces the risk of anterior segment ischemia.353 Finally, microsurgical repair has been used to restore functional recovery following surgical transection of the abducens nerve.493

6 Ocular Motor Nerve Palsies in Children

Multiple Cranial Nerve Palsies in Children In a retrospective study of children with cranial nerve palsies, Holmes et al234 found trauma to be the most common cause for multiple cranial nerve palsies. Harley218 described nine children with multiple acquired cranial nerve palsies and found orbital inflammation in four, trauma in three, and a neoplasm in two. Any infectious, inflammatory, or neoplastic disease process confined to the brainstem, skull base, cavernous sinus, or orbital apex can involve multiple cranial nerves.97,239,559 Bilateral trochlear and abducens palsies can follow halo spinal traction in children.435 Oculomotor and abducens palsies can develop following shunt misplacement.221 Bilateral abducens and facial nerve palsies can follow ventriculo-peritoneal shunting.525 The oculomotor and abducens palsies that can arise in the setting of leukemia are recognized to respond to whole-brain radiation.208 Leukemia can cause multiple cranial nerve palsies of unclear etiology. Intrinsic orbital disorders, such as Graves’ ophthalmopathy556 and a syndrome of unilaterally congenitally enlarged extraocular muscles,144 are extremely rare but should also be included in the differential diagnostic considerations. Most congenital disorders with multiple bilateral cranial nerve palsies are now classified as congenital cranial dysinnervation syndromes553 and are discussed in the following chapter. Table 6.6 summarizes the neurological and systemic disorders that, in our experience, warrant consideration in the child with multiple cranial nerve palsies. Most of these conditions are discussed elsewhere.369

Table 6.6 Causes of multiple cranial nerve palsies in children 1. Trauma Basilar skull fractures Closed head trauma without fractures 2. Neoplasm Pontine glioma and other structural brainstem lesions Lymphoma Pituitary apoplexy Metastasis (rhabdomyosarcoma, neuroblastoma, leukemia) Gliomatosis cerebri 3. Inflammation Guillain–Barré disease Multiple sclerosis Acute disseminated encephalomyelitis Neurosarcoidosis Graves ophthalmopathy 4. Infection Acute bacterial meningitis Septic cavernous sinus thrombosis Brainstem cysticercosis 5. Congenital Congenital Cranial Dysinnervation Syndromes (CCDS) 6. Teratogenic Thalidomide exposure

References

Congenital hereditary facial palsy is another isolated hereditary condition with two separate loci on chromosome 3q and 10q.566 Neuropathology shows a decreased number of neurons in the facial motor nucleus, with no signs of neuronal loss, gliosis, or calcifications, and no other structural abnormalities of the rhombencephalon (i.e., a developmental hypoplasia limited to the facial motor neucle rather than a primary developmental disorder of the entire lower brainstem).566 As discussed in Chap. 7, Möbius syndrome must also be distinguished from the autosomal dominant syndrome of horizontal gaze palsy and progressive scoliosis.148

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Recent advances in chemodenervation, electrical stimulation, muscle reinnervation, and the development of injectable agents to promote new muscle growth are promising future additions to the armamentarium of the strabismus surgeon.34,452 Substantial research has been undertaken to reanimate or replace paralytic muscle and to extend the length of existing muscle with contractile and noncontractile tissues.6,31,32,63,100, 101,106,118,194,230,451,459,460,505 Synthetic materials have been used to replace the superior oblique tendon and the lateral rectus muscle in some patients. Research is also under way to reinnervate denervated extra-ocular muscles and to re-establish the neural supply of damaged extra-ocular muscles in animals that may be applicable to humans in the near future.

Horizons High-resolution MR imaging oriented to the trajectory of the cranial nerves136–139 can now demonstrate the cranial nerves as they emerge from the brainstem, allowing neuroimaging confirmation of cranial nerve palsies. Furthermore, diffusion tensor tractography may offer a new way to potentially identify small infarcts of the cranial nerves within the brainstem.608 In diffusion tensor tractography, the MR signal is sensitized to the random motion (diffusion) of water molecules to provide local measures of the magnitude of water diffusion, which can be related to fiber structure in the brain. Diffusion is anisotropic in white matter (in contrast to CSF, in which diffusion is isotropic) with the preferred directions of diffusion parallel to axons. Hence, fiber tracts consisting of coherently oriented axons can be visualized using diffusion tensor imaging, which provides us with measurements of the preferred directions of diffusion at each voxel, the degree of anisotropy of the diffusion displacement distribution and the average magnitude of diffusion. Further computational analysis is then used to reconstruct white matter fiber tracts in 3D, allowing assessment of connectivity between different regions.120,258,386 Dynamic MR imaging should now be able to document cocontraction of the extraocular muscles in real time.432 Current surgical therapies for paralytic strabismus are based primarily on recession, resection, and transposition of extraocular muscles. Although these techniques improve alignment and motility, they frequently produce an incomplete solution to the complex static and dynamic motility problems that can arise in this setting. Current therapies rarely achieve full rotation in the field of action of the paretic muscle, and new limitations of ductions can be created by the surgical attempts to align the eyes in the primary position, resulting in large areas of diplopia. The best rotations following paralytic strabismus are achieved by the various muscle transposition procedures, but a review of the surgical results illustrates that none achieve normal rotation. New treatment techniques to provide greater rotation of the eyes in paralytic strabismus are currently being developed.

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6 Ocular Motor Nerve Palsies in Children 619. Zhang F. Clinical features of 2001 cases with Duane’s retraction syndrome. Zhonghua Yan Ke Za Zhi. 1999;35:280–282. 620. Zhang F. A clinical analysis of 25 cases with Duane’s retraction syndrome combined with congenital crocodile tears. Zhonghua Yan Ke Za Zhi. 2002;38:217–219. 621. Zhu-Tam LY, Gurwood AS. Bilateral familial Duane’s retraction syndrome. Optometry. 2007;78:465–468. 622. Znajda JP, Krill AE. Congenital medial rectus muscle palsy with simultaneous abduction of the two eyes. Am J Ophthalmol. 1969; 68:1050–1052.

Chapter 7

Complex Ocular Motor Disorders in Children

Introduction A number of complex ocular motility disorders are discussed in this chapter. The diversity of these conditions reflects the need for the ophthalmologist to maintain a broad working knowledge of pediatric neurologic disorders along with their ocular motor manifestations. Some clinical features of these conditions (e.g., congenital ocular motor apraxia, congenital fibrosis syndrome) are sufficiently unique that the diagnosis can be established solely on the basis of the clinical appearance. Other disorders either show overlapping manifestations or effectively masquerade as other entities. Unique features of some conditions, such as conjugate ocular torsion in patients with skew deviation, have been recently recognized and are considered worthy of emphasis because they significantly expand the differential diagnosis. Indeed, assessment of objective torsion (and subjective torsion when possible) is a necessary component of any comprehensive strabismological evaluation.323 Correction of coexisting torsion can be integrated into the surgical plan, except when the torsion serves a compensatory function, as in patients with skew deviation. Although the clinical history and physical examinations remain the “gold standard” for establishing the diagnosis, neuroimaging has become an integral part of the diagnostic evaluation. High-resolution neuroimaging can now depict the presence or absence of most ocular motor nerves and the size, position, and dynamic function of the extraocular muscles. In patients with craniosynostosis, for example, heterotopic extraocular muscles within the orbit can produce a motility disorder indistinguishable from innervational inferior oblique muscle overaction,736 absence of the isolated extraocular muscles can produce complex ocular motility dysfunction, and retrodisplacement of the trochlea can produce a motility pattern indistinguishable from congenital superior oblique palsy.580 Optimal surgical treatment depends on accurate recognition of the specific cause of a given patient’s motility disturbance.204 Thus, a detailed knowledge of clinical findings that characterize each condition is necessary to perform the diagnostic workup in an efficient, timely, and

cost-effective manner. A knowledgeable clinician is less likely to embark on “fishing expeditions.” The emphasis of this chapter is on ocular motility disorders of neurologic origin and their differential diagnosis. The most current pathophysiologic concepts of the disorders are summarized. A section at the end of the chapter is devoted to a few common eyelid and pupillary abnormalities encountered in children. Some of these disorders, such as excessive blinking in children, commonly represent benign transient tics that receive very little attention in the ophthalmologic literature, but are not rare in clinical practice. These bear only superficial resemblance to the more chronic benign essential blepharospasm of adults although, rarely, childhood tics and adult blepharospasm show clustering in the same family, suggesting a possible link. Occasionally, underlying ocular surface abnormalities and seizure disorders may be uncovered in children with excessive blinking. Other disorders, such as hemifacial spasm, which is more common in adults, may be the harbingers of more serious central nervous system (CNS) disorders if encountered in very early childhood. Pediatric Horner syndrome is treated in some detail at the end of the chapter, owing to its potentially ominous association with certain neoplasms, especially neuroblastoma. The human immunodeficiency virus (HIV) infection has joined the ranks of other great mimickers (e.g., myasthenia gravis, syphilis), with an ever-expanding list of neuro-ophthalmologic manifestations. No part of the nervous system is spared. Even though it is not specifically covered in this chapter, HIV-related neurological disease should be included in the differential diagnosis of childhood ocular motor disorders of cortical, brain stem,343 cerebellar, or peripheral nervous system origin.

Strabismus in Children with Neurological Dysfunction Common neurologic disorders of children are frequently associated with strabismus. These include cerebral palsy, Down syndrome, myelomeningocele, and hydrocephalus.

M.C. Brodsky, Pediatric Neuro-Ophthalmology, DOI 10.1007/978-0-387-69069-8_7, © Springer Science+Business Media, LLC 2010

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The features of the associated strabismus are often indistinguishable from the varieties found in otherwise normal children, but sufficient differences exist in a distinct minority of neurologically affected children to warrant separate consid-

7 Complex Ocular Motor Disorders in Children

eration. Children with neurologic disorders, who have horizontal strabismus, have a higher prevalence of constant exotropia and primary superior oblique muscle overaction than otherwise healthy strabismic children (Fig. 7.1).334,341

Fig.7.1 (a) Bilateral superior oblique overaction in child with lumbar myelomeningocele. Note resemblance to alternating skew deviation. (b) 1MR imaging characteristically associated Chiari II malformation with pronounced peaking of tectum and herniation of cerebellar vermis into cervical spinal canal

Strabismus in Children with Neurological Dysfunction

Cerebral palsy is perhaps one of the most common conditions seen in a pediatric neuro-ophthalmology practice.32 The term cerebral palsy defines a group of chronic neurologic disorders resulting from damage to the immature brain. Most cases nowadays are due to prematurity. Care should be taken to distinguish the static nature of cerebral palsy from the inexorably progressive neurodegenerative disorders such as Pelizaeus–Merzbacher disease. Cerebral palsy is characterized by the onset of neurologic deficits in the neonatal period and absence of progression. In addition to motor disorders, such as paralysis, weakness, and incoordination, children with cerebral palsy may display sensory deficits, as exemplified by the frequent findings of optic atrophy, deafness, and cortical visual impairment. Patients with cerebral palsy show ophthalmologic abnormalities with a frequency ranging from 50 to 90%. These include optic atrophy, amblyopia, refractive errors, visual field defects, congenital cataracts, corneal leukomas, retinal dysplasia, choroiditis, macular or iris colobomas, retinopathy of prematurity, ptosis, spastic eyelids, abnormal head postures, and ocular motility disorders.395,740 The latter include concomitant strabismus, ocular motor nerve palsy, nystagmus, gaze palsy, and other supranuclear disturbances of ocular movements.489 Children with cerebral palsy have a markedly increased incidence of strabismus.489 The strabismic deviations are usually horizontal and nonparalytic. Associated vertical incomitance is often seen, with A-pattern strabismus being particularly common. In one series, 691 54% of strabismic children with cerebral palsy showed A pattern, and 46% showed V pattern. Variability of the magnitude and direction of the strabismus are commonly noted in cerebral palsy.40 Some studies note a predominance of esotropia,40,489 while others have found exotropia to be more common. Momentary fluctuation from esotropia to exotropia has been termed dyskinetic strabismus and is considered unique to cerebral palsy.129 Dyskinetic strabismus is unrelated to accommodative effort or attention. In addition to the dyskinetic strabismus of cerebral palsy, the differential diagnosis of a variable strabismus shifting from exotropia to esotropia includes exotropia with a high AC/A ratio, as well as surgically overcorrected accommodative esotropia with high AC/A ratio, and exotropia with dissociated horizontal deviation. Patients with oculomotor palsy with cyclic spasm may also appear to switch from exotropia to esotropia during a spasm phase, but the associated features are unique enough to obviate diagnostic confusion. Generally, the subset of children with cerebral palsy who exhibit dyskinetic strabismus are poor candidates for surgical correction. Children with stable deviations respond favorably to strabismus surgery, although their overall outcome is not as good as in strabismic children without cerebral palsy.198,364 Unlike children with infantile esotropia, some

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esotropic children with cerebral palsy convert spontaneously to an exotropia over several years. For this reasons, current trends toward early surgery for infantile esotropia should not be loosely applied to these patients, and it is important to rule out occult neurologic disease when early strabismus surgery is contemplated in seemingly normal children. As children with cerebral palsy and esotropia seem to have a strong predilection for surgical overcorrection,371 standard surgical doses for treating esotropia should be reduced. In our experience, however, it is not necessary to reduce doses for bilateral lateral rectus muscle recession in neurologic exotropia. As detailed in Chap. 1, children with cerebral palsy may have abnormalities of gaze affecting pursuit and saccadic movements and vestibulo-ocular reflex suppression by fixation.417,618 The craniosynostosis syndromes often present with complex forms of horizontal and vertical strabismus that are both neurologic and anatomical in origin.144,206,280,541,558,580,646 Although hypertelorism is classically associated with exotropia with a V pattern, esotropia can also be seen.431 Good stereopsis is rare in the syndromic craniosynostosis and may sometimes be confined to certain positions of gaze.576 Some patients develop esotropia following craniofacial surgery, which can disrupt stereopsis.788 The frequent finding of overelevation of the adducting eye in children with bilateral craniosynostosis was previously attributed to recession of the frontal processes, creating a mechanical disadvantage for the superior oblique muscle. It now appears that excyclorotation of both orbits alters the horizontal rectus muscle positions, positioning the lateral rectus muscles lower than normal and the medial rectus muscles higher than normal (Fig. 7.2).156 This orbital excyclorotation is associated with marked excyclorotation of the globes, as is evident on retinal examination.736 Although the resulting motility pattern is indistinguishable from that produced by primary inferior oblique muscle overaction, inferior oblique weakening procedures produce negligible improvement. Rectus muscle transposition,172 in addition to superior oblique muscle strengthening (Harado–Ito procedure), is necessary to treat this condition. Other mechanisms for vertical deviations in the craniosynostosis include absent or anomalous superior rectus (or other) muscles.517,576,710 Preoperative orbital imaging allows the surgeon to anticipate the multitude of orbital anatomical disturbances that contribute to strabismus in children with craniosynostosis.580

Visuovestibular Disorders Some forms of esotropia and their associated ocular motility signs signify benignity. From a neuro-ophthalmological perspective, horizontal strabismus can be subdivided into the

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7 Complex Ocular Motor Disorders in Children

Fig. 7.2 Craniosynostosis. Left: Coronal orbital MR image in a girl with Crouzon’s disease and bilateral inferior oblique muscle overaction, V-pattern, and fundus extorsion showing excyclorotated extraocu-

lar muscle positions. Inferior oblique recession produced no improvement. Right: Schematic diagram showing affect of extraocular muscle heterotopia on binocular rotations

Table 7.1 Visuovestibular disorders

signify benignity, although it can be argued that they constitute a “physiologic” form of neurologic disease. Although they are more commonly associated with esotropia, patients with early-onset exotropia present with the same constellation of dissociated ocular motor signs discussed in the following lines. Brodsky and Fray117 have theorized that infantile esotropia may itself arise from a dissociated deviation. This occurs when unequal visual input generates dissociated esotonus, which leads to the gradual development of infantile esotropia, and explains the preponderance of infantile esotropia over infantile exotropia in nonneurologic infants.117 Visuovestibular eye movements produce binocular rotations that are evoked by unequal visual input to the two eyes.110 These consist of latent nystagmus, dissociated vertical

Dissociated vertical divergence Infantile esotropia (dissociated esotonus) Latent nystagmus Primary Inferior Oblique Overaction

common conditions that presumably arise from unequal visual input to the two eyes and the less common conditions associated with neurologic disease. The former conditions constitute the visuovestibular disorders (Table 7.1), which may present as acquired and thereby may simulate neurologic disease. As these conditions arise from unbalanced binocular visual input to the central vestibular system, they

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Strabismus in Children with Neurological Dysfunction

divergence, and primary oblique muscle overaction. These preternatural ocular rotations recapitulate the primitive eye movements induced by light or optokinetic stimulation in lateral-eyed animals. They are mediated by subcortical pathways extending from the optic nerves to the contralateral vestibular nucleus and cerebellum. Although present to a small degree in normals, they develop almost exclusively when infantile strabismus precludes the development of normal binocular cortical connections. As these visual reflexes are corrective for a central vestibular imbalance, they are not associated with dizziness, oscillopsia, or other neurologic symptoms that characterize vestibular disease. They are evoked by physiologic stimuli rather than by neurologic lesions. In the clinic, mechanical occlusion of one eye and cortical suppression of one eye can both activate in the subcortical visuovestibular pathways that evoke this visuovestibular response. The resurgence of visuovestibular movements in humans with infantile strabismus shows that our eyes function not only as visual organs, but as balance organs. Because they recapitulate visual reflexes in lateral-eyed animals, the absence of early cortical binocular development is a permissive factor that allows them to develop, the retention of primitive subcortical reflexes is the proximate cause of these movements.110 Infantile strabismus provides a natural experiment to uncover the primitive visual reflexes that lie buried within us. By disrupting the development of frontal binocular vision, infantile strabismus allows these reflexes to “bubble to the surface.” The resulting ocular motor “intrusions” correspond to an imbalance of binocular visual input in three planes of physical space. Latent nystagmus is characterized by conjugate horizontal nystagmus induced by monocular occlusion or cortical suppression. The fast phase (in both eyes) is directed toward the side of the fixating eye. Latent nystagmus corresponds to the optokinetic component of ocular rotation that is driven monocularly by nasal optic flow during a turning movement of the body in lateral-eyed animals.123 When infantile esotropia disrupts the establishment of binocular visual connections, visual input from the fixating eye to the contralateral nucleus of the optic tract evokes a counterrotation of the eyes which corresponds to a turning movement of the body toward the object of regard. The clinical expression of this visual reflex is also evident in the monocular nasotemporal asymmetry to horizontal optokinetic stimulation that characterizes infantile strabismus.123 Dissociated vertical divergence is characterized by an upward drift (sometimes accompanied by a dynamic extorsional movement) of a covered or cortically suppressed eye.105 Dissociated vertical divergence corresponds to the dorsal light reflex that has been observed in fish and other lateral-eyed animals when unequal luminance to the two eyes evokes a body tilt or vertical divergence of the eyes toward the side with greater luminance.105 In humans, dis-

sociated vertical divergence is a visual balancing reflex that uses weighted binocular visual input to orient eye position to the perceived vertical.105 The exaptation of a cycloversional movement into the human dorsal light reflex permits active modulation of perceived visual tilt when the eyes are frontally positioned.105,108,109 Primary oblique muscle overaction consists of bilateral overelevation or overdepression of the adducting eye. Primary inferior oblique muscle overaction corresponds to a similar dorsal light reflex that is induced in fish when a forward or backward shift in overhead luminance evokes an ipsidirectional body pitch or torsional rotation of the eyes backward to reorient the body with respect to the light.107 These binocular torsional rotations of the eyes constitute a physiologic form of primary oblique muscle overaction that can be induced by altering binocular visual input. In humans, a forward or backward rotation relative to overhead light sends excitatory innervation to each of the elevators or each of the depressors. Because the vestibular system segregates innervation to its target extraocular muscles, the vertical actions of the human oblique muscles can summate in adduction with those of the rectus muscles to produce the innervational overelevation of the adducting eye that defines primary inferior oblique muscle overaction. The fundamental association of primary oblique muscle overaction with loss of binocular vision in humans suggests that the brain registers loss of binocular visual input as forward rotation of the body.107 Although primary superior oblique muscle overaction is considered as a sign of neurologic disease (see section on “Skew Deviation”) in the United States and Europe, it is reported to accompany infantile esotropia more commonly than primary inferior oblique overaction in Argentina and South Africa,139,140,167 suggesting that it may also arise from a visuovestibular imbalance.107

Neurologic Esotropia A variety of prenuclear neurologic diseases are characterized by an esotropic deviation of the eyes717 (Tables 7.2 and 7.3). Spielmann has suggested that organic spasm of the near reflex, (Parinaud syndrome with convergence-retraction nystagmus or convergence excess), and thalamic esotropia Table 7.2 Complex neurologic disorders predisposing to esotropia Acute comitant esotropia Congenital cranial dysinnervation syndromes Convergence-retraction nystagmus Exercise-induced diplopia Periventricular leukomalacia (with or without cerebral palsy) Spasm of the near reflex Thalamic esotropia

314 Table 7.3 Exotropia as a sign of neurologic disease Congenital cranial dysinnervation disorders (congenital fibrosis syndrome) Constant exotropia (cortical visual insufficiency, congenital homonymous hemianopia) Convergence insufficiency Intermittent exotropia greater at near fixation than distance fixation

fall into a group of neurological diseases characterized by convergence excess.717 Many of these disorders have been detailed in their specific clinical context in other chapters. As many neurologic patients take medications with strong anticholinergic side effects, esotropia of neurologic origin must be distinguished from anticholinergic esotropia, a condition in which excessive accommodative effort leads to accommodative esotropia. Several recent cases of esotropia induced by systemic anticholinergic medications have recently been described.23,478 Anticholinergic esotropia seems to be precipitated by increased convergence of the eyes due to the increased accommodative effort in patients with an inherent tendency to develop esotropia.

Spasm of the Near Reflex Spasm of the near reflex is characterized by intermittent episodes of miosis, convergence, and accommodation. Patients exhibit variable esotropia and varying pupillary size. Unlike in other patients with intermittent esotropia, monocular refixation during alternate occlusion is often slow and inaccurate. The name “spasm of the near reflex” should not be used interchangeably with either accommodation spasm or convergence spasm, each of which may present separately as a distinct entity.67 Patients with spasm of the near reflex may present with diplopia, blurred vision (especially for distant objects), fluctuating vision, or nonspecific ocular discomfort. Due to its rarity, affected children may be misdiagnosed as having childhood esotropia, and unilateral or bilateral sixth nerve palsy, and, less commonly, divergence insufficiency, horizontal gaze palsy, ocular motor apraxia, convergence retraction nystagmus, true myopia, or Tensilon-negative myasthenia gravis.657 Careful attention to pupillary size, retinoscopy during episodes of spasm to confirm the fluctuating induced myopia, and the variable esotropia should help confirm the diagnosis. The disorder is most commonly considered to be functional in nature, possibly due to underlying emotional conflict, with some patients showing signs of hysteria, malingering, or personality disturbances.51 However, cases associated with organic disorders are occasionally reported, including head trauma, stroke, pretectal lesions, neurosyphilis, labyrinthine dysfunction, diphenylhydantoin intoxication, Wernicke’s encephalopathy, metabolic encephalopathy, Fisher’s syndrome

7 Complex Ocular Motor Disorders in Children

(two cases reported so far), Arnold–Chiari malformation, and photosensitive epilepsy.81,195,442,566,636,694 However, isolated spasm of accommodation can also follow neurologic injury.151 Several patients with intracranial tumors and spasm of the near reflex have been reported.178,195 It should be emphasized that most patients with spasm of the near reflex in association with other neurologic disease have other symptoms and signs that can be readily uncovered during a careful neurologic and neuro-ophthalmologic examination. Spasm of the near reflex in infants and children should be distinguished from nystagmus blockage syndrome and from convergence substitution. The latter is seen in patients with congenital or acquired horizontal gaze paralysis (e.g., Möbius sequence, multiple sclerosis), in which the patient substitutes a convergence movement for a lateral version movement when attempting to fixate an eccentric target. Spasm of the near reflex can manifest in patients with significant hyperopia who are unable to relax accommodation even when plus lenses are used.299 In this context, spasm of the near reflex can mimic deteriorating accommodative esotropia.259,661 We examined a 12-year-old boy who had undergone left medial rectus muscle resection (4 mm) for presumed convergence insufficiency 4 months before. Shortly after the surgery, he complained of fluctuating vision and varying ocular alignment ranging from orthotropia to 80 prism diopters of esotropia. He was noted to have episodic, pronounced spasm of the near reflex associated with severe spasms involving the eyelids and the facial musculature (Fig. 7.3). His neurological evaluation and MR imaging of the head were totally unremarkable otherwise. His symptoms continued unchanged during a follow-up period of 8 months. Patients with isolated spasm of the near reflex may improve with reassurance. Some patients require psychiatric counseling. Current ophthalmologic treatment of spasm of the near reflex involves administering cycloplegic eye drops and providing bifocal glasses for reading. Historically, some patients have shown improvement with miotic drops, placebo drops, benzodiazepines, special glasses with occlusion of the inner third of each lens, monocular occlusion, or narcosuggestion during an amobarbital sodium interview. In patients with underlying organic disease, spasm of the near reflex (like essential blepharospasm) may be a type of dystonia. Like other types of dystonia, some cases respond to botulinum injection.525,585 In patients without organic disease, this problem usually resolves spontaneously over months to years.

Exercise-Induced Diplopia Exercise-induced diplopia has rarely been reported in children.681,763 This condition may represent a breakdown of an esophoria,763 but warrants neuroimaging to rule out a midline cerebellar tumor.681

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Fig. 7.3 Spasm of near reflex. Twelve-year-old boy had undergone small left medial rectus muscle resection for presumed convergence insufficiency. Four months later, he was noted to have episodic, pronounced spasm of

near reflex (large esotropia, miosis, induced myopia with blurred vision) associated with severe spasms involving eyelids and facial musculature (a). In between spasms, only small esotropia was variably present (b)

Neurologic Exotropia

shown to improve proximal and tonic convergence, but not accommodative or fusional convergence.33 Convergence insufficiency is most commonly a primary condition presenting in young adults. In this setting, it is presumably caused by an inborn deficiency or acquired imbalance of vergence eye movements that has yet to be identified.33 In this setting, patients may present with sleeping on reading or near work, tearing, heavy lids, uncomfortable eyes, asthenopic symptoms, double vision, or blepharitis (from frequent rubbing of the eyes). These patients perform their near work optimally immediately after awakening. Convergence insufficiency is also a prominent accompaniment of neurologic disease, having been reported in association with head trauma,19,130,181,450,452,483,719 neurodegenerative disorders,75,125,631 infarction,390,593 thyroid ophthalmopathy,126 myasthenia gravis, toxic agents, medications,125,738 inflammation,125,620 decompression sickness,493 whiplash injuries,134 and attention-deficit hyperactivity disorder (ADHD).310 In the last mentioned condition, it is not always clear whether convergence insufficiency is the cause or effect, whether they are comorbid conditions, or whether medications used to treat the ADHD may contribute to the convergence insufficiency. Some believe that accommodative insufficiency is the primary source of symptoms in children diagnosed with convergence insufficiency,520 although this issue continues to be debated.680 Therefore, accommodative amplitudes and dynamic retinoscopy should be examined to rule out an underlying or associated accommodative paresis.653 It is also important to check for undetected ocular torsion, which can secondarily impair convergence. The potential pharmacological role of any medications in impairing accommodation should always be considered.130 Convergence insufficiency should not be confused with convergence paralysis, another neurologic disorder in which there is a constant exotropia at near. Although convergence exercises are the mainstay of treatment for convergence insufficiency,613 treatment with base in prisms has also been

The differential diagnosis of constant exotropia includes cortical visual insufficiency, craniofacial synostosis, and congenital fibrosis syndrome. Isolated infantile exotropia is a rare but well-recognized nonneurologic condition in which a large-angle exotropia is associated with the same constellation of visuovestibular disorders that accompany infantile esotropia. Some early-onset cases of intermittent exotropia also fall into this group.384 Some cases of infantile exotropia are hereditary, showing an autosomal dominant inheritance pattern.119 Nevertheless, the clinician must maintain a high index of suspicion for neurologic disease in the child with infantile exotropia. In our experience, constant exotropia is most commonly seen in the setting of cortical visual insufficiency secondary to hypoxic-ischemic encephalopathy.118 Associated signs include horizontal conjugate gaze deviation with little or no nystagmus and mild or sectoral pallor of the optic discs.118 Because children with congenital homonymous hemianopia may develop a constant exotropia that serves to expand the existing visual field, confrontation visual fields should be checked in this setting. Signs of craniofacial disease are usually apparent on initial examination. As detailed below, fixed downgaze, associated ptosis, sparing of pupillary function, and similar findings in other family members provide clinical clues to the diagnosis of congenital fibrosis syndrome. Convergence Insufficiency Convergence insufficiency is a common condition characterized by:(1) diplopia or blurring at near, (2) decreased convergence amplitudes, and (3) a recessed near point of accommodation.401 It seems to afflict intelligent patients and is considered to be the one form of strabismus that is treatable with eye exercises. Convergence training has been

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reported to be effective.721 In patients with convergence paralysis or convergence insufficiency that does not respond to these measures, bimedial resections325,360,464,786 and superior transpositions of the medial rectus muscles (to induce a physiologic V pattern and allow for single binocular near vision in downgaze) (Buckley EG: verbal communication) have been used. Because convergence insufficiency represents a kinetic problem rather than a static deviation, strabismus surgery may not provide an optimal approach. The superimposition of convergence insufficiency on a baseline exodeviation produces an exodeviation that is greater at near, which is often a soft sign of neurologic disease.616 Neurologic forms of exotropia are summarized in Table 7.3.

Skew Deviation Skew deviation of the eyes is a prenuclear vertical strabismus that is usually associated with posterior fossa lesions, particularly those affecting the brainstem tegmentum or the cerebellum.419 While causative lesions are usually structural, skew deviation does rarely result from elevated intracranial pressure due to idiopathic intracranial hypertension.281 The misalignment may be comitant or incomitant, simulate a paresis of an extraocular muscle, and alternate with time (slowly alternating skew deviation) or on lateral gaze (alternating skew on lateral gaze). As discussed below, it is usually accompanied by binocular torsion and torticollis. Although skew deviation has been historically considered to be a nonlocalizing sign, simply indicating involvement of the posterior fossa without further reference to a specific region, our understanding of its value as a clinical localizing sign has been revised in recent years. While early studies reported the absence of torsion in patients with skew deviation,94 this myth has now been dispelled.92,93 The degree of ocular torsion may or may not be equal in the two eyes. Skew deviation usually presents in the more general context of the ocular tilt reaction. The ocular tilt reaction is caused by unilateral injury to the otolithic pathways, which causes the brain to perceive the visual world as tilted.116 The ocular tilt reaction is a “righting reflex” that results from alteration in the otolithic and/or vertical semicircular canal pathways that occurs in patients with lesions of either peripheral or central vestibular system. The ocular tilt reaction rotates the eyes and head toward the tilted visual world to restore vertical orientation (Fig. 7.4). The result is an oculocephalic synkinesis consisting of vertical divergence of the eyes (skew deviation), head tilt in the direction of the lower eye, and ocular torsion in the direction of head tilt.92 These compensatory roll rotations strive to realign the interpupillary axis, head, and torsional position of the eyes, respectively, to the orientation that the patient erroneously perceives as vertical. The ocular tilt

Fig. 7.4 Ocular tilt reaction. Illustration depicts graviceptive pathways from the otoliths and vertical semicircular canals mediating the vestibular reactions in the roll plane. The projections from the otoliths and the vertical semicircular canals to the ocular motor nuclei (trochlear nucleus IV, oculomotor nucleus III, abducens nucleus VI), and the supranuclear centers of the interstitial nucleus of Cajal (INC), and the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) are shown. They subserve vestibuloocular reflex (VOR) in three planes. The VOR is part of a more complex vestibular reaction that also involves vestibulospinal connections via the medial and lateral vestibulospinal tracts for head and body posture control. Note that graviceptive vestibular pathways for the roll plane cross at the pontine level. Ocular tilt reaction is depicted schematically on the right in relation to the level of the lesion (i.e., ipsiversive with peripheral and pontomedullary lesions, and a contraversive with pontomesencephalic lesions). In vestibular thalamus lesions, the tilts of the subjective visual vertical may be contraversive or ipsiversive. With permission from Brandt et al95

reaction has been reported in patients with intra-axial brainstem lesions (midbrain tegmentum, dorso-lateral medulla oblongata), unilateral vestibular neurectomy, and labyrinthectomy (performed in patients with severe Meniere’s disease or acoustic neuroma).812 The skew deviation that accompanies the ocular tilt reaction may be subdivided into at least three distinct types, each with distinct clinical features, ocular torsion, and localizing significance.93 Because all three components of the ocular tilt reaction are compensatory for a subjective visual tilt, the head tilt does not serve to promote vertical fusion as it does in superior oblique palsy.116 Consequently, prismatic or surgical correction of the vertical deviation does not eliminate the associated head tilt. Patients with the ocular tilt reaction may be misdiagnosed as having a superior oblique muscle palsy, because the skew deviation may be incomitant, and both disorders can show a positive Bielschowsky Head Tilt test.284

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The diagnosis of ocular tilt reaction should be considered in patients with suspected superior oblique muscle palsy who show intorsion of the higher eye. Donahue et al217 described five patients with incomitant skew deviation that simulated superior oblique muscle palsy on the Bielschowsky Three Step test, and intorsion of the higher eye and extorsion of the lower eye. In the patient with superior oblique palsy, the finding of intorsion (rather than the expected extorsion) of the higher eye (on both Double Maddox rod testing and indirect ophthalmoscopy) should therefore signal the diagnosis of skew deviation. In other patients, skew deviation can simulate isolated inferior oblique palsy.217 Recently, Pareluker et al found that the vertical and torsional deviations associated with skew deviation resolve in the reclined position, a finding that provides another useful clue to the diagnosis.610 For reasons that are not understood, the utricles become functionally deafferented in the reclined position,113 which explains the disappearance of skew deviation and the disappearance of compensatory head tilt in supine patients with superior oblique palsy732 (once asymmetrical utricular output can no longer be accessed to neutralize the vertical deviation). The localizing value of skew deviation is now well established.93,94 In a study of 56 adults with unilateral brainstem infarctions and skew deviations, clinical and neuroimaging

analysis revealed the following: (1) The ipsilateral eye was hypotropic with caudal pontomedullary lesions and higher with rostral pontomesencephalic lesions. (2) All patients with skew deviation showed simultaneous conjugate bilateral ocular torsion toward the hypotropic eye. Ocular torsion was evaluated from fundus photographs. This and other studies demonstrate that skew deviation is a sensitive brainstem sign of localizing and lateralizing value.93,94 While the skew deviation in adults results primarily from infarction, skew deviation in children may be associated with a wide variety of conditions, including tumors,158 Chiari malformation,173 autoimmune disease,632 paroxysmal hemiparesis of childhood,214,357 and increased intracranial pressure.52,281,530 In one case, skew deviation was diagnosed on prenatal MR images in a fetus with a glioblastoma involving the brainstem.158 Incomitant skew deviation may mimic a primary overaction of an oblique extraocular muscle. One type of skew deviation, termed alternating skew on lateral gaze or bilateral abducting hypertropia, closely resembles bilateral superior oblique overaction (Fig. 7.5).332,339,341,567 Affected patients typically display a right hypotropia on downgaze and to the left and left hypotropia on downgaze and to the right. One study of children with brainstem tumors341 showed that alternating skew deviation on lateral gaze localizes to the lower

Fig. 7.5 Alternating skew on lateral gaze: Patient presented with new onset of downbeat nystagmus and oscillopsia. He was diagnosed with spinocerebellar degeneration. He was orthotropic in primary position

(b) but displayed left hypotropia on gaze down and to right (a) and right hypotropia on gaze down and to left (c). Note similarity to bilateral overaction of superior oblique muscles

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brainstem or cerebellum. Given the similar localization of neuroanatomic lesions in patients with myelomeningocele (most whom have Chiari II malformation) and the observation that these patients show a predilection for superior oblique overaction (Fig. 7.1), Hamed et al have argued that primary superior oblique overaction and skew deviation are phenomenologically indistinguishable.334,339,341 This hypothesis is further supported by the observation that strabismic children who have superior oblique overaction show a higher frequency of associated neurologic disorders compared with a control population consisting of strabismic children without superior oblique overaction.339 Superior oblique overaction is commonly seen in conjunction with more generalized neurological disease such as cerebral palsy, myelomeningocele, and hydrocephalus. Brandt and Dieterich96 later suggested that overlapping pathways modulate roll and pitch function of the vestibuloocular reflex, making efficient use of the vestibular network. According to their hypothesis, a unilateral skew deviation reflects a central graviceptive imbalance in the roll plane, while bilateral paramedian lesions or bilateral dysfunction of the cerebellar flocculus produces a tone imbalance in the pitch plane. The principle behind this operation resembles the guidance system of airplanes, wherein unilateral activation of a brake flap causes the plane to roll, while bilateral activation results in downward pitch. In a bilateral ocular tilt reaction, the vertical components summate to produce the slow phase vertical drift of both eyes while the torsional components cancel each other out. Thus, a roll imbalance manifests as an ocular tilt reaction, while bilateral otolithic imbalance produces upbeat or downbeat nystagmus in conjunction with an alternating skew deviation on lateral gaze.96 Zee835 presented an interesting model in lateral-eyed animals to demonstrate how a pitch disturbance (forward or backward) would generate the patterns of vertical deviation in lateral gaze that are seen in humans with bilateral alternating skew deviation. Thus, while unilateral skew deviation corresponds to central graviceptive dysfunction of otolithic pathways in the roll (tilt) plane, lateral alternating skew deviation corresponds to a central graviceptive dysfunction of otolithic pathways in the pitch plane.107 By viewing a pencil slanted forward or backward in the pitch plane, then closing one eye and then the other, the reader can see that each image appears tilted in opposite directions when viewed monocularly.109 Guyton and Weingarten323 hypothesized that primary oblique muscle overaction and A- and V-pattern strabismus are a result of sensory torsion that arises when fusion is absent. However, it now appears that true oblique muscle overaction, caused by premotor disinhibition in the presence of early binocular visual loss, is the cause, rather than the effect, of primary oblique muscle overaction.107

7 Complex Ocular Motor Disorders in Children

While most primary oblique muscle overaction is innervational in origin, heterotopia of the extraocular muscles and their surrounding connective tissues has been recognized as an anatomical cause of apparent primary oblique muscle overaction.169,203,204 Other conditions causing overdepression of the adducting eye (mimicking primary superior oblique muscle overaction) include inferior rectus muscle palsy, apparent overaction of the oblique muscles in exotropia, downshoot of the eye in Duane syndrome, physiologic “overaction” of the oblique muscles in eccentric gaze, and other restrictive or paretic conditions.334 Overelevation or overdepression in adduction is therefore an ocular sign that may reflect a variety of conditions. It is now possible to conceptualize oblique muscle overaction as comprising a visuovestibular type (primary inferior oblique muscle overaction), a bilateral vestibular injury (primary superior oblique muscle overaction), a leash-effect type (Duane syndrome), and a muscle heterotopia type.

Gaze Palsies, Gaze Deviations, and Ophthalmoplegia This section discusses conditions causing ophthalmoplegia (i.e., mixed vertical and horizontal ocular paresis), or gaze palsies (horizontal or vertical). Gaze palsy may reflect abnormalities of saccadic eye movements, as may result from frontal lobe or frontomesencephalic saccadic pathway damage, pursuit eye movements, as may result from occipito-parieto-mesencephalic damage, or both, as may result from damage to the brainstem gaze center. It is sometimes difficult to distinguish a horizontal gaze palsy from a unilateral oculomotor or abducens nerve paresis with a compensatory head turn.63 An infant or toddler with an abducens nerve palsy may appear to have a gaze palsy when he or she adopts a compensatory head position to achieve binocularity and resists any gaze shift out of the zone of binocularity. In such cases, one must place a patch on the suspected paretic eye, which leads to resolution of the head turn in ocular motor nerve paresis, but not in gaze palsy. Complete resolution of such a head turn may occasionally require several days of patching.63

Horizontal Gaze Palsy in Children The causes of horizontal gaze palsy in children are shown in Table 7.4. Generally speaking, inability to conjugately move the eyes horizontally to one side is caused by a lesion in the contralateral frontal eye field or the ipsilateral paramedian pontine reticular formation (PPRF) or abducens nucleus.

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Gaze Palsies, Gaze Deviations, and Ophthalmoplegia Table 7.4 Causes of horizontal gaze palsy in children Brainstem arteriovenous malformation Bilateral Duane syndrome Congenital horizontal gaze palsy and scoliosis Congenital horizontal gaze paralysis and ear dysplasia Familial, congenital paralysis of horizontal gaze Leigh syndrome Möbius sequence Neuronopathic Gaucher disease Pontine glioma Wildervanck syndrome

Such a lesion may be distinguishable with reflex maneuvers (e.g., caloric stimulation, Doll’s head maneuver) that would drive the eyes into the paretic gaze if the PPRF and abducens nucleus are intact. Neuronopathic Gaucher disease with hepatosplenomegaly can be associated with isolated horizontal gaze palsy. Children with type 2 Gaucher disease may also show a “fixed” esotropia, while those with type 3 may be accompanied by head thrusts suggestive of COMA.611 Causes of horizontal gaze palsy that are now classified as congenital cranial dysinnervation syndromes (such as congenital horizontal gaze palsy with scoliosis) are detailed later in this chapter. Congenital bilateral paralysis of horizontal gaze has been reported in association with facial paralysis, most likely representing a form of Möbius sequence (facial diplegia and sixth nerve palsy). It has also been described without facial paralysis. In the latter cases, the most typical findings are total absence of conjugate horizontal gaze, both volitionally and after stimulation of optokinetic and vestibular systems; preserved convergence with substitution of convergence movements for conjugate eye movements upon attempting horizontal lateral gaze; cross-fixation; and apparently normal vertical eye movements.61 These cases, which show overlap with the Wildervanck syndrome, have occurred either as an isolated abnormality or in association with other findings that included kyphoscoliosis, facial contracture and myokymia, and the Klippel–Feil syndrome (fusion of cervical and upper thoracic vertebrae) in one patient.311 The precise cause of these cases is unknown, but the underlying defect has been speculated to represent selective maldevelopment affecting either the horizontal gaze center in the PPRF or the motor neurons and interneurons in the abducens nuclei. Yee et al824 reviewed the evidence and concluded that a developmental anomaly affecting the abducens nucleus, but not the horizontal gaze center in the PPRF, is most consistent with the clinical findings in this syndrome. They further speculated that the involvement of the facial musculature associated with some cases may result from a similar developmental anomaly of the facial nucleus. Some cases of bilateral horizontal gaze paralysis are familial.824 In children with pontine gliomas, involvement of the abducens nuclei and/or the PPRF may lead to horizontal gaze palsy (Fig. 7.6).

Congenital Ocular Motor Apraxia Apraxia (Greek: inaction) literally denotes the inability to perform volitional, purposeful motor activity despite the absence of paralysis. In the context of eye movements, the term apraxia should be limited to describe conditions in which volitional saccades are defective, but reflex and random movements are preserved (i.e., the quick phases of vestibular or optokinetic nystagmus), underscoring the presence of intact lower motor neuron pathways. This apraxic defect becomes more readily understandable by noting the presence of at least two major classes of cerebrally triggered saccades, namely, intrinsically triggered (volitional) saccades and extrinsically triggered (reflexive) saccades. Children with true saccadic apraxia show a defect in the first class of saccades, but not in the second.695 COMA is characterized by the selective absence of horizontal saccades with preservation of vertical saccades.174 COMA was so named because it was thought to fulfill the strict definition of apraxia outlined above, namely, the reflex and random eye movements as well as the fast phases of optokinetic nystagmus are preserved. However, there is no clear evidence for a cortical etiology and it is now recognized that the quick reflexive fast phases are also defective in these patients.354 For these reasons, Harris et al354 advocate use of the term intermittent saccadic failure. Ocular motor apraxia is divided into congenital and acquired varieties. The acquired form is usually encountered in adults, following bilateral basal ganglia or cerebral hemispheric lesions,623 although some acquired cases have been reported in children. For example, two children developed isolated ocular motor apraxia following cardiac surgery.829 In children, the idiopathic form of COMA must be differentiated from the forms seen in Gaucher disease, ataxia telangiectasia, and Leigh disease (discussed later). Acquired ocular motor apraxia seldom fulfills the strict definition of an apraxic disorder.695 Most acquired cases more closely reflect a global saccadic dysfunction rather than an apraxic disorder and may be better designated as horizontal saccadic palsies or gaze palsies, depending on whether or not smooth pursuit is also affected.354 The natural history is one of gradual resolution over several years (with persisting subclinical defects), which may reflect the normal maturation process or the development of blink-induced saccades.354 A prominent feature of this syndrome is large-amplitude horizontal head thrusting to achieve visual fixation.268 However, head thrusting need not always be present. The quick phases of induced vestibular nystagmus and optokinetic nystagmus are intermittently or completely absent, causing the eyes to deviate and “lock up” at the mechanical limit of gaze at the end of the slow phase.354 The classical explanation of the head thrusts is that they are compensatory,

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Fig. 7.6 Horizontal gaze palsy. Child with pontine glioma shows paralysis of (a) right gaze and (b) left gaze but intact (c) upgaze and (d) downgaze. (e) MR imaging shows diffuse enlargement of pons from glioma

which explains why the head is thrust in the direction of an eccentric target, and the eyes rotate conjugately in the opposite direction under the influence of the resulting vestibuloocular reflex. The head excursion must then overshoot the intended target to allow the controversively rotated eyes to fixate the desired target. Once fixation is achieved, the head slowly reassumes its neutral position to allow a direct, straight gaze. The child is usually noted to blink at the onset of head thrusts.

The concept that head thrusts are always compensatory has been challenged by evidence suggesting that a thrustsaccade synkinesis is the explanation for head thrusts; in that, the thrusts may actually facilitate the initiation of saccades in a subgroup of patients.837 Eustace et al255 questioned whether, rather than being compensatory, the head thrusts in COMA may be a defect that reflects an inability to unlock or cancel the effects of the vestibulo-ocular reflex. Interestingly, some children with COMA display occasional head thrusts

Gaze Palsies, Gaze Deviations, and Ophthalmoplegia

or a low-amplitude horizontal head nodding, even when fixating a stable target. The head thrusts so characteristic of COMA appear when the baby acquires head and neck control (usually at 6 months). Therefore, although congenital, the disorder is rarely diagnosed until late infancy. At an earlier age, blindness may be suspected due to failure to follow objects. This failure to visually pursue objects is understandable given the defective saccadic system, because infants “follow” with a series of hypometric saccades. In this context, failure to pursue may be misconstrued as a visual deficit. Evaluation of the vestibuloocular response in such infants by spinning them elicits a slow but not a fast component, which helps establish the diagnosis. Although isolated COMA is usually sporadic, familial cases have been documented.84,175,293,320,628,775 Phillips et al615 described COMA in four children of an affected father, indicating probable autosomal dominant transmission. COMA has been associated with a wide variety of conditions ranging from the relatively benign to the rapidly progressive neurometabolic degenerations. COMA may be congenital or acquired.519 It may also be idiopathic or associated with structural brain abnormalities (e.g., cerebellar hypoplasia, agenesis of the corpus callosum), neurodegenerative disorders (e.g., ataxia telangectasia, Gaucher disease), perinatal problems (e.g., hypoxia, cerebral palsy, hydrocephalus), or acquired disease (e.g., herpes encephalitis, posterior fossa tumors, ischemia) (Table 7.5).354,519 These disorders should be suspected when vertical saccades are affected or when saccades are slow.354 While affected children are often judged to be otherwise healthy, most have associated deficits in other motor spheres, resulting in problems in oral-motor planning affecting speech output (speech apraxia), as well as truncal ataxia, hypotonia, developmental delay, or perceptual visual-spatial difficulties.312,396,519,635,674,725,726 In a recent study,519 11 of 14 patients with no structural abnormality on neuroimaging showed abnormal neurodevelopment, although it has been stated that speech delay in ocular motor apraxia is expressive and due to verbal apraxia.396,635 These included delayed speech and reading, and abnormalities of language development involving both receptive (comprehension) and expressive (language)

Table 7.5 Neurometabolic causes of congenital ocular motor apraxia (Adapted from Harris et al354) Ataxia telangectasia Gaucher disease Joubert syndrome Krabbe disease Niemann–Pick–syndrome Cockayne syndrome Pelizeus–Merzbacher disease Recessive ataxia with ocular apraxia Spinocerebellar ataxia type 2

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development. One mother of a 3-year-old girl stated, “Her speech has been good in terms of word acquisition, but she has an odd linking of phrases – lots of backwards phrases.” These studies indicate that COMA is the salient feature of a more generalized neurological disorder,312 and that “isolated” cases are at risk for mild-to-moderate educational difficulties. The association of COMA with CNS lesions has long been recognized.232,268,599 Neuroimaging often discloses vermian hypoplasia and dilatation of the fourth ventricle at the upper brainstem level.448 Sargent et al674 found hypoplasia of the cerebellar vermis in approximately 50% of patients with COMA, with preferential involvement of the inferior portion. Additional involvement of the superior portion correlated with more severe feeding difficulties, speech apraxia, or more severe generalized motor problems. Kim et al437 reported COMA with spasmus nutans in a child with cerebellar vermian hypoplasia. They speculated that hypoplasia of the vermal cortex could disinhibit the caudal fastigial nucleus, leading to an abnormally increased activity in the fixation region of the superior colliculus and results in the inhibition of saccadic generation. On the other hand, Harris et al found vermian hypoplasia in only one of two siblings with COMA, suggesting that this defect may not be causative, but a marker of some other underlying pathology.369 Shawkat et al found abnormal scans in 61% of patients with saccadic initiation failure.697 Most abnormalities involved the brainstem and cerebellar vermis, although other abnormalities of the cerebral cortex and basal ganglia were also detected. Other neuroimaging abnormalities have been reported less frequently, including porencephalic cyst, agenesis or hypoplasia of the corpus callosum,84 posterior fossa tumors such as medulloblastoma or lipoma, and gray matter heterotopias.27,505,725,731,833 Recently, a subgroup of autosomal recessive cerebellar ataxias was identified.473 It includes four distinct subtypes: ataxia-telangectasia, ataxia-telangectasia-like disorder, and ataxia with ocular motor ataxia types 1 and 2. The phenotypes share similarities, and the responsible genes ATM, MRE11, APTX, and SETX, respectively, are all implicated in DNA break repair. As in many other DNA repair deficiencies, neurodegeneration is a hallmark of these diseases.473 The first two conditions are detailed in Chap. 10. The third, ataxia with ocular motor apraxia type 1 (AOA type 1) is a recently described autosomal-recessive condition of childhood onset that is caused by mutations in the APTX gene, which encodes the protein aprataxin.826 Onset is usually 2–10 years (mean, 6.8 years), with gait and limb ataxia, dysarthria, ocular motor apraxia, mild peripheral neuropathy, and progression of neurological deficits.473,481 MR imaging may show cortical and cerebellar atrophy that is most prominent in the mid-vermis.267 Aprataxin mutations are associated with low coenzyme Q10 levels in muscle, which is not associated with duration, severity, or progression of the disease.473

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Ataxia with ocular motor apraxia type 2 (AOA type 2) is an autosomal recessive disorder associated with mutations in the Senataxin (SETX) gene.189,506,559 The age of onset is later (11–20 years), with sensory motor neuropathy, primary ovarian failure, chorea, and ocular motor apraxia in about half of affected patients. An elevated level of serum alpha-fetoprotein is a consistent finding.481 Ocular motor apraxia can also be a clinical manifestation of other well-known neurologic or systemic diseases. The association of COMA and a “molar tooth sign” should suggest the diagnosis of Joubert syndrome and Related Disorders (JRSD). First described in 1969, Joubert syndrome is characterized by the variable combination of episodic neonatal tachpynea and apnea, rhythmic protrusion of the tongue, ataxia, hypotonia, and a variable degree of psychomotor retardation.405 The episodic tachpynea presents in the neonatal period and alternates with periods of apnea, resembling the panting of a dog, and usually resolves or improves over time. Typical facial features include high rounded eyebrows, broad nasal bridge, anteverted nostrils, and low-set ears.89,513,609 The associated congenital retinal dystrophy was at first labeled as a variant of Leber congenital amaurosis but subsequently considered different because the visual loss is not as profound (20/60 to 20/200) in JRSD, compared with counting fingers or worse in Leber congenital amaurosis. In addition, the visual evoked potentials (VEPs) are relatively spared (mild-to-moderate reduction in amplitudes, compared with absent or highly attenuated signals). Both conditions show flat or highly attenuated electroretinograms (ERGs).516 Other ophthalmologic findings include ptosis, congenital ocular fibrosis, and colobomas.468 Systemic manifestations have been infrequently reported, including meningoencephalocele, microcephaly, polydactyly, kidney abnormalities, soft tissue tumors of the tongue, liver disease, and duodenal atresia.513 Ocular motor disorders described in JSRD include slow, hypometric saccades, ocular motor apraxia, strabismus, periodic alternating gaze deviation, pendular torsional nystagmus, seesaw nystagmus, skew deviation, and defective smooth pursuit, as well as optokinetic and vestibular responses.468,515,797a The ocular motor apraxia in JRSD differs from COMA in that both volitional saccades and quick phases of nystagmus are impaired in both the horizontal and vertical directions, and the problem does not resolve with time.757 The most common ocular motor abnormalities are saccadic dysfunction with head thrusts and primary position nystagmus (typically, seesaw nystagmus).432 Joubert syndrome is characterized by hypoplasia of the cerebellar vermis and a particular midbrain–hindbrain “molar tooth” sign, a finding shared by a group of Joubert syndrome-related disorders with a wide phenotypic variability. 432 The molar tooth sign is a complex malformation of the hindbrain–midbrain junction (brainstem isthmus) characterized by cerebellar vermis hypoplasia, thick and

7 Complex Ocular Motor Disorders in Children

Fig. 7.7 Axial T1-weighted MR image in patient with Joubert disease showing “molar tooth” sign

maloriented superior cerebellar peduncles, and an abnormally deep interpeduncular fossa. As first described by Maria, axial MR imaging at the pontomesencephalic level has shown that this malformation produces a peculiar appearance resembling a molar tooth (Fig. 7.7).456,515,516,651 The pathological findings include vermian hypoplasia or dysplasia, elongation of the caudal midbrain tegmentum, and marked dysplasia of the caudal medulla. The molar tooth sign (and the absence of associated hydrocephalus) distinguishes Joubert syndrome from the vermian agenesis that occurs with the Dandy–Walker variant, but 10% of patients with a Dandy–Walker-like cyst have the molar tooth sign and are clinically similar to classic Joubert syndrome patients. Such patients were referred to as “Dandy– Walker Plus” by Maria et al514 Importantly, the molar tooth sign is not seen in isolated vermian hypoplasia because the cerebellar peduncles and interpeduncular fossa can be normal in several vermian hypoplasia syndromes. The deep interpeduncular fossa and decreased anteroposterior diameter of the brainstem isthmus in the molar tooth sign can best be explained by nondecussation of the ascending superior cerebellar peduncles. The coincident finding of asymmetrical VEPs in some patients with seesaw nystagmus suggests failure of chiasmal decussation.432 This finding, together with the absence of decussation in both the superior cerebellar peduncles and the corticospinal tracts at the medullary pyramids,

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suggests that patients with Joubert syndrome have a defect of axon guidance in the motor circuits.265,432,626,715 Although the molar tooth sign is still considered essential to the diagnosis of Joubert syndrome, there are a number of Joubert syndrome-related disorders such as COACH, Arima, Debakan, and Senior-Løken that are much more rare and which may also show a molar tooth sign on MR imaging. In these conditions, there are numerous other abnormalities in addition to the neurological features of the Joubert syndrome; involvement of other organs such as eye, kidney, and liver, have been described.673,675 The Arima syndrome exhibits pigmentary degeneration suggestive of Leber congenital amaurosis, severe psychomotor retardation, hypotonia, characteristic facies, polycystic kidneys, and absent cerebellar vermis. Joubert and Arima syndromes may be distinguished by such clinical features as neonatal tachypnea, which is one of the cardinal features of Joubert syndrome. The identification of mutations in seven different cilium genes in up to 20% of patients with Joubert syndrome suggests that a certain percentage of Joubert syndrome is a celiopathy that can affect various organ systems, including the connecting cilium of photoreceptors.432,609 Although patients with the NPHP1 deletion often have juvenile nephronophthisis and rarely have retinal dystrophy, patients with AH1 mutations seem less likely to develop retinal dystrophy.609,767 Mutations in the AHI1 gene can also be associated with other CNS malformations (in non-Joubert patients) such as corpus callosal abnormalities, polymicrogyria, hydrocephalus, and encephalomeningocele.292 Patients with the CEP290 mutation seem to have both nephronophthisis and retinal dystrophy.91,679,772 Other phenotypes have included nonspecific renal cortical cysts, ocular colobomas, and encephaloceles.91,432,679,772 Joubert syndrome may be sporadic or familial, with familial cases inherited in an autosomal recessive pattern. Recent genetic analyses have suggested at least three loci, JBTS1 (9q34.3), JBTS2 (11.2-q12.3), and JBTS3 (6q23).770 Only the JBTS3 gene, AHI1, encoding Jouberin, has been cloned. JBTS1 and 3 primarily show features restricted to the CNS, with JBTS1 showing largely pure cerebellar and midbrain– hindbrain junction involvement, and JBTS3 displaying cerebellar, midbrain–hindbrain junction, and cerebral cortical features, most notably polymicrogyria. Conversely, JBTS2 is associated with multiorgan involvement of kidney, retina, and liver, in addition to the CNS features, and results in extreme phenotypic variability.771 Occasionally, COMA is one of the manifestations of a degenerative disorder such as ataxia telangiectasia.53,727 Some children with ataxia telangiectasia may pose a diagnostic quandary by showing no overt immune dysfunction, inconspicuous oculocutaneous telangiectasia, and an atypical neurological presentation with dystonia predominating over cerebellar ataxia.166 Vertical saccades are usually involved to some degree when COMA is associated with systemic disease.

Although ataxia telangiectasia is said to be associated with slow saccades, eye movement recordings in patients with ataxia telangiectasia have showed saccadic velocities to be faster than normal, but followed by slow eye movements that were not clearly saccadic in origin.492 A syndrome mimicking ataxia telangiectasia with slowly progressive ataxia, choreoathetosis, and ocular motor apraxia in the horizontal and vertical plane has been described.12 Although the neurological findings are indistinguishable from those of ataxia telangiectasia, the onset tends to be later and patients have not shown evidence of multisystem involvement. Ocular motor apraxia is often found in patients with Gaucher disease,253 a lysosomal storage disorder, and may even be the presenting feature of the disease.316 Other children with Gaucher disease show a supranuclear horizontal gaze palsy.611 In most patients with COMA, the ability to generate saccades improves over the first decade, with better eye movements and less noticeable head thrusts.177 This spontaneous improvement led Cogan to favor a delayed maturation of the ocular motor pathways rather than congenitally absent initiation pathway for horizontal saccades as the underlying cause. While the ocular motor abnormalities tend to improve with age, most affected children show some degree of delayed motor, speech, or cognitive development.726 Notwithstanding the benign course in most cases, it is advisable to obtain MR imaging to rule out intracranial pathology (tumor, congenital structural malformations), the occurrence of which has been well documented in a minority of children. Treatment of underlying pathology may ameliorate or cure the apraxia in some cases,833 but not in all.731 For instance, Zaret et al833 described a case of COMA that showed rapid improvement after surgical evacuation of a large cystic tumor in the rostral brainstem, while complete resection of a posterior fossa lipoma in a 10-month-old girl had no effect on the apraxia. Although typical COMA involves a bilateral palsy of volitional horizontal saccades and unilateral cases,146,434 cases involving only vertical saccades have been described.383,645

Vertical Gaze Palsies in Children Vertical gaze disturbances are generally less common than horizontal ones and, among vertical disorders, upgaze palsy and combined upgaze and downgaze paralysis are more common than downgaze palsy (Fig. 7.8). Most vertical gaze palsies are supranuclear and conjugate (i.e., upgaze palsy, downgaze palsy, and vertical gaze palsy). Supranuclear disconjugate vertical gaze syndromes are rare, and their topographic correlation is less precisely determined. They include skew deviation and variants (e.g., slowly alternating skew deviation), seesaw nystagmus, monocular upgaze palsy,

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Fig. 7.8 Supranuclear vertical gaze palsy. Five-year-old boy with cerebral palsy shows total paralysis of (a) upgaze and (b) downgaze. (c) Right gaze and (d) left gaze are intact. (e) Elevation of eye with Bell’s phenomenon indicates that upgaze paralysis is supranuclear

ocular tilt reaction, vertical one-and-a-half syndrome, and V-pattern pseudobobbing. Some of these disorders are not only location-specific, but also point to a specific mechanism of injury (e.g., acute downgaze palsy suggests bilateral infarction of the posterior thalamo-subthalamic paramedian territory). Occasionally, cases involving complete vertical ophthalmoplegia are described that remain unexplained despite thorough evaluation. Nightingale and Barton578 described a 6-year-old girl who had episodes of severe ataxia and vertical supranuclear ophthalmoplegia. Horizontal eye movements were not affected, and the patient was normal in between attacks. Congenital vertical ocular motor apraxia may occur as a benign nonprogressive condition similar to the horizontal variety or may signal the presence of intracranial tumors, especially if other neurological signs are present.231 Ebner

reported a case of purely vertical ocular motor apraxia in a 4-year-old boy whose MR imaging demonstrated bilateral subthalamic lesions.231 Rare cases of isolated vertical COMA have also been associated with birth asphyxia.27,383,645 The association of this disorder with perinatal hypoxic encephalopathy implicates injury to the frontal eye fields and posterior parietal cortex or their descending projections through the internal capsule and basal ganglia to the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF).

Downgaze Palsy in Children Isolated downgaze palsy usually results from a bilateral lesion (usually infarction) involving the midbrain reticular formation and affecting the lateral parts of the riMLF bilaterally.

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In general, an acquired isolated downgaze paralysis requires bilateral lesions at the level of the upper midbrain tegmentum, while a unilateral lesion may be sufficient to produce an upgaze palsy or a combined upgaze and downgaze palsy.79 Green et al311 reported a 9-year-old girl with selective downgaze paralysis following pneumococcal meningitis. MR imaging showed bilateral lesions in the riMLF. In the setting of a bilateral midbrain lesion, the examiner can often use horizontal eye movements to assess which side of the midbrain is more severely affected. If the right side of the midbrain is more severely affected, the patient will have a saccadic deficit to the left and a pursuit deficit to the right, because saccadic innervation from the hemispheres is crossed and pursuit innervation is uncrossed. In adults, downgaze paresis is most commonly an early sign of progressive supranuclear palsy. Kumagai et al455 described a patient with selective downgaze paresis who had a pineal germinoma with bilateral involvement of the thalamo-mesencephalic junction. Rhythmic vergence eye movements (alternating convergence and divergence) were observed at a rate of 3 Hz during eyelid closure. Downgaze palsy in children is a well-known feature of DAF (downgaze palsy, ataxia or athetosis, and foam cells in the bone marrow) syndrome, a neurovisceral storage disease considered to be a variant of Niemann–Pick disease type C. It is characterized by supranuclear gaze palsy in the vertical plane (typically downgaze palsy), hepatosplenomegaly, slowly progressive ataxia, mental deterioration, and other CNS disorders. Foamy cells or sea-blue histiocytes in the bone marrow as well as accumulation of sphingomyelin, cholesterol, and other glycosphingolipids are characteristic histopathologic findings. The acronym DAF was coined by Cogan to denote this triad of findings.176 Rarely, patients show predominantly horizontal supranuclear gaze palsy.373 An autosomal recessive inheritance pattern is suspected.42 The age of onset of neurologic symptoms is between 5 and 15 years. In addition to abnormalities indicated by the acronym, affected patients have hepatosplenomegaly, dementia, and widespread CNS dysfunction. Other neurological symptoms and signs include poor coordination, slurred speech, dysphagia, seizures, cerebellar dysfunction, hyperreflexia, and involuntary movements (dystonia, chorea, or athetosis).100 The DAF variant of Niemann–Pick disease should be suspected when evaluating school-aged children who have suffered a recent decline in intelligence or school performance and who show progressive neurologic disease and vertical supranuclear ophthalmoplegia. An acquired condition of bilateral downgaze palsy with monocular elevation palsy, termed the vertical one-and-onehalf syndrome, has been reported in a patient with bilateral infarction in the mesodiencephalic region.201 The authors speculated that the lesions may have affected the efferent fibers of the riMLF bilaterally and the supranuclear fibers to

the contralateral superior rectus subnucleus and ipsilateral inferior oblique subnucleus. This disorder should be distinguished from a different condition, also termed a one-andone-half syndrome, consisting of bilateral upgaze palsy and monocular depression deficit due to thalamomesencephalic infarction ipsilateral to the downgaze paresis.80

Upgaze Palsy in Children The most common causes of upgaze palsy in children include hydrocephalus (congenital and acquired) and various conditions associated with the dorsal midbrain syndrome, such as a tumor in the pineal region, arteriovenous malformations, encephalitis, and third ventricular tumors.421 Midbrain infarction, multiple sclerosis, and syphilis are rare causes in children. The eye signs of hydrocephalus are detailed in the chapter on neuro-ophthalmologic signs of intracranial disease. Ocular motility disorders reported in hydrocephalus are listed in Table 7.6. Upgaze paresis is the hallmark of the dorsal midbrain syndrome.326 Mild cases involve only upward saccades, but severe cases show paralysis of all upward movements. Attempts to produce upward saccades, best elicited by fixating a downward rotating optokinetic nystagmus drum, evoke convergence-retraction nystagmus. The pupils are usually mid-dilated and show light-near dissociation. The upper eyelid shows pathologic lid retraction (Collier’s sign) and lid lag, due to disruption of inhibitory fibers from the posterior commissure to the central caudal nucleus.182 The setting sun sign is unique to children and is suggestive of congenital hydrocephalus. It is not clear why a similar sign is not seen in adults with acquired hydrocephalus. The setting sun sign may be thought of as a combination of Collier’s sign and tonic downgaze, which has been reported in some children with hydrocephalus, with or without associated intraventricular hemorrhage.735

Table 7.6 Ocular motility disorders in hydrocephalus59,167 A-pattern esotropia with superior oblique muscle overaction Convergence insufficiency Convergence-retraction nystagmus Convergence spasm Fixation instability Lid retraction Mydriasis with light-near dissociation Pseudo-abducens palsy Setting sun sign (in infants) Skew deviation Superior oblique palsy (unilateral or bilateral) Upgaze paralysis (affecting saccades more than pursuit) V-pattern pseudobobbing (with shunt failure)

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The upgaze palsy of congenital hydrocephalus usually improves dramatically and quickly after shunt placement. Incomplete, delayed improvement over months to years suggests damage to the upgaze pathway either as a result of thalamic hemorrhage and infarction or by the hydrocephalus itself.735 Children with severe, congenital visual loss may have difficulty moving their eyes volitionally. In this context, upward gaze is the most severely affected.393 Jan et al393 theorized that a selective upgaze deficit exists because children with marked visual impairment rarely look up, because they see much more with their limited vision when viewing closer objects sideways or downward. Isolated paralysis of upgaze may be the presenting sign of the Miller Fisher syndrome.423 It may also result from vitamin B1 or B12 deficiency.671 Isolated bilateral elevation deficiency may be due to congenital restriction of the inferior rectus muscles in the congenital fibrosis syndrome.759 Diagnostic confusion arises because congenital fibrosis syndrome can produce convergent movements of the eyes in attempted upgaze, which simulates convergence retraction nystagmus. The distinguishing clinical feature is that patients with congenital fibrosis syndrome display ptosis rather than lid retraction. As discussed below, these restrictive phenomena can also be differentiated from the dorsal midbrain syndrome by the positive family history, positive forced ductions, and the finding of hypoplasia of the intracranial nerves and extraocular muscles in the congenital fibrosis syndrome, but not in dorsal midbrain syndrome. In adult patients, upgaze palsy is usually less disabling than downgaze palsy, because the superior visual space is comparatively less important. This is in contrast to downgaze palsies, which cause significant visual deficits due to the importance of downgaze for such tasks as reading, walking, and eating. However, the visual significance of upgaze palsy is much more profound in children who, by virtue of their short stature, spend a considerable amount of their time looking up.

Diffuse Ophthalmoplegia in Children The numerous manifestations of diffuse ophthalmoplegia in children can usually be differentiated by clinical history and associated findings (Table 7.7).305 Mitochondrial disorders and the spinocerebellar ataxias (SCAs) should be considered when the onset is gradual and the eye signs are progressive, and when myasthenia gravis has been ruled out. Ocular myasthenia gravis is associated with variability and fatigability, with or without muscle systemic weakness. Congenital cranial dysinnervation disorders, such as congenital fibrosis syndrome, are usually present at birth and often associated with ptosis and fixed downgaze. Many other conditions that

7 Complex Ocular Motor Disorders in Children Table 7.7 Diffuse ophthalmoplegia in children Bickerstaff brainstem encephalitis Botulism Chronic progressive external ophthalmoplegia Intrinsic brain stem tumors Kearns–Sayre syndrome Maple syrup urine disease Medications (e.g., toxic doses of phenytoin, amitriptylene) Miller Fisher syndrome Mitochondrial encephalopathy (CPEO, MELAS, MERRF, MNGIE, MDS, Pearson syndrome) Myasthenia gravis Olivopontocerebellar degeneration Tick fever Toxicity of chemotherapeutic agents (e.g., vincristine)

present with acute ophthalmoplegia, including Fisher syndrome, botulinum, and tick fever, can cause usually have telltale historical clues. Each disorder has a characteristic, if overlapping, clinical profile, making it possible for the diagnosis to be established on clinical grounds in most cases.

Chronic Progressive External Ophthalmoplegia Chronic progressive external ophthalmoplegia (CPEO) is an umbrella term that includes a number of diverse conditions having in common insidious onset of slowly progressive, typically symmetric, multidirectional external ophthalmoplegia. The various conditions encompassing CPEO range from disorders limited to the eyelids and extraocular muscles to ones that include systemic and encephalopathic features. Extraocular muscles have smaller motor unit sizes, higher motor neuron discharge rates, higher blood flow, and higher mitochondrial volume fractions than skeletal muscles.688 These differences suggest that the energy demands and therefore the susceptibility to mitochondrial dysfunction are greater in extraocular muscle. Because of the often gradual and symmetric involvement of the extraocular muscles, patients with CPEO generally do not experience diplopia.59,614,639,713 Ptosis and ophthalmoplegia generally occur together, but each can occur alone, and the ptosis can be asymmetrical. When strabismus does occur, the most common deviation is exotropia, with or without a vertical deviation.639,700 Confirmation of the diagnosis usually requires fresh muscle biopsy for histopathological examination (using cytochrome oxidase stain with electron microscopy to look for “parking lot” inclusions) and Southern blot analysis to look for deletions. Polymerase chain reaction (PCR) has recently been used to detect the mutation in swabbed buccal cells.386 Mitochondrial encephalopathy is divided into several clinical phenotypes, including Kearns–Sayre syndrome; the

Diffuse Ophthalmoplegia in Children

syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS); mitochondrial neurointestinal encephalopathy (MNGIE); and the syndrome of myoclonus, epilepsy, and ragged red fibers (MERRF).688 The later syndrome is not generally associated with external ophthalmoplegia. Kearns–Sayre syndrome is characterized by the triad of progressive external ophthalmoplegia, pigmentary degeneration of the retina, and heart block. Most cases are sporadic. The onset of the disorder occurs before age 20. Affected patients have short stature, other neurologic disorders, and an elevated protein concentration (>100 mg/dL) in the cerebrospinal fluid (CSF). Other findings may include hearing loss, cerebellar signs, mental retardation, delayed puberty, vestibular abnormalities, and “ragged red fibers” on muscle biopsy,688 mental deterioration, pyramidal signs, and diabetes.59,212,424,472,705,838 In addition to complete heart block, cardiac conduction abnormalities include bundle branch block, bifascicular disease, and intraventricular conduction defects and are thought to result from an associated cardiomyopathy. The heart block generally occurs years after onset of the ocular signs and may cause sudden death. The retinal pigmentary degeneration progresses slowly and may be too subtle early on to detect ophthalmoscopically. The associated ptosis may become visually significant, but surgical correction should be approached with caution because the limited eye movements and the absence of Bell’s phenomenon render patients prone to exposure keratopathy. Orbital neuroimaging is probably of little value in CPEO. One study found marked atrophy of the extraocular muscles,608 while another showed little or no reduction in extraocular muscle volume.601 Furthermore, myasthenia gravis may also show atrophic extraocular muscles late in the course of the disease, making it difficult to distinguish from CPEO.595 It has been suggested that the myopathic process that results in chronic progressive external ophthalmoplegia renders rectus muscle recessions less effective than resections for correcting the associated strabismus that occasionally develops in these patients.507,713 Postoperative prisms are occasionally necessary to fine-tune single binocular vision.791 CPEO may be sporadic, show Mendelian inheritance, or show maternal inheritance.386 Almost half of CPEO cases are sporadic and associated with single deletions of mtDNA.74,314,315,476,617 In sporadic cases of CPEO and Kearns– Sayre syndrome, all the mutant mtDNAs in an individual have the same deletion. Because Kearns–Sayre syndrome is an artificial construct of the most severe cases of the CPEO syndromes, it is always more likely to have deletions (90%) than CPEO in general, and it is more likely to be sporadic. However, some members of severe autosomal dominant CPEO pedigrees have had a high deletion load express the full-blown Kearns–Sayre syndrome phenotype, while other family members do not.74 Autosomal dominant or recessive inheritance is noted in about 15% of patients with CPEO. Autosomal dominant

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inheritance is characterized by accumulation of multiple dele tions of mtDNA in the patient’s tissues. Most single deletions are not inherited, but occur spontaneously after fertilization of the oocyte. Individuals with multiple different deletions likely come from pedigrees in which there is a nuclear mutation in a gene encoding a protein that regulates mitochondrial DNA replication and therefore is inherited mendelianly (usually autosomal dominant or autosomal recessive).59,74,315,838 No clinical difference between hereditary and sporadic CPEO can be demonstrated.59,838 Many patients without structural abnormalities of mitochondrial DNA have point mutations at many different nucleotide positions, which are inherited maternally.386 Point mutations causing CPEO are often homoplasmic. Large-scale deletions resulting in CPEO are almost always heteroplasmic; the more tissue with the deletions (i.e., the greater the degree of heteroplasmy), the more likely the phenotype will be severe (i.e., more toward Kearns– Sayre syndrome phenotype rather than the simple CPEO phenotype).47,783 While mitochondrial disorders that have both dominant and recessive modes of inheritance are usually caused by mutations at different loci, both can be caused by mutations in the polymerase gamma (POLG) gene.184,267a The risk of developing a severe phenotype (i.e., additional CNS symptoms with neurological manifestations) is higher when the age of onset is before age 9 and lower when the onset is after age 20.47 While mitochondrial disorders associated with ophthalmoplegia tend to affect adults, early symptoms are often experienced in childhood. MELAS is the mitochondrial disease that is most consistently associated with retrochiasmal visual loss. MELAS is characterized by recurrent abrupt attacks of headache, vomiting, focal and generalized seizures, and focal neurologic symptoms and signs lasting hours to days.74 There is a posterior cerebral predilection for damage, and visual disturbances have been reported in more than half of patients. It is not uncommon for patients with MELAS to have CPEO, pigmentary retinopathy, optic atrophy, or homonymous hemianopia. Patients may present with stroke-like episodes, seizures, headaches, progressive dementia, and exercise intolerance.539 Classically, the brain MRI of patients with MELAS demonstrates lesions that may mimic ischemia, except that they usually do not respect vascular territories and are often restricted to the cortex with relative sparing of deep white matter.366 However, lesions spanning both gray and white matter have been reported.554 The diagnosis of MELAS is established made from the characteristic neuroimaging findings, elevated lactic acid levels, ragged red fibers on muscle biopsy, or genetic sequencing. MELAS is often maternally inherited, with 80% of patients harboring the A3243G transition within the mitochondrial genome, although many other mutations have also been reported.162 Patients with MERRF syndrome present with combinations of myoclonic epilepsy, ataxia, spasticity, generalized seizures, optic atrophy, and/or dementia.315 They may

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also have muscle weakness, myopathy, neuropathy, ophthalmoplegia, ptosis, headache, foot deformity, cervical lipoma, or sensorineural hearing loss. Myoclonus is usually the presenting symptom and is often precipitated by noise, photic stimulation, or action. Myopathy is generally subclinical or mild. Biochemical aberrations may include elevations of serum pyruvate, or pyruvate and lactate, and reduced activities of complexes I and IV. The most common mutation, accounting for 80% of MERRF cases, is at np 8344 within the tRNA.346 Other mutations in the same tRNA gene, t8356C and G8363C, are also found in association with this phenotype.606 Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) syndrome is an autosomal recessive syndrome characterized by chronic progressive external ophthlmoplegia intestinal hypomotility, and neuropathy.795 Clinical presentation is usually in childhood, although gastrointestinal symptoms may be problematic long before other features of the disease appear. Some patients have diabetes mellitus, heart block, or cardiomyopathy. Long-term prognosis is poor, with most patients dying in early-to-mid adulthood from weight loss and other gastrointestinal complications.795 MR imaging may show an unsuspected leukoencephalopathy of the brain.184,365,542,581 Most patients have mutations in the nuclear-encoded thymidine phosphorylase gene.795 In the child with progressive external ophthalmoplegia, a history of marrow failure with transfusion-dependent sideroblastic anemia, and exocrine pancreatic dysfunction causing malabsorption or diarrhea should raise suspicion for the Pearson syndrome. This disorder is characterized by a progressive pigmentary retinopathy that initially spares the posterior pole. Older patients may develop symptoms of Kearn Sayre syndrome. It is caused by deletions in mitochondrial DNA.659a

Myasthenia Gravis Myasthenia gravis was the first recognized autoimmune neurologic disease. Myasthenia gravis is a disorder of neuromuscular transmission characterized by fatiguability and fluctuating muscular weakness, with a predilection for the extraocular muscles.48 In severe cases, acute respiratory failure and death may occur. About half of all patients with myasthenia present with ophthalmologic symptoms. These include ptosis, strabismus, and limited ocular ductions, all with a tendency to be highly variable. No pupillary involvement is clinically discerned in myasthenia, and the presence of pupillary signs effectively excludes the diagnosis. Myasthenia gravis has a well-known predilection for extraocular muscle involvement. Factors that may predispose the extraocular muscles to preferential involvement in myasthenia gravis include their higher discharge rates, differences in complement inhibitor proteins, and lack of action potentials

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in the tonic fibers. The more constant activity also makes the orbital extraocular muscle fibers more susceptible to fatigue.408–411,481 It has also been suggested that antibodies directed against the fetal form of the acetylcholine receptor, which may be found at synapses on extraocular but not skeletal muscles, may be an important factor that predisposes the extraocular muscles to involvement by myasthenia.407 Nearly 90% of patients with myasthenia develop ocular involvement at some point during their illness. Most patients with ocular myasthenia who develop systemic symptoms and signs do so within 2 years of onset.69,459 Three distinct myasthenic syndromes may be encountered in the pediatric age group: transient neonatal, congenital, and juvenile. This classification is not based on age at presentation but on pathophysiology. Both congenital myasthenia and juvenile myasthenia may present any time between infancy and adulthood, but are distinguished primarily by the fact that congenital myasthenia is not immune-mediated. However, this distinguishing feature is not absolute because juvenile- and adult-onset myasthenia may also be antibodynegative. Also, the defect in acquired myasthenia is postsynaptic, while the defect in congenital myasthenia may be either at the presynaptic or postsynaptic level.

Transient Neonatal Myasthenia Transient neonatal myasthenia gravis is due to transfer of antibody from the mother, tends to spare eye movements.285 Approximately 12% of newborn infants of myasthenic mothers develop transient myasthenic symptoms, presumably due to passive transplacental transfer of anti-AChR IgGs. Serum AChR antibody titers of affected neonates follow the same pattern as their mothers. Neonatal disease does not appear to correlate with the severity of maternal symptoms; affected mothers commonly have active myasthenia, but they may be in remission or, rarely, have undiagnosed subclinical disease. The onset of transient neonatal myasthenia occurs within a few hours after birth in two-thirds of patients, and within the first 3 days in all of them. Affected infants present with temporary skeletal muscle weakness producing hypotonia, a feeble cry, difficulty sucking and swallowing, facial diparesis, and mild respiratory distress. Occasionally, they may suffer respiratory depression that requires mechanical ventilation. Transient neonatal myasthenia tends to spare eye movements.285 Ocular involvement, including ptosis, limited eye movements, and orbicularis weakness, affects 15% of infants. An atypical, more severe form of transient neonatal myasthenia includes the above-mentioned manifestations in addition to multiple joint contractures and occasional prenatal difficulties such as polyhydramnios or decreased fetal movement. Unlike the typical variety, response to oral or parenteral

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anticholinesterase agents is poor. Severe cases may rarely require assisted mechanical ventilation for up to 1 year. The pathogenesis of the disorder is increasingly understood. It is controversial and uncertain whether the maternal and neonatal antibodies are similar and passively transferred, or different, with the neonate synthesizing their own antibodies, or whether both mechanisms are in play.479,760 Transient neonatal myasthenia is not fully explained by passive transplacental IgG transfer because these antibodies are also found in the serum of many newborns who are asymptomatic. Other infants are symptomatic without detectable antibodies in their maternal serum. Also, high IgG levels have been found in a few asymptomatic infants. There is now a report of transient neonatal myasthenia in an infant with anti-MuSK antibodies.579 Clinical symptoms usually last 2 or 3 weeks,560 but may resolve in 1 week or linger on for 2 months before complete recovery. Response to oral (e.g., pyridostigmine bromide) or parenteral anticholinesterase agents is very good, and these agents should be administered until spontaneous resolution occurs. No permanent neuromuscular sequelae are detectable after resolution. If this condition is not recognized and promptly treated, some affected infants may deteriorate from respiratory depression to respiratory arrest and death. The characteristic clinical features and the history of maternal myasthenia should be enough to confirm the diagnosis, but the diagnosis may be delayed if the mother’s disease has not been previously detected. Further verification of the diagnosis may be derived from a favorable response to neostigmine methylsulfate, with improvement of symptoms 10–15 min after intramuscular injection of 0.15 mg/kg of body weight. Alternatively, intramuscular edrophonium chloride (Tensilon) may be administered intramuscularly or subcutaneously (0.15 mg/kg) or intravenously (0.10 mg/kg). Sufficient differences exist between transient neonatal myasthenia and the congenital myasthenic syndromes (see below) to render diagnostic confusion rare. Congenital myasthenia does not occur in infants born to mothers with acquired myasthenia. The other condition affecting neuromuscular transmission in this age group, infant botulism, is readily ruled out because it occurs after the second week of life, 5 days after the infant ingests food contaminated with Clostridium botulinum, whereas the onset of transient neonatal myasthenia is within the first 3 days of life only.

Congenital Myasthenic Syndromes Congenital myasthenia constitutes a heterogeneous group of genetic disorders affecting neuromuscular transmission that presents in the first year of life, producing mainly ptosis, and usually has a benign course.239,240,242–246,351 Although rare, congenital myasthenic syndromes are an important cause of

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seronegative myasthenia gravis. Congenital myasthenic syndromes occur in infants born to nonmyasthenic mothers and that are associated with hypotonia and weakness.60,239,240 Congenital myasthenic syndromes should be suspected in patients with seronegative myasthenia gravis, in infants with hypotonia and poor development of motor milestones, and in patients with a childhood history of neuromuscular difficulties affecting cranial, respiratory, truncal, or limb muscles.351 In some patients, however, symptoms may not appear until later childhood or even adulthood. Forty-two percent of the cases present before the age of 2 years, and over 60% before 20 years.574 In contradistinction to juvenile and adult-onset myasthenia, which have an autoimmune basis and are attributable to antibodies that bind to the acetylcholine receptor and cause increased turnover and destruction of the receptor, congenital myasthenia is not immune-mediated.351 The congenital myasthenia syndromes are caused by structural or functional alterations at the myoneural junction.246,550,699 Most cases present in the neonatal period or shortly thereafter with poor feeding, failure to thrive, and weakness. Three congenital myasthenia syndromes (slow-channel syndrome, prolonged channel open time syndrome, and limb girdle myasthenia) may present later in childhood or adolescence and represent a specific, rare group of potential differential diagnoses.351 A distinction between congenital and acquired myasthenia cannot be made with certainty on the basis of the age of onset because both types may manifest during the neonatal period, infancy, or childhood, and acquired myasthenia may also be antibody-negative.288 Congenital myasthenia is usually characterized by ocular musculature with ophthalmoparesis, orbicularis weakness, and ptosis. We described a unique child who had a congenital oculomotor nerve palsy with aberrant regeneration and fatigable ptosis associated with congental myasthenia gravis. During periods of levator fatigability, gaze activation of the ipsilateral superior or medial rectus muscles produced instantaneous levator retraction with no fatigability (Fig. 7.9). The ability of this child’s synkinetic neuromuscular connections to override her myasthenia suggested that there was selective sensitivity of the myasthenic levator muscle to the misdirected oculomotor axons, which presumably provided fresh synaptic reserve of acetylcholine to their target fibers.111 Congenital myasthenic syndromes can arise from presynaptic, synaptic, or postsynaptic defects.244 The major syndromes in which the defect is presynaptic are related to defects in Ach synthesis, mobilization, or release.351 Presynaptic congenital myasthenic syndromes were previously called “familial infantile myasthenia.”355,647 Postsynaptic syndromes are mainly caused by endplate acetylcholinesterase deficiency and Ach receptor kinetics, including the fast- and slow-channel syndromes.785 The array of disorders and involved genes identified has increased significantly.351 While genes have been identified for many

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Fig. 7.9 Myasthenic ptosis in a child with congenital left oculomotor nerve palsy. Upper panel: Facial photographs depict the clinical variability of the left upper lid ptosis and the compensatory head turn before treatment. This child’s congenital myasthenia was worse on the day of the right photograph, as evidenced by the increased ptosis and left facial

weakness. Lower panel: Primary and secondary positions of gaze shing retraction of the left upper eyelid in adduction and supraduction due to oculomotor synkinesis. Even with prolonged fixation, fatigable ptosis could not be elicitied in these positions of gaze. With permission from Brodsky111

forms of congenital myasthenic syndromes, mutation analysis is not yet available on a commercial basis.60,239,240 Some cases may be familial, with other siblings affected, supporting a genetic basis for the disorder.733 Most commonly, congenital myasthenic syndromes are caused by mutations that reduce the expression or alter the kinetics of the acetylecholine receptor.245 Reduced receptor expression is also caused by mutations in rapsyn, a molecule that is produced by muscle and is important for acetylcholine receptor aggregation on the postsynaptic membrane.245 The second most common congenital myasthenic syndrome is caused by mutations of the acetylcholinesterase molecule.242 Mutations of choline acetyltransferase, the rate-

limiting enzyme in the synthesis of acetylcholine, cause the congenital myasthenic syndrome associated with episodic apnea (previously known as “familial infantile myasthenia”).591 Recently, a unique congenital myasthenic syndrome caused by mutations of a perijunctional skeletal muscle sodium channel has been discovered.521 Congenital myasthenia is not immune-mediated, in contradistinction to juvenile- and adult-onset acquired myasthenia, which have an autoimmune basis and are attributed to antibodies that bind to the acetylcholine receptor and cause increased turnover and destruction of the receptor.26 Serum antiacetylcholine receptor antibodies and other autoantibodies are absent. Congenital myasthenia is not associated with any autoimmune

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Diffuse Ophthalmoplegia in Children Table 7.8 Classification of congenital myasthenic syndromes (based on 271 index cases evaluated at Mayo Clinic) Presynaptic defects (7%) Choline acetyltransferase (ChAT) deficiency Paucity of synaptic vesicles Congenital Lambert–Eaton-like syndrome Other unclassified presynaptic defects Synaptic defect (basal lamina) (14%) Endplate AChE deficiency Postsynaptic defects (79%) Reduced AChR expression (with or without minor AChR kinetic abnormality) • AChR mutations (isolated or with plectin deficiency) – Rapsyn mutations – MuSK mutations – DOK-7 mutations (formerly “Limb-Girdle” myasthenia) • AChR kinetic abnormality (some with mild reduced AChR expression) – Slow-channel syndrome – Fast-channel syndrome • Sodium channel mutations AChE acetylcholinesterase; AChR acetylcholine receptor; ChAT choline acetyl-transferase; MuSK muscle specific kinase

disease or any particular human leukocyte antigen genotype, and cytohistochemical studies fail to reveal immune complexes at the myoneural junction. The condition is generally nonremitting. Once thought to be a single disorder, it is now known to represent a group of diverse disorders distinguishable by the specific site of dysfunction at the myoneural junction (Table 7.8). Multiple inherited defects of neuromuscular transmission at presynaptic or postsynaptic levels are known, but some defects have not yet been characterized. The putative inheritance of most of these defects is autosomal recessive, with the exception of the slow-channel syndrome, which is autosomal dominant. The precise characterization of these defects requires the combined use of clinical, electromyographic, in vitro electrophysiological, and morphological data. It is probably impractical to perform all tests needed for accurate characterization of the myoneural defect on each infant suspected with the diagnosis, especially when the infant is ill. However, determination of the specific subtype of congenital myasthenia would be helpful for therapeutic purposes and would enhance our understanding of the heretofore incompletely understood disorders that constitute congenital myasthenia. Certainly, a detailed history should be obtained on each child regarding the onset and severity of feeding difficulty, breathing dysfunction, choking episodes, drooling, facial weakness, ophthalmoparesis, ptosis, hypotonia, and muscular fatiguability. This would start the process of differentiation between the different syndromes involved. For example, a syndrome characterized by defective AChR shows neonatal respiratory difficulty, feeding difficulty, and ophthalmoparesis,

while a syndrome characterized by impaired ACh release shows few, if any, of these features. The developmental milestones, progression or regression of symptoms and signs during infancy and childhood, response to any therapeutic modalities, and a complete family pedigree should be recorded. In some congenital myasthenia syndromes, a specific diagnosis can be made by simple histological or EMG studies while, in others, a complex panel of in vitro electrophysiological, ultrastructural, and immunocytochenical investigations are needed for accurate diagnosis.244 Because the congenital myasthenic syndromes are not immune-mediated, neither plasmapheresis nor immunosuppression has any beneficial effect. Thymectomy usually produces negligible benefits, although a transient improvement has been reported in two patients, one of whom had an abnormal thymus.170,803 Because of the diversity of the underlying abnormalities, no specific conclusion can be drawn regarding the efficacy of the anticholinesterase preparations. Some types of congenital myasthenia (e.g., congenital acetylcholine receptor deficiency) respond favorably to anticholinesterase preparations, while other types (e.g., acetylcholinesterase deficiency, slow-channel syndrome) are refractory to such treatment and may even be made worse by it. Therefore, an effort to differentiate juvenile myasthenia from congenital myasthenia and to specifically identify the type of congenital myasthenic syndrome has important therapeutic implications. On the basis of the identified pathophysiology of the congenital myasthenic syndrome, a number of other pharmacologic interventions are tried in individual children, including fluoxetine, ephedrine, albuterol, and 3,4-diaminopyridine.

Juvenile Myasthenia Juvenile myasthenia is said to be similar to the adult form, but more frequently familial, showing slower progression, characterized by more severe ophthalmoplegia, and having a higher rate of spontaneous remissions.778 Children with myasthenia often first present to the ophthalmologist with symptoms such as ptosis, diplopia, strabismus, and ophthalmoplegia.90,285 Juvenile myasthenia is otherwise similar to the adult variety in presentation, pathogenesis, clinical course, and response to therapy. While it has been observed that there is an increased incidence of autoimmune disorders in children with acquired autoimmune myasthenia gravis and their first-degree relatives, acquired autoimmune myasthenia gravis is probably not a familial disease. However, some studies reveal the juvenile variety to be more frequently familial,571,574 to show more severe ophthalmoplegia, and to have slower progression and a higher rate of spontaneous remissions. An acute fulminating form of myasthenia gravis has been described, with onset between 2 and 10 years of age, with respiratory crisis as the presenting feature of the disorder.264

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Many medications have been reported to incite or worsen myasthenia.796,811 These drugs may interfere with neuromuscular transmission pre or postsynaptically.811 Cardiovascular drugs (antiarrhythmics and beta adrenergic receptor-blocking agents), anticholinergics, anticonvulsants, antirheumatics, immunosuppressives, psychotropics, and antibiotics have all been reported in association with myasthenia.811 Many antibiotics, including kanamycin, ampicillin, imipenem with cilastatin, ciprofloxacin, erythromycin, and clarithromycin, have also been reported to cause myasthenia.624,656 Interferon-alpha, a drug frequently used in the treatment of malignancies and viral hepatitis, has been found to exacerbate myasthenia.83,768 Wasserman reported ocular myasthenia in a 10-year-old girl taking nitrofurantoin that resolved after discontinuation of the drug.796 Rarely, myasthenia gravis in children can be precipitated by a viral illness. 260,530 Molecular mimicry between the acetylcholine receptor and viral proteins may be involved in the pathogenesis of postinfections myasthenia gravis. Autoimmune manifestations of hyperthyroidism and myasthenia gravis occasionally overlap.682 The finding of lid retraction in a myasthenic child should lead to suspicion of this phenomenon. A large proportion of young patients with juvenile myasthenia gravis are seronegative.25,26,256,708 Careful differentiation from late-onset congenital myasthenic syndromes is necessary in these cases. Children younger 5 years of age, who present with ocular symptoms of myasthenia gravis, frequently respond to anticholinesterase medications without requiring immunomodulating therapy and have low rates of progressing to generalized involvement.569,600 However, one retrospective study found a 43% prevalence of systemic involvement.524 Several studies have found that pediatric myasthenia gravis shows a female-to-male ratio of about 4:1.5,361,524 Myasthenia can often be diagnosed on clinical grounds when ptosis or ophthalmoplegia is accompanied by certain neuro-ophthalmologic signs. These include fatiguable ptosis, orbicularis weakness, variable strabismus, quiver-like eye movements, and a Cogan lid twitch sign. A Cogan lid twitch is elicited by having a patient rapidly refixate the eyes from a depressed position to the primary position, with a positive lid twitch sign indicated by the lids overshooting briefly upward before settling in their usual ptotic position. If the lid is first fatigued by sustained upward gaze, the lid twitch sign becomes more exaggerated. Apparently, the short relaxation of the upper lid allowed by fixating an object in downgaze allows for transient recovery of strength by the myasthenic levator muscle. Although ptosis is the most common sign, lid retraction may occasionally be encountered, especially unilaterally in patients with contralateral ptosis. This seemingly paradoxical finding is explained by Hering’s law of equal innervation, as the patient attempts to elevate the contralateral ptotic lid. Bilateral lid retraction, which is also rarely reported in

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myasthenia, is not readily explained by Hering’s law. In such cases, the possibility of concurrent thyroid eye disease must be excluded.412 Children with diffuse myasthenic ophthalmoplegia rarely present with myopia.652 Myopia occurs when medial rectus weakness leads to exotropia, which necessitates excessive accommodative convergence to maintain single binocular vision. These children are caught in the unpleasant situation of having to sacrifice clear vision to avoid diplopia. Jacqueline Winterkorn, M.D., has observed another unique ocular motor sign of myasthenia that can be elicited in patients with diffuse ophthalmoplegia. An optokinetic drum is spun horizontally for approximately 30 s, as the patient attempts to follow the targets. The drum is then spun diagonally and the resultant optokinetic movements are observed. In myasthenic ophthalmoplegia, the resultant movements are vertical rather than diagonal because the horizontal component has been prefatigued. Conversely, if the drum is first spun vertically for 30 s and then diagonally, the resultant optokinetic movements are horizontal (Winterkorn sign). In nonmyasthenic ophthalmoplegia, optokinetic preconditioning does not alter the trajectory of the patient’s diagonal optokinetic responses. Systemic myasthenia is often first suspected when weakness is demonstrated to be fatigable (worsening with use or exercise and relieved by periods of rest). The diagnosis of myasthenia may be confirmed with certain ancillary tests, including serologic testing for antibodies, clinical neurophysiologic testing (repetitive stimulation of motor nerves, needle electromyography, including single fiber testing), and pharmacologic testing. Because children with acquired autoimmune ocular myasthenia gravis have a higher incidence of seronegativity and normal clinical neurophysiologic testing, the diagnosis often depends on other measures. There are three main confirmatory procedures for myasthenia: response to acetylcholinesterase inhibitors, electrophysiologic testing, and antibody assays. In general, all share the same problem of a lower sensitivity in ocular myasthenia gravis than in generalized myasthenia gravis.58 The sensitivity of the edrophonium test is approximately 95% in generalized myasthenia gravis602 and is similar in patients with ocular myasthenia gravis with ptosis.257 However, diplopia fails to respond in approximately one-third of patients, and long-standing myasthenia may not respond at all. The repetitive nerve stimulation test is positive in most patients with generalized myasthenia gravis, but may be normal in well over 50% of patients with ocular myasthenia gravis.256,257 Single-fiber EMG of the orbicularis oculi is currently the most sensitive test for ocular myasthenia.481 When coupled with the standard EMG, it usually distinguishes myasthenia from other disorders such as mitochondrial myopathy or oculopharyngeal dystrophy.643 The sensitivity of single-fiber EMG is more than 90% in generalized myasthenia gravis669 and approximately 85% in ocular myasthenia gravis.764 Since needle

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EMG and repetitive nerve stimulation are usually positive in systemic myasthenia, these tests should first be performed to rule out denervation or atrophy in patients with limb weakness. Only when these tests are negative, or when there are purely ocular signs, is single-fiber EMG indicated.481 Because it is painful and requires patient cooperation, it may be difficult or impossible to perform in young children. Positive acetylcholinesterase antibodies are found in 90% of cases of systemic myasthenia, but in only 50% of cases of ocular myasthenia. Because myasthenic children have a higher frequency of negative anticholinesterase antibodies, a negative test is not especially useful in this setting. The recent identification of muscle-specific kinase (MuSK) as a target of the autoimmune process in a subset of patients indicates that autoimmune myasthenia gravis includes at least two distinct immunologic disorders directed against different antigens in the postsynaptic membrane of the neuromuscular junction.24 Autoantibodies targeting MuSK have been demonstrated in approximately 40% of seronegative patients.257,368,668,784 Although the numbers are small, our experience is that the anti-MuSK variant tends to be more severe and less responsive to therapy. The Tensilon (edrophonium hydrochloride) test is the most commonly utilized. For children less than 34 kg, a test bolus of intravenous edrophonium should be 0.1 cc or 1 mg, followed by repeated boluses at 1-min intervals to the point of positive response or maximum injection of 5 mg total dose. Cardiac monitoring is advisable. The dose of atropine given for excess parasympathetic response (primarily bradycardia or bradyarrhythmias) should be 0.02 mg/kg/dose, with a maximum of 0.5 mg/dose in younger children and a maximum of 1 mg/dose in adolescents (Fig. 7.10). Results of the Tensilon test may be equivocal, falsely negative, or falsely

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positive. False-negative results are more common than falsepositive ones. Therefore, if the clinical findings are suggestive of myasthenia, repeating an initially negative Tensilon test is recommended. False-positive results have been reported in patients with compressive lesions (brain tumors, intracranial aneurysm), botulism, Eaton–Lambert syndrome, amyotrophic lateral sclerosis, poliomyelitis, transverse myelitis, Guillain–Barré syndrome, and myositis.211,557 Because severe bradyarrhythmias, conduction pauses, and cardiac arrests have been reported, albeit rarely,389 cardiac monitoring and pretreatment with atropine should be considered in “at-risk” patients. In young children, neostigmine (Prostigmine) is administered intramuscularly, which produces a more prolonged response in myasthenic patients than does edrophonium chloride. Neostigmine can produce a more prolonged clinical response (onset, 10 min; duration, 60 min), which can allow for more leisurely assessment of the response. Doses are 0.04 mg/kg/dose administered intramuscularly or subcutaneously, with a maximum of 0.5 mg/dose. Side effects related to excess parasympathetic activity can also last up to 60 min and, as clinically indicated, are treated with atropine in a dose of 0.02 mg/kg/dose, intravenously, with a maximum 0.05 mg/kg/dose in younger children and 1 mg/dose in adolescents. To avoid the complications of pharmacological testing, a “sleep test” has been devised wherein the patient is evaluated for improvement of ocular signs immediately after a 30-min period of sleep (or eye closure) and for worsening of these signs shortly thereafter (Fig. 7.11).588 The “ice test,” performed in an outpatient setting, can similarly differentiate a neuromuscular transmission defect from other causes of ptosis.234,235,254,300,453 In this test, a surgical glove filled with ice

Fig. 7.10 Positive Tensilon test in juvenile myasthenia gravis. Child presented with variable ptosis and exotropia (a) that showed resolution upon administration of intravenous Tensilon (b)

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Fig. 7.11 Sleep test. Left: Child with myasthenic ptosis. Right: Resolution of ptosis following 5 min of gentle eye closure. Good WV, Hoyt CS. Strabismus Management. Boston, MA: Butterworth-Heinemann; 1996

chips is placed over the ptotic eyelid for 2 min after the eyelid has been fatigued by prolonged upgaze. Measurement of the millimeters of ptosis before and after the cooling is used to objectively measure response with lessening of the ptosis, suggesting the presence of myasthenia. The ice test is based on the observation that increased temperature has a detrimental effect, and decreased temperature a beneficial effect, on muscle force generation in myasthenia gravis.85 Both tests and the sleep test often produce dramatic resolution of myasthenic ptosis, and some of the observed effect of the ice test may be attributable to resting of the closed lid. The medical treatment of juvenile myasthenia is similar to that of the adult variety in that the ptosis shows a good therapeutic response while the strabismus often does not.436 In a recent retrospective study, children with ocular myasthenia were found to have a high incidence of ptosis (96%) and strabismus (88%), most commonly with exotropia and vertical heterotropia, and amblyopia (21%). The ptosis showed a good therapeutic response in 87%, but the strabismus improved in only 29%.436 Combined pyridostigmine and prednisone were most commonly used. Treatment with a short course of prednisone and long-term azathioprine is reported to reduce the risk and severity of generalized symptoms and to promote remission of the disease. Although thymomas are rare in myasthenic children,7 thymectomy has been observed to be associated with an increased rate of clinical remission in children with autoimmune myasthenia gravis.497,649 Early surgery (within 2 years of clinical onset), bulbar involvement without ocular signs of generalized weakness, clinical onset during adolescence (12–16 years of age) and presence of other autoimmune disorders were associated with increased probability of clinical remission after thymectomy.649 Surgeons have developed a technique of using video-assisted thorascopic thymectomy that has significantly decreased operative morbidity compared to transsternal thymectomy.749 Unanswered questions, regarding the impact of thymectomy early in life on the developing immune system, have kept thymectomy limited to children with generalized weakness and will likely lead to

additional review of the effectiveness of this operation as a therapeutic option. Because the disease is immune-mediated, unlike in congenital myasthenia, immunosuppression and plasmapheresis have a therapeutic role. Systemic therapy of myasthenia helps control ocular symptoms in most patients.220,221,711 In addition to producing superior resolution of ocular misalignment and diplopia,460 treatment with oral prednisone appears to reduce the conversion of ocular to systemic myasthenia gravis.457–460,528,556 After an initial period with immune suppressing dose of corticosteroids, the benefit may be maintained with doses that do not suppress the immune system and appear to cause few major systemic adverse effects.458 There is a theoretical basis for using corticosteriod treatment to prevent generalized myasthenia, even at doses that do not cause immunosuppression.457 Corticosteroid treatment of in vitro human muscle cultures increases the number of acetylcholine receptors98,414 and prevents receptor loss induced by the serum from generalized myasthenia gravis patients. Neuromuscular junctions increase in size, and the length, number, and depths of postsynaptic folds increase after weeks of corticosteroid exposure.43 In patients with ocular misalignment, strabismus surgery has been used to manage both stable3,64,197,335,594 and unstable563 diplopia with long-standing success. Brain tumors rarely produce clinical findings that are indistinguishable from myasthenia.413,633,730 These findings are attributed to a putative compression of the central caudal nucleus in the dorsal midbrain.413 Ragge and Hoyt633 described an adolescent girl with neurofibromatosis type I and a dorsal midbrain astrocytoma who had fatiguable ptosis, upgaze paresis, and a positive “lid twitch” sign. These findings improved significantly following radiotherapy of the astrocytoma, confirming that the muscular fatiguability was central in origin. Straube and Witt730 described four patients with posterior fossa tumors who presented only with fluctuating weakness of the external ocular muscles and/or the pharyngeal muscles, leading to an incorrect diagnosis of ocular myasthenia. Moreover, as noted earlier, false-positive results of Tensilon testing may

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occur in some instances involving tumors or even aneurysms. Branley et al97 reported a 7-year-old girl who developed an oculomotor nerve palsy of subacute onset due to a cerebral artery aneurysm. The condition was initially confused with myasthenia gravis because the ptosis improved after Tensilon administration (false-positive result), but the key clinical distinguishing findings were the presence of aberrant innervation and pupillary involvement, which are not features of myasthenia. Chemotherapeutic agents, such as, vincristine, may also cause neurological findings (ptosis, ophthalmoplegia, jaw pain) that can confound the diagnostic picture in children with intracranial tumors.15

Olivopontocerebellar Atrophy The nomenclature regarding olivopontocerebellar atrophy and the related hereditary spinocerebellar ataxias has undergone revision, first to the clinically based autosomal dominant cerebellar ataxias and, more recently, to the genetically defined spinocerebellar ataxias.611a Olivopontocerebellar atrophy (OPCA) is a pathological label implying not only olivopontocerebellar changes, but also cases with more widespread lesions involving the CNS.65 OPCA may also be part of the pathological hallmark of other disorders such as mitochondrial encephalomyopathies, prion disorders, and hereditary metabolic diseases. In 1983, Harding347 developed a clinicogenetic classification, which has been subsequently modified according to molecular genetic advances. Older diagnostic categories, such as olivopontocerebellar atrophy, are now known to carry mutations for spinocerebellar ataxia (SCA1, SCA2, and SCA3).65 The hereditary ataxias and loci now comprise around 80 loci, with 28 belonging to spinocerebellar ataxia and designated as SCA1–28 in order of discovery. Several SCA subtypes (SCA1, SCA2, SCA3, SCA6, SCA7) are caused by CAG trinucleotide expansions in their respective genes. Autosomal dominant cerebellar atrophy 1 (ADCA1), which presents with a range of findings, including ataxia, pyrimadal and extrapyramidal signs and ophthalmoplegia, corresponds to the current classifications SCA1–4. ADCA2, which is similar but includes retinal degeneration, corresponds to SCA7. ADCA3, which involves relatively pure cerebellar signs, corresponds to SCA6 and 7.136 Clinically, patients diagnosed with OPCA correspond to those with SCA1, SCA2, and SCA3. SCA1 maps to 6p23, SCA2 to 12q24, and SCA3 to 14q24.3-q31. Macular and retinal degeneration are seen predominantly in SCA7, but occasionally in SCA2.660 Patients with SCA7 have abnormal electroretinograms showing predominantly cone dysfuntion.547a MR imaging shows severe OPCA in SCA2, similar but milder changes in SCA1, and very mild atrophy with sparing of the olives in SCA3.132 An SCA panel can be ordered when the one of the spinocerebellar ataxias are suspected.

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Supranuclear ophthalmoplegia may be accompanied by gaze-evoked nystagmus in patients with SCA1, SCA3, and SCA6, and by rebound nystagmus in SCA1 and SCA3.136 Impaired saccadic velocity and latency are characteristic of SCA2 and SCA2. In SCA1, saccadic amplitude is significantly increased, resulting in hypermetria.132 A supranuclear ophthalmoplegia with severe saccadic slowing is highly characteristic of SCA2,133 which may show selective involvement of vertical saccades, impaired VOR, and gaze-evoked nystagmus.132,136 The constellation of impaired VOR, saccadic dysmetria, and slow-wave jerks are common to both SCA3 and Friedreich’s ataxia.565 The association of these ocular motor disorders with dystonia, spasticity, facial and lingual fasciculations, diplopia, and parkinsonism should suggest the diagnosis of Machado–Joseph disease (SCA3).187,687 Many reports have described a striking “ocular stare” or “prominent eyes,” which are thought to result from lid retraction rather than proptosis.229,734 SCA1–4 (previously known as ADCA type 1) are associated with optic atrophy and ophthalmoplegia. SCA7 (previously known as ADCA II) is distinguished by the presence of pigmentation macular dystrophy that includes early granularity and mottling, and is later associated with pigmentation changes that gradually spread to the periphery, with late optic atrophy and attenuation of retinal vessels.238,308,309,372,392,663,752 The ADCA type II locus, which corresponds to SCA7, has been mapped to chromosome 3p12-p21. SCA7 (or ADCA type II) is caused by an unstable CAG repeat in the SCA gene. Larger expansions are associated with earlier onset, a more severe and rapid clinical course, and a higher frequency of decreased vision, ophthalmoplegia, extensor plantar responses, and scoliosis. The mutation is highly unstable, with an increase in repeats with paternal transmission correlating with marked anticipation. This instability of transmission is more marked than with other SCA subtypes. A supranuclear ophthalmoplegia is commonly seen in more than half of SCA patients. The responsible gene for SCA7 has been cloned. Molecular testing of DNA from whole blood is now available to detect the SCA7 CAG repeat to confirm the diagnosis genetically. The fundamental neurologic lesions of the spinocerebellar ataxias are localized to the cerebellum, and the pontine, inferior olivery, arcuate, and pontobulbare nuclei.445 Cerebellar atrophy fundamentally involves Purkinje cells and predominates in the neocerebellum. CT scanning and MR imaging show the characteristic brainstem and cerebellar atrophy, with the most sensitive diagnostic feature being the diameter of the middle cerebellar peduncle.596 Intermediate and T2-weighted MR images may show cruciform hyperintensity (“hot cross bun” sign) of the ventral part of the pons, accounted for by demyelination and gliosis of transverse fibers of the pons secondary to atrophy of nuclei pontis.65

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It is important to remember that several metabolic disorders that present in infancy or childhood (abetalipoproteinemia, hexosaminidase A deficiency, cholestanolosis, the leukody strophies, [metachromatic, Krabbe’s disease, and adrenoleukomyeloneuropathy], and Refsum disease) can be associated with a progressive and unremitting ataxia that can first appear in early adulthood.598 Of the vitamin deficiencies, vitamin E deficiency is most often associated with the development of progressive ataxia, associated with areflexia, and loss of proprioception and vibration sensation (abetaliproteinemia or Bassen–Kornzweig disease).348 Affected patients develop pigmentary retinopathy and progressive gaze restriction. Some patients have vitamin E deficiency without fat malabsorption, inherited in an autosomal recessive manner, with symptoms similar to Freidreich’s ataxia.

Botulism Signs of total (internal and external) ophthalmoplegia, dry mouth, descending paralysis, obstipation, absence of fever, and lucid sensorium, as cardinal symptoms should raise suspicion of botulism. Clostridium botulinum produces seven distinct protein toxins, of which A, B, and E are the most commonly responsible for human botulism.815 The botulism toxin causes neural paralysis of skeletal muscle by disruption of both spontaneous and stimulus-induced release of acetylcholine from the presynaptic nerve terminal and by interfering with exocytosis of vesicle contents. The toxin enters the body via the following four routes: (1) ingestion of preformed toxin, as in the case of food poisoning; (2) toxin production by Clostridium spores or bacteria infecting a wound; (3) colonization of the gastrointestinal tract by Clostridium botulinum, with subsequent production of toxin; it is by this mechanism that infant botulism and the “infant form of botulism” that affects some adults occurs; and (4) the “hidden” form in which no identifiable route of entry of toxin or bacteria into the body can be identified. Botulism spores are ubiquitous, and have been isolated from yard and houseplant soil and vacuum cleaner dus.38 In adults, the disease usually results from ingestion of preformed botulinum toxin in contaminated foods such as poorly sterilized canned goods or raw fish. Infant botulism, first described in 1976,619 is caused by ingestion of live Clostridium botulinum organisms or spores, which subsequently release toxin in the intestine. Most pediatricians advise against feeding honey to infants younger than 1 year of age, as it has been documented as a source of spores causing infant botulism.38,745 Infant botulism was first recognized in 1976 and has since become the most frequently reported form of botulism.684,689,804 Most reported cases have been from North America.

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A history of honey ingestion or soil eating is frequently obtained. Because Clostridium botulinum is ubiquitous and is commonly ingested without adverse effects, a number of host factors may render a particular individual predisposed. Constipation, immune dysfunction, gastric pH, and unusual gut flora, among others, may permit the colonization and germination of Clostridium spores and subsequent local production of toxin. Infant botulism has been described in infants ranging from 10 days to 8.5 months old, but 98% of those affected are between 2 weeks and 6 months old.35 The earliest clinical sign of disease is usually constipation, which can be present for several days before other signs appear.34,745 Bulbar signs later predominate and include impaired sucking with poor feeding, a feeble cry, tachycardia due to loss of vagal tone.34 Isolated internal ophthalmoplegia may evolve into diffuse ophthalmoplegia with ptosis. Crouch et al reported an infant who had bilateral sixth nerve palsies following resolution of infant botulinum.192 Other signs of cranial nerve palsy include drooling, diminished gag reflex, and facial weakness. Generalized muscular weakness progresses in a descending fashion from the cranial nerves to the limbs. Generalized weakness, hypotonia, hyporeflexia, and cranial nerve weakness constitute the “floppy infant” syndrome. Respiratory arrest and death may follow, but most infants recover completely in 1–5 months. While mild cases are often managed on an outpatient basis, the age distribution of infant botulism closely mirrors that of the Sudden Infant Death syndrome (SIDS), and botulism toxin has been recovered from 5% of autopsy specimens of infants with the diagnosis of SIDS.37 Cases of infant botulism may also be mistakenly diagnosed as crib death, failure to thrive, sepsis, dehydration, viral infection, idiopathic hypotonia, poliomyelitis, meningitis, brainstem encephalitis, or other neuromuscular disorders such as myasthenia. To add to the diagnostic quandary, some patients with botulism may give false-positive response to intravenous edrophonium chloride.190 One important differentiating feature of botulism is the dilated, poorly reactive pupils, which are not seen in ocular myasthenia. The differential diagnosis also includes Reye’s syndrome, Guillain–Barré syndrome, hypothyroidism, tick paralysis, and toxins. The diagnosis is made when toxin or organisms are recovered from stool samples. However, the level of botulinum toxin is too low to be detected in the sera of patients with infant botulism. Electromyographic (EMG) studies are highly useful in the diagnosis of botulism, with a characteristic EMG pattern that has been given the acronym BSAP, for “brief duration, small-amplitude, overly abundant, motorunit action potentials.” Fibrillation potentials suggesting functional denervation are observed in about half the cases. Repetitive fast rates of stimulation (20–50 Hz) result in marked incremental response, a finding not present in older

Olivopontocerebellar Atrophy

children and adults with botulism, probably due to the large amount of toxin present. Other conditions showing an incremental EMG response, such as Eaton–Lambert (not seen in infants), hypermagnesemia, and aminoglycoside toxicity, can be readily excluded on clinical and laboratory grounds. Logistical problems in terms of application of EMG to the investigation of infant botulism include the need to transport the cumbersome equipment to the intensive care unit and electrical interference there with the EMG recording. Spontaneous recovery occurs through sprouting of new nerve endings with formation of new myoneural junctions. Treatment of affected patients includes insertion of a nasogastric tube with suction, enemas, antitoxin administration (benefit controversial), and mechanical ventilation, if indicated. The recently introduced botulinum immune globulin (BIG) appears promising. In a recent clinical trial, it reduced the severity of illness and reduced the mean length of hospital stay from 5.7 to 2.6 weeks without complications.39

Fisher Syndrome: A Variant of Guillain–Barré Syndrome The Guillain–Barré syndrome (acute infectious polyneuropathy) consists of progressive, usually symmetric muscular weakness that appears several days after a nonspecific infectious prodrome. Mild sensory disturbances, such as pain and parasthesias, are commonly present. The paralysis usually affects the lower extremities and then ascends. Cranial nerve palsy may appear at any time during the clinical course. Results of EMG studies are usually consistent with involvement of the lower motor neurons or peripheral nerves. Fisher syndrome is a variant of Guillain–Barré syndrome with the distinct triad of ataxia, areflexia, and ophthalmoplegia without concurrent peripheral neuropathy. Fisher syndrome constitutes about 5% of all reported cases of Guillain–Barré syndrome. There appears to be a gender predilection, with the male/female ratio being 2:1. Of the 223 cases reported before 1993, the average age was 43.6 years (range, 14 months to 80 years), with 14.3% of these being children.66 Most patients with Fisher syndrome suffer a preceding viral prodrome, usually respiratory, 1–3 weeks prior to onset of the syndrome.66 Most patients reach maximum neurologic deficit within 1 week of onset. Diplopia and ataxia are the most common presenting symptoms. Associated ophthalmoplegia is complete (including the parasympathetic fibers to the pupillary sphincter muscle) in about half of patients with Fisher syndrome,66 but pure external ophthalmoplegia or internal ophthalmoplegia may occur. Isolated ocular motor nerve palsy and combinations of horizontal and vertical gaze palsies may be noted. Internuclear ophthalmoplegia, oneand-a-half syndrome, gaze-evoked lid nystagmus, convergence

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spasm, and a dorsal midbrain syndrome with upward gaze paralysis, but intact Bell’s phenomenon, have also been reported.16,66,529 The presence of these latter disorders and similar findings pointing to brainstem involvement fuels the controversy about the nature of the disease as a peripheral (infranuclear, due to involvement of sensory fibers in the peripheral nerves and dorsal roots) or CNS (supranuclear) disorder or as a combination of both.529 Other cranial nerves may be affected, the most common being the facial nerve. Dysphasia and dysarthria may result when the lower cranial nerves are involved. Monoparesis, hemiparesis, or quadraparesis have been described. Patients may have sensory symptoms, including parasthesias, dysesthesia, and headaches. Other symptoms and signs include disturbance of consciousness, seizures, myoclonus, tremors, fever, vomiting, irritability, positive Babinski sign, and respiratory insufficiency. The CSF, if examined 2–3 weeks or later after onset, usually shows mild elevation in protein, with about 10% of cases in the literature showing pleocytosis. Some authors consider the Fisher variant to be due to pathologic changes exclusively within the peripheral nervous system. This concept is supported by reports of normal MR imaging scans in affected patients.655 While pure cases of Fisher syndrome are apparently attributable to peripheral neuropathy and are not uncommon, overlapping cases occur that bridge the spectrum from the benign Fisher variant to the more virulent Guillain–Barré syndrome. For instance, cases that include limb paralysis do not, strictly speaking, fall within the original definition of the Fisher syndrome and are transitional forms to the Guillain–Barré syndrome. On the basis of current evidence, some authors believe that Fisher syndrome represents an encephalomyeloneuritis.66 The triad of severe external ophthalmoplegia, ataxia, and areflexia in an otherwise alert child is fairly unique. The characteristic history and physical findings are usually sufficient to establish the presumptive diagnosis, but differentiation from posterior fossa tumors may be difficult without neuroimaging. Wernicke syndrome and phenytoin intoxication can show a similar syndrome complex, but these entities can be excluded by the clinical history. Both Fisher syndrome and botulism may show a similar early presentation consisting of extraocular muscle weakness and mydriasis. Other conditions included in the differential diagnosis of Fisher syndrome are brainstem stroke, pituitary apoplexy, cerebral sinus thrombosis, tick fever, and diphtheria. While some cases may follow a more virulent course, most cases of Fisher syndrome resolve spontaneously within 1–3 months. Corticosteroids as well as plasmapheresis have been used, but there is little evidence to support their efficacy in the limited form of the condition without brainstem signs. Intravenous immunoglobulin may be helpful in severe cases.30

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Serological, immunological, and pathological studies all implicated a role for complement-mediated damage to neuronal and Schwann cell membranes in Guillain–Barré syndromes.329 In vivo and in vitro models of Fisher syndrome have shown that anti-GQ1b ganglioside antibodies target the presynaptic motor nerve terminal axon and surrounding peripsynaptic Schwann cells, thereby mediating destructive injury through deposition of membrane attack complex (MAC). The anti-GQ1b antibody has been detected in the sera from patients during the acute phases of Fisher syndrome, Bickerstaff brainstem encephalitis, and Guillain–Barré syndrome with ophthalmoparesis.828 These cases seem to demonstrate a close relationship between ophthalmoparesis and serum anti-GQ1b antibody.159 It has been hypothesized that ganglioside epitopes on Campylobacter jejuni are the key to the development and characterization of Guillain–Barré syndrome.446 The presence of these bacterial epitopes in neuropathy patients correspond to autoantibody reactivity. In one study, patients infected with C. jejuni (Asn51) regularly expressed the GQ1b epitope (83%), whereas those with cst-II (Thr51) had the GM1 (92%) and GD1a epitopes. Patients infected with C. jejuni (Asn51) more often were positive for anti-GQ1b IgG (56% vs. 8%), and had ophthalmoparesis (64% vs. 13%) and ataxia (42% vs. 11%). Patients who had C. jejuni (Thr51) more frequently were positive for anti-GM1 (88% vs. 35%) and anti-GD1a IgG (52% vs. 24%) and had limb weakness. Thus, the genetic polymorphism of C. jejuni appears to determine autoantibody reactivity as well as the clinical presentation of Guillain–Barré syndrome, possibly through modification of the host-mimicking molecule.

Bickerstaff Brainstem Encephalitis Bickerstaff’s brainstem encephalitis is a clinical syndrome of ophthalmoplegia, cerebellar ataxia, and central nervous system signs.16,72 Diagnostic criteria include a progressive, relatively symmetric external ophthalmoplegia and ataxia with disturbance of consciousness or hyperreflexia.724 Positive antiGQ1b antibodies support the diagnosis.587,724 Conditions that mimic the disorder, including brainstem tumors, must be excluded. There is a clinical continuum between Bickerstaff brainstem encephalitis and Fisher syndrome.724 However, CNS signs, such as disturbance of consciousness and cogwheel rigidity, are more in keeping with brainstem encephalitis. In general, Bickerstaff brainstem encephalitis is a disease of the CNS, while Fisher syndrome is primarily a disease of the peripheral nerves.587 However, some clinical and pathologic overlap is found. It is interesting to note, for example, that one in three patients in the original description of Fisher syndrome had drowsiness, whereas Bickerstaff described four cases

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of Bickerstaff brainstem encephalitis in which the patients had areflexia. Both conditions have been described following Mycoplasma pneumoniae infection.724 Treatment with intravenous immunoglobulin or use of plasmapharesis has been reported to produce clinical improvement, although it is unproven that they affect the natural history of this disorder.

Tick Paralysis Tick paralysis should be considered in the differential diagnosis of Fisher syndrome in children in tick-infested areas who develop ophthalmoplegia and ascending paralysis.149 The diagnosis is confirmed by finding a tick embedded in the skin and observing for signs of improvement after tick removal. No other tests for confirming tick paralysis exist. Tick paralysis is thought to be caused by a toxin secreted in tick saliva that reduces motor neuron action potentials and the action of acetylcholine.263,307 Symptoms usually begin 4–7 days after tick feeding. Ascending flaccid paralysis progresses over several hours or days; sensory loss does not usually occur, and pain is absent.714 When the tick is not removed, the mortality rate resulting from respiratory paralysis is approximately 10%.575,686

Wernicke Encephalopathy Although classically considered an adult disorder, in 2003, an epidemic of Wernicke encephalopathy developed in Israeli infants fed a thiamine-deficient soy-based formula.427 These infants showed no neurologic signs for the first 6 months on the thiamine-deficient diet.627 Apathy, vomiting, and diffuse ophthalmoplegia brought these infants to medical attention and helped to establish the diagnosis. Wernicke encephalopathy preferentially affects neurons in particular areas of the nervous system such as the putamen, parts of the thalamus, and the periaqueductal gray matter. Thiamine turnover is higher in these areas and these structures have high rates of oxidative metabolism in neonates, which could make them more vulnerable.748

Miscellaneous Causes of Ophthalmoplegia Involvement of the respiratory and renal systems in the child with diffuse ophthalmoplegia should suggest the diagnosis of Wegener granulomatosis.488 A new autosomal recessive ophthalmoplegic disorder affecting highly inbred Arab families in Israel produces limited upgaze, slow saccades, and impaired

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Fig. 7.12 Transient esotropia in neonate. Infant showed 30 prism diopters of left esotropia (a) with mild limitation of abduction of left eye that totally resolved by 5 months of age (b). Estropia was caused by perinatal trauma to abducens nerve

convergence without ptosis or pupillary abnormalities. In addition, there is involvement of the face, orbicularis, and neck muscles, giving the appearance of a long, thin face. Onset is probably in childhood. Linkage studies identified markers on chromosome 17p13.1-p12, an interval to which several genes for sarcomeric heavy chain map.500

Transient Ocular Motor Disturbances of Infancy Healthy neonates may exhibit a variety of benign, transient supranuclear eye movement disturbances. These include horizontal heterophorias, tonic downgaze and upgaze, opsoclonus, skew deviations, and transient idiopathic nystagmus in infants. As each of these disorders may forebode serious neurological disease, especially in older children, their benign nature in healthy neonates must be recognized to avoid unnecessary diagnostic testing.

Transient Neonatal Strabismus Several nursery studies have shown that the eyes of otherwise healthy, full-term neonates are commonly misaligned. In one study of 1,219 neonates,583 48.6% had orthotropia, 32.7% had exotropia, 3.2% had esotropia, and 15.4% were not sufficiently alert to allow determination of ocular alignment. No cases of congenital esotropia were found in any neonate, supporting the concept that congenital esotropia does not manifest at birth. Follow-up studies of these patients have shown that the vast majority of children with transient heterophorias become orthotropic between 2 and 3 months of age, a stage coincident with development of stereoscopic vision.31,712 Unlike exotropia, which may be found transiently in the neonatal period, the finding of large esotropia in the

first several weeks of life should not be classified as congenital esotropia (which usually first appears after 6 weeks of age) until other conditions such as sixth nerve palsy and Möbius syndrome are ruled out (Fig. 7.12). It should also be recognized that the eyes of premature infants may transiently display exotropia with limited adduction. These findings have been speculated to result from immaturity of the medial longitudinal fasciculus in the premature infant. Large convergent movements of the eyes, producing esotropia, are often observed in the first 2 months of life.374,375 These convergent eye movements resolve spontaneously, giving way to normal ocular alignment. The fact that these large-angle convergent eye movements are predictive of the normal binocular alignment374,375 belies the notion that infantile esotropia results from excessive convergence.112

Transient Idiopathic Nystagmus Good et al described six infants with transient idiopathic nystagmus. Four of these infants had other visual abnormalities, including regressed retinopathy of prematurity, coloboma, and delayed visual maturation, which may have precipitated the nystagmus. They interpreted the transient nystagmus as indicative of a fragile period of postnatal maturation of the ocular motor system.304 It is also recognized that some infants with delayed visual maturation may exhibit transient nystagmus.71

Tonic Downgaze Tonic downward deviation of the eyes may occur as a transient phenomenon in neonates and does not necessarily indicate underlying neurologic dysfunction. 275,761,813 Both eyes are tonically deviated downward while the infant is

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awake, but can be maneuvered upward with oculocephalic or vestibulo-ocular stimulation; the condition resolves during sleep, with both eyes returning to the midline. It usually resolves within the first 6 months of life. Two infants who displayed this transient tonic downgaze also showed associated upbeat nystagmus, with complete resolution of both findings within the first few months of life.295 The authors proposed that immaturity of the vestibular system was the cause. In some cases, these transient episodes of downgaze can be followed by abnormal body movements.813 The benign, transient form of tonic downgaze differs from the “setting sun sign” associated with hydrocephalus by the absence of eyelid retraction. Yokochi825 described downward deviations of the eyes of neurologically affected infants that were paroxysmal rather than constant, as in the foregoing benign variety. The paroxysms were not associated with seizure activity. He considered this to be a sign found in braindamaged infants with cortical visual impairment. The paroxysms spontaneously resolved with time in many patients. We examined a blind infant with profound bilateral optic nerve hypoplasia, absent septum pellucidum, and developmental delay who showed sudden episodic downward deviations of the eyes occurring every 1–2 min and lasting 5–10 s (Fig. 7.13). The downward deviation was associated with lid lag. The patient also showed intermittent side-to-side head shaking. Episodic downgaze may be one of the presenting signs of Leigh subacute necrotizing encephalomyelopathy.511 Mak et al511 reported a previously healthy infant who, at 6 months of age, showed episodic downgaze with limited horizontal movements that resolved after 5 days, then recurred several times along with other abnormalities before a diagnosis of Leigh disease was made. It is not clear whether congenital hydrocephalus alone results in tonic downgaze. The setting sun sign, a feature of congenital hydrocephalus (Fig. 7.14), may be considered a

Fig. 7.13 Episodic tonic downgaze. Blind infant with profound bilateral optic nerve hypoplasia, absent septum pellucidum, and developmental delay showed sudden episodic downward deviations of eyes occurring every 1–2 min and lasting 5–10 s. These have occurred since birth. Downward deviation was associated with lid lag. Infant also showed intermittent side-to-side head shaking

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Fig. 7.14 Setting sun sign in hydrocephalus. Child presented with pronounced lid retraction and mild to moderate tonic downward deviation of eyes. Disproportionately large head and dilated ventricles on neuroimaging confirmed diagnosis of hydrocephalus

combination of lid retraction (Collier’s sign) and tonic downgaze. Acquired hydrocephalus in older patients does not produce tonic downgaze, suggesting a specific susceptibility of the neonatal brain to the mass effect of hydrocephalus on midbrain structures responsible for downgaze or suggesting a higher sensitivity of the pretectal area in infants to hydrocephalus, leading to more severe upgaze palsy (causing the eyes to deviate downward) than is seen in older patients. Tamura and Hoyt735 reported 11 premature infants with intraventricular hemorrhages who showed acute tonic downward deviation of the eyes, esotropia, and upgaze palsy. All patients showed associated hydrocephalus, shunting of which resulted in gradual improvement in upgaze, with persistence of the large-angle esotropia. The authors suggested that the gradual recovery of upgaze indicates that the upgaze palsy may not be simply due to the acute effects of the hydrocephalus. Rather, they suggested that the associated intraventricular hemorrhages act as a mass lesion, compressing (and hence paralyzing) the upgaze centers or irritating (and hence stimulating) the downgaze centers within the mesencephalon. They speculated that injury to these mesencephalic structures may contribute to the delay in recovery of upgaze after shunting. We most commonly see tonic downgaze in conjunction with esotropia in infants with periventricular leukomalacia, where it can occur in the absence of intraventricular hemorrhage.118 As with intraventricular hemorrhage, the tonic downgaze spontaneously resolves, and infants are usually left with an A-pattern esotropia with superior oblique muscle overaction. The telltale ocular intorsion can easily be missed if the retinas are examined in the esotropic position, which places the eyes in the vertical rather than the torsional field of action of the overacting superior oblique muscles. We have proposed that a posterior canal predominance caused by injury to bilateral central brainstem pathways mediating upward pitch could explain this constellation of

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finding.115 Neuroimaging often shows associated thalamic injury which may explain this combination of findings.118 In congenital hydrocephalus that is not caused by intraventricular hemorrhage, however, the upgaze palsy and/or the setting sun sign responds quickly to reduction of intracranial pressure. For instance, Hoyt and Daroff379 described a 3-month-old infant with intermittent hydrocephalus secondary to a tumor of the thalamus and septum pellucidum. The infant displayed tonic downgaze and esotropia whenever the ventricular pressure increased; eye movements normalized when the ventricular pressure became normal. Such cases demonstrate that a mass effect, independent of the effect of the hydrocephalus itself, need not be present for tonic downgaze to develop in infants with hydrocephalus. Children with hydrocephalus are predisposed to esotropia through several different mechanisms: (1) early-onset childhood esotropia, which is more common in neurologically impaired children; (2) unilateral or bilateral sixth nerve palsy; and (3) intraventricular hemorrhage in premature infants, which may involve the thalamus and mesencephalon and produce neuro-ophthalmologic signs of a thalamic infarction (tonic downward deviation of the eyes, upgaze palsy, and esotropia). The esotropia in these patients usually persists even after the vertical gaze deficits resolve. Visually significant upgaze limitation can be relieved with bilateral inferior rectus recessions in Parinaud’s syndrome.128 Tonic downgaze may be observed in very ill patients with impaired consciousness who have medial thalamic hemorrhage, severe encephalopathy, acute obstructive hydrocephalus, or severe subarachnoid hemorrhage. In this setting, it should be distinguished from V-pattern pseudobobbing, wherein the eyes show an abrupt downward jerk followed by a slow, upward drift to primary position. Keane420 reported this finding in five patients with acute obstructive hydrocephalus who had arrhythmic, repetitive, downward and inward ocular deviations at a rate of 1 per 3 s to 2 per second. The fast downward movements render the condition similar to ocular bobbing, but it differs by the presence of a V pattern, a generally faster rate, and associated pretectal, rather than pontine, signs. Keane speculated that V-pattern pseudobobbing represents a variant of convergence-retraction nystagmus that signals the need for prompt shunt placement or revision.

Tonic Upgaze Tonic upgaze is less common than tonic downgaze. It also tends to be more episodic. In 1988, Ouvrier and Billson605 described four patients with a new condition they termed “benign paroxysmal tonic upgaze of childhood.” This condition was characterized by onset during infancy of episodic

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tonic conjugate upward deviation of the eyes that was relieved by sleep. The children had impaired downgaze below the primary position, with downbeating nystagmus on attempted downgaze and apparently normal horizontal movements. The patients were otherwise neurologically intact, with the exception of mild ataxia. Results of metabolic, electroencephalographic (EEG), and neuroradiologic investigations were unremarkable. All eventually improved, with one child showing a favorable therapeutic response to levodopa. The following year, Ahn et al11 described three infants who had tonic upgaze with no associated seizure activity or neurologic disease. The vestibulo-ocular reflexes were intact, revealing a full range of vertical movements. These episodes were initially noted in the first month or two of life and were most conspicuous when the infant was ill or fatigued. These episodes diminished with time.11 Mets532 described a 9-month-old otherwise healthy infant with largeangle esotropia who displayed extreme sustained spasms of upgaze. This infant was noted to have full vertical range of ocular motion at times and could fixate in primary gaze. No EEG abnormality was found. These episodes resolved at age 3% months, but the esotropia with associated amblyopia required patching therapy and strabismus surgery. Tonic upgaze is not an epileptic phenomenon, and paroxysmal tonic upgaze may be exacerbated by treating coincident epilepsy with valproate.502 Phenomenologically, benign paroxysmal upgaze and congenital downbeat nystagmus are closely related conditions. Congenital downbeat nystagmus is distinguishable only by the presence of corrective downward refixational saccades.115a It is likely that benign hereditary downbeat nystagmus and the syndrome of benign tonic upward deviation of the eyes with ataxia are variants of the same disorder. In several affected children, tonic upgaze has evolved into downbeating nystagmus.605,605a We have proposed that, tonic upgaze an anterior canal predominance.115,116 Tonic upgaze is difficult to distinguish from the “overlooking” that was reported by Taylor741 in patients with neuronal ceroid lipofuscinosis. Instead of looking at the object of regard directly, affected children look above the object. Initially attributed to relative preservation of the inferior visual field associated with certain retinal disorders, it was later reported not to be disease-specific, but rather to represent a sign of bilateral central scotomas (and vision of 20/200 or worse) in children from a variety of causes.303 Recently, Cruysberg reported that some patients with overlooking display a tonic upgaze and a dystonic neck extension, the two conditions are not always distinct.194 When not associated with overlooking, tonic upgaze is more often associated with neck flexion than neck extension.502 Intermittent episodes of upward ocular deviation may be a manifestation of oculogyric crisis or of a seizure disorder,

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typically petit mal. Oculogyric crisis denotes an extreme, episodic upward rotation of the eyes, often obliquely to the right or to the left. The deviation is usually sustained and is often associated with rhythmical jerking or twitching of the eyelid. Each oculogyric movement lasts several seconds, after which the eyes return to the horizontal position before deviating again a few seconds later until the “crisis” passes, typically in 1 or 2 h. Patients may have associated thought disorders. Dopamine-blocking agents (neuroleptics) are the most common cause of drug-induced acute dystonic reactions such as oculogyric crisis, but other drugs have been incriminated, including carbamazepine, lithium carbonate, metoclopramide, and sulpiride, among others. Oculogyric crisis has also been reported after Tensilon administration.586 Similar eye movements have been observed in patients with various CNS disorders, such as herpetic encephalitis, pantothenate kinase-associated neurodegeneration, and Rett syndrome,270 and in one patient with cystic glioma in whom the onset of crisis was positional.722 Oculogyric crisis can be aborted with use of anticholinergics (e.g., Cogentin) and subsequently controlled by reducing the dosage of the offending medication or changing it altogether. Patients with petit mal seizures may show eye movements similar to oculogyric crisis, usually with concurrent eyelid flutter.28 Eye movement tics (see later in this chapter) may also superficially resemble intermittent episodic tonic upgaze. Barontini56 concluded that either dystonia or downgaze palsy can underlie the phenomenon of tonic upgaze. Acquired tonic upward deviation is also seen in comatose patients, wherein it indicates a very poor prognosis, or in patients with brainstem disease causing downgaze paralysis. Cherubism, a rare inherited disorder that involves the facial bones and produces facial fullness because of boney enlargement occurring between 2 and 4 years of age should also be considered in the differential diagnosis of tonic upgaze.273 This disorder was so named by Jones in 1933 because the marked fullness of the jaws and cheeks and the upward displacement of the eyes in patients were thought to resemble the heavenward gaze and round faces of Renaissance cherubs.404 Although this lesion was originally considered to be a form of fibrous dysplasia, cherubism was eventually accepted as a clinicopathologic entity, with features identical to giant cell reparative granuloma.161 This condition can be complicated by proptosis and optic neuropathy.358

Neonatal Opsoclonus Opsoclonus denotes bursts of chaotic repetitive back-to-back saccades in different directions (see Chap. 8). Although usually indicative of an underlying viral encephalitis or

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neuroblastoma, opsoclonus has been reported as a benign transient finding in healthy neonates. It usually resolves in 1–3 months, passing through a phase of ocular flutter. Given the apparent rarity of this observation, it is probably prudent to consider this benign transient variant a diagnosis of exclusion, especially in light of the serious nature of other potentially causative lesions such as neuroblastoma. When opsoclonus accompanies neuroblastoma, it imparts a poor long-term neurological prognosis,551 but a highly favorable prognosis for survival.572

Transient Vertical Strabismus in Infancy A transient vertical deviation of the eyes with or without a horizontal component has been reported in the neonatal period without associated evidence of posterior fossa dysfunction and is referred to as skew deviation.381 Some infants exhibiting this sign may subsequently develop large-angle esotropia typical for congenital esotropia or nystagmus compensation syndrome.381 Whether this transient vertical deviation of the eyes is an early manifestation of dissociated vertical divergence and whether it is a reliable premonitory sign for the subsequent development of congenital esotropia is not known.

Congenital Cranial Dysinnervation Syndromes The congenital cranial dysinnervation syndromes comprise a group of disorders characterized by deficient innervation to the extraocular muscles and facial musculature.321,621,750 These congenital neuromuscular disorders result from developmental errors in innervation of the ocular and facial muscles.821 They result from mutations in a number of genes, including ROBO3,400 PHOX2A,573 SALL4,14 HOXA1,747 and KIF21A,821 that are essential to the normal development of brainstem motor neurons or axons.87 Recognized disorders congenital ptosis, congenital fibrosis of the extraocular muscles, Duane’s syndrome and its variants, Möbius sequence, horizontal gaze palsy with progressive scoliosis, and congenital facial palsy.321 They present with varying degrees of ptosis and ophthalmoplegia from birth, together with signs of aberrant innervation. Many of these disorders were previously considered to be myopathic in origin. However, the congenital cranial dysinnervation disorders also include sensory disorders due to trigeminal nerve maldevelopment that cause congenital corneal anesthesia.

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Congenital Ptosis Our long-standing understanding of congenital ptosis as a primary myopathy has been overturned, as clinical signs of congenital cranial dysinnervation have been demonstrated.106 The notion of congenital ptosis as a primary myopathy was first challenged in 1996 when Steel and Harrad found an unrecognized form of oculomotor synkinesis in 44% of patients with unilateral congenital ptosis.723 Affected patients displayed excessive elevation of the ipsilateral eye beneath the ptotic eyelid in upgaze, but no vertical deviation in primary gaze. This upshoot disappeared when the ptotic eyelid was manually elevated. The authors insightfully attributed this phenomenon to a misdirection of levator innervation to the ipsilateral superior rectus muscle. They proposed that manual elevation of the ptotic eyelid reduced innervation to the levator muscles, thereby extinguishing the aberrant superior rectus innervation. In 2000, Harrad and Shuttleworth352 described another group of patients with long-standing unilateral ptosis that resolved in upgaze and increased in downgaze, suggesting that superior rectus innervation had become misdirected to a paretic levator muscle. These clinical observations suggest that prenatal and postnatal routing of the superior division of the oculomotor nerve is a delicate process that may be subject to directional modification, perhaps on the basis of the relative innervational recruitment by its two target muscles.106 For reasons that are unclear, an inverse Bell’s phenomenon (unilateral or bilateral) is occasionally observed postoperatively following levator resection. This phenomenon reverts to normal within 2 weeks.68 Congenital ptosis may be associated with other forms of ocular motor synkinesis. Khan et al429 described a large family in which two siblings exhibited ptosis with abnormal synkinetic elevation on ipsilateral abduction. One was bilaterally affected, while the other had unilateral findings. A third demonstrated classic bilateral congenital ptosis, while a fourth demonstrated Duane’s syndrome. Its association with congenital fibrosis syndrome is detailed below. Indeed, congenital ptosis can now be viewed as a limited form of congenital fibrosis syndrome selectively affecting the superior division of the third nerve. Several genes for isolated congenital ptosis have now been identified.248,527

Marcus Gunn Jaw Winking (Trigemino-Oculomotor Synkinesis) A normal synkinesis denotes simultaneous contraction of muscles normally innervated by different peripheral nerves or

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different branches of the same nerve. A pathologic synkinesis occurs when muscles are reinnervated by nerves other than their own following a nerve injury. Pathologic synkinesis may be congenital (Duane’s syndrome, synergistic divergence, Marcus Gunn jaw winking) or acquired (facial synkinesis or oculomotor synkinesis after trauma). The Marcus Gunn jaw winking (MGJW) synkinesis usually presents as variable unilateral ptosis noted at birth or shortly thereafter. Unlike ordinary congenital ptosis, when the infant nurses, the ptotic lid jerks upward with each suckling movement. In a series of nearly 1,500 cases of congenital ptosis,70 the Marcus Gunn phenomenon accounted for 80 patients (5%). Of these 80 patients, 42 showed right eye involvement, 35 showed left eye involvement, and three had bilateral synkinesis. No gender preponderance was identified, and only two cases were familial. Fifty-four percent of patients showed amblyopia, and 26% showed anisometropia. Some form of strabismus was found in 56%, including 19 cases of superior rectus palsy, 19 cases of double elevator palsy, and two cases of Duane’s retraction syndrome. The natural history of the disorder remains unsettled, with some authors noting that the synkinetic movement becomes less conspicuous with age, although patients may learn to camouflage the lid excursions. The pathogenesis of the MGJW synkinesis is controversial. The prevalent concept is that the disorder results from aberrant innervation of the levator palpebrae muscle by a branch of the motor division of the trigeminal nerve that supplies the muscles of mastication, hence the designation trigemino-oculomotor synkinesis. However, Sano672 has presented EMG evidence that the jaw winking phenomenon is a release phenomenon representing an exaggeration of a normally found but clinically undetectable physiologic cocontraction. Utilizing EMG studies of normal subjects, he demonstrated cofiring of the oculomotor-innervated extraocular muscles and the muscles of mastication innervated by the motor branch of the trigeminal nerve. He argues that congenital brainstem lesions may “release” phylogenetically older neural mechanisms, such as synkinetic movements from higher central control, which are similar to other synkinetic movements such as the palmomental and primitive grasp-feeding reflexes. Muller’s muscle is doubly innervated by an efferent sympathetic nerve and an afferent proprioceptive nerve.828a Muller’s muscle acts as a serial muscle spindle (similar to that seen in jaw closing periodontal receptors).828a Stretching of Muller’s muscle has been found to produce involuntary levator muscle contraction (the Hoffman reflex). These proprioceptive fibers function as mechanoreceptors to induce reflex contracture of the levator muscle against gravity as a type of length servomechanism. The central modulation of these levator and jaw closing pathways by motor trigeminal

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nucleus may give rise to the innervational crossover that manifests in the form of Marcus Gunn jaw winking.53a Sano672 has classified the trigemino-ocular motor synkinesis into two major groups: (1) external pterygoid-levator synkinesis (the most common type) with lid elevation upon thrusting the jaw to the opposite side (ipsilateral external pterygoid firing), upon projecting the jaw forward (both external pterygoids firing), or upon opening the mouth widely; and (2) internal pterygoid-levator synkinesis (relatively rare) with lid elevation upon teeth clinching. In the typical case of MGJW, firing of the motor branch of the trigeminal nerve is associated with firing of the oculomotor branch to the levator. A rare variant of this phenomenon, termed the inverse Marcus Gunn phenomenon,504 shows firing of the motor branch of the trigeminal nerve synkinetically, with inhibition of the oculomotor branch to the levator. Here, the affected eyelid falls as the mouth opens or as the jaw moves to the opposite side, without associated activity of the orbicularis oculi. Pathologic synkineses may cluster together. For instance, the MGJW synkinesis (congenital trigemino-oculomotor synkinesis) has been reported in association with Duane’s syndrome (congenital oculomotor-abducens synkinesis) and with synergistic divergence.120,337 This association generally occurs in the setting of congenital fibrosis syndrome.104,120,337 Other forms of ocular motor synkinesis have also been reported in patients with Marcus Gunn jaw winking. “Eye bobbing” was attributed to coactivation of the superior rectus muscle in one patient with Marcus Gunn jaw winking.603 Trigemino-abducens synkinesis444,466 and pseudo-inferior oblique muscle overaction have also been described.387 A frontalis suspension operation is usually recommended for cases severe enough to come to surgery. Some controversy exists regarding whether to disinsert the ipsilateral levator and whether to also disinsert the contralateral levator and perform a frontalis suspension on the opposite side to achieve a greater degree of symmetry.

Congenital Fibrosis Syndrome Congenital fibrosis of the extraocular muscles (CFEOM) is characterized by the presence of congenital restrictive ophthalmoplegia, fixed downgaze, horizontal strabismus, ptosis, and a compensatory backward tilting of the head.751 In this disorder, the extraocular muscles and the levator muscles are replaced by fibrous tissue to a variable extent.350 The disorder may be unilateral or bilateral and may be clinically limited to specific muscles in a given individual. The resultant ocular motility deficits depend on which of the extraocular muscles are involved. The inferior rectus muscle is most commonly involved, followed by the levator muscle and the lateral rectus muscle. In the presence of ptosis, inferior and lateral rectus muscle involvement may mimic unilateral or bilateral congenital oculomotor palsy. Rarely, all of the extraocular muscles,

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including the levator, are affected (generalized fibrosis syndrome). Historically, investigators have divided congenital ocular fibrosis into different subtypes that include congenital fibrosis of the inferior rectus with ptosis, strabismus fixus, congenital unilateral enophthalmos with ocular muscle fibrosis and ptosis,362 and the vertical retraction syndrome. Fixed downgaze and associated ptosis with sparing of pupillary function and similar findings in other family members provide critical clues to the diagnosis. Patients with CFEOM may show rapid convergent movements of the eyes on attempted upgaze, simulating convergence retraction nystagmus.104 The diagnosis of CFEOM should therefore be suspected when “convergence-retraction” nystagmus is accompanied by ptosis rather than lid retraction. Although this phenomenon could theoretically result from the mechanical tethering effect of tight inferior rectus muscles in attempted upgaze, the fact that these convergent movements persist following recession of the inferior rectus muscles suggests that they arise from a supranuclear deficiency of elevation, as suggested by several investigators.1,78,168,262 CFEOM has traditionally been regarded as a primary myopathy localized to the extraocular muscles on the basis of biopsy studies of affected muscles. Both light and electron microscopy studies show replacement of extraocular muscles by dense fibrous connective tissue and collagen.350 Histology of an affected levator showed reduction or absence of striations and Z bands and vacuolation of muscle cells. Muller muscle fibers appeared intact. Anomalous insertions of affected muscles may occur, presumably resulting from a maturational defect at or before the seventh week of gestation.29 Involved eyes may also have anomalous adhesions between the muscles, Tenon’s capsule and globe, and inelasticity or fragility of the conjunctiva so that conjunctival recession may also be necessary.266,487 Like in Duane syndrome, the involved extraocular muscles in congenital fibrosis syndrome are simultaneously tight and hypoplastic. Affected muscles often appear small and atrophic on orbital imaging studies.805 On the basis of the presence of multiple synkinetic eye movements in a patient with CFEOM, Brodsky et al, in 1989, proposed that is caused by failure of normal neuronal connections with the extraocular muscles to become established early in embryogenesis.120 Assaf independently concluded that congenital fibrosis syndrome must arise from a CNS abnormality.44,45 Our subsequent report of additional patients with CFEOM, who displayed both synergistic divergence and MGJW,120,337 provided clear evidence that congenital fibrosis of the extraocular muscles can result from the absence of normal innervation to orbital striated muscles early in development (Fig. 7.15). Unlike the synergistic divergence of Duane syndrome, the paradoxically abducting eye simultaneously abducted and depressed, suggesting that the synergistic divergence was attributable to aberrant innervation of the superior oblique muscle. A primary failure to establish normal neuronal connections with the extraocular muscles and levator muscle

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Fig. 7.15 Congenital fibrosis syndrome with synergistic divergence (simultaneous abduction during attempted lateral gaze) and Marcus Gunn jaw winking. (a) Bilateral ptosis, exotropia, and fixed downgaze.

(b) Retraction of the right upper eyelid with mouth opening. (c) Position of the eyes with eyelids manually elevated. (d) In attempted left gaze, the right eye abducts and depresses. From Brodsky104 with permission

would predispose to neuronal misdirection, which allows for limited preservation of innervated muscle fibers and replacement of the remaining muscle by fibrous tissue.120,702 Clinically, only deficient innervation could explain the superimposition of synkinetic eye movements on a diffuse congenital ophthalmoplegia,291 Other forms of aberrant innervation have since been documented in CFEOM.428 A neuropathologic study by Engle et al249 demonstrated that congenital fibrosis of the extraocular muscles 1 is associated with abnormal development of the oculomotor axis, primarily affecting the superior division of the oculomotor nerve, corresponding to alpha motoneurons in the midbrain, the target extraocular muscles, and the levator and superior rectus muscles. This study established that CFEOM can result from the failure of developing cranial nerves to form

appropriate neuromuscular connections with their target extraocular muscles, a finding supported by subsequent genetic studies.8–10,104,120,247,823 Because most patients with CFEOM do not display signs of neuronal misdirection, and because anomalous fibrous bands and adhesions are sometimes discovered to be attached to the globe during strabismus surgery,266,487 we now suspect that the genetically determined dysgenesis of CFEOM can directly influence the extraocular muscles, in addition to developing cranial nerves. It is therefore likely that the underlying pathophysiology of congenital fibrosis syndrome must lie along a spectrum from a primary absence of normal innervation to localized orbital dysgenesis of the extraocular muscles. Neuroanatomic abnormalities are often missed on routine intracranial MR imaging, which frequently shows no overt

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Fig. 7.16 CFEOM. Axial MR imaging showing bilateral hypoplasia of the ocular motor nerves. Courtesy of Joseph Demer, M.D.

structural malformations of the brain.104 However, highresolution images of the ocular motor nerve commonly show hypoplasia or absence of the oculomotor nerves and involved extraocular muscles (Fig. 7.16).205,432,494 To date, three genetic CFEOM loci have been identified and three clinical phenotypes have been delineated.252,508,753 is the most common form. The key clinical findings include bilateral nonprogressive ophthalmoplegia, bilateral ptosis, and an infraducted (downward) primary position of each eye with limited supraduction.252 CFEOM1 pedigrees demonstrate autosomal dominant inheritance with full penetrance and minimal variation in expression.820 CFEOM1 has been mapped to the centromeric region of chromosome 12.250–252,769 It has now been demonstrated that congenital fibrosis of the extraocular muscles type 1 results from heterozygous mutations in the KIF21A gene encoding a kinesin motor protein.820 Although the specific function of the KIF21A protein and its stalk are yet to be determined, the mouse ortholog, KIF21a, was found to be an anterograde microtubule-based motor protein expressed predominantly in neuronal tissues. Engle et al have found that human KIF21A is expressed most abundantly in developing neuronal tissues, suggesting that it plays an important role in neuronal development consistent with the congenital fibrosis of the extraocular muscles 1 phenotype.150,430,820 As kinesins affect axonal transport after development (microtubule function), it remains unclear how a kinesin mutation could lead to neural agenesis. Because KIF21A has also been observed in other tissues, including skeletal muscle, it remains to be determined whether the primary pathology of congenital fibrosis of the extraocular muscles, resulting from KIF21A mutations, is in the nervous system (neurogenic), the extraocular muscles (myopathic), or both. For example, the frequent finding of fibrous bands in the orbits of patients with congenital fibrosis of the extraocular muscles is clearly incompatible with a purely neurogenic mechanism.

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CFEOM2 is autosomal recessive, and its gene is localized on chromosome 11q13.1.793 Affected individuals have bilateral ptosis and restrictive ophthalmoplegia, with eyes partially or completely fixed in an exotropic position.750 Patients have severely limited ability to depress or adduct either globe. ARIX, previously called PHOX2A, is the gene that is mutated in CFEOM2550,793,822 ARIX is a transcription factor essential for the development of oculomotor and trochlear nuclei in mice and zebra fish.318 It is therefore believed that CFEOM2 results from hypoplasia of the oculomotor and trochlear nerve nuclei as a result of mutations in both copies of ARIX. CFEOM3 is an autosomal dominant disorder with variable expression and probably incomplete penetrance.750 The gene maps to markers on 16p24.2-q24.3.215 Severely affected patients have ptosis, with eyes fixed in a downward and exotropic position and bilateral severe restriction of eye movements (a phenotype resembling that of congenital fibrosis of the extraocular muscles 1). Mildly affected patients have normally positioned globes, with limitation of vertical gaze. Moderately affected patients may have asymmetric involvement, with one eye severely affected and the other mildly affected. Mackey and colleagues508 reported a family that maps to the CFEOM3, with involvement primarily of the vertically acting extraocular muscles. Because the involved extraocular muscles are both tight and hypoplastic, the surgical management of congenital fibrosis syndrome presents a unique set of challenges.103 Free tenotomies obviate the need for suture placement into the rectus muscles, which can be technically difficult due to severe restriction.103 Free tenotomies of tight rectus muscles are technically simple and rarely produce surgical overcorrection.103 The need for resections can be determined by examining the position of the eyes under nondepolarizing paralyzing anesthesias.823 It is also well to remember that surgical weakening of tight inferior rectus muscles can reduce their secondary adducting action and produce exotropia.103 In our experience, raising the globe does not produce improvement in associated ptosis, so surgical correction of ptosis often needs to be performed in conjunction with inferior rectus tenotomy. Surgical correction of ptosis should be modest to avoid exposure keratopathy. Despite multiple surgeries, some degree of ocular misalignment usually persists.103

Congenital Horizontal Gaze Palsy with Scoliosis In 1974, Dretakis and Kondoyannis described the autosomal dominant syndrome of horizontal gaze palsy and progressive scoliosis.223 In 2004, Jen et al400 described 11 patients with autosomal recessive congenital horizontal gaze palsy caused by a mutation of the ROBO3 gene on chromosome 11. Affected children are born with absent horizontal eye move-

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Fig. 7.17 Congenital horizontal gaze palsy with scoliosis. T2-weighted fast spin echo axial MR imaging shows butterfly configuration of the medulla with flattening of the ventral surface, reduced anterior–posterior diameter and midline medullary cleft. Courtesy of Joseph Demer, M.D.

ments and had variable strabismus, horizontal nystagmus, and defective vertical smooth pursuit. Convergence can be preserved, and some people use convergence substitution as a substitute for horizontal gaze.241 All patients developed progressive scoliosis during early childhood. The disorder is found in both consanguineous and nonconsaguinous families.241 Heterozygotes were unaffected. This disorder produces a pathognomonic brainstem malformation. MR imaging shows a hypoplastic pons and medulla,622 with overall diminished anterior–posterior dimension (Fig. 7.17). The ventral surface of the pons is flat. The medulla fans out both dorsally and ventrally in a butterfly configuration. There is a prominent midline cleft in the medulla that extends down to the cervicomedullary junction. Affected patients had electrophysiologic evidence of ipsilateral corticospinal and dorsal column-medial lemniscus tract innervation. In contradistinction to most other congenital cranial dysinnervation disorders, the abducens nerves are normal in size and configuration.241 ROBO3 mutations may disturb brainstem morphogenesis by failing to promote decussation of long motor and sensory tracts in the pons and medulla. Impaired decussation of pontine ocular motor pathways may explain the absence of horizontal eye movements in this disorder.88

Möbius Sequence Möbius sequence is a rare congenital disorder characterized by congenital facial weakness with horizontal gaze palsy296 or impairment of ocular abduction.781 Dysfunction of other cranial nerves, orofacial malformations, limb malformations, and musculoskeletal system defects are common associated features, but they are not obligatory for the diagnosis. Möbius sequence is a sporadic multiple-malformation complex that affects the face and horizontal gaze mechanisms bilat-

Fig. 7.18 Möbius syndrome. Note characteristic flattening of lower facial features. Courtesy of Joseph Demer, M.D.

erally.566 Affected children have mask-like facies, with the mouth constantly held open (Fig. 7.18). The upper facial nerves are affected more than the lower facial nerves, and facial asymmetry is common due to asymmetric facial strength. The eyes may be straight, esotropic or, rarely, exotropic.191,200,518a,555 Those with straight eyes tend to have horizontal gaze palsy,200 and some use convergence substitution to look to the side. Such children may be thought to have isolated bilateral sixth nerve paresis if the slow convergence movement and the associated pupillary constriction are not recognized. Another subset exhibits retraction of the globe on attempted adduction.518a As in Duane syndrome, congenital ocular motor synkinesis may contribute to the horizontal conjugate gaze paresis in some cases. Additional deficits affecting other cranial nerves, particularly V, IX, and XII, may produce feeding and sucking difficulties in the neonatal period and subsequent speech difficulties, with or without atrophy of the tongue.16 Rarely, the sixth cranial nerves may be spared.754 Möbius sequence may be associated with a wide variety of associated limb malformations (talipes equinovarus, brachydactyly, syndactyly, congenital amputations) as well as hypoplasia or absence of the branchial musculature, particularly the pectoralis muscle (Poland anomaly).16,454 Miller et al553 refer to the subgroup with associated limb anomalies as terminal transverse defects with orofacial malformations (TTV-OFM), a term originally used by Temtamy and McKusick.16 Endotracheal intubation may be especially

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difficult in children with Möbius sequence, owing to structural abnormalities of the mandible and palate.22 Cardiovascular abnormalities (most commonly dextrocardia, patent ductus arteriosus, and ventricular septal defects), micrognathia, structural abnormalities of the pinna, and mild mental retardation and autism are also occasionally present.16,54,193,403,545,547 Other abnormalities can include an A-shaped mouth, lagophthalmos, a “hidden” smile and laughter, syndactyly, a hypoplastic, asymmetric tongue that cannot be protruded over the lips, and a groove over the midline of the tongue. The ocular abduction deficit may be caused by congenital horizontal gaze paresis, Duane’s syndrome, simple abducens palsy, or congenital fibrosis.781 Children with Möbius sequence have difficulty relating to people in their environment because of an inability to convey their reaction of joy or sorrow. They are often incorrectly assumed to be mentally retarded and are predisposed to social and psychiatric problems.21a,547a,555 The successful management of Möbius sequence entails a multidisciplinary approach that includes the medical, speech, education, and mental health disciplines.16 Strabismus surgery can restore ocular alignment,718,777 and regional muscle transfer and microvascular free tissue transfer have been used to provide innervated dynamic muscle to restore facial movement.164,547,742 Because of their orofacial abnormalities, children with Möbius sequence are at higher risk of postoperative respiratory failure following general anesthesia.302 Although Möbius sequence is now classified as one of the congenital cranial dysinnervation disorders, it is more than a cranial nerve or nuclear developmental disorder. Möbius sequence is a rhombencephalic developmental disorder with hypoplasia of the entire brainstem, including the traversing long tracts, and signs of neuronal degeneration and other congenital brain abnormalities.782 Neurophysiologic studies suggest dysfunction at infranuclear, nuclear, and supranuclear levels.148,779 Aberrant regeneration may contribute to the horizontal conjugate gaze paresis in some cases of Möbius sequence. The associated feeding and respiratory problems, along with poor motor development, are consistent with this hypothesis.781 Often, the clinical features (facial weakness and impairment of ocular abduction) are only the most salient clinical features of a more extensive developmental disorder with probably diverse pathogenetic mechanisms. Neither etiology nor pathogenesis of this syndrome have yet been elucidated and are likely to be diverse in nature.780 Two major pathogenetic explanations have been suggested: a primary genetic cause, implying a maldevelopment of the brainstem, and a primary ischemic cause, possibly due to embryological or environmental toxic factors mediating an interruption in the blood supply of the brainstem during early embryologic development.781 These postulated pathogenetic mechanisms are based on a few postmortem observations, which include hypoplasia of the cranial nerve nuclei with or

7 Complex Ocular Motor Disorders in Children

without active neuronal degeneration and focal necrosis with neuronal loss, gliosis, and calcifications in the brainstem.781 MR imaging shows brainstem hypoplasia when measuring the pons (Fig. 7.17), supporting the hypothesis that Möbius sequence is a developmental disorder of the entire lower brainstem604,612,780 with other cranial nerve aplasia.225 Absence of the facial nerves despite residual function in some facial muscles suggests that other cranial nerves may aberrantly innervate some of the facial muscles.780 The finding of crocodile tears in patients with Möbius sequence also supports this association. A variant of Möbius sequence with normal brainstem anatomy has recently been recognized.225 Some investigators have suggested that ischemia of the lower cranial nuclei due to an insufficient blood supply in the pontine branches is the cause of Möbius sequence.80,226 Intrauterine brainstem infarction could result from premature regression or obstruction of the primitive trigeminal arteries before the establishment of a sufficient blood supply from the vertebral arteries, which may explain the variability in clinical expression.16 Brainstem calcifications, which have been attributed to vascular insufficiency,16,219 are not indicative of a specific mechanism and could equally support a maldevelopmental pathogenesis.782 Neuropathologic studies have emphasized the presence of brainstem atrophy and/or necrosis in Möbius sequence.188a Patients with Möbius sequence are predisposed to primary respiratory failure and recurrent apnea, which correlates with both tegmental necrosis with calcifications and marked brainstem hypoplasia at autopsy. The association of Möbius sequence with thalidomide embryopathy and misoprostol exposure191,518,774 demonstrates that early embryonic exposure to teratogens may produce a similar malformation complex.543a Möbius sequence is usually considered sporadic, however, rare instances of autosomal dominant, autosomal recessive, and X-linked recessive inheritance have been reported. Cytogenetic studies have suggested two loci for Möbius sequence: 1p22 and 13q12.2-13.782

Monocular Elevation Deficiency, or “Double Elevator Palsy” “Double elevator palsy” is a descriptive term denoting a congenital deficiency of monocular elevation that is equal in abduction and adduction. Generally speaking, an inability to elevate one eye may occur on a restrictive or paretic basis and may be congenital or acquired. The patient or his family frequently reports that one eye shoots up and disappears under the upper eyelid while, in fact, the contralateral eye is the one with abnormal motility. The patient frequently has associated hypotropia and ptosis or pseudoptosis. The term “double elevator palsy” was originally coined to reflect what was then thought to be the basis for the disorder, namely, con-

Congenital Cranial Dysinnervation Syndromes

genital palsy of the ipsilateral inferior oblique and superior rectus muscles,801 a concept that has since been abandoned. It has since become apparent that the concomitant limited elevation, very characteristic of double elevator palsy, may result from at least three disparate pathophysiologic disorders, namely, inferior rectus restriction, superior rectus paresis, and a supranuclear disturbance of monocular elevation.261 In truly paretic cases, dual palsy of the inferior oblique and superior rectus muscles does not occur; paresis of the superior rectus muscle alone (the dominant elevator of the globe) is sufficient to produce the clinical picture. The term monocular elevation deficiency is a more accurate descriptive term. The monocular elevation deficiencies undoubtedly overlap with the congenital cranial dysinnervation syndromes (discussed below).577 Several large series have shown that most patients with monocular elevation deficiency have a restrictive abnormality to elevation.533,534,690 Some of these cases represent unilateral inferior rectus muscle fibrosis, which can present with a tight inferior rectus muscle, hypotropia, and secondary ptosis in CFEOM3.207,350,750 Congenital inferior rectus fibrosis and neurogenic double elevator palsy may closely mimic each other because both may exhibit defective elevation associated with ptosis or pseudoptosis. Conversely, a long-standing hypotropia associated with neurogenic double elevator palsy may result in secondary contracture of the inferior rectus muscle and cause a positive forced duction test. Similar cases of inferior rectus tightness may result from perinatal orbital trauma.338 The diagnosis of contralateral superior oblique palsy should be considered in any child who has a monocular elevation deficiency, because fixation with the “paretic eye” can produce a contralateral inferior rectus contracture. Other conditions to be considered include orbital blowout fractures and orbital fat adherence syndrome. Patients with inferior rectus restriction due to orbital blowout fracture may also show a component of inferior rectus paresis.461 On the basis of studies utilizing scleral search coil techniques, Ziffer et al839 suggested the existence of at least three distinct etiologic categories: primary inferior rectus restriction, primary superior rectus palsy, and congenital supranuclear elevation defects. The inferior rectus restriction may be present primarily or may secondarily result from long-standing superior rectus weakness. Examination for the status of Bell’s phenomenon and other reflex upward movements is very useful. An intact Bell’s phenomenon, or the ability to produce an upward movement of the eye with the oculocephalic maneuver, suggests a supranuclear disturbance. An absent Bell’s phenomenon would indicate either inferior rectus restriction or superior rectus palsy. The two can be distinguished by saccadic velocity analysis, forced ductions, and active force generation. If restriction is absent and the eyes are orthotropic in the primary position, a superior rectus paresis is most unlikely, and a supranuclear disturbance is

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inferred.534 Scott and Jackson690 have noted that the appearance of an accentuated lower lid fold on attempted upgaze predicts the presence of an inferior rectus contracture. While the location of the “lesion” in the restrictive variety of the monocular elevation deficiency is readily apparent, generally pointing to tightness in the inferior rectus muscle complex, the location of a lesion in the other two classes of the monocular elevation deficiency is not as well determined.535 Cases resulting from isolated superior rectus weakness could theoretically result from disorders, affecting the muscle or its nerve supply anywhere from the superior rectus subnucleus to the orbit. Congenital absence of the superior oculomotor division could produce double elevator palsy with hypotropia and neurogenic ptosis. Hoyt described a patient who developed sudden monocular elevation deficit and features of superior rectus paresis, which he attributed to superior rectus subnucleus infarction precipitated by coexisting polycythemia vera.378 Mather and Saunders reported a case of bilaterally absent superior rectus muscles.522 As oculomotor fascicular fibers destined to the elevators of the eye and eyelid are believed to course laterally in the fascicle as it traverses the midbrain, a midbrain infarction involving a lateral portion of the oculomotor fascicle can cause an acquired unilateral ptosis and elevation deficit.145,382 A congenital lesion at this location could theoretically explain the paretic infranuclear form of monocular elevation deficiency. MR imaging has shown hypoplasia of the involved superior rectus muscle in one case,138 and focal thickening of the inferior rectus in another.435 However, the absence of these findings on neuroimaging in the great majority of cases support a prenuclear deficit in the unilateral center for upgaze.435,607 Olson and Scott noted that 9 of 31 patients with monocular elevation deficiency had dissociated vertical divergence manifesting in the affected eye.597 The findings of Bell’s phenomenon, dissociated vertical divergence, normal velocity of upgaze saccades when moving from a downward to primary position, negative Bielschowsky Head Tilt test, and elevation during stage II of general anesthesia provide evidence of a supranuclear etiology.548 Supranuclear disturbances of monocular eye movements are rare. The neuroanatomic substrate of unilateral supranuclear upgaze deficiency is controversial. It has been attributed to either lesions of the contralateral pretectum or lesions involving the upgaze efferents from the ipsilateral rostral interstitial nucleus of the medial longitudinal fasciculus. Most reports have been in adults in association with metastatic tumors. Lessell485 reported a man with bronchogenic carcinoma who developed left monocular elevation deficit, but with orthotropia in primary position and an intact Bell’s phenomenon. A metastatic tumor was found in the right pretectum at autopsy, which was speculated to have caused the double elevator palsy by interrupting axons destined for the ipsilateral superior rectus subnucleus and the contralateral

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inferior oblique subnucleus. Ford et al274 described a 52-yearold woman who developed right monocular elevation paresis who was demonstrated to have a focal, right-sided tumor of the mesodiencephalic junction in the region of the riMLF. Acquired unilateral double elevator palsy has been described in a child with a pineocytoma.570 The most recent evidence incriminates a lesion of the vertical saccadic burst or pause neurons of the riMLF. A genetic factor is suggested by the finding of identical twins concordant for supranuclear double elevator palsy on the same side, with preservation of Bell’s phenomenon.62 The possible neuroanatomic origins of monocular elevation deficit are summarized in Table 7.9. Patients with superior oblique palsy who habitually fixate with the paretic eye may present with limited monocular elevation of the contralateral (hypotropic) eye due to inhibitional palsy of the contralateral antagonist.208 This so-called “fallen eye syndrome” may lead to a contralateral inferior rectus contracture and thereby cause a monocular elevation deficiency. The correct diagnosis may be inferred by the three-step test and the comparison of ductions to versions. Cases of vertical retraction syndrome, wherein congenital unilateral restriction of elevation is associated with retraction of the globe and narrowing of the palpebral fissure,683 have been speculated to arise from a vertical innervational misdirection similar to that observed in Duane’s syndrome and in some cases of congenital fibrosis syndrome.291 The association of an isolated monocular elevation deficiency with congenital ptosis in general, and MGJW in particular, implies that aberrant misdirection may play a role in the pathogenesis of some cases of double elevator palsy.819 Undoubtedly, a subgroup of patients with monocular elevation deficiency fall into the classification of congenital cranial dysinnervation syndromes (discussed below). This view is supported by reports showing that the superior rectus muscle itself may be involved in the aberrant phenomenon. For example, Oesterle et al603 described a 9-month-old infant with congenital ptosis without jaw winking who showed an up-and-down movement of the left eye synchronous with nursing movements of the jaw. A 5-year-old girl with left ptosis, jaw winking, and left double elevator palsy showed up-and-down movements of the left upper lid and the left eye Table 7.9 Neuroanatomic differential diagnosis of monocular elevation deficiency Absence or hypoplasia of the superior rectus (e.g., Crouzon’s disease) Inferior rectus contracture (e.g., congenital fibrosis syndrome, “fallen eye syndrome”) Lateral oculomotor fascicular lesion Superior division oculomotor paresis Superior rectus myoneural junction disease (e.g., myasthenia gravis) Superior rectus subnucleus lesion Supranuclear lesion

7 Complex Ocular Motor Disorders in Children

synchronous with chewing. The eye movements persisted after levator excision and fascia lata sling procedures. The authors speculated that the up-and-down eye movements probably represented aberrant innervation of the superior rectus muscle in a manner analogous to the abnormal innervation of the levator muscle in MGJW. Surgical treatment consists of inferior rectus recession (in cases with a positive forced duction test),690 partial or full tendon width transpositions of the horizontal rectus muscles (in cases with a negative forced duction test),141,227,349,441 or innervation surgery with large recession of the contralateral superior rectus muscle (in cases with a negative forced duction test and some residual supraduction).629 Newer modifications of this procedure may include posterior fixation sutures to the transposed muscles and placement posterior fixation sutures on the normal superior rectus muscle.709 Inferior rectus recession alone or in combination with other procedures ameliorates the restrictive variety of double elevator palsy. Treatment of neurogenic double elevator palsy includes conventional vertical rectus muscle surgery (recess and/or resect) and vertical transposition of the tendons of the medial rectus-lateral rectus superiorly (Knapp procedure).135 The pseudoptosis disappears on correction of the vertical deviation, and any residual true ptosis can be addressed after ocular alignment is optimized.142

Brown Syndrome Brown syndrome can be distinguished from double elevator palsy by its increasing limitation of elevation in the adducted position.808a Brown syndrome must also be distinguished from the much less common inferior oblique palsy by the presence of little or no associated superior oblique overaction, a Y-pattern producing exotropia in extreme upgaze, and a positive forced duction test. Brown syndrome results from a congenital or, less commonly, an acquired dysfunction involving the trochlear-superior oblique tendon complex.808a Either form may be constant or intermittent (Fig. 7.19). Intraoperative forced duction testing can help distinguish an inferior rectus restriction from a severe Brown syndrome. Retropulsion of the globe into the orbit while performing forced supraductions reduces or eliminates an inferior rectus restriction, but exacerbates tightness due to Brown syndrome. Pulling on the globe does the opposite. Many acquired and some congenital cases of Brown syndrome improve spontaneously so that a conservative approach is reasonable. It has recently been argued that congenital superior oblique palsy with misinnervation to the medial or inferior rectus muscle can produce a motility pattern that is indistinguishable from Brown’s syndrome due to a tight superior oblique tendon.447

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Fig. 7.19 Intermittent Brown syndrome: Teenager complained of intermittent diplopia. On attempted gaze up and to his left, full ocular ductions and versions were noted on some trials (a), but intermittently, right eye failed to elevate in adduction (b)

Although classically viewed as a restriction syndrome, Neugebauer and colleagues have argued that Brown syndrome may be a congenital cranial dysinnervation syndrome.577 Using high-resolution dynamic MR imaging, Kolling and colleagues demonstrated absence of the fourth nerve within the orbit and hypoplasia of the superior oblique muscle on the affected side in patients with Brown syndrome.447 They have suggested that reinnervation of a paretic superior oblique muscle by branches from the medial or inferior rectus muscles can produce a motility pattern that is indistinguishable from Brown’s syndrome due to a tight superior oblique tendon.447 Treatment is undertaken for persistent cases with significant strabismus in the primary position and/or a significant compensatory anomalous head position. Superior oblique weakening (tenotomy or placement of a silicone spacer to lengthen the tendon),818 with or without inferior oblique weakening, is the treatment of choice in persistent congenital or idiopathic acquired cases with symptomatic diplopia or marked compensatory chin elevation. Local corticosteroid injections around the trochlea may be helpful in acquired inflammatory cases. The occurrence of Brown’s syndrome in multiple siblings331 and in monozygotic twins817 supports a genetic basis in some cases. Causes of acquired Brown syndrome include trauma, a rheumatoid nodule in the vicinity of the trochlea, peribulbar anesthesia, blepharoplasty, pansinusitis, frontal sinus osteoma, metastatic lesions, localized inflammation (orbital pseudotumor), surgical manipulation in the area of the trochlea, and surgical tucking of the superior oblique tendon.

Other Pathologic Synkineses Physiological synkineses are well-recognized. Opening the mouth causes the eyes to simultaneously open, a reflex that is useful in the ocular examination of children. In the less

known oculo-auricular phenomenon, horizontal gaze evokes a synkinetic retraction of the external ear muscles.808 Curling of both auricles during strong lateral gaze is said to be present in 40% of the normal population.765,808 This reflex is seen more easily in people who have prominent ears.765 As discussed in Chap. 6, other forms of ocular motor synkineses can occur in isolation or cluster together. A trigemino-abducens synkinesis may occur after trauma, and facial synkinesis is a common finding after facial nerve palsy. It should be noted that various forms of aberrant innervation have been reported in the thalidomide embryopathy, especially Duane’s retraction syndrome and aberrant lacrimation544 (crocodile tears). Platysma-levator synkinesis has been documented in a child with congenital third nerve palsy, demonstrating the potential for aberrant regeneration from a portion of the facial nerve.102 Rarely, deglutition-trochlear synkinesis may be noted,526 with the affected patient showing torsional diplopia associated with swallowing. This phenomenon suggests a synkinetic movement coupling the trochlear nerve with the bulbar musculature that is innervated by the trigeminal, facial, and hypoglossal nerves. Boehme and Graef described a 10-yearold boy with a right-sided Horner’s syndrome and a paresis of the recurrent laryngeal nerve, following neuroblastoma resection, whose right pupil distorted into an oval shape when he swallowed.77 They postulated that aberrant vagal sprouts had established connections with the cervical sympathetic chain. Some phenomena resemble synkinetic movements, but are difficult to explain on the basis of aberrant reinnervation. In some patients, voluntary gaze may evoke such phenomena as vertigo, tinnitus, blepharoclonus, eyelid nystagmus, eyelid closure, facial twitching, arm movements, or seizures.226,693,789,790 The pathogenesis of these “synkinetic” movements is unclear, but has been speculated to involve ephaptic transmission.693 Gaze-evoked upper lid jerks (lid nystagmus) may also be seen in patients with Fisher’s syndrome.666 and in patients with midbrain pseudomyasthenia (e.g., due to mesencephalic astrocytoma).114

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Internuclear Ophthalmoplegia The hallmark of internuclear ophthalmoplegia (INO) is weakness or absence of adduction in one or both eyes on lateral gaze, with nystagmus in the abducting eye.481,706,834 Despite this adduction limitation, the eyes remain orthotropic in the primary position. The adduction weakness may be profound and quite noticeable on testing of ocular ductions and versions or may be so subtle as to be discernible only by noting slow adducting saccades in the affected eye. Refixation from abduction to primary position causes the contralateral eye to momentarily overshoot the target.707 The slow, floating nature of the adducting saccades can be effectively elicited by having the patient fixate an optokinetic nystagmus target moving temporally with respect to the eye with limited adduction, which elicits a dysconjugate horizontal nystagmus of greater intensity in the abducting eye.707 Convergence is usually preserved, except in rostral cases that simultaneously affect the medial rectus subnucleus. However, decreased convergence in the setting of bilateral INO with multiple sclerosis may be due to central scotomas caused by optic atrophy, as opposed to a primary convergence disorder. Older children may complain of diplopia. A skew deviation often accompanies unilateral INO, while vertical upbeating nystagmus in upgaze often accompanies bilateral INO. Unlike most forms of skew deviation in which the lower eye is ipsilateral to the lesion, the higher eye is usually on the same side of the lesion in patients with INO. As INO resolves, the clinical picture evolves from absent or decreased adduction to slow adduction to normal-appearing adduction with retention of the abducting nystagmus (i.e., abducting nystagmus is the last to resolve). Internuclear ophthalmoplegia signifies intrinsic brainstem disease involving the pons or midbrain.706 It results from injury to axons that originate from interneurons in the abducens nucleus and project via the medial longitudinal fasciculus to the contralateral medial rectus subnucleus of the oculomotor nuclear complex. A number of mechanisms have been suggested to explain the dissociated nystagmus in the abducting eye.836 One popular explanation suggests that increased innervation to the medial rectus to overcome the adduction weakness is accompanied, under the influence of Hering’s law of equal innervation, by a commensurate increase in the innervation to the normal lateral rectus muscle of the contralateral eye. While increased innervation to the paretic medial rectus muscle would improve adduction, the increased innervation to the normal lateral rectus of the other eye would result in abducting saccadic overshoot followed by backward postsaccadic drift. This mechanism is supported by the observation that abducting nystagmus may also be noted in patients with adduction weakness resulting from medial rectus muscle recession.786

7 Complex Ocular Motor Disorders in Children

Other mechanisms invoke the possibility that the abducting nystagmus may result from: (1) increased convergence tone to improve adduction of the weak eye; (2) interruption of descending internuclear neurons that run in the medial longitudinal fasciculus from the oculomotor internuclear neurons to the abducens nucleus; (3) associated injury to fibers other than those of the medial longitudinal fasciculus; and (4) an associated gaze-evoked nystagmus, with the component of the nystagmus expected in the adducted eye being dampened by the coexisting adduction paresis.481,834 In unilateral cases, diplopia in the primary position is often vertical rather than horizontal and is attributable to a concurrent skew deviation. It can be eliminated with two to three prism diopters of vertical prism incorporated into glasses. Nystagmus and oscillopsia may complicate bilateral cases. The oscillopsia is a result of deficient vertical vestibuloocular reflex and pursuit movements or the abduction nystagmus. The role of strabismus surgery in selected patients has been recently analyzed.463 A lesion, encompassing both the medial longitudinal fasciculus and the ipsilateral PPRF or the abducens nucleus, results in an ipsilateral horizontal gaze palsy and an INO. The only preserved horizontal movement is abduction of the contralateral eye. This constellation of findings is called the “one-and-one-half syndrome.” Bilateral INO with unilateral abducens paresis gives a similar motility deficit. The one-and-one-half syndrome has a similar spectrum of causes as INO. In premature infants, one occasionally notes large-angle exotropia with decreased or no response of the medial recti to vestibular manipulations with rotation or calorics. This has been interpreted as possible bilateral INO, suggesting a maturational delay in the development of the medial longitudinal fasciculus. Such exotropia has a good prognosis for spontaneous ocular alignment as the medial longitudinal fasciculus matures, compared to the constant large-angle exotropia of infancy that shows no evidence of adduction weakness.381 This latter variety is usually observed in the setting of neurologic disease, but a subset is seen in otherwise healthy infants in a manner analogous to congenital esotropia. Duane type 2 syndrome, medial rectus entrapment in a nasal orbital wall fracture with associated paresis, myasthenia gravis, and Fisher syndrome may produce a similar motility pattern and must be excluded. Causes of INO in infants and children include demyelinating disease, stroke, brainstem tumors (particularly pontine glioma),180 vasculitis,439 inborn errors of metabolism, parainfectious encephalitis, structural malformations (Chiari malformation),816 drug intoxication,218,644 B12 deficiency,13 and trauma. Bilateral INO may be accompanied by exotropia, bilateral ptosis, and supraduction deficits in the midline mesencephalic cleft syndrome.131,465 Another increasingly

Cyclic, Periodic, or Aperiodic Disorders Affecting Ocular Structures

important cause of INO is HIV encephalitis. Myasthenia gravis is a recognized cause of pseudo-INO.422 Those with bilateral and intermittent exotropia (WEBINO syndrome) can be treated surgically with large bimedial resections (successful in our hands) or bilateral lateral rectus recessions.4 However, most cases without exotropia remit spontaneously. In adults, recovery is more likely in demyelinating than in vascular lesions and slower when there are other signs of brainstem injury.82,233 The relative prognosis for INO in children has not been established.

Cyclic, Periodic, or Aperiodic Disorders Affecting Ocular Structures A number of heterogeneous ocular disorders have in common a cyclic, periodic, or aperiodic pattern, that is, an involuntary process that repeats over time (Table 7.10). A major lesson Table 7.10 Cyclic, periodic, or aperiodic disorders affecting ocular structures Alternating anisocoria Cyclic esotropia Cyclic superior oblique palsy Cyclic vertical deviation Migrating pupil Oculomotor palsy with cyclic spasm Periodic alternating esotropia Periodic alternating gaze deviation Periodic alternating lid retraction Periodic alternating nystagmus Periodic alternating skew deviation Periodic head turns in congenital nystagmus Periodic mydriasis Ping-pong gaze Rhythmic pupillary oscillations (periodic pupillary phenomenon)

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to be learned from these cyclic phenomena is the importance of observing certain ocular disorders over time. The nature of the cyclic phenomenon and the duration of a complete cycle define each disorder. Cyclic esotropia is a relatively rare condition that is also referred to as alternate day, circadian, or clock-mechanism esotropia.333 The designation “circadian,” which denotes a 24-h cycle, is a misnomer because the usual cycle duration is 48 h. The typical case shows a 24-h period of manifest esotropia measuring 40–50 prism diopters, alternating with a 24-h period of normal ocular alignment (Fig. 7.20). Less common are cycles of 24, 72, or 96 h in duration. The esotropia is nonaccommodative and nonparalytic, with normal eye movements in both eyes when straight and also when esotropic. On days when the eyes are crossed, diplopia is rare, fusional amplitudes are defective or absent, and sensory anomalies are frequent. Whether other cyclic phenomena occur in association with this condition is debatable. Friendly et al279 monitored numerous psychological and physiologic functions and found no associated cyclical phenomenon. In contrast, Roper-Hall and Yapp654 described cyclical changes in behavior, frequency of micturition, and EEG activity. Cyclic esotropia may first appear in infancy, but the diagnosis may be delayed months to years, with the average age at diagnosis ranging from 2 to 4 years, although some cases may occur abruptly in adulthood. Generally, the condition occurs spontaneously without apparent cause, but may be precipitated by strabismus surgery, retinal reattachment surgery, ocular trauma, optic atrophy, or CNS disease.333 The natural history of this condition is not definitively known, but the cyclicity is thought to diminish with time, leading to a constant esotropia after several months to years. The mechanism of cyclic esotropia remains unknown,737 and no correlative abnormalities of the hypothalamic pituitary axis have been found.282 Some cases are associated with neurologic disease,282,625 one case was triggered by traumatic sixth nerve palsy,385 and one by surgery for intermittent exotropia.762 These reports suggest that patients

Fig. 7.20 Cyclic esotropia. Patient presented with history of intermittent esotropia but was found on further followup to have cyclic esotropia. She showed orthotropia (a) and esotropia (b) alternating daily

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with cyclic esotropia are basically strabismic with cycles of remission.536 This abolition of cyclic esotropia after visual improvement appears analogous to previously reported cases of periodic alternating nystagmus that resolved after visual rehabilitation by removing a cataract or clearing a vitreous hemorrhage. It is therefore advisable to provide maximal optical/refractive correction prior to considering extraocular muscle surgery. The treatment of cyclic esotropia consists of strabismus surgery to correct the maximum deviation that stops the overt cycles. Richter641 likened the effect of surgery to “removing the hand of the clock without altering its motor.” Cyclic esotropia has been reported in the aftermath of cataract, retinal detachment, intracranial surgery,625,642,756 intermittent exotropia,568 infantile esotropia,536 and accommodative esotropia.224 Cyclic esotropia should not be confused with periodic alternating esotropia.344 The latter is a rare condition with cycles of similar duration to periodic alternating nystagmus (about 200 s). The few reported cases occurred in association with congenital periodic alternating gaze deviation.342 Such patients probably had the neuroanatomic substrate of periodic alternating nystagmus, but with superimposed saccadic palsy leading to absent fast phases of nystagmus. Periodic alternating gaze deviation (PAGD) is a rare disorder consisting of a slow, conjugate horizontal deviation of the eyes from one side to the other.344,480,720 It may occur at any age (some cases have been reported in infancy) and is associated with concurrent, controversive, cyclic face turning to maintain fixation. During a complete cycle, the eyes rotate conjugately toward one side for 1–2 min, usually with compensatory head turning to the opposite side; return to the midline for a changeover period lasting 10–15 s; then conjugately deviate to the other side for 1–2 min, with compensatory head turning to the side opposite the direction of ocular rotation (Fig. 7.21). The patient may be orthotropic or esotropic. During eye closure, the alternating turning of the head ceases, even though the eyes continue the rhythmic movement. While the eyes are deviated, they exhibit abnormal voluntary movements, convergence, optokinetic nystagmus, and oculocephalic responses, but all of these normalize during the changeover phase. Caloric testing can override the eye and head movements, and the cycling stops during sleep. Periodic alternating gaze deviation may occur on a congenital basis (Fig. 7.20) or may be acquired. Most documented cases reported so far have been due to posterior fossa abnormalities. It has been reported in association with pontine vascular lesions, Arnold–Chiari malformation, Dandy– Walker malformation, congenital hydrocephalus, occipital encephalocele, cerebellar medulloblastoma, spinocerebellar degeneration, and Joubert’s syndrome with cerebellar vermis hypoplasia.342,425,480,720,728 In congenital or early onset PAGD, cerebellar vermis atrophy is the most common neuroradiologic abnormality.

7 Complex Ocular Motor Disorders in Children

The duration of a complete cycle of PAGD (3–4 min) is similar to that of periodic alternating nystagmus (PAN), suggesting that the two conditions may have a similar neuroanatomic substrate, the difference being an added saccadic palsy in the case of PAGD. This concept is supported by the findings in a patient with recurrent cerebellar medulloblastoma who sequentially demonstrated PAN, bilateral gaze palsy, PAGD, and then resumption of PAN.425 When encountered in a comatose patient, PAGD is usually considered a sign of bilateral cerebral hemispheric dysfunction with a relatively intact brainstem.728 In this setting, the total duration of the abnormal movements is usually short, a few hours to days, disappearing a few hours before death. Ping-pong gaze superficially resembles PAGDs, but the movements are much faster, although some authors have used the two terms interchangeably.638,692 It consists of conjugate horizontal ocular deviations that alternate rapidly every few seconds. Ping-pong gaze is usually seen in comatose or semicomatose patients and typically denotes cerebellar or bilateral cerebral hemispheric lesions, but a relatively intact brainstem. Ping-pong gaze has been speculatively ascribed to damage of the descending supranuclear inhibitory input on the horizontal gaze centers. Periodic alternating skew deviation is a rare condition in which the patient develops right hypertropia lasting one to several minutes, alternating with left hypertropia in a cyclic fashion. In some patients, the condition may be aperiodic or intermittent. Downbeat nystagmus may also be present. In one patient, a focal lesion affecting the interstitial nucleus of Cajal was demonstrated with computed tomography. In contrast to seesaw nystagmus, periodic alternating skew deviation has slower movements, larger excursions, and no torsional component. Periodic eye movement disorders with a cycle duration of about 200 s, which include PAN, PAGD, and periodic alternating skew deviation, may have similar pathophysiologic mechanisms and have been reported to occur in combinations in the same individual.425,491 One case of cyclic superior oblique palsy developed in a 10-year-old patient following trauma to the left trochlear area.809 Typical left superior oblique palsy alternated daily with orthotropia. A patient with cyclic vertical deviation of an unspecified nature, with a cyclic duration of 48 h, has been reported following craniofacial surgery.537 Other cyclic ocular motor disorders include paroxysmal ocular tilt reaction and oculomotor palsy with cyclic spasm. In patients with oculomotor palsy with cyclic spasm, the pupil may reportedly be the only structure to cycle although, more commonly, the extraocular muscles and levator muscle are also involved in the cyclic spasms. Cyclic or alternating phenomena may affect the pupils. Keane described a patient with traumatic oculomotor palsy in whom the ipsilateral pupil, although unreactive to light, showed continuous rhythmic involuntary oscillations.

Cyclic, Periodic, or Aperiodic Disorders Affecting Ocular Structures

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Fig. 7.21 Congenital PAGD. Two-year-old girl with Joubert syndrome displayed PAGD with cycle duration of about 200 s. During complete cycle, (a) eyes rotated conjugately to right over 90 s, usually with compensatory head turning to opposite side, (b) returned to midline for a

changeover period lasting seconds, then (c) conjugately deviated to other side over 90 s, with compensatory head turning to side opposite direction of ocular rotation. (d) MR imaging showed profound cerebellar vermis hypoplasia

He speculated that dysfunction of the central parasympathetic nervous system may have been responsible. Alternating anisocoria is a rare condition characterized by alternating

pupillary dilatation, with the dilated pupil showing little or no light reactivity in some cases, but normal reactivity in others.121 This may occur in otherwise neurologically normal children,

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but a similar phenomenon has been observed in a quadriplegic patient with a posttraumatic syringomyelic cyst.440 The pathophysiology of this phenomenon is unclear, but it may be due to either episodic oculosympathetic spasm producing alternating Claude Bernard–Horner’s syndrome or episodic oculosympathetic interruption producing Horner’s syndrome. Some other pupillary disorders have been intermittent rather than rhythmic and include intermittent mydriasis, cyclic sympathetic spasm with concentric dilatation lasting 40–60 s, and “tadpole pupils,” in which the sympathetic spasm is sectoral.746 Conditions with cycle duration of a few minutes sometimes become apparent when the clinician notices a reversal of a previously noted finding – for example, observation of conjugately turned eyes to the right in a patient whose eyes were previously noted to be conjugately turned to the left brings forth the diagnosis of PAGD. Conditions with a cycle duration of 24 h or longer cannot be definitively diagnosed from data collected during a single office visit. For instance, a patient with cyclic esotropia may be initially evaluated on a “crossed” day and be labeled as congenital or acquired esotrope. If the subsequent visit occurs on a “crossed” day, it may only consolidate the earlier false diagnosis. If it occurs on a “straight” day, the clinician may suspect spontaneous resolution or an accommodative element with variable angle and either question the observation of esotropia in earlier visits or correctly suspect cyclic esotropia. Conversely, initial evaluation of a patient with cyclic esotropia on a “straight” day may lead to missing the diagnosis, dubbing the condition pseudostrabismus. Cyclic phenomena in children are not limited to the neuroophthalmologic disorders discussed here, but involve other organ systems as well. Other biologic phenomena, such as sweating, salivation, and pulse rate, also have intrinsic periodicity, as do many manifestations of psychiatric dysfunction. Periodicity appears to be the norm in many biologic phenomena, and a normal person displays a complex array of biorhythms involving the various body systems.640 Numerous periodic or rhythmic disorders have been described – for example, periodic recurrence of fever, swelling of joints, fluctuations of circulating blood cells (periodic hematopoiesis), and edema. Accumulating evidence points to the existence of a biologic clock mechanism that keeps time with extraordinary accuracy and is independent of internal and external stimuli.

7 Complex Ocular Motor Disorders in Children

discharge in a peripheral nerve. Neuromyotonia describes neurotonia accompanied by fibrillations, fasciculations, myokymia, or sustained contraction of a muscle group. Ocular neuromyotonia describes sustained contraction of one or more extraocular muscles due to involuntary firing of the supplying ocular motor nerve. Ocular neuromyotonia is a relatively rare ocular motility disorder that manifests with brief paroxysmal monocular deviations with associated diplopia.701 Episodes generally last 10–60 s (range, 5 s to 3 min) and may recur 20 or more times per day. Some episodes occur spontaneously, while others are triggered by gaze in the direction of the involved muscle. Between attacks, affected patients usually show normal ocular motility, although some may show subtle evidence of aberrant innervation manifesting as minimal lid retraction in downgaze. The paroxysms result from tonic involuntary contraction of extraocular muscles innervated by the third (all muscles supplied by the nerve or any combination thereof), fourth, or sixth cranial nerves.57,486 Spontaneous discharges from axons with unstable cell membranes are presumed to underlie this condition. In some cases, ocular neuromyotonia may coexist with primary aberrant regeneration.160 Histopathologic studies of peripheral nerves in nonocular cases of neuromyotonia have shown segmental demyelination as well as axonal degeneration, sprouting, and remyelination.794 Most patients have a history of brain irradiation, typically for the treatment of tumors of the skull base, such as pituitary tumors or craniopharyngiomas.486,798 Idiopathic cases with no specific cause have been reported.798 The interval between radiotherapy and onset of neuromyotonia may be months to years. Two cases have been reported in teenagers following radiation therapy for parasellar lesions.199,562 A favorable response to membrane-stabilizing medications, such as carbamazepine is reported in many patients, supporting pathoetiology consisting of spontaneous or impulse-induced repetitive discharge of hyperexcitable trigger zones in ocular motor nerves. In some instances, the neuromyotonia has not recurred on cessation of the medication. Some cases may remit spontaneously. Several conditions not associated with radiation therapy may come to be classified as ocular neuromyotonia. Adie’s pupil and superior oblique myokymia are two common forms of ocular neuromyotonia seen in neuro-ophthalmologic practice.

Ocular Neuromyotonia

Ocular Motor Adaptations and Disorders in Patients with Hemispheric Abnormalities

Myotonia denotes delayed muscle relaxation after sustained contraction as a result of muscle membrane dysfunction. In contrast, neurotonia or pseudomyotonia represents delayed muscle relaxation as a result of impulse-induced repetitive

Cerebral hemispheric abnormalities are often associated with ocular motor abnormalities that may be subtle or profound depending upon the size, location, and other characteristics of the lesion. These are reviewed in detail elsewhere.

Eyelid Abnormalities in Children

Children with congenital hemianopsia develop a compensatory saccadic strategy, wherein they overshoot the intended visual target then “find it” as the eyes drift back.380 Some patients with congenital homonymous hemianopsia have been noted to also show concurrent exotropia, usually also of early onset. Some investigators have suggested that the exotropia in these patients is a compensatory phenomenon for the hemianopic field defect, essentially allowing the patient to have panoramic vision. For this to occur, anomalous retinal correspondence has to coexist, otherwise the patient would be diplopic.306,363 Some investigators raise the possibility that the exotropia in such patients is an epiphenomenon, possibly reflecting the type of strabismus one sees in many children with neurologic disease.380 It is not clear whether the concurrent exotropia in these children simply represents strabismus precipitated by infantile neurologic disease, or develops as a physiological compensatory phenomenon leading to the development of anomalous retinal correspondence and panoramic vision, or exists as a combination between these two mechanisms. The fact exotropia is so common in these children, who often show an uncanny ability to navigate through visual space without difficulty despite their homonymous hemianopia, suggests that the exotropia serves an important compensatory function. Therefore, the clinician should understand the potentially devasting sensory implications of performing strabismus surgery to straighten the eyes.286

Eye Movement Tics Tics are quick, jerky, sudden, and repetitive movements of circumscribed groups of muscles without apparent cause or purpose. They occur frequently in children and most often resolve spontaneously. Tics most commonly affect facial musculature, but may rarely affect the extraocular muscles, causing eye movement tics.696 It is important to recognize eye movement tics as such and not confuse them with more serious disorders. The few cases of eye movement tics reported to date have been mostly associated with facial tics, but isolated ocular tics may occur and may thus mimic nystagmus. Frankel and Cummings276 reported eye rolling tics in a group of patients with Tourette syndrome. The tics consisted of eye rolling, gaze abnormalities, staring, or forced gaze deviations resembling oculogyric crises. Two of the cases described a corneal sensation preceding their tics. All of these children also had blepharospasm, and most were taking neuroleptic or other medications. Neuroleptics have been implicated in the pathogenesis of a variety of movement disorders, including tics and oculogyric crisis. Binyon and Prendergast73 reported three cases with conjugate eye movement tics: one was associated with Tourette’s syndrome,

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one was associated with neurological and behavioral disorders, and one was isolated. The latter resolved spontaneously. Shawkat reported opsoclonus-like ocular tics associated with facial tics in an otherwise healthy child that resolved spontaneously. Affected children are sometimes able to imitate their tics in the clinic on request, which is a useful indicator that consciousness is not impaired during the tics, allowing the examiner to rule out epilepsy.

Eyelid Abnormalities in Children Congenital Ptosis As detailed above, congenital ptosis occurs most frequently as a congenital cranial dysinervation disorder. Because congenital ptosis can also be the presenting sign of several other neuro-ophthalmologic disorders (Table 7.11), however, specific attention to ocular motility, pupillary examination, and coexisting neurologic signs is imperative. Congenital ptosis must also be differentiated from pseudoptosis due to ipsilateral hypotropia, enophthalmos, or contralateral lid retraction. Motility abnormalities may include congenital oculomotor nerve palsy and double elevator palsy. The latter is a reason to be conservative with ptosis correction to prevent corneal exposure postoperatively due to absent Bell’s phenomenon. Pupillary abnormalities associated with unilateral ptosis may include a large unreactive pupil due to oculomotor palsy or a miotic pupil either due to Horner syndrome or to congenital oculomotor palsy with aberrant regeneration involving the pupil. Causes of pupillary abnormalities associated with bilateral early-onset ptosis include Fisher’s syndrome and botulism. Rarely, a cerebral hemispheric lesion causes unilateral or bilateral ptosis (termed cerebral ptosis) in the absence of other neurological signs.452 Lowenstein et al501 described two children with hemispheric arteriovenous malformations

Table 7.11 Differential Diagnosis of Congenital Ptosis Blepharophimosis syndrome Cerebral ptosis Congenital fiber-type disproportion Congenital fibrosis syndrome Congenital myotonia Horner syndrome Hypotropia with pseudoptosis Marcus Gunn jaw winking Microphthalmia, enophthalmos Myasthenia gravis Myotubular myopathy Oculomotor nerve palsy

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and contralateral ptosis that progressed over several years. In both cases, the ptosis resolved following resection of the arteriovenous malformation. One should consider the rare possibility of cerebral ptosis in the child with progressive nonmyasthenic ptosis, especially when a history of seizures or recurrent unilateral headaches is obtained. The finding of unilateral congenital ptosis with lid swelling should suggest the diagnosis of dural arteriovenous fistula.313 When accompanied by supraduction deficit, bilateral internuclear ophthalmoplegia, and exotropia, bilateral ptosis should suggest the possibility of midline mesencephalic cleft malformation.131,465 Tatli et al reported bilateral ptosis with lower extremity muscle weakness and dysautomomia as probable paraneoplastic effects of neuroblastoma in a 28-month-old girl.739 An extensive workup for myasthenia gravis was negative, and no paraneoplastic autoantibodies were identified.

Excessive Blinking in Children The spontaneous blink rate in infants under 18 months of age is low, ranging from 2 to 5 blinks per minute, whereas in older children, it is about 10, reaching approximately 20 blinks by the age of 20 years and remaining relatively constant throughout adulthood. Benign tics, (blinking eyes, twitching mouth, movements of head, jerking shoulders or other body parts) are common in children, with a prevalence as high as 12% between the ages of 6 and 12 years.471 Benign tics involving the eyes, may manifest as excessive intermittent blinking without associated ocular or systemic disorders. Eye winking or blinking tics in children represent exaggerated contractions of the orbicularis muscle. The tics usually increase in frequency when the child is bored, anxious, or tired. Most these tics are benign and transient, improving spontaneously with time, without any discernible causation. Unlike essential blepharospasm of adults, there is little, if any, functional visual impairment. Although tics have been thought to result from an underlying psychological conflict,509 recent evidence suggests that they may be of organic origin but triggered or exacerbated by stress. Elston et al236 described a family in which different members in three generations suffered eye-winking tics, excessive blinking, and/or blepharospasm. The proband in that study had eye-winking tics in childhood, then developed excessive blinking evolving to blepharospasm by the age of 21 years. They also described five patients with adult-onset blepharospasm, or Meige’s syndrome, who had a history of excessive blinking dating back to childhood. They speculated that eye-winking tics, excessive blinking, and blepharospasm may represent age-dependent manifestations of a common pathophysiologic disorder.236

7 Complex Ocular Motor Disorders in Children

Frequent eye blinking may be a manifestation of ocular surface, tear film, or eyelid disorders at any age. It may also accompany lacrimal drainage obstruction. Children with congenital glaucoma are classically described as presenting with the triad of epiphora, photophopia, and blepharospasm, but may also show frequent blinking, as do children with significant intraocular inflammation. Excessive blinking and blepharospasm also occur in conditions with damage to the basal ganglia, such as Wilson disease and Huntington disease.127 Seizure activity is associated with a variety of neuroophthalmologic signs and symptoms that include nystagmus, gaze deviations, spasm of the near reflex, hemianopsia, cortical blindness, as well as a variety of eyelid signs. Lid signs may consist of eyelid nystagmus or eyelid fluttering resembling tics and spells of eyelid spasms. For instance, Cogan et al179 described a 7-year-old girl with methylmalonic aciduria and homocystinuria who exhibited spells of fluttering of the eyelids and elevation of the eyes. The EEG showed 2.5-s polyspike and wave discharge during the spells, characteristic of petit mal seizures. Excessive blinking and eyelid myoclonia has been reported in association with typical absence seizures,28 and this condition has been reported in monozygotic twins.202 Finger waving and rapid eyelid blinking is a feature of photoconvulsive epilepsy. Eyelid myoclonia may occur on eye closure in association with electrical status epilepticus without altered consciousness.776 Patients with occipital lobe epilepsy may exhibit a variety of neuro-ophthalmologic manifestations, including elementary visual hallucinations, ictal or postictal amaurosis, eye movement sensations, eye and/or head deviation, visual field deficits, and early forced blinking or eyelid flutter.807 Seizure activity may also be associated with abnormal eye movements such as gaze deviations (usually to the contralateral side) and nystagmus.415,426,758 The terms “lid nystagmus,” “upper lid jerks,” and “lid hopping” have all been applied to a neuro-ophthalmologic phenomenon in which a series of rapid, rhythmic, jerky movements of the upper lids occurs alone or in conjunction with specific movements of the eyes or head.114 Most previously reported cases have been associated with posterior fossa disease and can be subdivided into lid nystagmus evoked by convergence and lid nystagmus evoked by horizontal gaze.377,664 Children have been described with signs and symptoms of myasthenic ophthalmoplegia in whom gaze-evoked lid hopping signaled the presence of intrinsic midbrain tumors.114,633 Other rare causes of lid nystagmus include the lateral medullary syndrome, pretectal lesions, and Fisher syndrome.666 While horizontal eye movements in myasthenia gravis may be accompanied by occasional twitching or fluttering movements of the upper lids, lid nystagmus is uncharacteristic of neuromuscular disease and should prompt neuroimaging. Lid nystagmus would appear to necessitate a dissociation between the output of the levator and the

Eyelid Abnormalities in Children

superior rectus subnuclei within the oculomotor nuclear complex. Convergence-evoked lid nystagmus often signifies a structural lesion within the posterior fossa. Howard377 described a patient with convergence-evoked eyelid nystagmus without ocular upbeating nystagmus, who had a large vascular lesion distorting the blood supply to the pontomesencephalic and pontomedullary junctions. Safran et al664 described two similar patients with convergence-evoked eyelid nystagmus. Patient 1, a 29-year-old man, developed a cerebellar syndrome after sustaining severe head injuries. Patient 2, a 12-year-old girl, had a tumor of the anterior cerebellar vermis. Treatment with corticosteroids (patient 1) and surgery (patient 2) led to gradual resolution of the eyelid nystagmus, which the authors attributed to cerebellar dysfunction. The cause of tic disorders may lie in the dopaminergic system of the brain, as well as in genetic and other biological factors.406 Coats et al171 found the most common etiologies of excessive eye blinking to be anterior segment or lid abnormalities in children. Occasionally, children show frequent eye blinking as a manifestation of Tourette syndrome.406 Some children may exhibit lower eyelid pulling as a transient behavior lasting weeks to months.147 These children are otherwise healthy, and the condition is thought to initially be triggered by ocular irritation, but then develops into a “bad habit.” This functional disorder is readily distinguishable from eye poking (oculodigital sign) encountered in children who are blind secondary to congenital retinal disease (i.e., Leber congenital amaurosis, retinopathy of prematurity, retinal dysplasia)394 and vigorous eye rubbing seen in patients with Down syndrome. Eyelid myokymia may occur alone or in association with facial myokymia. Facial and eyelid myokymia are characterized by unilateral involuntary fine rippling movements, spreading across the surface of affected muscles. Facial myokymia has been reported in association with multiple sclerosis, Guillain–Barré syndrome, Bell’s palsy, rattlesnake bites, brainstem tumors, and others. The clinical features of facial myokymia are sufficiently distinctive to avoid confusion with other facial dyskinesias such as essential blepharospasm, tardive dyskinesia, facial tics, focal seizures, aberrant regeneration of the facial nerve, hemifacial spasm, and benign facial fasciculations. Some cases of facial myokymia have occurred in association with spastic paretic facial contracture, which is characterized by tonic spasm of the paretic facial muscles, with typical prominence of the nasolabial fold and deviation of the nose toward the affected side. We have examined a patient with diffuse disseminated encephalomyelitis who showed left facial myokymia, spastic paretic facial contracture, and one-andone-half syndrome and who also showed scattered lesions in the brainstem on MR imaging. Gilles de la Tourette syndrome is a bizarre but relatively common disorder that comprises multiple involuntary motor tics and obscene utterances. There is a predilection for whites

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and for boys (male-to-female ratio ranges from 3:1 to 5:1). The condition is familial in about one-third of cases, appears to be transmitted as an autosomal dominant trait, and has been mapped to the long arm of chromosome 18. Symptoms usually appear between ages 5 and 10 years, with presenting features consisting of multifocal tics of the face and head. In addition to clonic motor tics (most commonly blinking and facial twitching) and vocal/phonic tics seen in all patients, many patients exhibit one or more dystonic tics that may include oculogyric deviations, blepharospasm, and dystonic neck movements.398 The globes may also show dystonic tics. For example, Frankel and Cummings276 reported eye rolling tics in a group of patients with Tourette syndrome who also had blepharospasm. The motor tics are followed by vocal tics such as grunting, sneezing, coughing, barking, coprolalia (compulsive monosyllabic swearing), and echolalia. Tiqueurs may be able to voluntarily suppress the tics, but a resulting mounting tension eventually leads to further discharge of tics. Patients may show associated obsessivecompulsive traits, self-mutilation, attention-deficit disorders, learning disabilities, and serious psychiatric illness. Haloperidol and pimozide are useful in controlling the symptoms. Epileptic disorders and their treatment may cause eye rolling or eyelid myoclonia.188 When accompanied by absence spells, eyelid myoclonia is highly suggestive of Jeavon’s syndrome (i.e., eyelid myoclonia and absences). In this condition, there is marked jerking of the eyelids with upward deviation of the eyes, associated with spike-wave discharges that are often irregular, immediately after eye closure and invariably evoked by intermittent photic stimulation. This diagnosis is likely when the eyelid myoclonia is combined with photosensitivity and pathognomonic when it also occurs after eyelid closure (in some cases, it can look like the child is purposefully closing the eyes to initiate a seizure). EEG shows characteristic eye closure-related discharges and photosensitivity. Rhythmic or random closing of the eyes is often seen in other forms of idiopathic generalized epilepsy, with absences or the eyelid jerking that may occur at the opening or the initial stage of the discharges in typical absence seizures of childhood or juvenile myoclonic epilepsy. Toxicity from the antiepileptic drug clobazam in a 4-yearold boy has been reported to cause episodes of eye rolling, ataxia, and back arching, which were nonepileptic.50,188 Chung et al found ictal eye closure to be a reliable indicator of psychogenic nonepileptic seizures.165 The workup of tics is conservative, consisting mainly of observation, unless otherwise dictated by the presence of associated clinical findings. Explanation and reassurance of patients and their families is helpful in steering them away from becoming too focused on the tics. Neuroleptics and other drugs should be reserved for severe cases. The longterm prognosis of tics is good, with about two-thirds of cases spontaneously remitting.186

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Hemifacial Spasm Hemifacial spasm is primarily a disorder of middle-aged and older individuals, but a variety of cases have been reported in childhood. Hemifacial spasm is characterized by involuntary, intermittent unilateral twitching of the muscles innervated by the facial nerve, almost uniformly including the orbicularis oculi. They differ from tics in several ways, including the inability of the patient to suppress the twitches or initiate them, and the absence of compulsion to make them. In about half the patients, a particular position of the head (most commonly, the contralateral lateral decubitus position) diminishes or halts the spasms. The patient may hear ipsilateral clicking sounds if the stapedius muscle is involved. Hemifacial spasm should be differentiated from blepharospasm and facial myokymia. Essential blepharospasm consists of bilateral, localized, repetitive spasms of the orbicularis oculi muscle that, in severe cases, leads to visual impairment. The rare case of bilateral hemifacial spasm can be distinguished from essential blepharospasm because the bilateral contractions do not occur synchronously. Essential blepharospasm is not seen in children, but excessive blinking due to tics or blepharospasm due to ocular disorders, such as congenital glaucoma, may bear superficial resemblance to essential blepharospasm. Facial myokymia consists of continuous, fascicular rippling movements of the face that usually begin in the orbicularis muscle. It is not affected by voluntary or reflex activity of the face. The most common causes include multiple sclerosis and brainstem glioma. Most adult cases of hemifacial spasm are caused by vascular compression of the facial nerve at the root exit zone of the brainstem.397,806 The offending vessels are usually arterial, most commonly the anterior or the posterior inferior cerebellar artery or the posterior inferior cerebellar artery.667 This neurovascular compression theory was challenged by an MR imaging/MR angiography study that concluded that the development and severity of hemifacial spasm were not associated with a specific blood vessel or multiple neurovascular contact points.367 “Cross talk” between the sensory and motor branches of the seventh nerve has been suggested as an underlying pathophysiology. Congenital or acquired cholesteatoma is the most common associated tumor. Vascular malformations of the posterior fossa have also been implicated. Rare familial cases suggest a component of genetic transmission. Friedman et al278 described a family in which hemifacial spasm occurred in five members through three generations. Aside from neurovascular compression,490,540 a variety of rare causes of hemifacial spasm have been identified in children. These include venous sinus thrombosis,271 masses of the fourth ventricle, 271 ganglioneuroma,470 pilocytic astrocytoma,538,667 congenital or acquired cholesteotoma,630 tuberculous meningitis,670 thickening of the arachnoid membrane,443 and possible intrauterine facial nerve injury.831 The diagnosis

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of epilepsy should also be considered, as hemifacial spasm has been reported as part of a seizure phenomenon.21,41,356 The presence of hemifacial spasm in an infant should therefore be considered an ominous sign. Langston and Tharp470 described a case of infantile hemifacial spasm beginning at 6 weeks of age. Surgical exploration at 5½ years of age revealed a ganglioneuroma of the fourth ventricle. Flueler et al271 described three infants who presented with the onset of hemifacial spasm in the first year of life. One patient had occlusion of the straight sinus and large collateral vessels at the base of the brain, supporting the concept of vascular compression of the facial nerve at its exit from the brainstem as a mechanism for the production of hemifacial spasm. Each of the other two patients had an intrinsic mass compressing the fourth ventricle: one was located in the lower pons and extended into the cerebellar vermis and right cerebellar peduncle; the other involved the cerebellar vermis and right middle cerebellar peduncle. Interestingly, hemifacial spasm has been described in some cases of Joubert syndrome, which includes cerebellar vermis aplasia or hypoplasia.438 Unlike the usually benign nature of the late childhood and adult variety, it appears that earlyonset hemifacial spasm should raise suspicion of an underlying CNS malignancy. Neuroimaging is therefore warranted in cases of hemifacial spasm with onset in the first 2 years of life. In older children with typical, isolated, hemifacial spasm, neuroimaging should be obtained when atypical features (headaches, facial pain, cranial neuropathy, cerebellar dysfunction) are present.46 In the toddler with apparent hemifacial spasm, the diagnosis of accommodative esotropia should also be considered.122 In this setting, a young child may have to exert a hemifacial contraction to close one eye to prevent diplopia. For this reason, a cycloplegic refraction should be included in the diagnostic evaluation of hemifacial spasm.122 Both botulinum injection and surgical decompression of the facial nerve have been used with good results in both adults and children.153,704 Microvascular decompression of the facial nerve is considered the definitive treatment by some authors. Jho and Jannetta402 described improvement of hemifacial spasm with microvascular decompression of the facial nerve in two children and eight adults who had the onset of hemifacial spasm before the age of 20.

Eyelid Retraction The margin of the upper eyelid is normally located 1–2 mm below the upper corneoscleral limbus. Upper eyelid retraction is more commonly considered in the adult age group, where it occurs most commonly in patients with thyroid eye disease, dorsal midbrain syndrome, trauma, proptosis,

Eyelid Abnormalities in Children

and seventh nerve palsy, amongst other conditions. SCAs, such as Machado–Joseph disease, are known to produce a peculiar “ocular stare” that is has been attributed to lid retraction rather than proptosis. The causes of eyelid retraction in children are heterogeneous (Table 7.12).729 Graves orbitopathy is rare in children. When it occurs, it is less severe than in adults,317,766,827 and most cases require no treatment.228 Most children are clinically hyperthyroid at the time of diagnosis.228 Exophthalmos is notably less common in the prepubescent group, presumably because there is room for the orbit to grow and produce a physical decompression. In our experience, diplopia is rare, Table 7.12 Causes of eyelid retraction in children Setting sun sign/hydrocephalus/dorsal midbrain syndrome (Collier sign) Congenital, cryptogenic Oculomotor palsy with aberrant innervation Oculomotor palsy with cyclic spasm Marcus Gunn jaw winking Eyelid retraction to darkness (normal in first year of life) Neuromyotonia Graves disease/hyperthyroidism Familial periodic paralysis Orbital hemangioma Optic nerve anomalies with vertical nystagmus Contralateral ptosis with compensatory superinnervation of both levators (fixation duress) Myasthenia gravis Hepatic cirrhosis Cushing syndrome Levator muscle fibrosis Inferior rectus muscle restriction with fixation duress Iatrogenic after surgical repair of ptosis Eyelid scarring (e.g., after inflammation from herpes zoster) Claude Bernard syndrome (sympathetic irritation) Volitional lid retraction “Startle” reflex to dimming light in infants

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and orbital fat expansion is more common than extraocular muscle enlargement on imaging studies. Compressive optic neuropathy is rare.228 Secondhand smoke has been implicated as a possible pathogenetic factor.152 Unless specific clinical or neuroimaging findings suggest the diagnosis of Graves orbitopathy, neurological causes should be primarily considered. Bilateral lid retraction in dorsal midbrain syndrome is attributable to disruption of inhibitory fibers from the posterior commissure to the central caudate nucleus.182 Rarely, patients with medial midbrain lesions demonstrate a “plus minus lid syndrome” characterized by ipsilateral ptosis (from injury to the oculomotor fascicle) and contralateral lid retraction (from disruption of bilateral inhibitory fibers to the central caudal nucleus). When the ptosis resolves, the ptotic lid can assume a retracted position.283,287 Lid retraction in children is often intermittent, as in aberrant reinnervation associated with congenital oculomotor palsy or the MGJW phenomenon. Cases of neuromyotonia affecting only the levator muscle would also be expected to show isolated intermittent lid retraction. Cases of oculomotor palsy with cyclic spasm show intermittent momentary elevation of the eyelid on the affected side, but careful scrutiny of the ocular alignment and the mandatory pupillary involvement in the cyclic process confirm the diagnosis.499 A single case of posttraumatic, bilateral, pupillary-involving oculomotor palsy has been reported, wherein the patient showed bilateral nonsynchronous episodic eyelid retractions not associated with eye movement or pupillary changes.467 Patients with unilateral inferior rectus restriction and alternating fixation may show intermittent contralateral eyelid retraction, which occurs as a result of Hering’s law when the restricted eye takes up fixation. Healthy infants also frequently display eyelid retraction to darkness, which resembles the setting sun sign (Fig. 7.22). Eyelid retraction to darkness can be elicited by turning off the

Fig. 7.22 Pseudo-setting sun sign. Healthy infant showed eyelid retraction immediately after room light was turned off (a) that resolved when ambient illumination was restored (b)

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room lights while observing the palpebral fissures. It can be a clinically useful sign that an apparently blind infant has at least light perception vision. The phenomenon, which appears to be limited to the first year of life, disappears when ambient illumination is restored and is thought to represent a primitive startle reflex.

Apraxia of Eyelid Opening Apraxia of eyelid opening is a nonparalytic motor disorder of the eyelids. It is characterized by the inability to volitionally initiate eyelid opening despite intact reflex lid elevation, lack of concurrent orbicularis oculi muscle contraction, and intact ocular motor nerves. Affected patients open the eyes manually or may employ a head thrusting movement to do so.484 It may be differentiated from blepharospasm by the absence of Charcot’s sign (orbicularis contraction forces the eyebrows to a level lower than the superior orbital margin). The condition usually appears in older patients with extrapyramidal disease, but may be seen in patients with unilateral or bilateral hemispheric dysfunction. It may respond favorably to Botulinum injections.418

7 Complex Ocular Motor Disorders in Children

normal in 3–14 months in all cases. Similar cases of isolated accommodative paresis in otherwise healthy young patients have been previously reported.163,222 Idiopathic paralysis of the near vision triad has also rarely been described.449 Organic causes of accommodative paresis include head/ neck trauma, pharmacologic agents, systemic diseases (diphtheria, diabetes mellitus, decompression sickness), neuromuscular disease (myasthenia gravis, myotonic dystrophy, botulism, tetanus), neurologic diseases (dorsal midbrain syndrome, encephalitis, Wilson disease, hemispheric hematoma, oculomotor nerve palsy, Adie tonic pupil), ocular disease (uveitis, trauma, metastasis, glaucoma), and presbyopia. Isolated accommodation palsy can also be functional in origin. Accommodative paresis can be one of the earliest symptoms of dorsal midbrain syndrome, resulting from either hydrocephalus or compression by an extrinsic tumor such as a solid pineal tumor.592 Blurred vision and isolated accommodative palsy have been reported in patients with symptomatic pineal cysts,86 which are usually considered to be an incidental radiologic finding (1.2–2.4% of all MR studies).301,477,677 Accommodative paresis is a common component in children with Down syndrome, leading to the frequent need for bifocals. The extra accommodative effort exerted by these patients may explain the development of esotropia and the common undercorrections experienced after strabismus surgery for this condition.

Pupillary Abnormalities Congenital Bilateral Mydriasis Congenital mydriasis is a rare defect that was first described by White and Fulton in 1937.802 Lindberg and Brunvand described a 12-year-old girl with congenital bilateral mydriasis in association with aneurysmal dilatation of a persistent ductus arteriosus.496 They attributed these findings to a hypoplastic or aplatic sphincter and ciliary body because there was also absent accommodation. Khan et al reported two patients with dilated pupils with hypoplasia of the iris, Moyamoya angiopathy, dolichoectatic internal carotid arteries, and patent ductus arteriosus. The mechanistic link between the ocular and cardiac defects is unclear.433

Accommodative Paresis A recent report described five children with a syndrome of benign transient loss of accommodation. No child had other ocular, neurological, or systemic abnormalities that could be associated with accommodative paralysis.18 All had preserved pupillary responses to light and near, and preserved convergence. All did well with bifocals, and accommodation returned to

Adie Syndrome Isolated internal ophthalmoplegia is commonly due to trauma or pharmacological dilatation of the pupil or is a feature of Adie syndrome. Adie syndrome is rare in childhood,498 having an average age of onset of approximately 32 years and a predilection for females. It is characterized by unilaterally or bilaterally enlarged, tonic pupils that show markedly slow constriction to either light or near stimulation, followed by a very slow, tonic, redilatation. Patients with Adie’s syndrome also show regional corneal hypesthesia due to interruption of fibers of the ophthalmic division of the trigeminal nerve as they traverse the ciliary ganglion. The light-near dissociation found in Adie syndrome differs in pathophysiology from that seen in mesencephalic disease; it may be attributed to either diffusion of acetylcholine from partially innervated or reinnervated ciliary muscle to the supersensitive pupillary sphincter muscle343 or by aberrant misdirection to the pupillary sphincters of nerve fibers that originally synapsed in the ciliary muscle.744 An accommodation paresis may also be associated, which is understandable if one considers that the ciliary ganglion has 30 times more neurons destined for the ciliary muscle than for the iris sphincter. Following acute onset, most of the sprouting new axons arise from accommodative neurons, but many of

Pupillary Abnormalities

these end up in the iris sphincter (i.e., aberrant regeneration). Hence, although the pupils tend to be large at presentation, they become smaller with the passage of time and may eventually be confused with Argyll Robertson pupils if the examiner is not aware of their earlier dilated status. With the slit lamp, segmental vermiform movements of the iris and sectoral palsy are seen. Sectoral palsy produces shifting of the iris stroma toward the area of active contraction, a phenomenon known as “iris streaming.”743 An associated sectoral palsy of the ciliary muscle causes lenticular astigmatism that may blur vision during near tasks. The iris vermiform movements noted at the slit lamp represent normal contractile activity of those iris sectors still innervated by light-responsive neurons. Citing two young adults who were found to have long-standing miotic pupils in association with typical features of Adie’s syndrome, Rosenberg658 has argued that some cases of Adie syndrome primarily present with miotic pupils in a manner analogous to primary aberrant regeneration of the oculomotor nerve. However, the observation of Adie syndrome with dilated pupils in children as young as 4 years6 (with subsequent development of miosis) argues against this hypothesis. Because oculomotor palsy rarely presents with isolated mydriasis,495,799 it is important to look closely for an exophoria that increases in adduction and for alternating hyperphorias in vertical gaze to rule out subclinical oculomotor nerve palsy. It is now recognized that cholinergic supersensitivity of the iris sphincter may also develop in oculomotor palsy with pupillary involvement.391 Other clinical signs usually attributed to postganglionic damage (light-near dissociation, segmental sphincter palsy) can also be seen,391 so it is important to differentiate Adie pupil from an early or resolving oculomotor nerve palsy. One case of Adie syndrome involved a 4-year-old boy who developed bilateral consecutive, idiopathic Adie syndrome over a follow-up period of 6 years.6,230 At the age of 4 years, he was diagnosed with right Adie syndrome and was found to have amblyopia, because the associated accommodative difficulty unmasked his latent hyperopia.6 Examination at age 10 revealed additional myotonic involvement of the left pupil and absent or sluggish deep tendon reflexes.230 Two children with unilateral congenital tonic pupils were found to have ipsilateral orbital neural-glial hamartoma.124,298 Two children with Adie pupil have recently been found to have an endodermal cyst of the intracranial oculomotor nerve.561,799 Tonic pupils have also been described in a child with neuroblastoma and attributed to a paraneoplastic process.800 Lambert et al469 reported bilateral tonic pupils in two infants with a congenital neuroblastoma, Hirschsprung disease, and central hypoventilation syndrome. Children with congenital hypoventilation syndrome tend to have miotic pupils with light-near dissociation, convergence insufficiency, and other defects in autonomic control such as absence of normal variability in heart

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rate.294a Whether the tonic pupils result from result from a paraneoplastic disorder or from the effects of a generalized neurocristopathy is unclear. Recently, a case of reversible posterior leukoencephalopathy was reported in association with an Adie’s tonic pupil in a 9-year-old boy following measles vaccination.49 Botulism should also be considered in the differential diagnosis of bilateral tonic pupils. In this setting, the tonic pupils may persist as a chronic condition.277 Thompson743 classified patients with tonic pupils into three general categories on the basis of their underlying pathophysiologic disorders: (1) Local pathologic disorders within the orbit that involve the ciliary ganglion (e.g., inflammatory processes such as herpes or sarcoid, trauma). These conditions are commonly unilateral. (2) Neuropathic conditions causing diffuse peripheral or autonomic neuropathy. These include syphilis, diabetes, Guillain–Barré syndrome, Ross syndrome,798 and several hereditary neuropathies, such as Shy–Drager and Charcot–Marie–Tooth diseases. These conditions are typically bilateral. The presence of Adie-like pupils in an infant younger than 1 year of age should raise the possibility of familial dysautonomia (Riley–Day syndrome).294 Cryptogenic tonic pupils, or true Adie syndrome, begins unilaterally, but eventually at least 20% of patients develop the syndrome bilaterally. In addition to the ocular signs, the deep tendon reflexes, especially the knee and ankle jerks, may be diminished or absent. Adie syndrome bears some resemblance to Ross syndrome, which is a rare, presumably degenerative peripheral neuropathy characterized by the triad of unilateral or bilateral tonic pupil, hyporeflexia, and segmental anhidrosis.798 The recent demonstration of subclinical segmental hypohidrosis in patients with Adie syndrome suggests that the two conditions may be related.327 The diagnosis of Adie syndrome can be confirmed by demonstrating constriction of the dilated pupil in response to a dilute solution of pilocarpine (0.125%), which confirms the presence of pupillary supersensitivity due to parasympathetic denervation. This supersensitivity may not be demonstrable acutely, with some acute cases failing to constrict even to strong solutions of pilocarpine, making a differentiation from pharmacologic blockade difficult. Pharmacological misadventures are a common cause of isolated pupillary dilation, resulting from instillation of mydriatic agents, exposure to certain plants that contain belladonna or atropine-like alkaloids (e.g., jimsonweed ), or exposure to certain perfumes or cosmetics. The mydriatic pupils associated with ophthalmoplegic migraine, oculomotor palsy with cyclic spasm, botulism, Fisher syndrome, and the dilated pupil accompanying the dorsal midbrain syndrome do not usually cause a diagnostic problem due to the other associated features of these disorders. Various infectious diseases have been associated with pupillary mydriasis or tonic pupils, including herpes zoster, measles, diphtheria, syphilis, pertussis, scarlet fever, smallpox, influenza, and

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hepatitis, but a history of an infectious illness is usually present. Chickenpox may produce a tonic pupil in children, which may present during the incubation period, the active disease stage, or during convalescence.297,359,584,650,659 The mydriasis and decreased accommodation in the setting are presumed to reflect direct infectious or inflammatory involvement of the ciliary ganglion; however, the coexistent iridocyclitis with iris stromal vasculitis and sphincter necrosis could also contribute in some cases. The finding of mutton-fat keratoprecipitates and/or sectoral iris stromal atrophy would favor the latter mechanism. Traumatic injury, either to the iris sphincter or to the ciliary nerves (e.g., panretinal photocoagulation, orbital surgery), may also produce pupillary mydriasis or tonic pupils.76 Some children may present with isolated episodic unilateral or bilateral mydriasis accompanied by head pain328,832; these may represent a variant of ophthalmoplegic migraine or represent a migraine equivalent and are usually self-limited.773

Horner Syndrome Horner syndrome results from a lesion affecting the sympathetic supply to the eye and may be encountered at any age (Fig. 7.23). The clinical features found on the affected side include the following: (1) 1–2 mm of miosis, with greater anisocoria in dim illumination and a dilation lag. The miosis results from denervation of the sympathetically innervated pupillary dilator muscle. Oculosympathetic denervation of the pupillary dilator muscle can be demonstrated by dimming the ambient light and observing an immediate but transient increase in anisocoria, because the affected pupil does not dilate as rapidly as the normal pupil (dilation lag). (2) Mild upper lid ptosis measuring 1–2 mm (due to denervation

Fig. 7.23 Congenital Horner syndrome. Note right upper lid ptosis, right miosis, and mild heterochromia. Right lower lid shows mild reverse ptosis, covering more of cornea than its left counterpart

7 Complex Ocular Motor Disorders in Children

of the sympathetically supplied superior tarsal muscle) and corresponding elevation of the lower eyelid (upside-down ptosis) due to denervation of the lower eyelid retractors. The upside-down ptosis may be confirmed by matching the lower limbus to the lower lid margin in each eye; more scleral showing would be found on the normal side. The resulting narrowing of the palpebral fissure leads to an apparent enophthalmos. (3) Anhidrosis if the lesion is proximal to the carotid bifurcation. Lesions distal to the carotid bifurcation do not affect sympathetic innervation of facial sweat glands. Both acquired and congenital Horner’s syndrome rarely causes Harlequin syndrome, a neurocutaneous phenomenon in which one half of the face fails to flush during thermal or emotional stress as a result of damage to vasodilator sympathetic fibers.101,564 In some cases, however, this condition cannot be attributed to straightforward sympathetic injury.157 Some children show a different pattern of scalp hair growth, with straight hair on the affected side.698 Congenital or perinatal Horner syndrome results in failure of the iris to become fully pigmented, resulting in heterochromia, with the ipsilateral iris appearing lighter in color. Iris heterochromia takes several months to develop and may be difficult to detect in infants who normally have lightly colored irides. Wallis et al reported the unusual case of a 20-month-old boy with congenital Horner syndrome, with the darker iris on the affected side attributable to concomitant Waardenburg syndrome.792 Much less commonly, heterochromia may also follow acquired lesions in adults.209 Subtle iris heterochromia can sometimes be made more visible by examining the child in sunlight. Some congenital cases may present with ipsilateral facial flushing.665 Patients with acute Horner syndrome may also exhibit decreased Schirmer response, transient myopia, transient hypotony, and transient conjunctival hyperemia. The last three signs are seen only in acquired cases. The location of the causative lesion along the sympathetic pathway may be inferred clinically and confirmed pharmacologically and/or neuroradiologically.210 For instance, the combination of Horner syndrome and ipsilateral abducens palsy implicates a lesion in the cavernous sinus. Mesencephalic lesions, involving the trochlear nucleus or fascicles before decussation in the superior medullary velum and adjacent sympathetic fibers, may produce an ipsilateral Horner syndrome and contralateral superior oblique muscle paresis.322 Pharmacological testing consists of topical instillation of autonomically active drugs to confirm oculosympathetic paralysis (cocaine test) and to distinguish a preganglionic from a postganglionic lesion (hydroxyamphetamine test). However, a preganglionic congenital Horner syndrome may show a false-positive hydroxyamphetamine test because of transynaptic degeneration.216 Recently, apraclonidine 0.5% has been touted as a diagnostic test for Horner syndrome on the basis of its alpha-2

Pupillary Abnormalities

inhibitory effects in normal eyes and weak alpha-1 adrenergic/excitatory effects in Horner eyes. Apraclonidine makes the Horner pupil dilate and the normal pupil constrict slightly.154,416 The reversal of anisocoria is more obvious with the room lights on.155 Apraclonidine is reported to be safe and effective in the pediatric population because it does not cross the blood–brain barrier, thereby reducing the incidence of centrally mediated effects.155 However, a recent report documenting CNS and respiratory depression in three children (one requiring intubation) suggests that its use in children should probably be avoided.634 Iris pigmentation, which occurs within the first year of life, requires sympathetic stimulation. Interestingly, Mindel et al549 reported a 21-year-old woman with neurofibromatosis type I who had a unilateral congenital Horner syndrome with heterochromia. The patient showed symmetric Lisch nodules, which are melanocytic hamartomas, in both eyes, suggesting that, unlike iris pigmentation, the formation of Lisch nodules is not influenced by sympathetic innervation of the iris. Other causes of heterochromia, such as iris nevus or melanoma, neurofibromatosis, hemosiderosis, hemochromatosis, Waardenburg syndrome, Fuch heterochromic iridocyclitis, and essential iris atrophy, should be excluded. Most cases of congenital or early acquired Horner syndrome are of a benign nature.289,399,814 Rarely, congenital Horner syndrome may occur as an autosomal dominant disorder. Hageman et al324 reported a Dutch family with five cases of congenital Horner syndrome spanning five generations. A history of perinatal trauma, such as brachial plexus injury (Klumpke paralysis),20,797 neck or cardiothoracic surgery, carotid dissection,319,648 peritonsilar lesions, and surgical or nonsurgical intraoral trauma, may be elicited in many cases, but some cases remain cryptogenic despite extensive investigations. Permanent postganglionic Horner syndrome can develop in children with a middle ear infection.370,716 Brachial plexopathies caused by forceps injury at birth are the putative cause in some cases.101 MR angiography has recently brought to light the association of congenital Horner syndrome with agenesis of the ipsilateral internal carotid artery.213,388,662 Congenital Horner syndrome has also been reported with hemifacial atrophy, synergistic divergence, basilar impression and Chiari malformation, cervical vertebral anomaly and an enterogenous cyst, and viral infections such as congenital varicella469 or cytomegalovirus infections, and PHACE syndrome.531 In acquired pediatric Horner syndrome, it is important to look for Lisch nodules and café au lait spots, because schwannomas, plexiform neurofibromas, or malignant peripheral nerve sheath tumors may affect the sympathetic tract in neurofibromatosis 1.137 A case of congenital postganglionic Horner syndrome and fibromuscular dysplasia of the ipsilateral internal carotid artery incited speculation that prenatal or neonatal cervical trauma might have been responsible for both findings.637

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Congenital tumors, including neuroblastoma of the neck, chest, or abdomen have been reported to underlie some cases of congenital Horner syndrome.143,676,678,814,830 Most reported cases of neuroblastoma occurred in the neck,2 where they are frequently mistaken for infectious adenitis, or in the mediastinum,703 but three patients with abdominal neuroblastoma have also been described.290,572 Because the cervical sympathetic chain does not descend to the abdominal level, the Horner syndrome in these cases was probably caused by metastatic cervical lesions or a second (undiagnosed) primary lesion. Cervical neuroblastoma causing Horner syndrome can be associated with other paraneoplastic disorders such as cerebellar degeneration.237,810 Other systemic clues to the presence of neuroblastoma may be present. Nonophthalmologic symptoms of neuroblastoma include pain (due to primary tumor, bone marrow involvement, or abdominal distension), watery diarrhea (due to paraneoplastic secretion of a vasoactive intestinal peptide),552 and acute cerebellar encephalopathy,99 which may be related to antineural antibodies such as anti-Hu, formed in response to the tumor that react to the normal cerebellum.269 There is an unusually high rate of spontaneous regression in the neuroblastoma of young infants, even in the disseminated form.523 Asymptomatic infants may have biologically favorable tumor with higher rate of spontaneous regression.523 Horner syndrome acquired in early life may be very difficult to distinguish from congenital cases, but close scrutiny of previous photographs may be helpful. In a large retrospective study, Mahoney et al510 found responsible mass lesions in six of 56 children. Two cases with congenital Horner syndrome were caused by mass lesions (neuroblastoma in one case, neurofibroma in the other). They recommended that the brain, neck, and chest MRI with and without contrast, as well as urinary catecholamine metabolite testing, be performed in any child without a surgical history. This study found direct imaging to be more sensitive than urine testing in this setting. Gibbs and colleagues290 reported a 2-year-old child with congenital Horner syndrome who was healthy until the age of 2 years, when a remote neuroblastoma of the adrenal gland was diagnosed. They argued that both congenital Horner syndrome and neuroblastoma may represent widespread dysgenesis of the sympathetic system. The rare occurrence of underlying tumors, especially neuroblastoma, in a few congenital cases justifies thorough neurodiagnostic evaluation. Mahoney et al510 recommended palpation of neck, axilla, and abdomen, spot urine for homovanillic acid and vanillylmandelic acid as a ratio of creatinine (which can be falsely negative in patients with small neuroblastomas), and MR imaging of the brain, neck, and chest, with and without contrast (abdomen is unnecessary because the cervical sympathetic chain does not descend to this level). Because of the recognized association of congenital Horner syndrome with ipsilateral agenesis of the internal

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carotid artery, we believe that MR angiography should also be included in the evaluation. While it has been suggested that a history of forceful manipulation of the neck during birth may reduce the need for extensive systemic evaluation,399 the possibility of carotid dissection should now be considered and evaluated by MR angiography in this setting.319

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Chapter 8

Nystagmus in Children

Introduction The most common forms of nystagmus in infancy and childhood differ clinically and pathophysiologically from adultonset nystagmus. Acquired nystagmus in both childhood and adulthood may often be associated with neurological lesions involving the vestibular and ocular motor pathways in the brainstem and/or cerebellum. On the basis of the clinical and electrophysiological characteristics of the nystagmus and any associated neurological signs or symptoms, neurotopical localization can often be inferred and then confirmed by neuroimaging. The initial evaluation of pediatric nystagmus is simplified by the fact that most affected children have either infantile nystagmus or latent nystagmus. The clinical appearance of infantile nystagmus usually distinguishes it from the rarer forms of pediatric nystagmus caused by neurologic lesions. Children with this condition frequently present with a head turn, which is used to maintain the eyes in the position of gaze of the null point (position of minimum nystagmus). Oscillopsia is almost never spontaneously reported in infantile nystagmus, but can sometimes be evoked by having patients look away from their null position. Head oscillations, which can also be part of the infantile nystagmus syndrome, are not used as the strategy to improve vision except in those rare patients with abnormal gain of their vestibuloocular reflex. Infantile nystagmus can occur in association with congenital or acquired defects in the visual sensory system (e.g., albinism, achromatopsia, congenital cataracts, optic nerve hypoplasia). Accurate, repeatable classification and diagnosis of nystagmus in infancy are best accomplished through a combination of clinical and motility findings; in some cases, the latter are indispensable for diagnosis. Infantile nystagmus may result from abnormal “cross-talk” from a defective sensory system to the developing motor system at any time during the sensitive period of the motor system. The primary ocular motor instability underlying infantile nystagmus is the same, but its clinical and oculographic expression is modified by both initial and final developmental integrity of

all parallel afferent visual system processes. The cause and precise mechanism of infantile nystagmus have not been elucidated. Visual loss should be highly suspected in any infant or toddler with the onset of nystagmus after early infancy because mild-to-moderate visual loss may not be readily apparent in the preverbal years. If a child with nystagmus has suspected visual loss but a normal ocular examination, an afferent system and a neurological evaluation are necessary because retinal dysfunction may be detected even in the absence of pigmentary degeneration. Optic nerve dysfunction is usually recognizable ophthalmoscopically by the presence of optic atrophy or hypoplasia. In contrast, underlying retinal disorders are often clinically occult and may be identifiable only through electrophysiological testing. Because infantile nystagmus is often an epiphenomenon of bilaterally decreased visual acuity, the identification of infantile nystagmus should be viewed as the initial step in the diagnostic evaluation. Determination of the presence or absence of an associated underlying sensory system visual disturbance is important, as it may be present in at least 50% of patients with infantile nystagmus.279 An inherent problem that vexes the diagnostic interpretation of pediatric nystagmus is that infantile nystagmus cannot be definitively distinguished from the manifest form of latent nystagmus without eye movement recordings. This problem renders the clinician less able to categorically establish the diagnosis of infantile nystagmus unless the patient has a clinical picture of latent nystagmus and fixes with the preferred eye in adduction (i.e., a patient with a right head turn fixes with the right eye and has a “latent” component to the nystagmus). Most examiners necessarily rely on time-honored clinical parameters, despite the inherent uncertainty that the clinical examination provides.279 The most common diagnostic error in the evaluation of infantile nystagmus is the acquisition of neuroimaging studies in the child who is otherwise neurologically normal. We continue to be impressed by the fact that parents of the child with infantile nystagmus so often arrive for neuro-ophthalmologic consultation with negative neuroimaging studies in hand.

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On the basis of our own experience and a review of the literature, brain tumors do not cause infantile nystagmus in children unless optic nerve atrophy or hypoplasia is inevitably present. With the rare exception of achiasma (in which infantile nystagmus is accompanied by seesaw nystagmus), there exist no data to support routine neuroimaging in infantile nystagmus.

Infantile Nystagmus Clinical Features Infantile nystagmus is an involuntary, conjugate, rhythmic, horizontal oscillation of the eyes. It may appear as a pendular or jerk nystagmus in primary gaze, and it usually has a torsional component (seen in recordings but not clinically obvious). The intensity of infantile nystagmus increases on lateral gaze and becomes right-beating in right gaze and left-beating in left gaze. The fact that infantile nystagmus appears to disobey Alexander’s law (which states that in peripheral vestibular nystagmus, the direction of the nystagmus increases in the direction of the fast phase and decreases in the direction of the slow phase) is often useful in distinguishing it from horizontal peripheral vestibular nystagmus and from manifest latent nystagmus (which obeys Alexander’s law under conditions of monocular fixation). Infantile nystagmus remains horizontal in upgaze, in contrast to acquired horizontal vestibular nystagmus, which becomes upbeating in upgaze. Parents of the child with infantile nystagmus often report that the nystagmus becomes worse with attempted fixation or intense visual effort. It seems to be the visual importance of the task to the individual rather than the inherent difficulty of the visual demand that exacerbates the nystagmus.534,578 This history is useful in further distinguishing the nystagmus from peripheral vestibular nystagmus, which becomes worse with occlusion and is damped by fixation. To distinguish these two forms of nystagmus, the examiner can observe one optic disc with the direct ophthalmoscope while periodically occluding the other eye. Increased nystagmus intensity with occlusion suggests a peripheral vestibular nystagmus, while either no change or a decrease in nystagmus intensity suggests infantile nystagmus.365 Anxiety, anger, fear, excitement, or fatigue also increase the infantile nystagmus intensity and thereby degrade visual acuity.13 Unlike adult-onset nystagmus, it is rare for individuals with infantile nystagmus to experience oscillopsia (an illusory to and fro movement of the environment), although exceptions to this rule are well documented.14,155,156 The absence of oscillopsia in older children and adults with conjugate horizontal nystagmus should therefore suggest the

8 Nystagmus in Children

diagnosis of infantile nystagmus. Infantile nystagmus often damps during convergence, which results in a near visual acuity that is better than the distance acuity.492,557 Parents may report that children with infantile nystagmus view objects at a very close distance. This visual adaptation, which provides the combined benefits of axial magnification and convergence damping of the nystagmus, should not be discouraged. Clinical observation and eye movement recordings have demonstrated that the amplitude, frequency, and waveform of the nystagmus can vary with eye position, giving rise to a region of gaze (referred to as the null zone) in which the nystagmus intensity (amplitude x frequency) of the oscillation is minimal.139,557 In most individuals with infantile nystagmus, the head position corresponds roughly to the minimal intensity zone of the nystagmus. When the angle of the null zone exceeds 15 degrees, however, the angle of the head turn may fall short of the null zone.208 In some children, the anomalous head position appears to be dictated by the velocity distribution of the slow phase (i.e., the percentage of time for which the slow phase is less than or equal to 10 degrees per second) and the nystagmus beat direction (which can be influenced both by the prior position of gaze and by the length of time a subject has maintained a fixed gaze position).9 The multiplicity of factors that influences the null zone in infantile nystagmus might explain why the anomalous head posture in infantile nystagmus has been observed to change with time.9 Bagolini et al45 have recognized that some individuals with infantile nystagmus use large head turns to place their eyes in extreme sidegaze and actively block their nystagmus. Unlike positioning the eyes in a null zone, in which electromyographic activity decreases, the mechanism of active blockage utilizes the increased electromyographic activity associated with lateral gaze innervation to damp infantile nystagmus. The same mechanism of active blockage occurs when infantile nystagmus is damped by convergence. Individuals with active blockage of nystagmus by sidegaze momentarily move their eyes into extreme lateroversion when they seek good vision. This maneuver may cause them to complain of discomfort brought about by the extreme torticollis that is necessary to block their nystagmus.45 Head turns associated with horizontal null positions are usually less extreme than those associated with active blockage, and the nystagmus associated with a null zone can often be observed to increase if the eyes are carried further into sidegaze. Infantile nystagmus may be accompanied by head shaking during periods of intense fixation. Head shaking seems to be more common in children (who are presumably less concerned about their cosmetic appearance).149 Head oscillations were originally thought to be an adaptive strategy to cancel the effects of the ocular oscillations, but it is now clear that this is not the case.365 Older children and adults are aware of

Infantile Nystagmus Table 8.1 Clinical findings in infantile nystagmus Horizontal pendular or jerk nystagmus Increased intensity on side gaze Right-beating in right gaze and left-beating in left gaze Horizontal in upgaze Damps during convergence Null zone, often with associated head turn Worse with attempted fixation and intense visual effort No oscillopsia “Reversed” horizontal optokinetic responses With-the-rule astigmatism Head nodding in 10%

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medical evaluation for neuroblastoma. Although the term congenital nystagmus is somewhat misleading, it is deeply entrenched in the literature (much like “congenital esotropia,” which is also acquired in early infancy). While some consider the distinction between congenital and infantile nystagmus to be more semantic than scientific, we now favor the term infantile nystagmus, which implies aberrant development after birth and does not require that the causative defect be present in utero.

Terminology their head movements and do not feel that these involuntary movements help them see. With rare exceptions,98 simultaneous eye and head movement recordings have demonstrated that head oscillations in individuals with infantile nystagmus represent an associated involuntary movement of pathological origin and not an adaptive strategy to improve vision.149,365 Many patients with infantile nystagmus also have a withthe-rule astigmatism that has been attributed to the increased force applied to the corneas by the eyelids when the eyes are oscillating.96,435 The amount of astigmatism increases with age in children with nystagmus.313 The clinical characteristics of infantile nystagmus are summarized in Table 8.1.

Onset of Infantile Nystagmus The term congenital nystagmus is fundamentally inaccurate because the nystagmus is rarely noted at birth. When questioned, parents and relatives usually relate an onset of nystagmus between 8 and 12 weeks of age. In hereditary cases, however, infantile nystagmus has been documented at birth by the obstetrician and the family, who are aware of the possibility and therefore carefully observe the baby’s eyes. Rarely, infantile nystagmus manifests for the first time in the teens or beyond and can cause blurred vision and oscillopsia by disrupting the long-standing sensory and motor adaptations that the patient has developed to remain asymptomatic.176,241 The presence or absence of an underlying visual sensory deficit does not affect the time of onset of infantile nystagmus. Often, the infant is first evaluated in the third month of life, when irregular eye movements are noted. The incorrect notion that infantile nystagmus should be present at birth can lead the ophthalmologist or neurologist to conclude that the infant has an acquired form of nystagmus and to suspect an underlying neurological problem. When infantile nystagmus first appears, it is often arrhythmic and intermittent, consisting of a series of irregular horizontal and oblique deviations of the eyes from side to side. At this stage, the erratic eye movements may simulate opsoclonus, leading to an unnecessary

The term motor nystagmus has been applied to individuals with infantile nystagmus in whom the sensory visual system appears intact both clinically and electrophysiologically. This term implies that the oscillation is driven by a primary abnormality in the ocular motor circuitry. The term sensory nystagmus has been applied to patients whose infantile nystagmus is attributable to an underlying sensory visual disorder.107 Cogan106 originally proposed that, in sensory nystagmus, the poor visual acuity interrupts sensory afferent input to the oculomotor control system, which causes fixation to become unstable and leads to a pendular oscillation of the eyes. In contrast, motor nystagmus was attributed to signal errors intrinsic to the ocular motor control centers, leading to a jerk nystagmus with relatively good visual acuity.107,441 However, the myth that the presence or absence of a primary sensory deficit can be predicted on the basis of the clinical appearance (i.e., pendular versus jerk nystagmus) has long been dispelled.139,144,150 Pendular and jerk waveforms often coexist in the same individual with infantile nystagmus so that waveform analysis alone cannot be used to predict the presence or absence of afferent visual pathway dysfunction. In the case of infantile nystagmus, all of the known waveforms have been recorded in patients with and without sensory visual deficits. Infantile nystagmus has also been recorded in patients with visual acuities ranging from 20/20 to no light perception. Thus, infantile nystagmus does not “result” from poor acuity (which all babies have). Similarly, the age of onset for the nystagmus cannot be used to predict the presence or absence of an underlying sensory visual deficit. The neurophysiological mechanism by which abnormal sensory visual input from both eyes promotes the expression of infantile nystagmus is unknown. The realization that one usually cannot predict the presence or absence of an underlying sensory visual disturbance on the basis of the clinical features or eye-movement waveform of the nystagmus (with the possible exception of the rapid, smallamplitude nystagmus that characterizes achromatopsia) led some investigators to speculate that all infantile nystagmus may be attributable to a primary sensory disturbance, with

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occult or subclinical forms simulating what has traditionally been referred to as “motor nystagmus.” For example, isolated foveal hypoplasia is increasingly recognized as a hereditary “cause” of infantile nystagmus in individuals with normal ocular pigmentation.437 Mutations in the PAX6 homeobox gene have been identified in this condition, although other ocular malformations often coexist when this mutation is present.43,44 Many patients with this condition have undoubtedly been classified as having motor nystagmus. However, there is strong evidence to support the notion that the afferent visual pathways in some individuals with infantile nystagmus are clinically and electrophysiologically normal.34 Thus, in referring to individuals in whom no clinical or electrophysiological signs of afferent visual pathway dysfunction are found, we advocate the term idiopathic infantile nystagmus.

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dominant inheritance pattern,213,490,581 singleton cases are also seen. Nevertheless, the absence of a family history in a child who appears to have idiopathic infantile nystagmus combined with low vision or other signs or symptoms of neurological disease, and visual acuity lower than 20/40 should raise suspicion of an underlying visual system or neurological disorder.100,307 Although the clinical features and time of onset cannot be used to predict the presence or absence of an underlying visual sensory disorder, other aspects of the history and physical examination are highly suggestive of primary visual impairment associated with infantile nystagmus. It is toward the detection of afferent visual pathway disease that the remainder of the parent interview and patient examination is directed.

Relevant History

History and Physical Examination Until recently, it was believed that individuals with primary visual disorders accounted for a minority of infantile nystagmus cases, and electrophysiological testing was not routinely performed. Early studies utilizing electroretinography (ERG) and the testing of routine and hemispheric visual evoked potentials (VEPs) have demonstrated anterior visual pathway (i.e., bilateral retina or optic nerve) abnormalities in over 90% of patients with infantile nystagmus.213,570 Taking into account the ascertainment biases that exist in different ophthalmologic and neurologic practices, it is now thought that approximately 50% of patients with infantile nystagmus have infantile nystagmus in the absence of underlying sensory visual defects.279 The diagnosis of infantile nystagmus therefore necessitates a directed investigation with the goal of identifying any obvious structural opacity or occult retinal dysfunction.89,90,213,570 Notably, infantile nystagmus associated with bilateral congenital cataracts has been noted to improve or even disappear when the cataracts are removed, and clear vision is restored within 1 month of the onset of the nystagmus.590 The decision of whether to perform further electrophysiological studies in an individual patient is predicated on the degree of clinical suspicion that a primary sensory disorder is likely to be present. Gelbart and Hoyt213 have emphasized that individuals with idiopathic infantile nystagmus have significantly better visual acuities (20/40 to 20/70) than those with primary visual disorders (usually 20/70 or below). This finding reflects the fact that normal visual sensory systems are conducive to better foveation strategies. Although patients with only infantile nystagmus usually have a positive family history of nystagmus that suggests either an X-linked or autosomal

When evaluating an infant or child with infantile nystagmus for the first time, certain historical points suggest afferent visual pathway dysfunction at the retinal level. A directed history in the child with infantile nystagmus should include the following inquiries: 1. Is the child unusually light sensitive? Photophobia in a child with infantile nystagmus suggests the presence of a congenital retinal dystrophy (which may be present despite a grossly normal retinal appearance). Children with achromatopsia or blue cone monochromatism are the most photophobic. 2. Does the child see better in daytime or at night? A history of night blindness suggests the possibility of congenital stationary night blindness (CSNB) or a rod–cone dystrophy. Children who are debilitated in daylight but function better in dim illumination may have congenital achromatopsia. 3. Is there a family history of poor vision, nystagmus, hypopigmentation, or easy sunburning? A family history of cutaneous hypopigmentation suggests the diagnosis of oculocutaneous albinism. A family history of nystagmus in the absence of hypopigmentation is consistent with infantile nystagmus, isolated foveal hypoplasia, or congenital retinal dystrophy, but is rare in optic nerve hypoplasia.

Physical Examination In infants with infantile nystagmus, the ability to generate vertical optokinetic responses should be examined. In infants with relatively good vision, targets on a vertically moving optokinetic drum elicits a vertical optokinetic nystagmus superimposed on the child’s ongoing horizontal nystagmus. When vision is poor, a vertical optokinetic response cannot be

Infantile Nystagmus

elicited. Cogan106 pointed out the importance of eliciting vertical optokinetic nystagmus in prognosticating vision in the infant with infantile nystagmus. The ability of a child to follow vertical optokinetic targets can be used to identify children who will be “mainstreamed” and educable in regular schools from those with severe visual impairment and will probably require visual aids and special services. Because infants with underlying sensory deficits may have a superimposed delayed visual maturation within the first 6 months of life, it may be important to wait until this age before conferring a poor visual prognosis on the child on the basis of absent vertical optokinetic responses. Conversely, it remains possible that delayed visual maturation or subcortical visual impairment in the first one to 3 months of life may be the facilitating inciting sensory system event in some children with infantile nystagmus, who are later called “idiopathic.” In older children with infantile nystagmus, examination of visual acuity involves a number of additional steps. Visual acuity must be checked at distance and at near, with both eyes open and with each eye covered. This examination should be performed without correcting the anomalous head position to determine the real-life acuity (and also to elicit the full degree of torticollis necessary to see small objects). To avoid inducing a latent nystagmus during monocular occlusion, most examiners place a +5.00 lens rather than an occluder to blur the nonexamined eye.189 Placement of a green “Worth Four Dot” lens while the child views a duochrome slide reportedly accomplishes this goal to a greater degree. If children are wearing base out prism in their glasses, visual acuity should be checked only binocularly because the prism can move the monocular visual image away from the null point and reduce the measured acuity. It is also important to examine the near vision with the child spontaneously holding the near card in his or her preferred position (often very close to the face), because the acuity at this distance represents the child’s real-life reading acuity. As mentioned earlier, near visual acuity often exceeds distance visual acuity, in part because of the damping effect of convergence. Although similar near and distance visual acuity in children has been attributed to functional changes in the visual system resulting from the nearly incessant retinal image motion blur that is produced during development,5,60,259 this assumption is dubious because children whose nystagmus damps at near experience the same retinal image motion. The results of visual acuity examination must then be placed in proper perspective. Clinic visual acuity provides restricted assessment of how the child with infantile nystagmus functions under real-world circumstances, both because it can decrease on a moment-to-moment basis when the child is nervous and because it generally assesses only a single gaze point. Because anxiety can exacerbate infantile nystagmus, children with infantile nystagmus often see better outside than in the elevated psychological state of measuring visual

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acuity. They may also show a higher visual acuity when a friendly female technician administers the test than when an imposing, white-coated, male physician does. Several studies have found that it is the associated anxiety and not increased attentional demand of acuity testing that augments the nystagmus.13,578 It is also important to recognize that the clinical appearance of the nystagmus may not give an accurate impression of what the child sees. Although the intensity of nystagmus is a function of amplitude times frequency, it is the amplitude and not the frequency that is appreciated clinically. Foveation time is the primary indicator of visual function, while amplitude and frequency are secondary measures that only sometimes march in lockstep with visual acuity. Thus, patients with a high-frequency nystagmus may have better visual acuity than others with low-frequency infantile nystagmus, simply because they have more total foveation time. Recently, Dell’Osso et al have developed a nystagmus acuity function (NAFX) that depends solely on foveation quality with the primary emphasis on foveation time.167 All other portions of the infantile nystagmus waveform are discarded by the function. The next goal of the ocular examination in the child with infantile nystagmus is to rule out ocular structural abnormalities that may reduce vision and lead to infantile nystagmus. Signs of aniridia, congenital cataracts, corneal opacities, iris transillumination defects, and macular hypoplasia are sought. When signs of partial aniridia are accompanied by midface hypoplasia, mental retardation, and nonprogressive cerebellar ataxia, the diagnosis of Gillespie syndrome can be established.215,426,478 If these features are absent, an examination of the optic discs to look for optic disc anomalies (most notably optic nerve hypoplasia or atrophy) should be undertaken. When the optic nerves are normal in appearance, the possibility of an underlying congenital retinal dystrophy must be considered (Table 8.2). Most congenital retinal dystrophies are characterized by a grossly normal retinal appearance in the early stages (although a sedated examination using direct ophthalmoscopy reveals diffuse narrowing of the retinal arterioles, often accompanied by a subtle wrinkling of the internal limiting membrane over the macula). When structural ocular abnormalities are absent in infantile nystagmus, the following four clinical signs of congenital retinal dystrophy should be sought (Table 8.3): 1. Severe photophobia in a child with infantile nystagmus is strongly suggestive of a congenital retinal dystrophy. (Children with optic nerve hypoplasia, dominant optic atrophy, or cortical visual loss may be mildly photophobic).308 2. Bilateral high myopia in a child with infantile nystagmus should lead the examiner to suspect a congenital retinal dystrophy. 3. The paradoxical pupillary response is suggestive of either CSNB or achromatopsia.49,203 The paradoxical pupillary

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Table 8.2 Infantile nystagmus associated with sensory visual loss Ocular structural abnormalities or media opacities Diagnostic modality Aniridia Congenital Cataracts Bilateral vitreous hemorrhage Bilateral corneal scarring Macular traction (e.g., retinopathy of prematurity) Inflammatory macular scarring (e.g., toxoplasmosis) Isolated foveal hypoplasia Nonstructural ocular disease Congenital retinal dystrophies Leber congenital amaurosis Achromatopsia (complete, blue cone monochromatism) Congenital stationary night blindness Albinism Isolated foveal hypoplasia

Achiasma Optic nerve hypoplasia Optic atrophy

Ocular examination

Electroretinography

Hemispheric visual evoked potentials Optical coherence tomography, multifocal electroretinography Ocular examination, hemispheric visual evoked potentials Ocular examination MR imaging

Table 8.3 Clinical signs of congenital retinal dystrophy in infantile nystagmus Photophobia Paradoxical pupillary phenomenon High myopia Oculodigital reflex

reaction consists of an initial pupillary constriction (rather than dilation) when the room lights are turned off. This phenomenon is best observed by holding a penlight laterally to the globe to dimly illuminate the pupil while turning off the room lights.50 When a paradoxical pupillary reaction is observed, there is usually a lag time of approximately 1 s before the initial pupillary constriction is seen. It is now recognized that the paradoxical pupillary phenomenon can rarely be seen in a congenital optic nerve disorders and even in normal patients.89,90,206,456 In the setting of infantile nystagmus, however, the paradoxical pupillary phenomenon remains highly suggestive of a congenital retinal dystrophy. The paradoxical pupillary phenomenon appears to be agerelated in that it is difficult to see in adults or infants younger than 6 months of age.50 The paradoxical pupillary phenomenon has recently been linked to the intrinsic responses of melanopsin-containing ganglion cells, which continue to function when the photoreceptors are disabled.212

4. The oculodigital sign refers to a repetitive pushing on the eyes with the thumbs or fists. It is speculated that repetitive eye rubbing is a self-stimulatory behavior that elicits phosphenes (entoptic flashes of light) in infants with extremely poor vision. The oculodigital sign is commonly described in infants with Leber congenital amaurosis, in whom the effects of chronic eye rubbing may contribute to the associated findings of enophthalmos, keratoconus, and cataract.

ERG If any of the foregoing four signs is present, a congenital retinal dystrophy should be suspected and ERG should be obtained to further characterize it.213,221,570 When ordering ERG in the child with nystagmus, it is important to recognize that the ERG is often subnormal in infancy.209,574 Unless the clinician has access to an electrophysiology laboratory with normative values for infants of different ages, it is best to wait until at least 1 year of age (at which time the amplitude, sensitivity, and latency of the electroretinographic waveform approach adult values) before obtaining this study.209 If, at that time, the ERG is normal, the diagnosis of a congenital retinal dystrophy can be effectively ruled out. An abnormal ERG obtained after 1 year of age confirms the presence of an underlying congenital retinal dystrophy and, in some cases, establishes a specific diagnosis.

Hemispheric Visual Evoked Potentials The ERG may be supernormal in tyrosinase negative albinism, but is usually normal in other forms of albinism and may be subnormal in the Hermansky Pudlak syndrome. In all patients with infantile nystagmus, a careful search for iris transillumination, macular hypoplasia, and chorioretinal hypopigmentation should again be undertaken because these signs may be difficult to detect in infancy. If these abnormalities are mild or equivicol, recording of VEPs to detect hemispheric asymmetry can be used to confirm the diagnosis. Simonsz and Kommerell503 studied patients with infantile nystagmus and found a high incidence of subtle oculocutaneous albinism when careful iris transillumination and retinal examinations were performed. Apkarian et al30 have demonstrated that hemispheric VEPs provide the most sensitive and specific means to establish the diagnosis of albinism. Because we see little prognostic value in distinguishing clinically occult albinism from idiopathic infantile nystagmus, we rarely find occasion to measure hemispheric VEPs in children with infantile nystagmus.

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Infantile Nystagmus

Overlap of Infantile Nystagmus and Strabismus Estimates of the prevalence of strabismus in infantile nystagmus range from 8% to 33%.81,146,157,205,213 Strabismus is essential for latent nystagmus, but incidental to infantile nystagmus.146 Latent nystagmus is much more likely to be accompanied by strabismus than is infantile nystagmus.146 However, the type of the nystagmus that accompanies pediatric strabismus is to a great extent determined by the type of practice. In strabismus clinics, latent nystagmus is by far the most common accompaniment of strabismus. In neurology clinics, however, infantile nystagmus is seen much more commonly than latent nystagmus, so there is empirically a greater chance that the patient with strabismus and nystagmus will have congenital nystagmus. The presence and nature of an underlying sensory visual disorder seems to influence the likelihood of associated strabismus. In a study of 82 children with infantile nystagmus (diagnosed clinically), Brodsky and Fray81 found the prevalence of strabismus to be 82% in children with optic nerve hypoplasia, 53% in children with albinism, 36% in children with congenital retinal dystrophies, and 17% in children with idiopathic infantile nystagmus. However, clinical assessment of the true incidence of strabismus in the setting of sensory visual disorders is confounded by the fact that children with Leber congenital amaurosis and other congenital visual disorders lack central fixation, making the assessment of strabismus difficult. The finding of esotropia and nystagmus compels the examiner to rule out manifest latent nystagmus that accompanies congenital esotropia and that differs from infantile nystagmus in its visual prognosis. When latent nystagmus and strabismus coexist, treatment of the strabismus often produces resolution of the manifest component of the nystagmus.

Eye Movement Recordings in Infantile Nystagmus

fixation followed by a period of foveation and an increasing-velocity slow phase, which again pulls the fovea away from the object of interest. A few residual triangular and pendular cycles continue to be interspersed in the increasing-velocity waveform. Using more accurate eye-movement measurement techniques, Dell’Osso has found that mature infantile nystagmus waveforms are present and continue to develop during infancy, with an evolution of waveforms from pendular to jerk, (consistent with the notion that jerk waveforms reflect modification of the oscillation by growth and development of the visual sensory system).280,283

Mature Infantile Nystagmus Waveforms Dell’Osso and Daroff139 have subdivided infantile nystagmus waveforms into 12 distinct categories on the basis of their electro-oculographic characteristics. Although infantile nystagmus waveforms are often subdivided for classification purposes, it is important to recognize that most infantile nystagmus patients display an average of three to five waveforms. These oscillations exist as a continuum of oscillations characterized by a period of foveation followed by an increasing-velocity slip away from the target and, finally, a corrective saccade back toward the target139 (Fig. 8.1). The visual acuity associated with each waveform is related primarily to the length of the foveation period. There is no evidence that any particular waveform is associated with better acuity (such an assessment would require knowledge of which waveform is predominating at the exact instant that visual acuity is being tested). Rather, pure pendular or jerk waveforms without foveation periods are usually associated with poorer vision, whereas waveforms of either type with extended foveation periods indicate better vision. Eye movement recordings raise doubt about the ability to clinically differentiate between pendular and jerk forms of infantile nystagmus as saccades may be seen in a clinically pendular nystagmus, and a pendular waveform without saccades may be seen in a clinically jerk nystagmus.139

Immature Infantile Nystagmus Waveforms Fixation in Infantile Nystagmus Using electro-oculographic recordings, Reinecke et al found a stereotyped waveform evolution in infants with infantile nystagmus.466 When the nystagmus first appears at 2–3 months of age, it takes on a triangular pattern that is occasionally punctuated by small plateaus.280,283 At about 7–12 months of age, the nystagmus transforms into a pendular waveform. Between 10 months and 1½ years of age, the pendular waveform gives way to an increasing-velocity jerk waveform characterized by a saccade to the target of

Although infantile nystagmus has been attributed to a faulty fixation mechanism, Dell’Osso et al158 have performed detailed examinations of foveation periods (intrabeat dynamics, accuracy of target foveation, effects of gaze angle, convergence, and base-out prisms on foveation period) and found that idiopathic infantile nystagmus is associated with strong fixation reflexes in that individuals are able to accurately achieve and maintain fixation for long periods. Bedell

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Fig. 8.1 Eye movement recordings showing three common waveforms in infantile nystagmus. (Upward deflections denote rightward eye movements; downward deflections denote leftward eye movements). (a) Eye position (POS) and velocity (VEL) record of pure jerk nystagmus. Target foveation occurs briefly at termination of each rightward saccade. Velocity spikes clearly identify rightward-jerk direction. (b) Eye position (POS) and velocity (VEL) record of jerk nystagmus with extended foveation. Note that target is foveated for longer period following each saccade than with pure jerk nystagmus. The velocity wave-

form readily demonstrates leftward direction of saccades, which is difficult to discern from position tracing alone. (c) Eye position (POS) and velocity (VEL) record of pseudo-cycloid form of jerk nystagmus. In waveform, leftward saccades are corrective in nature but are of insufficient amplitude to fully refoveate target. Each saccade is followed by smooth eye movement that refoveates target. This waveform is often misidentified clinically as pendular nystagmus. Velocity waveform is particularly useful in identifying saccadic component of each cycle. Adapted, with permission, from Dell’Osso LF et al139

et al58 found greater standard deviations in foveation periods of two albinos than in patients with idiopathic infantile nystagmus and suggested that the effects of macular hypoplasia on the fixation mechanism may have a secondary effect on vision in albinism. Visual acuity in infantile nystagmus has been found to correlate with fixation parameters such as the accuracy of target foveation, the duration of target foveation, and the repeatability of foveation from cycle to cycle.58,158 According to Dell’Osso, the fixation subsystem is only able to prolong foveation and maintain temporary fixation when the target image is on the fovea and moving with a velocity (or acceleration) that falls below a critical value (estimated at 4 degrees per second).155,156 This may explain why foveation periods are part of the infantile nystagmus but not the acquired nystagmus waveform because the initial slow-phase velocities in acquired nystagmus are usually too high for the fixation subsystem to extend foveation and improve visual acuity.161 While the fixation mechanism appears to be robust in infantile nystagmus, the observation that infantile nystagmus increases during attempted fixation and ceases during nonvisual tasks such as daydreaming or sleep158 suggests that the presence of an abnormal circuitry between the fixation system and the remaining ocular stabilization systems that allows the effort associated with fixation to influence the oscillation.158 Alternatively, the effort to see appears to be one of many psychological inputs (e.g., excitement, fear, anxiety) that raise the gain of the circuitry controlling the inherent oscillatory nature of the smooth pursuit system.

Smooth Pursuit System in Infantile Nystagmus The smooth pursuit waveform in the infantile nystagmus patient bears little resemblance to that of the normal individual.159 This lack of correspondence has, in the past, been misconstrued as a possible smooth pursuit deficit in infantile nystagmus.341,441,591 Dell’Osso has stressed that the fundamental error of equating the summation of smooth pursuit movements plus the superimposed infantile nystagmus waveform with the pursuit movement alone inevitably leads to the erroneous conclusion that there is an inherent defect in the pursuit system. He has further demonstrated that during pursuit of a visual target, the slow phases of infantile nystagmus consist of normal pursuit movements plus the nystagmus itself, but that the eye position and velocity consistently matches the target position during foveation periods.148,159 If one examines the upper tracing in Fig. 8.2 (in which eye position has been superimposed on target position) and confines this examination to only the foveation periods, it becomes evident that the eye position accurately matches the target position during most of the foveation periods.148,159 Such findings cast serious doubt on the hypothesis that defective pursuit is either the cause of, or the necessary result of infantile nystagmus.159 The notion of “inverted pursuit movements” and “inverted optokinetic responses” has created further confusion regarding the role of smooth pursuit in infantile nystagmus. It is widely recognized that patients with infantile nystagmus often show an apparent reversal of their optokinetic responses

Infantile Nystagmus

Fig. 8.2 Eye movement recording from patient with infantile nystagmus demonstrating smooth pursuit of moving, constant-velocity target. Upper tracing shows target position with right eye (RE) position superimposed. Lower tracing shows left eye position. (POS position; VEL velocity.)

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Note that congenital nystagmus waveform is punctuated by brief foveation periods in which eye position precisely matches target position. Adapted, with permission, from Dell’Osso LF.148 Published with permission from the journal Neuro-Ophthalmology. Copyright by Aeolus Press)

(i.e., during pursuit of leftward optokinetic stimuli, a left-beating nystagmus rather than a right-beating nystagmus is seen).254 This clinical observation is consistent with eye movement data showing that horizontal optokinetic targets often induce an increasing-velocity slow-phase movement of opposite direction to the target motion in the patient with infantile nystagmus, which has led to the mistaken assumption that infantile nystagmus could be caused by an inherent “reversal” in either the smooth pursuit or the optokinetic system.441 Although reversed optokinetic responses have been described in patients with albinism111,516 and in animals with achiasmia,298 the phenomenon of inverted horizontal pursuit movements in idiopathic infantile nystagmus is now attributed by most investigators to a dynamic shift in the null zone induced by the moving stimulus.148,159,254,353

Vestibulo-ocular Reflex in Infantile Nystagmus Many attempts to evaluate the vestibulo-ocular reflex (VOR) in subjects with infantile nystagmus have failed to successfully separate the slow-phase velocity associated with the underlying nystagmus from that due to the VOR itself.160 Because of the superimposition of an ever-present and changing infantile nystagmus waveform on the eye movements resulting from the normal VOR, the measured responses do not resemble normal ones. Dell’Osso et al160 have stressed that calculation of the VOR gain in infantile nystagmus must be limited to foveation periods (Fig. 8.3). At any other point in the infantile nystagmus cycle (when there is neither target foveation nor clear vision due to the obligate retinal slip), the calculation of VOR gain is meaningless, both in the mathe-

Fig. 8.3 Vestibulo-ocular reflex in infantile nystagmus. Note that during head movement, nystagmus continues to be punctuated by foveation periods (middle tracing) during which position of gaze remains steady. Adapted, with permission, from Dell’Osso LF et al160

matical sense and as an indication of the performance of the VOR. Failure to recognize this interrelationship has led some to suggest that the VOR itself is deficient.98,173,210 Others have recognized that the infantile nystagmus confounds the calculations of VOR gain and have concluded that the VOR was not deficient.148,237,240,254,353 Symptomatically, it is noteworthy that patients with infantile nystagmus rarely complain of oscillopsia or exhibit symptoms that normally accompany deficits in the VOR during ambulation.

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Saccadic System in Infantile Nystagmus Although visual feedback provides a means of sampling and assessing the accuracy of foveation periods in infantile nystagmus, a number of observations suggest that fast phases are not produced in response to a retinal displacement error signal between the fovea and the target image.589 Worfolk and Abadi589 have offered the following evidence to support this supposition: 1 . Jerk infantile nystagmus can continue with the eyes closed. 2. Infantile nystagmus continues and its parameters remain unchanged as individuals track paracentral afterimages, suggesting that the timing and direction of the fast phases are not dependent on retinal feedback.342 In pendular infantile nystagmus with foveating saccades (Fig. 8.1b), the retinal displacement error signal is opposite in sign to the forthcoming fast phase until about 70 ms before the saccade, allowing insufficient time to program the quick phases using visual information. The foregoing evidence suggests that the fast phases in infantile nystagmus are likely to be initiated on a predictive basis or in response to efference-copy information.589 The peak fast-phase velocity in infantile nystagmus is reduced by approximately 10% with respect to normals.8 This finding is consistent with the slightly reduced saccadic velocity in normals who are making saccades on the basis of nonvisual information rather than visually-guided saccades,8 and further suggests that factors responsible for the fast phase in infantile nystagmus may include nonvisual elements.8,342 Saccades and gaze holding are normal in infantile nystagmus, and the saccades contained within the nystagmus waveforms are always corrective and not the initiating movement responsible for the nystagmus.8,168

Suppression of Oscillopsia in Infantile Nystagmus Several mechanisms have been proposed to account for the stability of the perceived world in the face of nearly constant motion across the retinas in individuals with infantile nystagmus.10 These include the notion of visual information sampling only during foveation periods with suppression at other times,12,14,155,156,170 use of an extraretinal signal to cancel out the visual effects of eye motion, central elevation of motion detection threshold,3,134,219,341 and adaptation to retinal image motion.17,56 Such extraretinal signals include efference copy of the relative image motion,56,57,135,147 and proprioception.10 The suggestion that individuals with infantile nystagmus periodically sample their visual environment only during foveation periods with total suppression at all other times14 (i.e., “stroboscopic” vision) was a simplistic inference drawn from the observation that clear

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and stable vision was possible only during foveation periods, and has been dispelled.15 Temporal modulation studies demonstrate that individuals with infantile nystagmus process retinal information continuously rather than selectively during foveation periods.314,568 It is not surprising that infantile nystagmus patients have elevated motion detection thresholds when compared to normal patients with still eyes.179 The fact that these individuals are unable to see their nystagmus in a mirror presumably results from the simultaneous movement of the mirror images with the eyes (retinal image stabilization) because these same individuals can recognize their nystagmus on a videotape. The observation that the vision is clearest during foveation periods when the eyes are relatively still and degraded during ocular movement is a normal physiological finding that should not be misconstrued as an a priori elevation in motion detection thresholds. Bedell59 found no evidence of decreased sensitivity to oscillatory target motion in patients with infantile nystagmus compared with control patients viewing a target with sinusoidal or ramp motion to simulate the retinal image motion that occurs with retinal eye movements. Based on his experimental results, an abnormally low sensitivity to oscillatory target motion cannot be invoked to explain the absence of oscillopsia in individuals with infantile nystagmus. The fact that retinal image stabilization produces oscillopsia in individuals with infantile nystagmus suggests that an extraretinal signal (efference copy) is used by the brain to cancel out the infantile nystagmus waveform.10,342,363 Dell’Osso and colleagues154,159 have demonstrated that individuals with infantile nystagmus also require well-defined, repeatable foveation periods from one cycle to the next to perceive a nonmoving visual world (Fig. 8.4).154,159 Perturbations in the infantile nystagmus cycle related to external or internal factors (e.g., head trauma, medications) can result in oscillopsia.14 In one patient, oscillopsia was present only when the waveform failed to enter the foveation window;155 in another, when the foveation period fell below a minimal duration.14

Summary of Ocular Stabilization Systems in Infantile Nystagmus In examining how the ocular stabilization systems function in the setting of infantile nystagmus, one must confine the analysis to the foveation periods. It is during this portion of the infantile nystagmus waveform that the oscillation has subsided, vision is clear, and some degree of ocular stabilization is possible. Eye-movement recordings and phase-plane portraits in infantile nystagmus demonstrate the following:79 1. The oscillations of infantile nystagmus supersede the ocular stabilization systems but do not extinguish them.

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improve when the infantile nystagmus oscillation is reduced.1,3,5,6,178,287

Theories of Causation

Fig. 8.4 Phase plane portrait demonstrating multiple consecutive cycles in patient with infantile nystagmus. Figure does not depict the trajectory of eyes. Its purpose is to simultaneously display position and velocity of eye at any point in nystagmus cycle. By touching line at any point with pencil, examiner can simultaneously assess position and velocity of eyes at that point in time. Phase plane portraits are useful in understanding visual acuity and suppression of oscillopsia in congenital nystagmus. For good visual acuity, eye position must simultaneously fall within ½ degree of fovea (bracketed by vertical lines) and have velocity of less than about 4 degrees per second (bracketed by vertical lines). Time function is not linear along each tracing; relatively less time is spent in positions of high velocity, and more time is spent in positions of low velocity. Note stereotyped appearance of each repetitive cycle, which appears to be prerequisite for suppression of oscillopsia. Adapted, with permission, from Dell’Osso LF et al158

2. Amidst the ongoing oscillations of infantile nystagmus, these systems exert their primary influence on vision during foveation periods. 3. Defects in ocular stabilization are neither the cause nor the necessary result of infantile nystagmus.

Contrast Sensitivity and Pattern Detection Thresholds in Infantile Nystagmus The threshold for acuity, contrast sensitivity, motion detection, and stereoacuity are typically elevated in patients with infantile nystagmus.57,60a A reduction in contrast sensitivity for medium to high spatial frequency vision and increased pattern detection thresholds in infantile nystagmus impairs the detection of vertically oriented stationary and moving grating patterns more so than horizontal ones. The increased contrast sensitivity and pattern detection thresholds are secondary to the oscillation itself and

Early theories regarding the cause of infantile nystagmus focused on the notion that the oscillation must result from an inherent abnormality in one of the ocular stabilization systems (i.e., smooth pursuit system, optokinetic system, VOR, or fixation system). Over the last two decades, however, the accumulated clinical and eye movement evidence has refuted these hypotheses. Attempts to attribute the oscillation to a neuronal misdirection as seen in albinism or achiasma298 provide insight into the specific mechanism by which chiasmal misrouting may precipitate infantile nystagmus, but do not explain the wide variety of other visual disorders associated with infantile nystagmus. Harris and Berry261 have resurrected the century-old theory of Swanzy522 that infantile nystagmus results from a failure of sensorimotor integration in infancy and beautifully elaborated it in modern neurobiological terms. The first few months of life are a period of rapid visual development in which motor development can be influenced by postnatal visual experience.261 This plasticity may be under active genetic control that can itself be influenced by visual experience.384 Abnormal postnatal visual experience may induce an adaptive oculomotor response that leads to nystagmus during a critical period of heightened plasticity.261,262 Contrast sensitivity to low spatial frequencies is enhanced by motion of the image across the retina. Harris and Berry have proposed that the best compromise between moving the image and maintaining the image near the fovea (or its remnant) is to oscillate the eyes with jerk nystagmus with increasing velocity waveforms, as seen empirically.261,262 The result may be a developmental “funnel,” in which loss of high spatial frequency information (whether caused by foveal, optic nerve, or optical aberrations) could lead to oscillatory strategies to maximize low-frequency information.261,262 VEP testing in children with idiopathic infantile nystagmus shows decreased responses relative to normals, suggesting that a delay in the development of high spatial frequency contrast could indeed precipitate infantile nystagmus.571a This perspective views infantile nystagmus not as a defect but as a maladaptation in which the developing visual system has the potential to develop many different adaptive control systems. According to Harris and Berry, “evolution would need to tread a fine line by programming the development of ocular motor control in tandem with foveal maturation to maximize visual contrast without causing nystagmus.”212 This developmental theory is supported by the finding that patients with idiopathic infantile nystagmus do not have any known

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“lesions,” only miscalibrated motor control systems. However, it hinges on a perturbation in the developing visual system and does not explain the occasional finding of hereditary and spontaneous infantile nystagmus documented at birth, long before any problems with the visual system could have precipitated an oscillation. Barriero et al have presented a mathematical model in which infantile nystagmus can be derived from an abnormal neural integrator network tuned by adaptive cerebellar neurons.50a However, too much positive feedback around a leaky neural integrator would cause acceleration in a centrifugal direction, while in infantile nystagmus, the slow phases drift centripetally toward the neutral region. This neural integrator model would also produce a nystagmus that is dependent on the saccade that preceded nystagmus, which does not happen in infantile nystagmus. Dell’Osso et al have concluded that infantile nystagmus conforms to an increase in the oscillation of the normally functioning pursuit system.163,277,302 Indeed, some infants display a transient nystagmus that disappears as the visual system matures during the postnatal period.225 Nystagmus may be associated with visual system deficits or be present with no visual system deficits. In the former situation, the visual system deficits precipitate one or more ocular motor system instabilities that cause it. In the latter situation, a number of genetic mutations may facilitate the instability.250,371,445,484,489 A number of genetic mutations may also facilitate this oscillation. There are at least three distinct loci for autosomal dominant infantile nystagmus.491 In practice, pedigrees that include male-to-male transmission (and are therefore not X-linked) are much rarer than apparent X-linked pedigrees. For example, the FRMD7 mutation, which is associated with X-linked infantile nystagmus, is expressed in the ventricular layer of the forebrain, midbrain, cerebellar primordium, spinal cord, and developing neural retina.526,532 This protein is homologous to another protein that is known to alter the neurite length and degree of branching of neurons as they develop in the midbrain, cerebellum, and retina, which could provide a motor and combined visual and motor underpinning for the occurrence of infantile nystagmus.526 Leigh and Khanna364 recently raised the possibility that infantile nystagmus could result from a congenital channelopathy, which causes similar hereditary acquired forms of nystagmus such as episodic ataxia type 2. Harris and Berry proposed the infantile nystagmus may develop as a developmental response to reduced contrast sensitivity to high-spatial frequencies in an early critical period.261,262 Because contrast sensitivity to low spatial frequencies is enhanced by motion of the image across the retina, they propose that the jerk nystagmus with increasing velocity waveforms may provide the best com-

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promise between moving the image and maintaining the image near the fovea (or its remnant). As succinctly stated by Kommerell, “The pathogenesis of infantile nystagmus is still an unresolved riddle.”341

Visual Disorders Precipitating Infantile Nystagmus Albinism Albinism is an evolutionary maladaptation424 that is ubiquitous in mammalian vertebrates. It is likely that the myriad mutations that underlie this complex phenotype may confer some nonvisual evolutionary advantage, at least in the heterozygote. Part of our fascination with this disorder lies in its atavistic effects on the developing visual system, causing the frontal-eyed animal to exhibit the same predominance of crossed axons as is normally found in lateral-eyed afoveate animals. The other part lies in the complex interrelationship between the pigmentary abnormalities, structural derangements, and neurologic rerouting that together characterize the albinotic visual system.245 Despite these problems, the great majority of children with albinism are intellectually bright and neurodevelopmentally normal. The preponderance of evidence suggests that hypopigmentation within the retinal pigment epithelium disrupts retinal maturation183,311,569 and causes the associated chiasmal misdirection.101,299,300,377,378,458 Because the position of the vertical retinal meridian is determined primarily by the decussation of ganglion cells at the chiasm and retrograde influence may also determine the position at which the fovea develops,425 it has also been argued that chiasmal misrouting could secondarily interfere with foveal development later in gestation.505,545 While it is likely that all of the clinical findings in albinism are dictated to various degrees by genetic determinants that simultaneously affect pigmentation and axonal migration, van Genderen et al545 documented crossed VEP asymmetry in three darkly pigmented patients with foveal hypoplasia. Albinism is not a single entity; it encompasses a heterogenous group of congenital hypomelanotic disorders.7,334 These disorders can be divided into three general categories of regional hypopigmentation involving neuroectoderm (ocular albinism), neural crest (albinoidism), or both (oculocutaneous albinism).288 In ocular albinism, there is hypopigmentation of ocular neuroectoderm (iris and retinal pigment epithelium) that manifests clinically with iris transillumination, macular hypoplasia, chorioretinal hypopigmentation, photophobia, and nystagmus. The

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term albinoidism is applied to a condition in which hypopigmentation is limited to tissues of neural crest origin (skin, hair, and iris stroma). Unlike patients with ocular albinism, those with albinoidism do not manifest macular hypoplasia, nystagmus, photophobia, or decreased vision.288 In oculocutaneous albinism, there is diffuse hypopigmentation involving tissue of neuroectodermal and neural crest origin. Considerable clinical heterogeneity occurs in human albinism, as evidenced by the multiple forms of oculocutaneous and ocular albinism that have been defined at the molecular level.7 Molecular mechanisms underlying many different types of albinism have been elucidated.97 The normal process of melanogenesis involves conversion of the amino acid tyrosine into melanin by the action of the enzyme tyrosinase.7,334 In albinism, there appears to be an intracellular block of this metabolic pathway. Pigmentary dilution in oculocutaneous albinism is due to inadequate melanization of a normal number of melanosomes,7 while in ocular albinism, it is due to an abnormally low number of mature ocular melanosomes.434 In 2008, Eiberg et al at the University of Copenhagen found the genetic mutation common to all blue-eyed people to be a single letter change, from A to G, on the long arm of chromosome 15, which reduces the expression of the OCA2 gene that is involved in the manufacture of pigment that darkens the eyes.187 Oculocutaneous albinism also results from mutations in OCA 1-4.187 Eiberg calculated that this mutation occurred only 6,000–10,000 years ago, in an individual near the Black Sea.187 As people in northern climates become more dependent on grain as a food source, which is deficient in vitamin D, it has been hypothesized that the paler skin associated with this trait may admit more sunlight for the synthesis of vitamin D, and thereby enhanced survival.469 Alternatively, it may have enhanced sexual selection if blue eyed descendents happened to be more attractive to the opposite sex in that geographic region.469 An interesting question that arises is whether melanopsin, the nonvisual photoreceptor that is localized to retinal ganglion cells and plays a predominant role in circadian phototransduction, can be normally synthesized in these disorders. Experimental evidence suggests that it continues to be synthesized in albino rats.258 As aberrant circadian rhythms have long ago been noted in some patients with albinism,438 this problem clearly merits further study. Although some children with albinism show delayed visual development (see Chap. 1), they show surprisingly normal neurodevelopment without significant problems with motor coordination, balance, or ambulation.354 A number of inherited diseases with nystagmus show a combination of immunological and pigmentation defects. Chediak-Higashi, Hermansky-Pudlak, Griscelli, and paroxysmal autonomic instability with dystonia syndromes are all autosomal diseases with these characteristics. The

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molecular links between immunodeficiencies and albinism reflect the fact that both melanosomes and secretory lysosomes are not secreted normally.242 Key proteins such as Rab27a are critical for secretion of specialized “secretory granules,” which are modified lysosomes. These secretory lysosomes use specialized mechanisms of secretion not found in other cell types. Chediak-Higashi syndrome, a disease characterized by repeated infections and albinism, shows the presence of abnormally large lysosomes and melanosomes, suggesting that melanosomes are not secreted normally and supporting a functional link with the secretory lysosomes of hematopoietic cells. These disorders share a defect in the molecular mechanisms controlling sorting to a novel lysosomal compartment that acts as a secretory organelle in a number of hemopoietic cell types and melanocytes.242 In the Vici syndrome, albinism, immunodeficiency, cataracts, and cardiomyopathy are associated with agenesis of the corpus callosum.102a Individuals with mild ocular or oculocutaneous albinism are often misdiagnosed as having idiopathic infantile nystagmus.503 Periodic alternating nystagmus is said to be particularly common in albinism.7,252,349 Abadi and Pascal7 reported periodic alternating nystagmus in over 30% of their patients with albinism. Infants with albinism may also rarely display a seesaw nystagmus that later reverts to horizontal nystagmus.297 The finding of subtle signs of ocular hypopigmentation in some infantile nystagmus patients with good vision once led to speculation that patients with idiopathic infantile nystagmus may actually be heterozygous for albinism. Simon et al503 have found that when patients with infantile nystagmus are carefully examined, many show iris transillumination, blunting of the macular reflex, and chorioretinal hypopigmentation consistent with albinism. In evaluating the infantile nystagmus patient, it is critical to carefully perform a slit lamp examination with the room lights turned off, the door closed, and a retro-illumination through a thin, axial light beam to detect basal iris transillumination. Varying degrees of macular hypoplasia (absence of the foveal pit, macula lutea pigment, and normal macular pigment epithelial hyperpigmentation and the passage of retinal vessels through the fovea), together with other signs of ocular hypopigmentation, suggest the diagnosis of albinism. Moreover, isolated foveal hypoplasia may also occur as a hereditary condition in children with normal pigmentation.437 This finding should be sought in all children who seem to have idiopathic infantile nystagmus. Multifocal ERG, which shows a uniform cone response across the macular area in patients with albinism, may provide a more definitive way to confirm the presence of foveal hypoplasia in patients with infantile nystagmus.325 Other valuable clinical signs of albinism are often overlooked. For example, patients with albinism have a positive angle kappa that is usually absent in patients with idiopathic

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Fig. 8.5 Child with albinism showing positive angle kappa bilaterally. Use with permission, from Brodsky MC et al84

Fig. 8.6 Distribution of optic axons from nasal and temporal retina in left eye (viewed from above) in albinism. In ocularly pigmented humans, nasotemporal border corresponds with fovea. In albinism, nasotemporal border is shifted approximately 20 degrees into temporal retina, resulting in majority of retinal ganglion fibers crossing at optic chiasm. Adapted, with permission, from Brodsky MC et al78

infantile nystagmus (Fig. 8.5). This positive angle kappa can simulate exotropia on Krimsky testing, while alternate cover testing shows the absence of a manifest exodeviation.84,388 This clinical sign presumably reflects the temporal displacement of the zone of transition between crossed and uncrossed retinogeniculate axons. In Siamese cats (which are homozygous for an allele of the albino gene), the nasotemporal transition is located 1.7–3.0 mm temporal to the area centralis. Because there is minimal foveal development in albinism, this altered nasotemporal junction may reposition the fixation point temporally to prevent any gap in the continuous representation of visual space. A temporal displacement of the fixation point for each retina corresponds to the observed nasal displacement of the corneal light reflex. Unfortunately, this temporal displacement of the fixation point has not been factored into the interpretation of visual field testing, hemispheric VEP testing, or functional magnetic resonance (MR) testing in patients with albinism.75 Schatz and Pollock480 have identified a characteristic optic disc appearance in albinos consisting of a small, cupless disc, with temporal entrance and situs inversus of the vessels and an oblique long axis of the disc (Fig. 2.33). The major retinal vessels also traverse the central retina abnormally close to the position where the fovea is normally located. We have observed that most infants with albinism also have gray optic discs and that the gray cast often disappears over the first few years of life.77 The temporal entrance of the retinal vessels and the mild optic nerve hypoplasia that is evident both clinically and on MR imaging483 probably corresponds to the relative absence of the papillomacular nerve fiber bundle associated with macular hypoplasia. The visual and auditory pathways in albinos have anomalous neuroanatomical connections that are similar in all types of animals studied.7 Initially, the loss of a nonpigmentary function of tyrosinase was considered responsible for these

neural defects, but work by Silver and Sapiro and Strongin and Guillery has implicated the presence of melanin and the stage-specific lysis of melanosomes at the distal end of the developing optic stalk close to the optic disc as being vital for normal retinofugal axonal migration.30,502,520 In humans and animals with albinism, the extent of chiasmal misrouting is inversely proportional to pigmentation level.552 Neuroanatomical and electrophysiological studies of albino visual pathways have demonstrated that retinogeniculate axons arising from ganglion cells in the portion of the temporal retina within 20 degrees of the vertical meridian decussate abnormally in the optic chiasm to synapse in the contralateral lateral geniculate nucleus (Fig. 8.6).118,119,121,246–248,496 Although hemispheric VEPs probably provide the most sensitive and specific means by which to establish the diagnosis of albinism, an absence of asymmetry is occasionally seen in patients with otherwise clear clinical signs of albinism. MR imaging of the anterior visual pathways shows smaller optic nerves, chiasm, and tracts, with a wider angle between the two optic nerves and the two optic tracts.483 New molecular findings in the albino retina underscore the hypothesis that zinc finger transcription factor, Zic2, determines the uncrossed retinal projection.458 Zic2 is a vertebrate homolog of the Drosophila gene odd-paired that is expressed in retinal ganglion cells with an uncrossed trajectory during the period when this subpopulation grows from the ventrotemporal retina toward the optic chiasm. Zic2 controls downstream events that may direct the avoidance of chiasm midline cells by retinal ganglion cells with an uncrossed trajectory. Zic2 may be necessary and sufficient to regulate retinal ganglion cell axon repulsion by cues at the optic chiasm midline. Zic2 expression reflects the extent of binocularity in different species, suggesting that it serves as an evolutionarily conserved determinant of retinal ganglion cells that project ipsilaterally.

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Albino mice display a reduction in the number of uncrossed fibers and a concomitant reduction in Zic2-expressing cells. This reduction might arise because the tempo of retinal neurogenesis is accelerated in the albino. A slight alteration in the numbers of cells born on each day of retinal neurogenesis could bias the production of retinal ganglion cells in favor of one population or the other by affecting postmitotic expression of Zic2.458 Although mammals and amphibians use different strategies to establish binocular vision during their lifetime, the fact that Zic2 expression correlates with the degree of binocularity suggests a conserved function for Zic2 in modulating the uncrossed retinal ganglion cell axon projection.275 Other ocular and systemic hypopigmentation disorders should be considered in the differential diagnosis of albinism. Creel et al120 have reported asymmetrical hemispheric VEPs in patients with Prader–Willi syndrome (a condition characterized by hypotonia, hypomentia, hypogonadism, and hyperphagia).120 Albinism is seen in approximately 1% of patients with Prader– Willi syndrome.361 In contradistinction, Apkarian et al32 found no evidence of hemispheric VEP asymmetry in Prader–Willi syndrome but noted lateralization of the VEP response to the right or left hemisphere regardless of which eye was stimulated in half of their Prader–Willi patients. Because both studies were carried out by highly experienced investigators, the discrepancy in findings may merely reflect the greater degree of albinism in the small group of patients tested by Creel et al.120 Patients with oculocutaneous albinism, ocular albinism, Prader–Willi syndrome, and Angelman’s syndrome have mutations of the P gene, which has been mapped to 15 q11q13.361 The P gene codes for a polypeptide that appears to be an integral membrane protein with structural homology to transporters of amino acids, and it has been speculated that this gene might transport tyrosine (the precursor of melanin).361 Interestingly, Prader–Willi syndrome is associated with deletions of the paternally inherited P gene, whereas Angelman’s syndrome (the “happy puppet syndrome”), which has an entirely different phenotype, is associated with deletions of the maternally inherited P gene.429 Differential expression of genetic material depending on the sex of the transmitting parent is referred to as genomic imprinting. Åland eye disease (Forsius–Eriksson syndrome) is a form of ocular hypopigmentation associated with ERG findings of CSNB.216 It is no longer classified as a form of ocular albinism, and patients with this disorder do not manifest hemispheric VEP asymmetry. Waardenburg reexamined the original Finnish family with this disorder and found the multiple areas of focal fundus depigmentation in Åland eye disease to differ from the diffuse hypopigmentation of albinism.216,561 Other ocular and systemic hypopigmentation disorders such as Waardenburg’s syndrome and phenylketonuria also lack the hemispheric VEP asymmetry seen in albinism.349 The finding of asymmetrical hemispheric VEPs in human albinos provides an electrophysiological correlate to the

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neuroanatomical finding of abnormal decussation in animals. For example, a light or pattern stimulus to the albino’s right eye would produce a signal of larger amplitude over the left occipital cortex than the right, due to the preponderance of crossing optic axons in albinos (Fig. 8.7). Although considerable interindividual variability exists,292 the extent of chiasmal misrouting seems to be inversely proportional to the pigmentation levels.552 Functional MR imaging during monocular stimulation has also demonstrated the presence of abnormal decussation,271,291,408 as has magnetoencephalography.359 While the great majority of children with albinism show crossed hemispheric asymmetry, rare children with otherwise classic albinism show normal hemispheric symmetry on VEP testing.69,510

Fig. 8.7 Hemispheric VEP asymmetry to pattern onset responses in adult albino (top), and absence of hemispheric VEP asymmetry in adult with idiopathic infantile nystagmus (bottom). Five traces for each patient are derived from electrodes positioned from left (trace 1) to right occiput (trace 5). Bottom trace is obtained by subtracting trace 4 (right) from trace 2 (left). Contralateral asymmetry in upper figure is shown by polarity reversal of difference potentials (arrows) and by crossover of CI component measured at time instant indicated and plotted as function of electrode for OD and OS. VEP topography for patient with infantile nystagmus shows slight interocular amplitude difference and midline response attenuation. Adapted, with permission, from Apkarian et al34

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The finding of chiasmal misrouting in albinism initially led to early speculation that patients with idiopathic infantile nystagmus may too have afferent visual pathway miswiring as the neuroanatomical substrate for their nystagmus.383 However, most studies have found no electrophysiological evidence of afferent visual pathway misrouting in idiopathic infantile nystagmus.34,249 Furthermore, the absence of hemispheric VEP asymmetry in patients with aniridia and macular hypoplasia further suggests that it is the ocular hypopigmentation rather than the associated macular hypoplasia in albinism that alters the trajectory of retinogeniculate axons.349 Shatz496 has performed neuroanatomical studies in albino (Siamese) cats and found an altered visual cortical topography and abnormal interhemispheric connections via the splenium of the corpus callosum. Although albino cats demonstrated different targets for their visual callosal connections, the organization of fibers was similar to that seen in normally pigmented cats. Apkarian and Reits have demonstrated that, despite the paucity of binocularly driven cortical neurons in areas 17, 18, and 19 of the albino visual cortex, many patients with albinism retain global stereopsis.31 Humans with albinism show a regionally specific decrease in gray matter in the occipital poles on MR imaging, corresponding to the cortical representation of the central visual field.551 This reduction is presumed to be a direct result of decreased ganglion cell numbers in the central retina in albinism. Although it has been suggested that nystagmus in albinism is the direct result of retinogeniculate and/or subcortical visual pathway misrouting, occasional patients with albinism and asymmetrical hemispheric VEPs show no nystagmus.34 Furthermore, the nystagmus waveform is identical in idiopathic infantile nystagmus (in which there is no afferent visual pathway rerouting) and albinism, suggesting that the decreased vision associated with macular hypoplasia interferes with ocular motor calibration in the same way as other congenital or early infantile sensory system deficits to produce an anomalous recalibration that is primarily responsible for infantile nystagmus in albinism.34 Apkarian35 has suggested a testing paradigm for full-field monocular stimulation in the testing of hemispheric VEPs consisting of a luminance flash stimulus in children younger than 3 years old, both luminance flash and pattern onset for children 3–6 years old, and a pattern-onset stimulus in older patients. Pattern reversal VEP waveforms are not generally used to test for hemispheric VEPs because it has been shown that pattern reversal stimulation produces small VEPs in albinos compared with pattern-onset stimulation.349,350 Confirmation of hemispheric VEPs in neonates can be obtained using special testing methods.33 In addition to retinogeniculate, cortical, and intracortical neural misrouting, albino animals have also been found to have misrouting of their subcortical visual pathways, which are intimately involved in optokinetic responses. This find-

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ing has led some to attribute the ocular instability in the albino rabbit to an abnormality in the opticokinetic pursuit system.582 In the rabbit, retinal error signals reach the inferior olivary nucleus through the accessory optic tract, independent of geniculocortical projections.524 The nucleus of the optic tract plays an important role in mediating the opticokinetic response in rabbits. In the normal animal, opticokinetic mechanisms act as a negative feedback system using retinal motion as input. If the visual world (e.g., an optokinetic drum) is rotated about the animal, a smooth ocular rotation is reflexively elicited in the direction of drum rotation by the movement of the image of the visual world across the retina.582 This negative feedback system normally acts to stabilize the eye with respect to the visual surroundings. If the “sign” of the signal flowing through the optokinetic system were to be inverted, there would be a positive feedback system that would then destabilize the eyes with respect to the visual surroundings (once the eye moves, it continues to move).252,582 Such is the case in the albino rabbit, in which anomalous retinal innervation inverts the directional selectivity of those cells in the nucleus of the optic tract that have receptive fields in the temporal retina.582 The notion that misrouting of the accessory optic tract through the inferior olive is the cause of nystagmus in albino rabbits109,252,374,375 once led to the inference that it may also cause infantile nystagmus in humans.441 However, the frequent finding of infantile nystagmus in normally pigmented individuals with no misrouting (who constitute the great majority of individuals with infantile nystagmus) makes it difficult to invoke a unique mechanism for the identical nystagmus in children with albinism.159 Boylan and Harding70 have argued that infantile nystagmus in albinos is likely attributable to poor central fixation due to lack of foveal differentiation but that afferent visual pathway miswiring might be related to the high prevalence of strabismus in children with albinism. Despite foveal hypoplasia, spectacle or contact lens correction should be encouraged in children with albinism, because improved visual acuity and ocular alignment and reduction of abnormal head positions are among the recognized benefits.24 Children with albinism may similarly appreciate improved vision from infantile nystagmus surgery and from eye muscle surgery to treat secondary torticollis.

Achiasmia Achiasmia is a rare condition that has been reported in several unrelated families after its initial discovery in a family of Belgian sheepdogs.162,528 In isolated achiasmia, the midchiasmal bar is absent, while the intracranial optic nerves and optic tracts remain normal in size (Fig. 8.8). These cases show no evidence of additional midline central nervous

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Fig. 8.8 MR imaging of human achiasmia showing isolated absence of the optic chiasm. Courtesy of Richard Hertle, M.D.

system (CNS) abnormalities, migrational anomalies, spaceoccupying lesions, or destructive processes noted on MR imaging.62 Belgian sheep dogs with isolated achiasmia have a combination of infantile nystagmus and seesaw nystagmus.29,36,38,136,140,164,165,171,172,579,580 Absence of the human chiasm was first documented by Apkarian et al, who applied the term “Non-decussating retinal-fugal fibre syndrome.”36,37 In these patients, the entire optic nerve projects to the ipsilateral visual cortex so that the visual acuity remains normal,367,533,549 the visual fields remain full, and the optic discs appear normal, but affected patients have no stereoacuity.36,37 Early onset seesaw nystagmus is a frequent feature.39,165,345,367,442 Using three-dimensional eye movement recordings, Dell’Osso et al169 found that, even in the absence of achiasmia, a subclinical seesaw nystagmus can usually be detected in patients with idiopathic infantile nystagmus. Functional MRI analysis under monocular viewing conditions has indicated extensive bilateral activation of

striate and prestriate areas, suggesting efficient transfer of information between hemispheres.549 The polarity of the VEP distribution across the occiput is the reverse of the crossed asymmetry that has been described in albinism.29,36 Partial or complicated achiasmia may also accompany more complex malformation syndromes such as septo-optic dysplasia, midfacial defects, and basal encephaloceles.367 Unlike in isolated achiasmia, however, associated optic disc malformations and bitemporal hemianopia are usually present. Achiasmatic zebrafish display a reversed optokinetic response that correlates with failure of the retinal ganglion cells to cross the midline and form the optic chiasm.533 Huang et al298 have hypothesized that, in the achiasmatic condition, the signal from the eye always feeds into the wrong hemisphere, leading to a nasal-temporal reversed perception. They postulated that the resulting positive feedback loop is incapable of stabilizing the visual system, causing the nystagmus, and that the attempt to compensate for the retinal slip takes the

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wrong direction, thereby increasing the retinal slip. However, there is no evidence that humans with achiasmia perceive horizontal movement as reversed. Indeed, the fact that the recorded waveforms in achiasmia and albinism are indistinguishable makes it unlikely that different mechanisms are responsible for infantile nystagmus in the two populations.

Isolated Foveal Hypoplasia Rarely, isolated foveal hypoplasia causes infantile nystagmus.437 Affected patients have no other signs of albinism and no chiasmal misrouting. This condition should be considered in the patient who appears to have infantile nystagmus and a negative family history. Optical coherence tomography and multifocal ERG are useful in confirming the diagnosis.465 Mutations in the PAX6 homeobox gene have been identified in this condition.43,44

Congenital Retinal Dystrophies Cone and Cone-Rod Dystrophies The cone dystrophies are characterized by bilateral visual loss, color vision abnormalities, central scotomata, and variable degrees of nystagmus and photophobia, together with electrophysiologic or psychophysical evidence of abnormal cone function. There is considerable clinical and genetic heterogeneity, with autosomal-dominant, autosomalrecessive, and X-linked variants all having been reported.392 To date, seven genes for autosomal recessive and one for autosomal dominant forms of cone and cone-rod dystrophy have been identified, along with two x-linked genes.339a They may be stationary or progressive, with most congenital subtypes stationary and displaying normal rod function. Birgit Lorenz has observed that achromats squint to get into the mesopic range. Unlike patients with retinitis pigmentosa, it is easy to examine the retina with indirect ophthalmoscopy and to obtain retinal photographs once the rods are bleached with light (personal communication). The progressive subtypes have their onset in childhood or early adulthood and develop additional variable rod dysfunction later in life.392

Achromatopsia Achromatopsia is an autosomal recessive condition characterized by decreased visual acuity, absent color vision, photophobia, and nystagmus. Although histopathological studies have demonstrated conelike structures in the retina,190,217,263

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psychophysical studies have shown the complete achromat to have no functional cone vision.495 Parents of a child with this condition typically give a history that the child shuns daylight and “comes to life when the twilight falls.” The photophobia in children with achromatopsia may more accurately be designated as a light aversion (photodysphoria), because the children become debilitated when light bleaches their rods. Under normal circumstances, the cones feedback on the rods and damp them down; but in achromatopsia, the rods work over a larger dynamic range. Although children with this condition are unable to distinguish colors, many can identify basic colors on the basis of hue discrimination. Children with achromatopsia usually demonstrate a paradoxical pupillary phenomenon.203 These paradoxical pupillary constrictions are neither age nor gender related and are not accompanied by accommodative or convergence changes.436 The terms incomplete or atypical achromatopsia (formerly applied to blue cone monochromatism) are best reserved for individuals with autosomal recessive disease in which the phenotype is a variant of complete achromatopsia. Individuals with incomplete achromatopsia retain residual color vision and have slightly better visual acuity (20/80 to 20/200) than those with complete achromatopsia.392 Incomplete achromats are thought to benefit more from reddish brown lenses than from deep red lenses, which tend to eliminate residual color discrimination owing to their narrow spectral transmission.253,392 Yee et al593 studied eye movement recordings in patients with achromatopsia and found a lower-amplitude, higher-frequency nystagmus than seen in infantile nystagmus. Monocular optokinetic stimulation in achromats demonstrates marked directional asymmetry characterized by a higher gain during rotation of the drum in the temporal-nasal direction of the visual field than during the same rotation in the nasal-temporal direction.46,593 Similar directional asymmetry is seen in afoveate animals. Additionally, achromats and afoveate animals also demonstrate a slow buildup of slow-phase optokinetic velocity during monocular optokinetic stimulation that is not seen in humans with infantile nystagmus.46,593 Gottlob and Reinecke228 observed that patients with achromatopsia and blue cone monochromatism have a distinct form of nystagmus characterized by an oblique trajectory in younger patients, decreasing-velocity slow phases, oscillations of equal frequency that may be in phase or out of phase but retain equal frequencies and head nodding. This constellation of findings may mimic spasmus nutans. The diagnosis of achromatopsia is established by ERG that shows normal rod function with absent cone function (absent flicker response). The dark adaptation curve is monophasic; achromats have no Purkinje shift, and spectral sensitivity studies show that rods mediate thresholds under both photopic and scotopic conditions.433,495 In older children, the Sloan Achromatopsia test utilizes the superior ability of achromats

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over normals to match central hues with surrounding shades of gray on the basis of brightness.421,433 The retinal appearance remains normal in most cases and cone-like structures have been identified histologically in the photoreceptor layer.190,264 OCT usually shows a normal thickness of the foveal nerve fiber layer, but some cases have missing outer segments in the center of the retina. Achromatopsia is recessively inherited and genetically heterogeneous. The three genes associated with achromatopsia (CNGA3, CNGB3, and GNAT2) encode proteins in the cone phototransduction cascade.338,339 CNGA3, on region 2q11, encodes the a subunit of the cGMP gated (CNG) cation channel in human cone photoreceptors, the final critical effector in the phototransduction cascade. CNGB3, on region 8q21-q22, encodes for the b subunit of cone photoreceptor CNG cation channels. GNAT, on region 1p13, codes for the a subunit of cone specific transducin. CNGA3 and CNGB3 mutations seem to be responsible for most cases.585, 531a Some cases of incomplete achromatopsia can have residual function of C, M, or S cones. There are no discernable phenotypic differences between the genotypes.173,547 The finding of rough brown teeth in the child with apparent achromatopsia is a signature of amelogenesis imperfecta.182,305,393 Glasses or contact lenses with a deep, round tint is most effective, allowing wavelengths of low luminous efficiency for rod photoreceptors to be transmitted to the retina, while those of a higher luminous efficiency (short wavelength light) are absorbed by the filter.315,392 Although associated systemic findings are usually absent, a child with congenital achromatopsia with short stature, mild developmental delay, premature puberty, small hands and feet, minimal dysmorphism, and unilateral parental isodisomy of chromosome 14 has been described.446 In achromatopsia, cone photoreceptors are probably present but lack the full complement of protein necessary for phototransduction, making this condition potentially responsive to gene therapy (as has been demonstrated in mice and dogs). Therapeutic intervention may hold promise as subretinal gene therapy in mice has produced striking visual improvement in the GNAT2 form of achromatopsia by restoring the visual transduction cascade.266

Blue Cone Monochromatism Blue cone monochromatism is a partial form of achromatopsia in which the blue cone mechanism predominates. The diagnosis is suggested by the presence of X-linked inheritance and high myopia in a child with achromatopsia.571 In 1957, Blackwell and Blackwell65 first described this disorder in three brothers with congenital achromatopsia who had the residual ability to discriminate blue and yellow objects. Lewis et al368 have defined two classes of mutations localized to the long arm of the X chromosome (Xq28) that are responsible

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for blue cone monochromatism.368,417 These defects involve one or more regions of the contiguous red and green cone pigment genes on the terminal end of the long arm of the X-chromosome, causing affected individuals to have minimal functional red or green cone pigments.417,418 Blue cone pigments, which are coded on chromosome 7, are unaffected. Magenta tints, which prevent rod saturation while allowing transmission of blue light, are indicated in blue cone monochromatism.253,392 Whereas the L (red) and M (green) pigment genes are located on the X chromosome, the S cone (blue) pigment is located on chromosome 7. Mutations in the L and M pigment gene array that result in the lack of functional L and M pigments, and thus inactivate the corresponding cones have been identified in most cases of blue cone monochromatism.417,418 Clinically, patients with blue cone monochromatism present with infantile nystagmus although nystagmus is occasionally absent. Gottlob and Reinecke228 believe that individuals with blue cone monochromatism and achromatopsia share an electro-oculographically distinct form of nystagmus (see achromatopsia). The finding of a fine-amplitude, upbeat, jerk-type nystagmus in carrier females with normal visual acuity raises the possibility that the nystagmus may be caused independently by the mutation in the absence of an underlying visual deficit.229 Gottlob229 found abnormal eye movements in carriers of blue cone monochromatism, suggesting that the nystagmus is intrinsic to the disease and independent of the visual defect. Some patients have tilted optic discs. Unlike in achromatopsia, in which visual acuity is usually no better than 20/200, children with blue cone monochromatism (and other less-common forms of incomplete achromatopsia) often have acuities better than 20/200, indicating residual cone function.571 Affected patients show a preferential ability to identify blue-yellow color plates. Farnsworth Panel D-15 tests show consistent errors directed along the protan and deutan axis but not the tritan axis, in contrast to the random pattern of errors seen in complete achromatopsia.571 Unlike achromats, blue cone monochromats and their carriers do not show paradoxical pupillary defects.436 The long-term visual prognosis of blue cone monochromatism is paradoxically worse than that of complete achromatopsia as teenagers and adults develop a progressive atrophic maculopathy that secondarily reduces central acuity.200,418 ERG is useful in establishing the diagnosis of achromatopsia (minimal photopic response with preservation of scotopic response), but it does not separate out the blue cone response unless special techniques are used. Spectral sensitivity testing shows maximum sensitivity near 440 nm in the blue region, dropping rapidly at longer wavelengths.571 The basis of the better acuities in children with blue cone monochromatism compared with those with complete achromatopsia is difficult to explain because psychophysical data suggests that the center of the normal fovea is tritanopic.265 It is

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possible that functioning blue cones in the parafoveal region account for the slightly improved acuity. Some have suggested that the improved acuity results not from residual blue cone function but from retention of a lesser degree of additional residual red and green cone function,571 because some blue cone monochromats have residual sensitivity to longer wavelengths,508 as evidenced clinically by their ability to correctly identify some red–green color plates. The observed genetic heterogeneity in blue cone monochromatism could account for this observation.418 Recent advances in functional brain imaging have allowed insights into the large-scale reorganization of the visual pathway that occurs in rod monochromatism. A large-scale developmental reorganization of the visual pathway was shown in rod monochromats who lack cone photoreceptor function. In rod monochromats, the cortical region that normally responds to cones during functional MR imaging activation responded powerfully to rod-initiated signals.51,232

Leber Congenital Amaurosis Leber congenital amaurosis is usually an autosomal recessive retinal dystrophy characterized by congenital blindness, nystagmus, sluggish pupillary responses to light, and minimal retinal abnormalities in infancy. As detailed in Chap. 1, numerous different genes have been identified that cause Leber congenital amaurosis.536 Some mutations produce cone-rod dystrophies while others produce rod-cone dystrophies. Affected patients may manifest roving eye movements or a large-amplitude, low-frequency nystagmus (in keeping with the low visual acuity).307 Less commonly, the nystagmus may be upbeating, in which case it may be asymmetrical.222 Pupillary responses are absent or sluggish. These infants characteristically demonstrate the “oculodigital” sign in which the thumbs or fists are habitually used to apply pressure to the closed eyes. Facial features of Leber congenital amaurosis may include enophthalmos (possibly from chronic eye rubbing) and maxillary hypoplasia. Unlike other congenital retinal dystrophies characterized by myopia, high hyperopia is seen in about half of patients with Leber congenital amaurosis. The diagnosis is established by a nonrecordable or highly attenuated ERG. Over time, retinal pigmentary abnormalities become evident and the optic discs become pale. Acquired retinal pigmentary abnormalities can range from a fine pigment granularity to diffuse marbleization of the fundus. Occasionally, infants with Leber congenital amaurosis have bilateral staphylomatous macular lesions. Despite the fact that retinal pigmentary changes are acquired, most patients do not experience progressive visual loss.272 Early studies noted a high incidence of mental retardation and neurological problems in Leber congenital amaurosis. It is likely that these studies included patients with a variety

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of primary neurometabolic and neurodegenerative diseases that would be more readily detected with modern diagnostic techniques. Although the great majority of children with Leber congenital amaurosis appear to be intellectually and neurologically normal, mental retardation, developmental delay, hearing loss, epilepsy, hypotonia, and cerebellar abnormalities are seen in a small subset of patients. Leber congenital amaurosis is usually an autosomal recessive condition that is genetically heterogenous. As discussed in chapter 1, numerous causative mutations have now been identified,

Alström Syndrome The association of tachypnea with nystagmus is well recognized in Joubert syndrome, but can also be a presenting sign of Alström syndrome.130,391,475 Alström syndrome is an autosomal recessive disorder characterized by obesity, sensorineural deafness, and cone-rod dystrophy, all appearing during the first decade of life. Infants can manifest respiratory distress, tachycardia, and hepatomegaly secondary to a dilated cardiomyopathy with left ventricular dilation and decreased myocardial function. Infants that survive the initial episode often show progressive improvement, with little evidence of a long-term deleterious effect in cardiac function. The onset of the cardiomyopathy in infancy suggests that the heart defect may be expressed only during a specific developmental stage and that the minimal but persistent dilation observed on followup is a sequel to the decompensation in infancy, rather than the result of an active process.391 An evaluation of 182 Alström patients by Marshall and colleagues380 led to the identification of additional phenotyping features, including urological, gastrointestinal, pulmonary, and neurobehavioral abnormalities. Although there is overlap with Bardet-Biedl syndrome, there is no polydactyly, mental retardation, or hypogonadism in Alström syndrome.535 The ALMS gene is mutated in Alström syndrome. This gene is ubiquitously expressed, and the encoded protein localizes to centrosomes and ciliary basal bodies.112 However, mutant alleles are associated with age-dependent loss of primary cilia, suggesting that the Alström syndrome phenotype results in impaired cilia function rather than abnormal cilia development.112,174

Rod-Cone Dystrophies Congenital Stationary Night Blindness Congenital Stationary Night Blindness (CSNB) is characterized by night blindness, nystagmus, decreased visual acuity, and a normal retinal examination. Visual acuity can range

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from 20/20 to 20/200. High myopia is common and affected children frequently have paradoxical pupillary responses to light. Pieh et al447 analyzed the nystagmus in 10 patients with CSNB and found a continuous pendular, oblique and mostly dysconjugate nystagmus of high frequency and low amplitude in all patients. In seven patients, a large, mostly intermittent and conjugate horizontal or vertical jerk nystagmus was superimposed. The nystagmus of CSNB was similar to the nystagmus reported in blue cone monochromatism and rod monochromatism.447 Profound fear in darkness can be the presenting symptom.184a Tonic downgaze with a chin-up head posture can be another presenting feature of CSNB.504a CSNB can be inherited in an autosomal dominant, autosomal recessive, or X-linked fashion, with X-linked inheritance being the most common pattern.447 Decreased visual acuity, myopia, and nystagmus are seen in X-linked CSNB and in some patients with autosomal recessive CSNB, but not in autosomal dominant CSNB.288,447 In X-linked CSNB, visual acuity generally ranges from 20/30 to 20/100.421 Congenitally tilted discs and optic disc pallor have been noted in some patients with X-linked CSNB.270,287a The diagnosis of CSNB is established by ERG. Most patients with the X-linked and autosomal recessive forms of CSNB have a near-normal a wave and a substantially reduced b wave (referred to as an electronegative ERG) when tested under dark-adapted bright-flash conditions (Schubert– Bornschein type).404,405,474 When the intensity of the test stimulus is increased, the amplitude of the a wave increases while that of the b wave remains unchanged. The photopic b wave may also be reduced together with a characteristic loss of the early components of the oscillatory potentials, leading to a “squared-off” appearance to the photopic ERG a wave.270,575 In pedigrees with autosomal dominant CSNB, the scotopic waveform is electropositive; and there is a reduced but normal photopic response that does not decrease in amplitude under scotopic conditions210 although rare electronegative waveform have been reported267,134,430 CSNB is caused by mutations arising in genes that encode components of the phototransduction cascade or proteins that may be involved in signaling from photoreceptors to adjacent second-order neurons.447 CSNB1 (the complete type) results from mutations in the NYX gene (nyctalopin gene) that is located on the X chromosome.211 These mutations lead to a complete defect of the ON-bipolar cells or their synapses in the rod and cone visual pathways, leaving the OFF pathway intact.54,55 X-linked recessive CSNB2 (the incomplete type) arises from mutations in the calcium channel (CACNA1F) gene, which encodes the retina-specific alpha 1-subunit. Alterations induce severe changes in channel activity, leading to an incomplete defect of the ON and OFF bipolar cells or their synapses in the rod and cone visual pathways.289 Mutations in CABP4, a member of the calciumbinding protein family have also recently been found to lead

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to CSNB2.603 CSNB1 and CSNB2 both show a negative ERG with a decreased b-wave in the scotopic as well as the photopic ERG.410 Rod function is most severely affected in CSNB1 and less impaired in CSNB2.72 The oscillatory potentials of the multifocal photopic ERG show reduction of only the first peak amplitude in CSNB1, whereas in CSNB2, both peak amplitudes are barely discernible from noise, suggesting possible involvement of a postreceptor pathway of cone signal processing.447,486 No histologic abnormality of the retina in CSNB has been identified, and rhodopsin concentration and regeneration, as determined by retinal densitometry, are also normal.470,575 An acquired form of night blindness with electronegative ERGs that are similar but not identical to those in CSNB can be seen as a paraneoplastic effect in patients with cutaneous malignant melanoma. Immunohistochemistry has demonstrated heavy immunostaining of rod bipolar cells in patients with this condition.394 The combination of ocular hypopigmentation and an electronegative ERG may be seen in Forsius–Erickson syndrome (Åland eye disease). Åland eye disease is an X-linked disorder characterized by subnormal visual acuity, myopia, astigmatism, dyschromatopsia, night blindness, nystagmus, hypopigmentation of the iris, and chorioretinal hypopigmentation, foveal hypoplasia, normal skin melanosomes, and an electronegative ERG.449 Alitalo et al22 have localized Åland eye disease to the pericentromeric region of the X chromosome.22,216 Although this condition has been considered a form of ocular albinism, its nosology is open to question because affected patients do not have the hemispheric VEP asymmetry seen in ocular albinism.544 Weleber et al have suggested that Åland eye disease and the incomplete form of CSNB may be the same disease.575 Linkage data from patients with incomplete CSNB support this hypothesis.412 VEP evidence of interhemispheric asymmetry with contralateral dominance (indicating misrouting of optic nerve fibers) has been found in approximately 15% of patients with CSNB.543 About 80% of patients with Duchenne muscular dystrophy have electronegative ERGs that are similar to but distinguishable from those seen in CSNB.105 Most affected patients have point mutations in the dystrophin gene. Unlike in CNSB, patients with muscular dystrophy are not myopic, photophobic, or nyctalopic, either clinically or by dark adaptation studies.132 Visual acuity is generally unaffected, although many patients have increased macular pigmentation.501 Fitzgerald et al197 were the first to localize the abnormal retinal signal transmission in Duchenne muscular dystrophy to the photoreceptor/ depolarizing bipolar cell synapse. Pillers et al have identified an additional subgroup of patients with muscular dystrophy, glycerol kinase deficiency, and adrenal hypoplasia that appears to be attributable to a contiguous gene syndrome that includes the muscular dystrophy gene. They have termed this disorder “Oregon eye disease” and tentatively mapped the deletion to Xp21.449

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Fig. 8.9 Comparison of ERG responses to scotopic blue, scotopic white, and photopic flicker (30/s) stimulation of 3-year-old with Leber congenital amaurosis, 5-year-old boy with X-linked incomplete achromatopsia,

5-year-old boy with X-linked CSNB, and 4-year-old normal control. ERG responses were recorded using corneal electrodes and Ganzfeld stimulator. Adapted, with permission, from Lambert SR et al355

Rarely, the nystagmus associated with CSNB mimics spasmus nutans.356 Lambert and Newman356 have therefore recommended that patients with spasmus nutans who are myopic undergo ERG to rule out CSNB. Figure 8.9 summarizes the electroretinographic features that distinguish the more common congenital retinal dystrophies.

n ystagmus is sensory in nature (resulting from optic nerve hypoplasia), the purpose of neuroimaging is not to delineate the cause of the nystagmus, but rather to search for associated CNS anomalies that commonly coexist with optic nerve hypoplasia. It should be parenthetically noted that congenital suprasellar tumors (e.g., craniopharyngioma, chiasmal glioma) rarely disrupt optic axonal migration during embryogenesis and present with optic nerve hypoplasia, tilting of the optic discs, or other disc anomalies.529 Routine MR imaging of infants with optic nerve hypoplasia insures that this rare association is overlooked. 2. We obtain MR imaging in any infant with infantile nystagmus and optic atrophy to rule out a congenital suprasellar tumor (e.g., chiasmal glioma, craniopharyngioma) or hydrocephalus. In our experience, there are few noncompressive causes of congenital or early infantile optic atrophy (see Chap. 4). 3. We routinely obtain MR imaging in children in whom the diagnosis of infantile nystagmus is uncertain and the possibility of spasmus nutans exists to rule out chiasmal gliomas or other suprasellar tumors. 4. When infantile nystagmus is accompanied by seesaw nystagmus, we obtain neuroimaging to look for achiasmia.281

When to Obtain Neuroimaging Studies in Children with Nystagmus We have emphasized that it is a common mistake to obtain neuroimaging studies in a neurologically normal infant or child with infantile nystagmus because brain tumors and other compressive CNS lesions generally do not cause infantile nystagmus. Nevertheless, there are three clinical situations in which neuroimaging is warranted: 1. In infants with infantile nystagmus and optic nerve hypoplasia, we obtain MR imaging to evaluate the structural status of the pituitary infundibulum, cerebral hemispheres, and midline intracranial structures (septum pellucidum, corpus callosum). Because it is understood that the

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Treatment General advice to parents and teachers Teachers should be instructed to sit the child at the front of the class on the side that allows them to utilize their null zone and to let the child hold reading materials close to his or her face. Parents can be told that, although the nystagmus will persist, children with infantile nystagmus have good vision and do not see the world albinism as moving. In infants with underlying sensory defects (albinism, optic nerve hypoplasia), parents can be told that visual attention may dramatically increase in the sixth month of life. Parents can be assured that the nystagmus improves considerably over the first five years of life and that optical and surgical treatment may improve it further. Medical Treatment Drug therapy for acquired nystagmus has been directed toward augmenting the inhibitory neurotransmitter system (e.g., gamma-amino-butyric acid [GABA]) or inhibiting the excitatory neurotransmitter system (e.g., glutamate).99 Most notably, downbeat nystagmus has been treated successfully with clonazepam (a GABA-ergic inhibitor), and acquired periodic alternating nystagmus has been successfully treated with baclofen (an inhibitor of glutamate release). In many ways, one-time surgical treatment of infantile nystagmus can be considered a more conservative and economically feasible therapy than life-long medical treatment, especially when the long-term side effects of medications have not been established. Until recently, the pharmacological treatment of infantile nystagmus has met with limited success. One study noted objective improvement in visual acuity by one or two lines, together with subjective improvement in four of seven infantile nystagmus patients who were treated with baclofen.594 Another study357 purported improved vision in two infantile nystagmus patients with 5-hydroxytryptophan therapy. Given the well-documented visual improvement obtained by optical and surgical treatment of infantile nystagmus, drug therapy has not been included in the therapeutic armamentarium for infantile nystagmus.99 Recently, gabapentin and memantine have been shown to be effective in the treatment of adults with infantile nystagmus.386,498 Neither medication is currently approved for use in children. Optical Treatment A recent study by Woo and Bedell588 found that children with infantile nystagmus retain some ability to recognize words outside the foveation period. Large size text (i.e., larger than the

level of near acuity would indicate the need for) could therefore serve to improve reading performance by keeping text legible during a larger portion of the infantile nystagmus waveform.588 Correction of significant refractive error in children and adults is the single most powerful therapeutic intervention for improving vision and visual function.279 Sometimes, anomalous head positions are satisfactorily reduced by refractive correction alone.279 The primary optical treatment for infantile nystagmus is glasses. Reinecke467 has stated that fusional convergence damps infantile nystagmus while accommodative convergence does not, so it is advisable to give the full hyperopic refraction. In patients with torticollis, glasses can be prescribed with the optical centers offset to compensate for the eccentric position of gaze. Because infantile nystagmus is damped by physiological convergence, some authors have advocated incorporating base-out prisms into spectacle lenses to increase tonic convergence.389 It is now widely accepted that base-out prisms can be incorporated into spectacle lenses to increase foveation time and to improve vision in infantile nystagmus.155 However, glass prisms are thick and cumbersome, which reduces patient acceptance, especially in children. When prescribing base-out prisms in children, it is usually necessary to incorporate minus-one lenses into the prescription, because the act of converging usually evokes some degree of accommodation. Soft contact lenses offer several advantages over glasses including direct damping of nystagmus, elimination of peripheral aberrations, and clearer vision in null positions. The value of biofeedback in reducing the intensity of infantile nystagmus and improving vision has been demonstrated in several independent studies.6,16,123,390 Several forms of cutaneous stimulation (including acupuncture) are said to reduce infantile nystagmus.153,301 Dell’Osso and coworkers have also demonstrated that infantile nystagmus is markedly reduced simply by placing contact lenses on the eyes,152,477 as well as by cutaneous stimulation in the dermatome supplied by the ophthalmic division of the trigeminal nerve (i.e., tactile or vibrational stimulus applied to the forehead).153 Surgical Treatment Strabismus surgery in the treatment of infantile nystagmus falls into two general categories: surgery to treat torticollis and slow to see and take longer acuity. Surgery to Improve Torticollis For the most part, treatment of infantile nystagmus has consisted of transferring the null position into primary gaze, thereby eliminating the prominent head turn in some patients with infantile nystagmus.347 This is accomplished by performing a horizontal recess-resect procedure on both eyes (Kestenbaum–Andersen procedure), moving all four

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h orizontal rectus muscles to essentially rotate the eyes in the direction of the head turn. The same approaches have been successfully applied to torticollis secondary to acquired nystagmus with oscillopsia.95 For example, a child who assumes a right head turn to maintain the eyes in left gaze is treated with a left lateral rectus recession, left medial rectus resection, right medial rectus recession, and right lateral rectus resection to surgically rotate the eyes conjugately to the right and effectively transfer the null zone to primary gaze. The Kestenbaum–Anderson procedure both moves and broadens the null zone, causing better foveations in a broader

Fig. 8.10 Proposed effects of tenotomy and reattachment on vision in infantile nystagmus. (a) The patient with poor acuity limited to a small region of gaze angles (b) develops better acuity at more gaze angles (a broader NAFX peak curve). Courtesy of Lou Dell’Osso, PhD

8 Nystagmus in Children

range of horizontal gaze.141 It thereby improves visual function even when an improvement in visual acuity cannot be detected (Fig. 8.10). The field of clear vision in infantile nystagmus can be likened to the field of binocular vision in the patient with strabismus. While the purpose of strabismus surgery is often to expand the field of single binocular vision, the goal of all surgery in infantile nystagmus with torticollis should be viewed as both shifting the null point and expanding the field of clear vision. Before planning a Kestenbaum–Anderson procedure, it is important to observe the torticollis at distance and near to

Infantile Nystagmus

rule out a second abnormal head position, which can be worsened by additional surgery. For example, some children manifest a large right head turn when viewing at distance, and a large left head turn when viewing at near. Intermittency of the head turn should not factor into the decision of whether to operate. Head turns are uncomfortable to maintain and chldren who turn their heads to see clearly would do so constantly if they could. As measurements of head turn are notoriously variable in children with congenital nystagmus, the gaze position of minimal nystagmus is a better indicator of null position. In general, the presence of even a small head turn indicates that the horizontal range of good vision is extremely narrow and that gaze acuities and latencies for target recognition must be low in all but a narrow range of horizontal gaze. For this reason, Hertle has recommended performing two muscle recessions with simple tenotomy and reattachment of the other two horizontal muscles for even small head turns (in the range of 10 degrees).276,284 The relative diminution in ocular rotation from two versus four muscle surgery has not been investigated. The Kestenbaum procedure is most effective when measured gaze-angle nulls are used to determine the amount of eye rotation necessary rather than patient-controlled and inaccurately measured head turns.141,201,202 Reports of “regression” and the need for additional surgeries appear to be due to inadequate initial procedures and not a return of the null angle. Even with “augmented” Kestenbaum–Andersen procedures, late regression continues to be a problem that limits long-term efficacy. Reports touting the efficacy of this procedure should therefore be interpreted with caution in the absence of long-term (several years) follow-up data. Even when coexistent strabismus is present, the major etiology for anomalous head positions in infantile nystagmus is to adopt a gaze null.278 The coexistence of congenital or manifest latent nystagmus and strabismus can often be managed by surgically moving the fixing eye for the anomalous head posture, combined with moving the nonfixing eye for the resulting strabismus.278 In addition to shifting the null zone, Dell’Osso and Flynn have shown that the Kestenbaum–Anderson procedure expands the null zone and improves visual acuity in some cases.141 Serial ocular motor studies performed by Abadi and Whittle have demonstrated that the final face position following a Kestenbaum procedure does not always correspond precisely to the null zone, suggesting that other unrecognized factors influence the outcome.9,11 In our experience, adjustable sutures are contraindicated following a Kestenbaum procedure as the eyes are rotated to one side postoperatively, and it is difficult and painful for patients to attempt to fixate in primary position for the adjustment. We and others42,251 perform supramaximal two-muscle recessions (Anderson procedure)25 of two horizontal muscles for head turns of less than 20 degrees associated with con-

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genital nystagmus. We simultaneously tenotomize and reattach the other two horizontal rectus muscles to expand the null zone. We perform the Anderson procedure25 with simple tenotomy and reattachment of the other two horizontal rectus muscles for head turns of less than or equal to 20 degrees associated with infantile nystagmus. We have been impressed that the results are equal to those obtained with recess-resect surgery, but our impression (especially the null broadening) has not been verified by ocular motor data. It is unclear whether simple tenotomy and reattachment of the other two muscles would add any null-broadening effect. If one assumes that the surgical weakening of extraocular muscles increases exponentially with the amount of recession, and that large resections ultimately loosen up, it can be argued that this approach could produce an even greater therapeutic effect. If one further assumes that some of the therapeutic effect of four-muscle surgery comes from improved foveation and improved vision from the tenotomy alone, then this component is preserved without the large resection (which is especially painful for the child in the postoperative period). For children with head turns greater than 20 degrees, we initially perform large two-muscle recessions combined with tenotomy of the other two horizontal muscles, reserving additional muscle resection for undercorrections following this approach. Because a Kestenbaum procedure expands null zone, it has been inferred that one need not produce a horizontal ophthalmoplegia to eliminate head turn. It is unclear whether simultaneous tenotomy of the other two horizontal rectus muscles during an Anderson procedure would further expand the null zone and reduce torticollis in this setting.566 As discussed above, Bagolini et al45 have emphasized that some large head turns must be conceptually distinguished from null positions; such patients use active blockage of nystagmus associated with increased innervational effort (similar to that seen with active convergence) to damp their nystagmus. In such patients, it may be necessary to induce a complete horizontal gaze palsy to eliminate the torticollis. Rare patients with infantile nystagmus may assume a vertical head posture or a head tilt to achieve their null position. Vertical null positions can be eliminated with a recess-resect procedure of the vertical rectus muscles. (In a patient with a chin-down position, the inferior rectus muscles are resected, and the superior rectus muscles are recessed.) However, children with infantile nystagmus and vertical head positions may have unrecognized A or V patterns that cause them to assume a vertical head position to produce a large exophoria that allows them to converge and damp their nystagmus. It is therefore important to search carefully for an A or V pattern (which is difficult to detect in a child with nystagmus) before attributing a vertical head position to a vertical null position. If none is found, surgery can consist of recess-resect procedures of the vertical rectus muscles (for small vertical head positions) or combined

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rectus and oblique muscle weakening for large vertical head positions.146,235 The former approach has the potential to induce bilateral disconjugate torsion, which is usually asymptomatic and can be minimized by simultaneous horizontal transposition of the vertical rectus muscles. The latter approach is more effective but also tends to produce a more significant gaze paresis. The resulting vertical null shift, just as an accurate horizontal null shift, should preclude the need for a gaze sift to see better and thereby eliminate torticollis. Head tilts resulting from torsional null positions are rare but well recognized in infantile nystagmus.500 Head tilts resulting from a torsional null point can be treated by “torsional Kestenbaum procedures” that involve transposition of the vertical or horizontal rectus muscles or oblique muscle surgery to produce bilateral ocular torsion.115,131,133,513,559 Conceptually, one can view this procedure as taking off all vertical rectus muscles, rotating the eyes in the direction of the head tilt and then reattaching the muscles. Thus, in a child with a right head tilt, the goal of surgery would be to surgically induce clockwise torsion in both globes (as viewed from the patient’s perspective, not the examiner’s perspective) to induce a leftward environmental tilt that is compensated for by straightening the head.559 (This rationale suggests that rightward tilt in the subjective visual vertical may underlie both the head tilt and the nystagmus damping in this position). The optimal treatment paradigm for more complex cases of torticollis associated with infantile nystagmus is the subject of ongoing investigation. For multiplanar torticollis, Hertle278 has recommended performing initial surgery to correct the largest plane of torticollis. This approach broadens the null zone in all planes so that they often don’t need additional surgery. The parents should, of course, be told that additional surgery may be necessary.278 Rarely, children with alternating horizontal null zones affecting both fields of lateral gaze may benefit from large four-muscle recessions, taking care to recess the medial rectus muscles slightly less than the lateral rectus muscles (unless an additional artificial divergence effect is desired).

Surgery to Improve Vision Nystagmus surgery is an underutilized means of improving vision in patients with infantile nystagmus. Patients with infantile nystagmus report that they are slow to see, and take longer to recognize people in a crowd.565 Recognition time may be reduced by nystagmus surgery, even when visual acuity is unchanged. Cosmetic considerations often also weigh heavily in the patient’s mind. Many patients are happy with a medical or surgical treatment that reduces the intensity of their nystagmus, even when visual acuity is

8 Nystagmus in Children

unchanged. As mentioned above, examination of pre-andpostoperative Snellen visual acuity does not provide an accurate measure of patient satisfaction. Surgical procedures can also increase the horizontal range of clear vision and decrease the recognition time for objects of interest. As stated by Dell’Osso, “patients who used to have an island of clear vision now have an ocean.”286 Patients also see faster, more efficiently, and feel more confident, all of which are probably more important than improving visual acuity by one line.565 Since affected patients develop foveation periods by three months of age, it is unclear whether early surgery is necessary to minimize the amblyogenic effect of the oscillation. The optimal age for surgery to improve vision has not been established. The goal of surgery is not to reduce the amplitude or frequency of infantile nystagmus (although these benefits occur), but to improve the quality of foveation over a wide range of gaze. In this regard, it is important for the clinician to check visual acuity in primary position, right gaze, and left gaze pre-and-postoperatively. To quantitatively assess this function, Dell’Osso et al328 have developed the expanded NAFX, a mathematical function that incorporates duration, positional accuracy, and velocity accuracy of the foveation period. Because the NAFX applies to only one position of gaze, a postoperative improvement does not reveal the true degree of visual benefit that comes from improved sidegaze acuity and quicker target recognition and target acquisition, but the later may be determined directly from eye movement data. Also, the NAFX is the foundation for the only known method to estimate a priori the percent improvement in visual acuity that will result from a four-muscle surgical procedure (e.g., the tenotomy procedure).137 This estimation has never before been possible and is impossible from visual acuity data alone. Tenotomy with Reattachment First devised by Hertle and Dell’Osso142,151 tenotomy with reattachment involves taking the four horizontal extraocular muscles off the globe and then reattaching them to their original insertions. Despite the early studies that showed little therapeutic effect,138,402,403 recent studies have suggested that this procedure may improve the NAFX in the null position to broaden the field of vision of the null position, and to decrease the latency of object recognition in the visual field.282,563,565 According to Dell’Osso and Hertle, this procedure allows patients to see better off to the side (because they can look around without increasing their nystagmus and degrading their vision) and refoveate faster (normal individuals foveate a moving object in about 200 ms, whereas the same act takes 1–1.5 s in an individual with infantile nystagmus).286 By decreasing their foveation time, tenotomy is said to improve their real-world level of functioning.

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Tenotomy can be viewed as a neurosurgical procedure rather than an orthopedic procedure.286 Presumably, the afferent proprioceptive receptors are irritated by tenotomy, causing them to increase their baseline firing rate. The feedback loop to the brain relaxes the signal that keeps the muscles in a steady state tension, thereby putting the muscles on a lower slope of firing and tension. Unlike large four-muscle recessions, tenotomy does not reduce saccadic amplitudes or velocities, so the brain is not driven to compensatorily increase the signal.564 Despite its strong proponents, the supporting data, its muscle-sparing reversibility, and its surgical simplicity, the clinical value of four-muscle tenotomy with reattachment as an isolated procedure to treat infantile nystagmus remains highly controversial. It represents a paradigm shift in nystagmus surgery that prior to recent anatomical discoveries,92,542 was considered implausible.142 Because over 90% of children with infantile nystagmus have an abnormal head position that needs to the addressed, free tenotomy with attachments is indicated in less than 10% of cases.279

Four Muscle Recession Numerous authors have advocated simultaneous large recessions of four horizontal rectus muscles in the treatment of infantile nystagmus.21,63,273,346,558 In this procedure, the medial rectus muscles must be recessed less than the lateral rectus muscle to avoid postoperative exotropia, a complication that has been observed and remains problematic, especially in binocular patients, where diplopia results. Diplopia from exotropia in lateral gaze also remains a problem in some patients regardless of whether the medial rectus muscles are recessed a little less than the lateral rectus muscles, and the long-term effects of this procedure on lateral gaze accuracy are unknown. Results suggest that it generally improves acuity measurements by an average of one line and produces considerable subjective visual improvement without inducing oscillopsia or diplopia.204,273 In evaluating the purported benefits of this and other surgical procedures for infantile nystagmus, it should be remembered that increased foveation time (rather than decreased intensity of the nystagmus) is the fundamental correlate of acuity. Also, many early investigators recessed all four horizontal rectus muscles equally, which may have induced large exophorias, so it is difficult to assess the degree to which any postoperative improvement resulted from an unintentional artificial divergence effect. Although this procedure seems more intuitively appealing than free tenotomy without recession, Dell’Osso has cautioned that four muscle recessions may actually be counterproductive because it produces hypometric saccades, necessitating that

the ocular motor centers work to increase the central gain of horizontal eye movements and thereby work against the surgery. Also, it has been demonstrated that the obligate four-muscle tenotomy and reattachment alone (that is built into the maximal-recession procedure) accounts for the therapeutic improvements claimed, rendering the problematic aspects of large recessions unnecessary. Thus, despite its advocates, four-muscle recession seems to confer little objective or functional benefit in patients with infantile nystagmus.71

Artificial Divergence Surgery Cüppers first advocated strabismus surgery in infantile nystagmus to diverge the eyes, requiring active convergence for fusion, which dampens the nystagmus.124 Artificial divergence surgery is the best single operation for improving visual acuity in infantile nystagmus. Unfortunately, it is suitable only in about 10% of cases – because of the fact that only about 50% of the total group of infantile nystagmus patients damp with convergence and, of those, many have overt strabismus or poor fusion.279 In planning artificial divergence surgery, it is important to first confirm the presence of fusion and stereoacuity in the preferred head position and to quantitate fusional convergence amplitudes by placing 7-10 PD base-out prisms before the eyes. It is also important to observe damping of the nystagmus during convergence. Bimedial recessions of 3 or 4 mm are sufficient to induce a large exophoria that allows the patient to use fusional convergence, thereby damping the nystagmus. Confirming the presence of these features minimizes the risk of overcorrection with loss of fusion. Overcorrection to exotropia negates any surgical benefit and requires reoperation to reduce the deviation in an attempt to convert the exotropia to an exophoria. Spielmann515 has coined the term “pseudo-latent infantile nystagmus” to describe the dramatic increase in infantile nystagmus intensity when convergence is blocked by monocular occlusion. This finding provides indirect evidence of active convergence in the binocular state and therefore indicates an ideal result following artificial divergence surgery.514 Medical and surgical treatments of infantile nystagmus are summarized in Table 8.4. Zubcov et al608 compared the efficacy of the artificial divergence procedure of Cüppers124 with the Kestenbaum– Andersen procedure in improving visual acuity. They found that a visual improvement of approximately one line is seen in about half of patients following either procedure and that combining the two procedures further improves vision. In practice, artificial divergence surgery can be combined with two-muscle recession (by recessing the medial and lateral rectus muscles the same amount) to simultaneously treat the torticollis and improve visual

410 Table 8.4 Treatment of infantile nystagmus Treatment to improve visual acuity Medical treatment 1. Base-out prisms to induce convergence and dampen nystagmus 2. Biofeedback to improve acuity during periods of attention or concentration 3. Contact lenses Surgical treatment 1. Cüppers divergence procedure to induce convergence and dampen nystagmus 2. Tenotomy with reattachment. 3. Large recession of four horizontal rectus muscles Procedures to relocate the null zone to primary position Horizontal null zone 1. Kestenbaum–Andersen procedure (recess-resect procedure of horizontal rectus muscles of both eyes) 2. Andersen procedure (large recession of two horizontal rectus muscles) Vertical null zone 1. Recess-resect procedure of four vertical rectus muscles Torsional null zone 1. Horizontal transposition of vertical rectus muscles 2. Vertical transposition of horizontal muscles (DeDecker procedure) 3. Spielmann procedure: Slanting of the insertion of the rectus muscles 4. Recess-resect procedure of four oblique muscles

acuity. However, this may be the only infantile nystagmus procedure that need not be combined with tenotomy of the other two horizontal muscles to achieve an optimal therapeutic benefit.492 It is fortunate, however, that surgically damping the nystagmus with artificial divergence surgery also negates a head turn.

Spasmus Nutans The term spasmus nutans (Latin: nodding spasm) refers to the constellation of nystagmus, head nodding, and torticollis. Although the term “acquired nystagmus” has been applied to spasmus nutans as a differentiating feature from infantile nystagmus, it should be remembered that infantile nystagmus is also “acquired,” albeit usually earlier in infancy. Unlike infantile nystagmus which becomes apparent between 8 and 12 weeks of age, the age of onset in spasmus nutans is generally quoted as 6–12 months of age442 although cases with onset ranging from 2 weeks to 3 years of age have been documented.431 Clinically, spasmus nutans remits spontaneously, usually within 1–2 years of onset but persists, on rare occasions for up to 8 years.365,431 Eye movement recordings show that the nystagmus may persist subclinically even after clinical resolution.572 Following clinical resolution, it exerts no lasting effect on vision395 except in the rare cases in which a markedly asymmetrical nystagmus leads to amblyopia.

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Spasmus nutans appears as an extraordinarily fine and rapid nystagmus that has been likened to an ocular quiver.295,431 It is usually horizontal in direction but may also be vertical or torsional.290 It is often described as an intermittent nystagmus that is asymmetrical in appearance and occasionally monocular.227,572 A key clinical electro-oculographic observation is the variable phase difference between the two eyes, which is reflected clinically as an asymmetry in the oscillations between the two eyes.572 On lateral gaze, the dissociation may increase with nystagmus of the abducting eye predominating.431 Some case series suggest an increased prevalence of esotropia in spasmus nutans.230,431 Gottlob et al230 found a high incidence of esotropia, latent nystagmus, dissociated vertical divergence, and amblyopia in children with spasmus nutans. Conversely, patients with infantile esotropia rarely display horizontal or vertical head oscillations that resolve following surgical realignment of the eyes.86 In contradistinction to infantile nystagmus, visual acuity is minimally affected in spasmus nutans. Spasmus nutans is more common in African-American children and has been reported in several sets of identical twins (some of whom may have had achromatopsia or CSNB).194,274,290,295,324 The head nodding associated with spasmus nutans is a combination of vertical head nodding and a lateral shaking of the head in an unpredictable pattern.290,519 The head nodding is of lower frequency than the nystagmus227 and becomes prominent when the child attempts to inspect something of interest. It disappears during sleep but may persist when the child is lying down.290 Because some children with infantile nystagmus also have head nodding, this finding alone cannot be used to confirm the diagnosis of spasmus nutans in the child with nystagmus. Earlier controversy surrounding the issue of whether associated head nodding in spasmus nutans is compensatory (i.e., performed for the purpose of improving vision) or an involuntary movement of pathologic origin similar to the nystagmus itself is now resolved. Gresty and colleagues236–238 examined patients with spasmus nutans in whom head nodding abolished the nystagmus and a normal VOR stabilized the eyes during head movements. These authors were the first to demonstrate electrooculographically that the head nodding in spasmus nutans is an adaptive behavior that serves to improve visual acuity by suppressing the nystagmus rather than a separate pathological phenomenon.236–238 Eye movement recordings from these patients demonstrated that the head nodding in spasmus nutans functions to abolish the nystagmus through some mechanism, which is independent of the vestibulo-ocular response.239 Gottlob et al227 confirmed and refined these conclusions in a large number of patients with spasmus nutans using electro-oculographic recordings. In these patients, the head nodding changed the spasmus nutans waveform from a fine, pendular, dissociated nystagmus of high frequency to a

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Spasmus Nutans

Fig. 8.11 Eye movement recording from child with spasmus nutans. (a) When head is still, eyes oscillate disconjugately and rapidly. (b) During periods of head nodding, eyes oscillate conjugately and oppositely to head, resulting in steady gaze that is conjugate in space. Adapted, with permission, from Gottlob et al227

larger, slower waveform that is symmetrical between the two eyes (Fig. 8.11). There is now general agreement that head nodding in spasmus nutans is compensatory. The head tilt in spasmus nutans is a variable finding that is present in less than half of cases. Although the reason for the associated head tilt is unclear, Gottlob et al227 have suggested that it may serve to directionalize the head nodding to its optimal trajectory. Although early authors stated that the head nodding was the first sign of spasmus nutans to appear and the last to resolve, it is now generally agreed that the nystagmus is the most constant feature of spasmus nutans and that it probably precedes the head nodding, although the head nodding may be the abnormality that first attracts attention.365,395 The clinical characteristics of spasmus nutans are summarized in Table 8.5. Weissman found persistence of the nystagmus in some of their patients, and Gottlob et al found persistence of nystagmus on electro-oculographic recordings in all patients who had clinical resolution of the condition, suggesting that the nystagmus diminishes to a subclinical level but does not entirely resolve.227,572 Early reports considered spasmus nutans to be pathogenetically related to diverse causes that included light deprivation, dietary factors, the season, rickets, epilepsy, autoarousal, and poor socio-economic conditions.122,194,317,442,463,519,572 Hermann274 noted a strong predisposition for the onset of spasmus nutans to occur during the winter months with 70% of cases having their onset during December, January, or February. In 1897, Raudnitz463 published the classical description of spasmus nutans, in which he collated previously reported cases with 15 cases of his own. He emphasized the fact that virtually all of his patients belonged to a certain dark quarter of Prague. When

Table 8.5 Clinical findings in spasmus nutans Rapid, small amplitude, “ocular shiver” Variable phase in nystagmus of both eyes Horizontal, vertical, or oblique Intermittent, asymmetrical, or monocular Head nodding Variable head tilt Onset at 6 months to 1 year of age Visual acuity normal or nearly so Spontaneously resolves over months to years

this district was later sanitized, no further cases of spasmus nutans developed.442 Raudnitz viewed darkness as the primary etiologic factor, speculating that the eyes of affected children were somehow damaged by the “irritant effect” of insufficient light during a critical period of fixation development. According to the translation by Osterberg, Raudnitz believed that “efforts at fixing resulted in erratic movements of the eye, as certain ganglion cells cannot settle down till the eyes are satisfactorily focused, incidents will still be asserting themselves, they extend into larger areas of innervation, and headnystagmus, etc., are brought about secondarily.”442 Raudnitz noted that pups who were reared in total darkness for several months developed eye nystagmus and head nystagmus.463 Still519 attributed spasmus nutans to “an index of nervous instability” associated with rickets and with “confinement in a closed, ill-ventilated room” and directed therapy toward remediating these problems. Lower socioeconomic status may represent a risk factor for the development of spasmus nutans. In a study comparing spasmus nutans with infantile nystagmus, Wizov586 found African-American or Hispanic ethnicity to be significantly

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more common in spasmus nutans. Patients with spasmus nutans also had lower than average gestational ages, lower home luminances at birth, fewer married parents living together, and more psychiatric disorders, including alcohol and drug abuse.586 For a century, numerous reports emphasized that spasmus nutans was a visually and systemically benign and self-limited clinical entity.290,511 Since 1967, however, many infants with spasmus nutans have been found to have congenital suprasellar tumors (most commonly, chiasmal gliomas).180 In retrospect, it seems likely that some children with spasmus nutans who were felt to have either rickets or malnutrition might have harbored suprasellar tumors and would currently be classified as having Russell diencephalic syndrome, discussed below. While there is no longer any question that congenital suprasellar tumors can produce a constellation of neuro-ophthalmologic signs that are clinically and electroculographically indistinguishable from spasmus nutans,20,181,191,226,326 it is curious that this association went largely unnoticed for more than a century of observation. Based on these previous reports, we advocate MR imaging in all children for whom the diagnosis of spasms nutans is being entertained. Although King et al have emphasized that the absence of afferent pupillary defects, optic atrophy, or papilledema makes the diagnosis of chiasmal glioma less likely,333 children with with spasmus nutans and no pupillary or optic nerve abnormalities have been reported to have chiasmal gliomas, demonstrating that the absence of these abnormalities does not totally preclude an underlying neoplasm.27,337,428 The clinical findings of hydrocephalus, café au lait spots, or other clinical signs of neurofibromatosis make it more likely that a child with spasmus nutans will have a chiasmal glioma.181 A substantial proportion of patients presenting with spasmus nutans-like nystagmus have important underlying ocular, intracranial, or systemic abnormalities.330 Neurodegenerative disorders such as Pelizaeus–Merzbacher disease and Leigh’s disease may produce nystagmus and head nodding that are indistinguishable from spasmus nutans.41,485 These disorders should be suspected in children with clinical signs of ataxia or developmental delay or with MR evidence of white matter signal abnormalities. One child with a history of spasmus nutans had congenital ocular motor apraxia, developmental delay, and hypoplasia of the cerebellar vermis.331 Achromatopsia, CSNB, and Bardet Biedl syndrome can also masquerade as spasmus nutans. The findings of photophobia, decreased vision, night blindness, and myopia are especially suggestive of an underlying congenital retinal dystrophy.228,231,356,506 The fact that infants with spasmus nutans, in rare cases, are later found to have congenital retinal dystrophies or neurodegenerative disease has led some authorities to conclude that spasmus nutans is a diagnosis that can only be made in

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retrospect after the nystagmus has resolved.100,310,531 However, nowhere else is medical diagnosis predicated on future resolution of clinical signs. Clinical diagnosis is, by its nature, tentative.193 As such, the distinctive clinical appearance of this nystagmus and its associated signs, together with the absence of decreased vision or other signs or symptoms of a congenital retinal dystrophy, allows us to assign the presumptive diagnosis of spasmus nutans and order both neuroimaging and ERG.231,506 After a century of observation and conjecture, the pathogenesis and neuroanatomical substrate of this selflimiting form of vertical disconjugate nystagmus is still unknown.572

Russell Diencephalic Syndrome of Infancy An infant with congenital chiasmal/hypothalamic glioma is often brought to medical attention because of weight loss and failure to thrive after a period of normal growth.360 Russell diencephalic syndrome refers to the constellation of emaciation, hyperactivity, and euphoria.116 Radiological examination shows an almost complete absence of subcutaneous fat in the extremities.116 Affected infants often display a euphoria and affectionate spontaneity that contrasts strikingly with their profound emaciation116,396 (Fig. 8.12a). Minor features of the syndrome include skin pallor despite a normal hemoglobin level, hypotension, hypoglycemia, and an alert appearance that has been attributed to Collier’s sign. Neuro-ophthalmologic examination may reveal spasmus nutans or seesaw nystagmus with a variable degree of optic atrophy.116 The great majority of children with Russell diencephalic syndrome have chiasmal/hypothalamic glioma (Fig. 8.12b). Children with Russell diencephalic syndrome usually have elevated growth hormone levels, which may be an important factor in causing emaciation despite adequate food intake.199 In this setting, the normal linear growth with emaciation provides a model for partial growth hormone resistance.199 The cytokine TNA-(alpha) is implicated as a mediator in this disorder.39 This potent lipolytic agent may be involved in the genesis of the emaciation that is characteristic of Russell diencephalic syndrome.409 Infantile diencephalic syndrome is usually due to a lowgrade hypothalamic glioma that is unusually radiosensitive, with a return to normal weight gain and normal growth hormone levels following treatment in many patients.416 More recent treatment with a carboplatin and vincristine regime results in demonstrable weight gain and may produce tumor shrinkage and delays in the need for alternate therapies.244 Burr91 found an average survival time in untreated patients averaging 12.3 months, compared to at least 25 months in the

Nystagmus Associated with Infantile Esotropia

413

Fig. 8.12 (a) Two-year-old boy with thalamic glioma and Russell diencephalic syndrome. Courtesy of William F. Hoyt, M.D. (b) MR scan demonstrating chiasmal glioma and hydrocephalus in child with Russell diencephalic syndrome. Courtesy of Neil R. Miller, M.D.

treated patients. The natural history of Russell diencephalic syndrome following radiation therapy is extremely variable,116 however, with survival of up to 12 years having been documented.96,416

Table 8.6 Monocular nystagmus in children

Monocular Nystagmus

some suggestion that the amplitude of the larger waveform may correlate with the duration of visual loss.457 In our experience, most affected patients display a slow-velocity and large-amplitude oscillation that makes it easily distinguishable from other forms of nystagmus. One report documented successful treatment of this condition with oral gabapentin.459 Episodic monocular nystagmus can also be a rare manifestation of epilepsy.303

In 1956, Cogan106 stated that spasmus nutans is the most common, if not the only, cause of unilateral horizontal nystagmus in infancy. With the added caveat that chiasmal gliomas can present with paradigmatic spasmus nutans,180 this generalization still applies to most infants with monocular nystagmus (Table 8.6). Rarely, severe unilateral visual loss causes a slow, unilateral horizontal nystagmus in the affected eye.77,223,224 In the second decade of life, a monocular vertical oscillation may develop in an eye with reduced vision (20/200 or less) of long duration (the Heimann–Bielschowsky phenomenon). Yee et al592 described the vertical drift with monocular visual loss as small-amplitude, low-frequency, pendular and accentuated by refixation or eccentric gaze. Smith et al507 subsequently described this oscillation as large in amplitude and low in frequency. Pritchard et al457 attempted to reconcile these two views by demonstrating that some patients have small rapid oscillations superimposed on larger oscillations of lower frequency. There is

Spasmus nutans Chiasmal/hypothalamic glioma Heimann–Bielschowsky phenomenon Congenital unilateral visual loss

Nystagmus Associated with Infantile Esotropia Torsional Nystagmus Infants with esotropia may display a subtle conjugate torsional nystagmus with no horizontal component. This fine conjugate torsional rotation seems to be a progenitor to latent nystagmus and does not carry additional neurological significance.86,143

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Horizontal Nystagmus As discussed in Chap. 9, children with infantile esotropia, in rare cases, have horizontal nystagmus associated with head shaking, or head nodding that resolves following surgical realignment.86 Because many patients with spasmus nutans manifest esotropia, dissociated vertical deviation, and latent nystagmus,230 it is not known whether this condition represents a variant of spasmus nutans.

Latent Nystagmus Latent nystagmus refers to a bilateral conjugate horizontal jerk nystagmus that occurs when either eye is occluded.85 It accompanies infantile strabismus and is most commonly seen in children with a history of infantile esotropia. In most conditions in which the ocular oscillation of latent nystagmus occurs under binocular viewing conditions, complete absence of nystagmus occurs only when patients bifixate. In most patients with this condition, the intensity of the nystagmus increases as monocular occlusion increases. The oscillation can appear clinically “silent” under binocular viewing conditions, but is always present when measured with eye movement recordings.145 In latent nystagmus, the nasally directed slow phase in the fixating eye is followed by a temporally directed corrective saccade.85 The amplitude of latent nystagmus increases when the fixating eye is moved into abduction and decreases in adduction. Latent nystagmus obeys Alexander’s law (which states that, in patients with peripheral vestibular nystagmus, the amplitude of the jerk nystagmus increases in the direction of the fast phase and decreases but never reverses in the direction of the slow phase), whereas infantile nystagmus may appear to obey this law if the patient has a “latent” component and is examined under monocular conditions. The fact that manifest latent nystagmus obeys Alexander’s law reflects the fact that it is tied into the same circuitry as peripheral vestibular nystagmus.85,471 The finding of latent nystagmus correlates with the finding of nasotemporal asymmetry when either eye follows horizontal optokinetic targets.85 Nasotemporal asymmetry refers to the clinical finding of normal nasally directed optokinetic responses and impaired temporally directed optokinetic responses under conditions of monocular viewing. Monocular nasotemporal optokinetic asymmetry is normal in infants until approximately 22 weeks of age.413 Absence of cortical binocularity leads to the retention of this primitive optokinetic bias.85 Although nasotemporal asymmetry is usually observed in the setting of infantile esotropia, it may occur with other forms of early infantile strabismus as well. In patients with a history of

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s trabismus, the finding of nasotemporal asymmetry confirms that the eyes were misaligned within the first year of life.85 Tychsen and colleagues540,541 proposed that latent nystagmus and its underlying nasotemporal asymmetry reflect the effect of the immature visual motion processing system on the smooth pursuit movements. The extrastriate motion processing system is localized to the dorsal parieto-occipital pathways, which extend from the primary visual area to the extrastriate middle temporal (MT) visual area. It receives its major inputs from the magnocellular neurons in the geniculate body. This mechanism has not received experimental support.340,493 Single unit recordings from middle temporal neurons of monkeys with early-onset artificial strabismus have suggested that the pursuit defect is not due to altered cortical vision motion processing, but that the asymmetry in pursuit may be a consequence of an imbalance in binocular visual input to downstream areas responsible for horizontal optokinetic nystagmus.335 Brodsky and Tusa85 have proposed that latent nystagmus is a unique form of vestibular nystagmus that is evoked by unbalanced visual input from the two eyes rather than unequal rotational input from the two labyrinths. According to their hypothesis, the two eyes function as accessory vestibules, allowing unbalanced visual input to modulate optokinetic responses in the horizontal plane. As discussed in Chap. 7, latent nystagmus and dissociated vertical divergence are primitive visuo-vestibular eye movements that are expressed in the setting of infantile strabismus. The neurophysiologic substrate for latent nystagmus is operative in lateral-eyed, afoveate animals, which have a monocular nasotemporal asymmetry to horizontal optic flow. The same subcortical optokinetic bias is present in early human infancy and persists when strabismus precludes maturation of normal binocular cortico-pretectal pathways from MT/MST. Because this optokinetic bias influences horizontal pursuit velocity, latent nystagmus is easily misinterpreted as a cortical pursuit imbalance. When this primitive monocular nasal optokinetic bias is operative, visual input from the fixating eye to the contralateral nucleus of the optic tract evokes a visuo-vestibular counterrotation of the eyes that corresponds to a turning or twisting movement of the body toward the object of regard (Fig. 8.13). In this setting, unbalanced binocular visual input can induce a motion bias in the vestibular nucleus to generate the visual counterpart of horizontal labyrinthine nystagmus, namely latent nystagmus. As the eyes rotate frontally during evolution, this visuo-vestibular function is sacrificed, but the CNS retains these latent subcortical visual pathways. Thus, strabismus disrupts binocular cortical connections to provide the permissive cause while primitive subcortical visuovestibular reflexes that are operative in lateral-eyed animals provide the proximate cause of latent nystagmus.

Nystagmus Associated with Infantile Esotropia

415 Table 8.7 Manifest latent nystagmus Small-amplitude, horizontal jerk nystagmus Fast phase to the right when left eye occluded; fast phase to the left when right eye occluded Increases in abduction, dampens in adduction of the fixating eye Head turn to fixate in adduction with the preferred eye May improve or resolve with treatment of amblyopia or strabismus

Fig. 8.13 Neuroanatomical pathways modulating latent nystagmus. Cortical input to temporally directed movement, which is present only in frontal-eyed animals, requires the establishment of normal binocular cortical connections. This input is absent in humans with infantile strabismus. Direct crossed pathways from the eye to the nucleus of the optic tract provide nasalward subcortical optokinetic responses even when binocular cortical connections are absent (R and L represent monocular cortical cells corresponding to the right and left eyes, respectively). Note that the nucleus of the optic tract (NOT) relays horizontal visuo-vestibular information to the vestibular nucleus (VN), where it is integrated with horizontal vestibular input from the labyrinths to establish horizontal extraocular muscle tonus. LGN indicates lateral geniculate nucleus; CC, corpous callosum; V1, abducens nucleus; III, oculomotor nucleus; LR, lateral rectus muscle; MR, medial rectus muscle; AC, anterior canal; PC, posterior canal; and HC, horizontal canal). Used, with permission, from Brodsky MC, et al85

Vestibular eye movements (which involve gaze holding) and pursuit eye movements (which involve gaze shifting) are normally thought of as diametrical functions that require different control centers. However, visuo-vestibular eye movements provide the afoveate pursuit system. While pursuit is conducted by moving the eyes with the target, “pursuit” in afoveate animals is accomplished by holding the eyes still in space during head or body movements. The phylogenetic continuum between “pursuit” eye movements and “visuovestibular” eye movements may explain why higher cortical centers such as MS/MST connect to lower centers such as NOT to orchestrate latent nystagmus. Eye movement recordings show that most patients who appear to have latent nystagmus have subclinical nystagmus under binocular conditions.4 Manifest latent nystagmus can be viewed as a latent nystagmus that is made manifest by amblyopia or strabismus. In manifest latent nystagmus, the brain suppresses one eye, which causes it to be physiologically “occluded.” Under such circumstances, both eyes develop a small-amplitude conjugate horizontal jerk nystagmus that

increases when the fixating eye moves toward abduction and decreases when the fixating eye is in adduction. From a neurological perspective, the association between manifest latent nystagmus and congenital esotropia and a head turn has also been given the eponym of Ciancia syndrome. Hertle has pointed out that a nystagmus that reverses direction with alternate occlusion must be either latent nystagmus or infantile nystagmus with a latent component. This finding therefore signifies benignity.278 Affected children assume a head turn to place the fixating eye in adduction and thereby damp the nystagmus (Table 8.7). A child with conjugate horizontal nystagmus who fixates monocularly in abduction cannot have latent nystagmus and must therefore have infantile nystagmus. Latent nystagmus offers parents a unique opportunity to self-monitor their child for the development of amblyopia. Several clinical features of latent nystagmus predict the progression of amblyopia. First, a new-onset manifest latent nystagmus indicates the development of amblyopia, and parents can be trained to occlude or penalize the appropriate eye (right eye for a right-beating nystagmus and left eye for leftbeating nystagmus) when it occurs. Second, the appearance of an increasing head turn indicates amblyopia of the eye that is not fixating in adduction. Third, the intensity of latent nystagmus is greater during fixation with the poorer-seeing eye, so parents can cover each eye and institute therapy when increasing asymmetry in the intensity is observed. In contradistinction to infantile nystagmus, eye-movement recordings in manifest latent nystagmus show a rapid slip off the fovea following refixation saccades (referred to as a decreasing-velocity or decreasing-exponential waveform) (Fig. 8.14). The primary defect in latent nystagmus is a linear slow-phase drift that displaces the image of regard from the fovea to the nasal retina, followed by a refoveating fast phase.166 However, Dell’Osso161,166 has demonstrated that some patients with manifest latent nystagmus develop a strategy of making a saccade beyond the target, thereby allowing the decreasingvelocity tail of the waveform to provide foveation. Patients who have latent nystagmus with slow-phase velocities greater than 4 degrees/s develop a secondary adaptation that permits foveation at the end of the slow-phase deceleration. This saccadic overshoot is not part of the primary defect but an adaptation to improve vision in the setting of manifest latent nystagmus. This adaptive strategy serves to transfer the slow component of the drift onto the fovea, which probably accounts for the good visual acuity in these children.

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p rematurity and walking difficulty should be sought. It is unclear whether the latent nystagmus in periventricular leukomalacia results from horizontal strabismus, from an afferent disturbance at the level of the optic radiations, or from selective involvement of efferent corticotectal pathways that subserve monocular temporal optokinetic responses by the bilateral subcortical periventricular white matter lesions. Older patients who develop manifest latent nystagmus occasionally note oscillopsia.370

Fig. 8.14 Comparison of eye movement recordings (position tracings) in manifest latent nystagmus and infantile nystagmus. Upward deflection corresponds to rightward eye movement. In manifest latent nystagmus (top) each leftward fast phase is followed by decreasing-velocity drift off target with no intervening foveation period. In infantile nystagmus (bottom), each rightward fast phase is followed by foveation period before eyes drift off target in increasing-velocity slow phase. Adapted, with permission, from von Noorden et al556

Manifest latent nystagmus may be mistaken for acquired nystagmus because it may not become clinically apparent for several years. Affected children may be subjected to an extensive neurological workup if the associated ocular findings are not recognized. The characteristic clinical finding is that manifest latent nystagmus changes direction when the eyes are alternately occluded (i.e., it is right-beating when the left eye is occluded and left-beating when the right eye is occluded). Although this clinical finding is highly suggestive of manifest latent nystagmus, it can also reflect infantile nystagmus with a latent component. In the child with congenital esotropia, latent nystagmus, and alternating fixation, the manifest latent nystagmus may superficially resemble periodic alternating nystagmus.257 Some patients with latent nystagmus can induce a manifest latent nystagmus by simply imagining that one eye is occluded. Bright illumination in one eye often has a similar effect to occlusion and causes a latent nystagmus to manifest.504 Patients, in rare cases, have been reported to release and suppress latent nystagmus at will.343 In addition to occurring in patients with congenital esotropia and amblyopia, manifest latent nystagmus is a common manifestation in infants with congenital unilateral visual loss resulting from microphthalmos, congenital cataract, or optic disc anomalies.104,370 These infants develop a face turn toward the good eye (i.e., an infant with left microphthalmos takes a right face turn to damp the nystagmus in the right eye by keeping it positioned in adduction). Parents may misinterpret this phenomenon and believe that the child is turning his face to view objects with his bad eye. Infants with congenital unilateral visual loss also tend to develop a sensory esotropia. Latent nystagmus is common in patients with periventricular leukomalacia, so a history of

Treatment of Manifest Latent Nystagmus Manifest latent nystagmus should be viewed as a treatable form of nystagmus. Zubcov et al606 have shown that successful occlusion therapy or surgical realignment of the eyes diminishes the intensity of manifest latent nystagmus. It is a common misconception that occlusion therapy is futile or even contraindicated in patients with amblyopia and latent nystagmus.556 Some authors have advocated optical or atropine penalization for amblyopia treatment in patients with latent nystagmus. It is now well established, however, that occlusion therapy is effective in patients with latent nystagmus.556 Simonsz and Kommerell504 have demonstrated that the slow-phase speed of latent nystagmus in the amblyopic eye diminishes over 2 or 3 days during prolonged occlusion of the better eye and that the slow-phase speed in the better eye increases by a commensurate amount. They caution that early visual improvement during occlusion therapy probably reflects an occlusion-induced short-term change in the nystagmus waveform rather than true sensory visual improvement. Because manifest latent nystagmus often occurs in the setting of congenital esotropia with superimposed amblyopia, it is not surprising that treatment of the underlying conditions can convert a manifest-latent nystagmus to a latent nystagmus (i.e., eliminate the manifest component).606 Children who have manifest-latent nystagmus associated with unilateral congenital visual loss (unilateral microphthalmos, congenital cataract, or optic disc anomalies) may require a large recession of the medial rectus muscle of the adducted eye to transfer the null zone into primary position and eliminate the sensory esotropia.306,512 Parents are understandably reluctant to permit surgery on the seeing eye, despite the fact that the torticollis may be more cosmetically and functionally disabling than the strabismus. In this particular situation, Jampolsky306 has cautioned that it is often necessary to perform additional recessions of the medial and lateral rectus muscles of the normal contralateral eye to eliminate horizontal incomitance. Adults with congenital blindness in one eye and large

Vertical Nystagmus

head turns associated with manifest-latent nystagmus may benefit from oculinum injection into the medial rectus muscle of the fixating eye or from a recess-resect procedure of the fixating eye to simultaneously eliminate the face turn and the large esotropia.370

Nystagmus Blockage Syndrome The nystagmus blockage syndrome is a rare variant of infantile nystagmus. It is characterized by an intermittent horizontal nystagmus accompanied by a large-angle, variable esotropia.553 The following three clinical characteristics typify the nystagmus blockage syndrome: 1. The esotropia increases as the nystagmus damps and decreases as the intensity of the nystagmus increases. 2. The esotropia disappears or markedly diminishes when one eye is occluded and the fixating eye is moved into abduction. 3. The angle of esotropia increases when prisms are placed before the eyes to neutralize the deviation. The child with nystagmus blockage syndrome invokes excessive convergence to damp an underlying infantile nystagmus or convert it to a low-amplitude manifest latent nystagmus by a purposive esotropia and improve acuity.145 During periods of convergence, pupillary constriction may or may not be observed, suggesting that some children have the ability to partially dissociate accommodation from convergence, which would predispose to nystagmus blockage syndrome by making it a visually beneficial adaptive strategy. When viewing objects of interest, children with nystagmus blockage syndrome display tonic convergence that may simulate a bilateral sixth nerve palsy. Fixation with the adducted eye necessitates a head turn toward the fixating eye to view objects that are in primary position.149An alternating head turn may signify alternating fixation during periods of esotropia. Some children with nystagmus blockage syndrome eventually develop a constant esotropia, suggesting that a progressive medial rectus contracture can develop. The active blockage of infantile nystagmus by convergence must be distinguished from the variable esotropia that can accompany latent nystagmus.87 In the setting of infantile strabismus, monocular fixation with either eye may exert dissociated esotonus, causing an existing exotropia to decrease or an existing esotropia to increase. The resulting convergent eye movement has been misinterpreted as an active convergence blockage mechanism.233,607 Any reduction of latent nystagmus associated with dissociated esotonus is an epiphenomenon (because the same process occurs in patients with no latent nystagmus).146

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Treatment of Nystagmus Blockage Syndrome Nystagmus blockage syndrome has been successfully treated with strabismus surgery that consists of bilateral medial rectus posterior fixation sutures (if the eyes are straight during periods of relaxation) or bimedial recession with or without posterior fixation sutures, or unilateral recession and resection.555

Vertical Nystagmus When the onset of vertical nystagmus is noted in the first 3 months of life, neuroimaging studies are frequently normal. In children with acquired vertical nystagmus, neuroimaging is warranted to rule out a posterior fossa lesion. In this context, upbeating and downbeating nystagmus in infancy are each associated with a distinct clinical profile and visual prognosis.

Upbeating Nystagmus in Infancy Unlike upbeating nystagmus in adulthood, which is associated with a structural lesion involving the brainstem or cerebellum,448 upbeating nystagmus in infancy is usually associated with anterior visual pathway disease.222,297 Good et al222 found anterior pathway disease in 11 children who presented with upbeating nystagmus in infancy. The underlying diagnosis included Leber congenital amaurosis (seven cases), optic nerve hypoplasia (two cases), aniridia (one case), and congenital cataracts (one case). Upbeating nystagmus in infancy may be asymmetrical and may convert to a horizontal nystagmus in the first 2 years of life.222 When the optic nerves appear normal, ERG usually reveals the abnormality. Simonsz et al recently described 20 children who presented at three to six months of age with chin-up posture, high frequency, large amplitude upbeating nystagmus on attempted upgaze and who were found to have congenital stationary night blindness.504a Neuroimaging can be reserved for cases in which the results of ERG are normal. If ERG is also negative, the diagnosis of hereditary vertical nystagmus should be considered (discussed later).323,379,509 The positive family history and good visual acuity in patients with familial upbeating nystagmus readily distinguishes it from infantile upbeating nystagmus associated with anterior visual pathway disease.222

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Congenital Downbeat Nystagmus Congenital downbeat nystagmus is rare. Little is known about its pathogenesis, but an accumulating body of evidence suggests that it is usually hereditary and rarely associated with a structural CNS lesion.80 It differs fundamentally from the horizontal and upbeating forms of infantile nystagmus in its tendency to resolve spontaneously in the first few years of life.80,573 The infant with a downbeat nystagmus and negative neuroimaging is likely to have a benign form of downbeat nystagmus characterized by (1) a chindown position; (2) some degree of ataxia and imbalance when learning to walk; (3) resolution of nystagmus and anomalous head posture by 2 years of age; and (4) a firstdegree relative with a history of a chin-down position in infancy that resolved (Fig. 8.15).64 A parent may also show subtle evidence of central vestibular imbalance (gaze-evoked nystagmus, subtle, downbeating nystagmus on oblique gaze downward).64 Unlike acquired hereditary forms of downbeat nystagmus that may have their onset in childhood and may be harbingers of spinocerebellar degeneration, congenital hereditary downbeating nystagmus seems to impart a benign neurological prognosis. Eye movement recordings have demonstrated a linear slow-wave configuration, unlike the increasing exponential waveform considered classic for infantile nystagmus. In contradistinction to the anterior visual pathway disease that frequently underlies upbeating nystagmus, patients with transient familial downbeating nystagmus of infancy have good vision once the nystagmus resolves. Phenomenologically, tonic upgaze and downbeat nystagmus are closely related conditions, differing only in the

8 Nystagmus in Children

presence or absence of rhythmical downward saccades. It is likely that benign hereditary downbeat nystagmus and the syndrome of benign tonic upward deviation of the eyes with ataxia are variants of the same disorder. In several affected children, tonic upgaze has evolved into downbeating nystagmus.64,443,444 In benign tonic upward deviation of the eyes, the conjugate upward deviation usually improves following sleep and becomes worse with fatigue or stress.19,175,185,214 Several children have improved following treatment with levodopa.94 Prismatic therapy may be a useful therapeutic adjunct in the treatment of this condition while awaiting resolution.573 Both conditions probably result from an imbalance in central vestibular tone that is gradually compensated.94 In a child with acquired downbeat nystagmus, MR imaging should therefore be obtained to rule out an underlying CNS malformation at the level of the craniocervical junction, such as Arnold–Chiari malformation, basilar impression, platybasia, syringobulbia, and Klippel–Feil anomaly.482 In many of these conditions, the downbeat nystagmus results from compression of the herniated cerebellum against the caudal brainstem rather than an intrinsic abnormality of the ocular motor pathways, as demonstrated by the clinical improvement that often follows surgical decompression.47,482 Hereditary conditions such as episodic ataxia type 2 can present with downbeat nystagmus with recurrent attacks of ataxia that are provoked by physical exertion, emotional stress, or alcohol.521 Migraine headaches occur in more than half of cases.312 Cerebellar atrophy, especially of the anterior vermis, can be detected on MR imaging.550 Episodic ataxia type 2 usually begins in early childhood, most often before age 20.521 Between spells, more that 90% of patients exhibit central ocular motor disturbances such as gaze-holding

Fig. 8.15 Hereditary congenital downbeat nystagmus. Left: Photo of affected infant showing compensatory chin down position before the nystagmus resolved. Right: Photo of mother as an infant showing similar chin down position before the nystagmus resolved. With permission from Brodsky MC80

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Periodic Alternating Nystagmus

d eficits, saccadic smooth pursuit, impaired visual suppression of the VOR (especially downbeat nystagmus) or, rarely, bilateral internuclear ophthalmoplegia. Episodic ataxia 2 is allelic with familial hemiplegic migraine type 1, which is almost exclusively caused by gain-of-function mutations, resulting in an increase of calcium flow through the CACNA1A channel.439 As discussed in the section on skew deviation, downbeat nystagmus (a pitch movement) may be a bilateral form of the ocular tilt reaction (a roll movement) at least in some patients.76 Brandt and Dieterich73 suggested that overlapping pathways modulate roll and pitch function of the VOR, making efficient use of the vestibular network. According to their hypothesis, a unilateral skew deviation reflects a central graviceptive imbalance in the roll plane while bilateral paramedian lesions or bilateral dysfunction of the cerebellar flocculus produces a tone imbalance in the pitch plane. The principle behind this operation resembles the guidance system of airplanes, wherein unilateral activation of a brake flap causes the plane to roll, while bilateral activation results in downward pitch. In a bilateral ocular tilt reaction, the vertical components summate to produce the slow-phase vertical drift of both eyes while the torsional components cancel each other out. Thus, a roll imbalance manifests as an ocular tilt reaction, while bilateral otolithic imbalance produces upbeat or downbeat nystagmus in conjunction with an alternating skew deviation on lateral gaze.73 Humans have a physiological upward velocity bias because the gain of all upward slow eye movements is greater than that of downward slow eye movements in normal human subjects and in monkeys.68 Because gravity influences the vestibular system, it is hypothesized that the excitatory superior vestibular nucleus and ventral tegmental tract pathways, along with their specific floccular inhibition, have incorporated an upward drift bias to counteract the gravity pull.448 In adults, 4-aminopyridine and 3,4 aminopyridine have recently been used to successfully treat downbeat nystagmus with minimal side effects, presumably by intensifying the excitability of Purkinje cells and their inhibitory cerebellar input on vestibular nuclei neurons.316,521

Hereditary Vertical Nystagmus Several families have been described with vertical pendular (or occasionally upbeating) nystagmus, cerebellar ataxia, and negative neuroimaging studies.323,379 In one report,323 the cerebellar findings were progressive, suggesting that these patients had a hereditary, cerebellar degeneration. Hereditary vertical nystagmus does rarely occur as an intermittent phenomenon.509

Periodic Alternating Nystagmus Up to 17% of the infantile nystagmus population (with or without sensory visual deficits) has a periodicity to their nystagmus.177,279,494 These patients are found on prolonged observation to have a reversal in the direction of their nystagmus at approximately 2-min intervals. As the nystagmus finishes one half-cycle (e.g., right-beating nystagmus), there is a brief transition period in which upbeating nystagmus, downbeating nystagmus, or square wave jerks may be seen before the next half-cycle (e.g., left-beating nystagmus) commences.365 Careful examination usually shows that the nystagmus is actually aperiodic, in that one phase generally predominates. It is also common for the duration of each phase of the cycle to vary from one cycle to the next. It is important (and often difficult) to distinguish periodic alternating nystagmus from infantile nystagmus with “double torticollis,” in which two separate horizontal null points exist and the patient randomly uses one or the other. In some families, periodic alternating nystagmus is inherited as an isolated X-linked condition.285 Structural CNS lesions are rarely seen in congenital periodic alternating nystagmus and the underlying pathophysiology remains elusive. Congenital periodic alternating nystagmus is associated with a high incidence of albinism.2,494 Therefore, pupillary light reflexes should be examined for a positive angle kappa, and slit lamp examination should be carefully performed to look for iris transillumination. Those with albinism tend not to have compensatory head positions, perhaps because of poor vision which does not improve sufficiently to warrant this adaptation.494 Those who do have anomalous head turns may show a unidirectional head turn despite the fact that the nystagmus reverses direction.494 In some cases, the cycles have been found to be as long as 5 min.234 Gradstein et al234 have found that a four muscle recession works best in the treatment of head turns associated with periodic alternating nystagmus. Acquired periodic alternating nystagmus is usually seen in older children or adults but may present in early childhood. Causes of acquired periodic alternating nystagmus include multiple sclerosis, posterior fossa lesions, encephalitis, otitis media, syphilis, aqueductal stenosis, and Arnold–Chiari malformation.257 Unlike congenital periodic alternating nystagmus, acquired periodic alternating nystagmus is usually associated with structural lesions involving the cerebellum or its central connections. Kalyanaranman317 reported three siblings who had periodic alternating nystagmus with associated head nodding as part of cerebrocerebellar degeneration. Reports of acquired periodic alternating nystagmus following visual loss (e.g., vitreous hemorrhage or cataract) and its disappearance with restoration of vision provide an important clue to the underlying pathophysiology.309

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Animal experiments combined with additional data in humans suggest that acquired periodic alternating nystagmus probably requires concurrent CNS dysfunction at two separate levels. The nodulus and uvula of the cerebellum are believed to control post-rotational nystagmus, which is prolonged following ablation. Periodic alternating nystagmus can be produced in animals following ablation of these structures if visual deprivation is superimposed. It is believed that normal vestibular repair mechanisms act to reverse the direction of the nystagmus. Under normal circumstances, the oscillations of periodic alternating nystagmus would be blocked by visual fixation, smooth pursuit, and optokinetic mechanisms. When these visual stabilization systems are held in abeyance (in the setting of visual deprivation with concurrent disease of the cerebellar flocculus), removal of Purkinje cell inhibition on the vestibular nuclei allows the central velocity storage mechanism to become unstable,362,366 and the acquired form of periodic alternating nystagmus develops. It is therefore likely that patients who acquire periodic alternating nystagmus following loss of vision may harbor a congenital lesion of cerebellum that is clinically silent until there is a reduction in retinal input.252 Pharmacological evidence suggests that the nodulus and uvula maintain inhibitory control on the vestibular rotational responses via the inhibitory neurotransmitter GABA.99 Halmagyi et al255 documented successful treatment of the acquired form of periodic alternating nystagmus with the GABA-ergic drug baclofen. The finding that acquired periodic alternating nystagmus is abolished by baclofen, both in humans and in animals following ablation of the nodulus and uvula, further supports the accepted pathogenetic mechanism for acquired periodic alternating nystagmus. Although congenital periodic alternating nystagmus is reportedly refractory to baclofen, patients occasionally improve with treatment.99,113

8 Nystagmus in Children

Seesaw nystagmus characteristically increases in bright light and dampens with accommodation or convergence.604 Although it is accepted that seesaw nystagmus can be an ominous neuro-ophthalmologic sign and that it often correlates with the presence of a suprasellar mass lesion, the precise neuroanatomical site of injury remains speculative. The two major theories of causation center on abnormal ocular motor output and anomalous visual sensory input. The motor theory states that large parasellar lesions compress the adjacent diencephalon and compress, injure, or disrupt the adjacent interstitial nucleus of Cajal. Discrete lesions involving the interstitial nucleus of Cajal at the junction of the rostral midbrain and diencephalon have been described in two patients with seesaw nystagmus.320,462 Stimulation of the interstitial nucleus of Cajal in the monkey produces an ocular tilt reaction consisting of extorsion and depression of the eye on the stimulated side and intorsion and elevation of the other eye, which is similar to a half cycle of seesaw nystagmus.577 The sensory hypothesis of Nakada and Kwee415 purports that chiasmal lesions disrupt subcortical pathways that carry signals from the inferior olive and cerebellar flocculus, which may normally be used for adaptive control of vestibular responses. According to this hypothesis, associated bitemporal hemianopia alters retinal error signals that reach the inferior olivary nucleus through two discrete pathways, independent of the geniculocortical projections.524 Retinal error signals in the inferior olivary nucleus and their connections with Purkinje cells in the cerebellum are utilized for VOR adaptation, which renders the visuovestibular control system unstable,415 while the pursuit system is unaffected. Nakada and Kwee415 speculated that integrity of the inferior-olivary nodulus connections in seesaw nystagmus could explain the 180-degree phase difference that distinguishes it from the midline form of oculopalatal myoclonus, where these connections are disrupted.

Seesaw Nystagmus

Congenital versus Acquired Seesaw Seesaw nystagmus is an uncommon form of pendular nystag- Nystagmus mus characterized by simultaneous elevation and intorsion of one eye, with depression and extorsion of the other eye, followed by a reversal of the cycle.128,365 Seesaw nystagmus usually occurs in patients with large suprasellar tumors involving the optic chiasm and extending into the third ventricle. These children usually have a bitemporal hemianopia.128 However, it is now recognized to accompany infantile nystagmus in patients with achiasmia.140 Most patients with idiopathic infantile nystagmus also display a subtle seesaw nystagmus on eye movement recordings.169 Less commonly, focal lesions confined to the rostral mesencephalon produce seesaw nystagmus in conjunction with other brainstem ocular motility disorders. Mild seesaw nystagmus is easily misinterpreted as torsional nystagmus if the vertical component of the nystagmus is overlooked.

In congenital seesaw nystagmus, neuroimaging must be obtained to look for achiasmia (discussed above). Congenital seesaw nystagmus is rarely seen in infants with albinism and other sensory visual disorders who later convert to a horizontal nystagmus.297,600 It has been noted that congenital forms of seesaw nystagmus may lack the torsional components or even show the opposite pattern (i.e., extorsion with elevation and intorsion with depression).128,481 Zell and Biglan604 have stressed that the direction of cyclodeviation of the globes on vertical excursion cannot be relied on to clinically differentiate the congenital from the acquired form of seesaw nystagmus. Acquired seesaw nystagmus in children is most commonly caused by craniopharyngioma and other parasellar tumors but

Saccadic Oscillations that Simulate Nystagmus

may also be seen with other neurological conditions (e.g., hydrocephalus, acute febrile illness), trauma, and rarely with congenital retinal dystrophies,604 septo-optic dysplasia,129 Chiari malformation,604 and syringobulbia.192 Strabismus, most commonly exotropia, is common in children with seesaw nystagmus.184,604 The finding of null-point torticollis suggests the possibility of an associated ocular tilt reaction.40 Pendular seesaw nystagmus is most often described in patients with achiasmia37,38 or large parasellar tumors.256 It has also been reported with visual loss,382 retinitis pigmentosa,61 traumatic bitemporal hemianopia,186 and septo-optic dysplasia.129 Jerk seesaw nystagmus (hemi-seesaw nystagmus) usually occurs in patients with lesions in the region of the interstitial nucleus of Cajal.256 Such patients may also have a contralateral ocular tilt reaction.366 However, hemi-seesaw nystagmus has also been reported in patients with lesions involving the medulla,103 Chiari malformation,605 and oculopalatal myoclonus. It therefore seems likely that visual loss activates the recalibration mechanism for eye movements that compensate for head roll, and that certain mesodiencephalic or medullary lesions disrupt visual motion calibration of the normal physiological response.366 Drugs and medications such as alcohol,207 baclofen,99 and clonazepam99 have been reported to abolish seesaw nystagmus.

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of convergence-retraction nystagmus with dorsal midbrain syndrome (which results from a lesion of the posterior commissure) gives strong localizing value to the dorsal mesencephalon. Dorsal midbrain syndrome in infancy suggests the diagnosis of aqueductal stenosis, while its recurrence in children who have had a ventriculoperitoneal shunt placed for hydrocephalus usually signifies shunt failure.117 The onset of dorsal midbrain syndrome in an older child suggests pineal tumor. Midbrain vascular malformations or traumatic injury may also cause dorsal midbrain syndrome in childhood.365,531 We have observed convergence-retraction nystagmus as the presenting sign of Leigh’s disease in a 4-year-old boy, and Plange450 has documented a similar case. The finding of jerky convergent movements of the eyes on attempted upgaze in association with bilateral fixed downgaze and bilateral ptosis (rather than lid retraction) is highly suggestive of congenital fibrosis syndrome. In this setting, the apparent convergence-retraction nystagmus may be either by aberrant innervation or by the secondary adducting effects of tight inferior rectus muscles and the contracting superior rectus muscles during attempted upgaze.83

Opsoclonus and Ocular Flutter Saccadic Oscillations that Simulate Nystagmus Convergence-Retraction Nystagmus Convergence-retraction “nystagmus” is a disorder in which attempted upward saccades evoke repetitive, simultaneous saccadic contractions of all rectus muscles, producing a series of rapid, jerky convergent movements with associated retraction of the globes. In some patients, convergence retraction nystagmus seems to be a saccadic disorder, consisting of asynchronous opposing adduction saccades whenever upward quick phases are stimulated.365,432 In others, a vergence disorder is suggested by synchrony of the vergence response in both eyes.461 Convergence-retraction nystagmus is seen almost exclusively in the setting of dorsal midbrain syndrome, which is characterized by impaired upgaze, upper lid retraction (Collier’s sign), pupillary dilation with light-near dissociation, and impairment of either convergence or divergence.365 Infants with dorsal midbrain syndrome from congenital hydrocephalus may display the “setting sun” sign, in which upper lid retraction and an upgaze palsy occur together with tonic downward deviation of the eyes. Convergenceretraction nystagmus is best elicited by having a child follow downward-moving optokinetic targets that necessitate repetitive upward saccades. It may be overlooked if only vertical pursuit movements are examined. The invariable association

Opsoclonus is a striking ocular motility disorder characterized by involuntary, chaotic bursts of multidirectional, high-amplitude saccades, without an intersaccadic interval.497 Opsoclonus differs fundamentally from nystagmus in that the oscillations are saccadic and not rhythmical and consist of long silent periods punctuated by intermittent bursts of activity. In opsoclonus, three-dimensional eye movement recordings show a combination of horizontal, vertical, and torsional eye movements in adult opsoclonus.587 Although opsoclonus has a fairly characteristic clinical appearance, Leigh and Zee365 have emphasized the uncertainty in diagnosing opsoclonus without eye movement recordings because it is impossible to ascertain the pattern of back-to-back saccades with no intersaccadic interval by mere clinical observation. When the oscillations are clinically horizontal, they are termed ocular flutter.93,365 While continuous and intermittent forms of opsoclonus seem to correlate with the severity of the underlying disease, the presence of opsoclonus versus ocular flutter does not.93

Causes of Opsoclonus Neonatal Opsoclonus Neonatal Opsoclonus is now a well-recognized phenomenon. Hoyt et al have reported that opsoclonus may occur as a transient phenomenon in healthy neonates.296,407 In one study,

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opsoclonus was identified clinically in 3 of 528 (0.6%) preterm infants screened for retinopathy of prematurity. On follow-up examination, the opsoclonus disappeared by the age of 6 months with no complications. Such reports of benign opsoclonus in term and preterm infants may be, at least in part, related to the insertion of an eyelid speculum. Paraneoplastic Opsoclonus The major diagnostic consideration for opsoclonus in the first several years of life is a neural crest tumor such as neuroblastoma. An opsoclonus-myoclonus-ataxia syndrome affects 2–3% of patients with neuroblastoma, an acute neurologic disorder characterized by involuntary chaotic jerking and ataxia.268,269,381 Conversely, neuroblastoma is found in approximately half of cases with opsoclonus in this age range.527 However, the high incidence of spontaneous regression of neuroblastoma could account for some of the remaining cases.527 Children with and without a tumor differ little in neurologic symptoms. The earliest neurological symptoms are staggering and falling. Later symptoms include body jerks, drooling, refusal to walk or sit, speech problems, decreased muscle tone, opsoclonus, rage attacks, and inability to sleep.454,527 Patients with opsoclonus-myoclonus-ataxia and neuroblastoma have excellent survival but a high risk of neurologic sequelae.23,118,473 Musarella et al410 found a 100% 3-year survival rate in children with neuroblastoma who presented with opsoclonus, compared with 78.6% in those who presented with Horner’s syndrome and 11.2% in those with orbital metastasis. Improved survival in the subgroup with opsoclonus could not be accounted for by earlier diagnosis or a higher percentage of low-staged cases. Late neurologic sequelae can be drastic and affect the quality of life.400 These sequelae include delays in motor function, speech, and cognition, or persisting abnormalities such as myoclonus, ataxia, dysarthria, and hypotonia.473,476 MR imaging may be normal in the acute phase,125 but children with opsoclonus-myoclonus-ataxia may show late development of cerebellar atrophy.268,269 Although the opsoclonus usually resolves, residual behavioral, language, and cognitive problems occur in most and significantly affect the quality of life.399 Some children show a clinical course suggestive of a progressive encephalopathy, rather than a timelimited single insult, as indicated by a significant negative correlation of functional status with age at testing.401 It has been hypothesized that the opsoclonus myoclonus in these children may be pathogenetically related either to a peptide produced by the tumor directly causing myoclonus and opsoclonus, or to an immunological cross-reactivity between the tumor and normal cerebellar neurons, with persistent anticerebellar antibodies being produced long after the tumor is removed. 236,399,410 Increasing evidence supports

8 Nystagmus in Children

this immune hypothesis.420,473 Several forms of immunosuppressive therapy have been successful in treating opsoclonus-myoclonus-ataxia. Patients have had resolution of acute symptoms after treatment with steroids of adrenocorticotrophic hormone (ACTH).452 ACTH, prednisone, and intravenous immunoglobulin, and plasmapheresis are used, with ACTH associated with the best early response.527,548,597 A paraneoplastic panel should be obtained in the young child with opsoclonus, because antineuronal antibodies have been identified in several children with neuroblastoma.114,196,336,344 If antineuronal antibodies are found, this indicates the presence of a cancer (usually neuroblastoma). Anti-Hu antibodies have been found in a few patients with opsoclonus and neuroblastoma, but most cases have shown no detectable autoantibodies.28,53,66,344,453 Because antineuronal immune reactivity does not appear to be a long-term feature of opsoclonus in most children with neuroblastoma,268 a negative paraneoplastic panel does not rule out neuroblastoma as a diagnostic possibility. If not found, one cannot rule out the presence of a cancer because antineuronal autoantibodies have been identified in several children with neuroblastoma.114,196,336,344

Kinsbourne Encephalitis Opsoclonus also occurs commonly as part of a “benign” encephalitis (Kinsbourne myoclonic encephalopathy, dancing eyes, and dancing feet).352,399 In affected patients, vertigo and truncal ataxia follow a prodrome of malaise and fever. Cerebellar and long-tract signs accompany shivering movements of the head and body. Along with the constantly changing, often forceful myoclonic jerking of the extremities and trunk (polymyoclonia), there are shocklike torsions of the head and neck, as well as opsoclonus.420 Spinal fluid protein may be elevated. Cerebellar and long-tract signs may also occur, but the sensorium remains clear apart from emotional lability.366 Although the illness usually resolves over weeks to months, the clinical course may be protracted and recovery incomplete. Recent findings of small neuroblastomas or ganglioneuroblastomas in children with the chronic form of myoclonic encephalopathy have led some investigators to suggest that myoclonic encephalopathy may reflect the presence of an indolent neural crest tumor that was previously impossible to identify without high-resolution CT scanning or MR imaging.399 This theory is compatible with the finding that several neuroblastic tumors in infancy tend to regress or mature into tissue with benign neural crest cells.74 Many children fail to improve neurologically following resection of the tumor and develop a chronic ataxic syndrome that worsens with minor febrile illnesses and is associated with chronic symptoms of delayed speech and motor develop-

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Saccadic Oscillations that Simulate Nystagmus

ment.399 The favorable response to steroid treatment suggests possible immunologic mechanisms, although an autoimmune pathogenesis has yet to be proven.497 Intravenous immunoglobulin, corticosteroids, ACTH, azathioprine, or monoclonal antibodies directed against B-lymphocytes may hasten recovery.52,366,451,455 Isolated reports suggest that clonazepam and propranolol may occasionally be effective in the treatment of this disorder.99,365

Miscellaneous Causes Opsoclonus has also been attributed to exposure to toxins or drugs, systemic disease, trauma, meningitis, hydrocephalus, intracranial tumors, carbohydrate-deficient glycoprotein syndrome,518 immune reconstitution,546 neuroborreliosis,560 and poststreptococcal dyskinesia.126,464 It has been suggested that girls with Turner’s syndrome may be predisposed to the development of neuroblastoma and related tumors.67

Pathophysiology The precise anatomical localization of the abnormality underlying opsoclonus is unknown.497 Early findings of abnormal cerebellar Purkinje cells led to the supposition that opsoclonus resulted from cerebellar dysfunction.188 The clinical observation that opsoclonus regresses through phases of flutter and dysmetria lends credence to this hypothesis.479 The subsequent discovery of burst neurons (that are active immediately prior to saccades and carry information specifying the parameter of the imminent saccade) and pause neurons (that inhibit burst neurons that generate saccades) led Zee and Robinson602 to hypothesize that disorders that selectively impair pause cell function could lead to opsoclonus. Pause cells lie in the nucleus raphe interpositus, which is located in the midline between rootlets of the abducens nerves. They discharge continuously except immediately prior to and during saccades when they pause. They pause either before eye movements in a specific direction (directional pause neurons) or before eye movements in all directions (omni-pause neurons). Their function is to inhibit saccades. However, an autopsy study of opsoclonus patients showed no abnormalities in the pontine region, where pause cells are located.468 Patients who display MR signal abnormalities in the pontine tegmental raphe (where pause cells are located) demonstrate gaze palsies or internuclear ophthalmoplegia with slowing of saccades rather than opsoclonus.88 Likewise, experimentally induced lesions of the pause cell region in monkeys have produced slow saccades rather than opsoclonus, although some areas of burst cells may have also been affected.318 It is possible that pause cell dys-

function could result from metabolic or neurotransmitter abnormalities in the absence of a discrete lesion or visible histopathological changes.468 The pathophysiology of opsoclonus is also unclear.260,587 It has been suggested that any input driving the burst cells could also inhibit the pause cells via inhibitory burst neurons, thereby resulting in opsoclonus.365,487,497 One hypothesis suggests that opsoclonus results from damage to omnipause cells that are found in the nucleus raphe interpositus (rip) adjacent to the midline of the paramedian pontine reticular formation (PPRF).602 Omnipause cells inhibit saccade burst neurons in the PPRF and riMLF, preventing unwanted saccades. According to that hypothesis, saccadic oscillations occur when the pause cells fail to tonically inhibit the burst neurons. However, experimental lesions of omnipause neurons cause slowing of saccades, but not saccadic oscillations319 and patients with opsoclonus have demonstrated an absence of histopathologic changes in omnipause neurons.294,468,587 However, cerebellar dysfunction has also been invoked in the pathogenesis of opsoclonus. Although injury to Purkinje cells, granule cells, and the dentate nuclei have been demonstrated,108,188,260,472 these abnormalities can also occur in individuals without opsoclonus. Furthermore, partial ablations of the cerebellar cortex440 or cerebellectomy, including the deep cerebellar nuclei in monkeys,440,576 have not been observed to produce opsoclonus. Shawkat et al497 have demonstrated overshoot dysmetria on eye movement recordings of patients with opsoclonus who had no concurrent abnormalities of smooth pursuit, optokinetic nystagmus, or vestibuloocular reflex. They suggested that these findings are compatible with a lesion affecting the cerebellar fastigial nuclei that spares the flocculus and paraflocculus.

Voluntary Nystagmus The prevalence of voluntary nystagmus has been estimated to be 5% in a normal population of undergraduates.414 The diagnosis of voluntary “nystagmus” should be considered in any child who appears to have ocular flutter or opsoclonus. Not surprisingly, some patients with voluntary nystagmus report oscillopsia.423 Voluntary nystagmus is usually brought on by a strong convergence effort that causes the patient to display a strained facial expression, mild widening of the palpebral fissures, and occasional fluttering of the eyelids. Voluntary nystagmus appears as an extremely fineamplitude, rapid, conjugate, horizontal oscillation that resembles an ocular shiver. The strong convergence effort necessary to evoke the oscillation usually dissipates after 20–30 s, after which the facial appearance normalizes. The

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A number of derivative terms have been coined to describe the many clinical variants of ocular bobbing.322 These include:

Fig. 8.16 Electro-oculographic recording of voluntary “nystagmus,” demonstrating that it consists of a series of back-to-back saccades with no intersaccadic intervals. Same electro-oculographic pattern is seen in opsoclonus. Adapted, with permission, from Shults WT et al499

inability to sustain the oscillation provides a clue to the diagnosis. The ability to generate voluntary ocular tremor appears to be familial in some instances,218,327,422,423 suggesting an autosomal dominant inheritance, possibly with incomplete penetrance.423 A tonic imbalance in the vestibulo-optokinetic subsystem can cause infantile nystagmus but have a linear slow-phase jerk nystagmus that simulates voluntary nystagmus, as has recently been reported in a 27-month old girl.369 Rare cases of voluntary vertical nystagmus have also been reported.351 Eye movement recordings have shown that, unlike true nystagmus, voluntary “nystagmus” consists of a series of back-to-back horizontal saccades with no intersaccadic interval (Fig. 8.16), making this oscillation electro-oculographically indistinguishable from opsoclonus.499

Ocular Bobbing Ocular bobbing was defined by Fisher as intermittent, usually conjugate, rapid downward movement of the eyes followed by a slower return to the primary position.195 It is not clear which pathophysiological mechanism causes the bobbing movement.127,358 Bobbing is primarily a sign of an intrinsic pontine lesion. Vertical movements should be dependent on pontine lesions in which the vestibular nucleus and vertical tracts are protected as these movements develop on the loss of horizontal movements. Larmande et al358 suggested that ocular bobbing need not be regarded as an abnormal eye movement but as the residual movement of patients who are totally deprived of both horizontal and upward movements. Most types of bobbing develop as a result of pontine hemorrhage.322

·· Ocular bobbing: An intermittent, usually conjugate, rapid downward movement of the eye(s) followed by a slower return to the primary position ·· Reverse bobbing: A rapid deviation of the eye(s) upward and a slow return to the primary position ·· Inverse bobbing: The eye(s) slowly moves downward then rapidly restores to its normal position ·· Converse bobbing: The eye(s) slowly moves upward and then rapidly restores to its normal position Although reverse bobbing is usually observed in patients who are unconscious and who have significant pathology and disruption of the reticular formation, unilateral reverse ocular bobbing was recently reported in a child with tuberous sclerosis and a midpontine lesion.322

Neurological Nystagmus The term neurological nystagmus, which has been used to describe pediatric nystagmus associated with neurodegenerative disorders, is somewhat ambiguous, because all nystagmus is fundamentally neurological in origin. As is clear from the preceding discussion, some of the rarer forms of nystagmus (spasmus nutans, monocular nystagmus, seesaw nystagmus, convergence-retraction nystagmus) should be recognized as ominous neuro-ophthalmological signs, as they often portend intracranial lesions at specific neuroanatomical sites. These forms of nystagmus are usually distinguishable from infantile nystagmus by their clinical appearance. Neurodegenerative disease occasionally produce a horizontal nystagmus in infancy prior to the development of other neurological signs.100,372,581,595,596 In our experience, it is not uncommon for infants with neurodegenerative disease to be initially diagnosed as having infantile nystagmus, only to have the diagnosis amended as developmental delay, hypotonia, seizures, or other neurological problems supervene. The prevalence of children with neurodegenerative infantile nystagmus in our pediatric patient population is less than 5%. In contrast, retrospective neurological reviews that purport a high prevalence of neurodevelopmental delay in “nonhereditary infantile nystagmus”423,517 probably draw from neurological pediatric populations biased toward these disorders. The clinical overlap between infantile nystagmus and the horizontal pendular nystagmus associated with neurological disease should not be misconstrued as an indication for neuroimaging in infants with paradigmatic infantile nystagmus, because neuroimaging is rarely helpful early in the course of

Pelizaeus-Merzbacher Disease

a neurodegenerative disorder if no other neurological signs are apparent. In other neurologic conditions, awareness that the nystagmus is neurologic may alter its treatment. In children with hydrocephalus, for example, neurosurgical treatment such as shunting may alter abnormal head positions associated with neurologic nystagmus. Strabismus surgery to change the null position should be performed after any effects of neurosurgical treatment can be evaluated.220 The neurodegenerative disorders discussed below are particularly prone to cause nystagmus.

Leigh Subacute Necrotizing Encephalomyelopathy Leigh disease is an autosomal recessive mitochondrial disorder leading to progressive neurological degeneration in infancy or childhood. Its onset is usually heralded by the insidious development of psychomotor retardation and brainstem and cerebellar dysfunction resulting in ataxia, dystonia, and nystagmus. Limb weakness and optic atrophy are often noted. T2-weighted MR imaging in Leigh disease shows characteristic symmetrical hyperintense lesions involving the basal ganglia and brainstem, with predominant involvement of the putamen.387 Patients with Leigh disease usually have metabolic acidosis, with elevated lactate and pyruvate concentrations in the blood and CSF, suggesting that a disorder of pyruvate metabolism may be the primary biochemical defect. Specific mitochondrial enzyme deficiencies associated with Leigh disease have been reported to include pyruvate carboxylase deficiency, pyruvate dehydrogenase complex defects, and cytochrome c oxidase deficiency.317,398 Current evidence suggests that a nuclear DNA-encoded factor is responsible for the mitochondrial enzyme deficiencies in most patients with Leigh disease.243,460 Nystagmus, ophthalmoplegia, and optic atrophy are the predominant neuroophthalmologic findings in Leigh’s disease. In addition to nystagmus of virtually any type, children with Leigh disease can manifest with a variety of brainstem ocular motility deficits, including dorsal midbrain syndrome,450 internuclear ophthalmoplegia, and horizontal gaze palsy. Leigh disease can also produce nystagmus and head nodding, thereby mimicking spasmus nutans.488

Pelizaeus-Merzbacher Disease Pelizaeus-Merzbacher disease is an X-linked recessive leukodystrophy with a fairly characteristic clinical picture.18 It often presents in infancy with abnormal tremu-

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lous movements of the eyes and intermittent shaking movements of the head that may simulate spasmus nutans.18,41,376 Electro-oculography shows a distinctive combination of elliptical pendular and upbeat nystagmus that has not been described in other neurodegenerative diseases.537 These early findings are followed by loss of developmental milestones, choreiform and athetoid movements, severe cerebellar signs, and difficulty initiating saccades. Seizures, pyramidal signs, and spasticity appear later. Standing and talking are not possible, and some infants do not even develop head control.18 In contrast, intellectual function is often preserved until the terminal stages of the disease. Children may also display ocular motor apraxia and cerebellar eye signs, including saccadic dysmetria.366,427,537 MR imaging shows lack of myelination without frank evidence of white matter destruction.48 The presumptive clinical diagnosis is confirmed on postmortem examination that shows a diffuse, patchy, “tiger-stripe” demyelination throughout the brain. Pelizeus-Merzbacher disease affects primarily the white matter of the CNS and is caused by mutations of the proteolipid protein 1 gene, which codes for proteolipid protein (PLP), one of the major structural proteins of myelin.298a Most affected patients have duplications of the PLP gene, which has been mapped to Xq21.1.298a These mutations probably result in the accumulation of PLP in the oligodendrocytes, with resultant impaired cell function and early oligodendrocyte death, resulting in impaired myelin formation.298a

Joubert Syndrome Joubert syndrome comprises the triad of congenital retinal dystrophy, episodic panting tachypnea, and variable absence of the cerebellar vermis.332 Affected infants also exhibit profound developmental delay and hypotonia.355 The congenital retinal dystrophy in Joubert syndrome was initially classified as Leber congenital amaurosis.406 Unlike Leber congenital amaurosis, however, Joubert syndrome is associated with good visual acuity (visual acuity may be as high as 20/60) and relatively preserved VEPs.355 The nystagmus in Joubert syndrome may consist of a torsional pendular nystagmus or a seesaw nystagmus.355 Alternating hyperdeviation of the eyes, tonic deviation of the eyes laterally, periodic alternating gaze deviation,257 and abnormal saccadic movements (decreased velocity, hypometria, increased latency) have also been described.355,406 Children may have congenital ocular motor apraxia and use head thrusts to view objects of interest in the lateral visual field.355,406 The important role

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of the cerebellar vermis in stabilizing saccades suggests that the severe vermal hypoplasia must significantly contribute to the complex ocular motility dysfunction seen in this condition.

Santavuori-Haltia Disease Santavuori-Haltia disease is characterized by a period of normal visual development followed by visual failure, speech and motor deterioration that begins between six months and two years of age.477a This infantile form of ceroid lipofucsinosis differs from acquired forms in that poor vision, nystagmus, retinal lesions, and optic atrophy are present early in the course of the disease. Blindness, ataxia and myoclonic jerks are frequent accompaniments.477a

Infantile Neuroaxonal Dystrophy Infantile neuroaxonal dystrophy is an autosomal recessive neurodegenerative disorder with onset in the first or second year of life.525 Clinically, affected children show difficulty in walking, psychomotor regression, marked hypotonia, muscular atrophy, pyramidal tract signs, and optic atrophy progressing to blindness.525 MR imaging demonstrates marked cerebellar atrophy, with a striking diffuse hyperintensity of the cerebellar cortex on T2-weighted imaging that is probably secondary to extensive gliosis and shrinkage of the cerebellar cortex.525 The basic metabolic defect is unknown. The diagnosis can be established by skin, nerve, conjunctiva, or muscle biopsy that shows large dystrophic axons (spheroids).583 Children with infantile neuroaxonal dystrophy may have a pendular nystagmus that is clinically indistinguishable from infantile nystagmus.464 The mutation responsible for this disease was recently mapped to the gene encoding phospholipase A2 group VI on chromosome 22q13.1.329,464

Carbohydrate-Deficient Glycoprotein Syndromes The carbohydrate-deficient glycoprotein syndromes are a group of lysosomal storage disorders in which there is defective glycosylation of secretory, lysosomal, and membrane-bound glycoproteins.304,348 The most common form

8 Nystagmus in Children

(type 1a) produces prominent neurologic dysfunction in infancy. Ophthalmologic features are common and include strabismus, nystagmus, and a retinal degeneration with severely diminished scotopic electroretinographic waveform.26,198 Stark et al518 described an infant with carbohydrate-deficient glycoprotein syndrome type 1a who had diffuse cerebellar hypoplasia with congenital ocular motor apraxia and an ocular flutter that manifested when the child was awakened or startled.

Down Syndrome Nystagmus is seen in 30% of patients with Down syndrome. While a visual sensory etiology (e.g., congenital cataract, high myopia) is occasionally present, many children with Down syndrome and nystagmus have no visually significant ocular disease.562 Patients with Down syndrome may display a fine rapid horizontal nystagmus. Less commonly, a dissociated pendular nystagmus or a manifest latent nystagmus may be seen. Most children with Down syndrome and nystagmus have associated esotropia.562

Hypothyroidism About 10% of children with hypothyroidism are reported to have a high-frequency, low-amplitude nystagmus.373,385 Strabismus, most commonly esotropia, is seen in approximately half of hypothyroid children.373 Some children reported to have hypothyroidism and nystagmus actually had bilateral optic nerve hypoplasia with anterior pituitary hormone deficiency.485

Maple Syrup Urine Disease Maple syrup urine disease is an autosomal recessive disorder of amino acid catabolism in which affected infants present with intermittent lethargy, poor feeding, irregular respirations, and fluctuating muscle tone.601 Biochemical studies show severe metabolic acidosis and ketosis. Older children can present with ataxia or dystonia.531 Various forms of gaze palsies (upgaze paresis, mixed vertical and horizontal paresis, adduction paresis) are frequently seen, as is bilateral ptosis.530 Nystagmus is usually confined to the recovery phase (after dietary restrictions are instituted) and consists of

Summary

intermittent, brief bursts of flutterlike movements of the eyes and lids.365,530,601 Rapid diagnosis is essential, as the outcome is worse after the first 24 h, with progressive and permanent neurological sequelae.419,531

Nutritional Nystagmus Young children with severe malnutrition may develop an acquired, gaze-evoked nystagmus with a Wernicke type of encephalopathy that resolves following administration of B group vitamins.541,599

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Familial Vestibulocerebellar Disorder Harris et al described an autosomal dominant from of gazeevoked nystagmus characterized by saccadic horizontal pursuit movements, rebound nystagmus, and a slow build up of optokinetic nystagmus.259a These ocular motor findings reflect dysfunction of the cerebellar flocculus. Onset was at one year of age and patients had no associated ataxia. Ragge et al subsequently localized the gene to the long arm of chromosome 13.458a

Summary Epileptic Nystagmus Epileptic or ictal nystagmus is an uncommon phenomenon characterized by rhythmic saccadic eye movements occurring during epileptic seizures.321,366,539 Epileptic nystagmus has been reported in patients with typical absence seizures567 and with infantile nystagmus.293 Rarely, it manifests as convergence nystagmus598 or as isolated lid fluttering.397 Large-amplitude nystagmoid movements were reported in a newborn baby with severe birth asphyxia and probable periventricular leukomalacia and were followed 15–29 s later by ictal discharges in the occipital region.102

Cobalamin C Methylmalonic Aciduria and Homocystinuria The cobalamin C form of methylmalonic aciduria and homocystinuria is an inherited deficiency of the two coenzymatically active vitamin B12 derivatives, methylcobalamin and deoxyadenosylcobalamin.538 Its clinical manifestations include feeding difficulties, neural dysfunction, and ophthalmologic abnormalities (visual impairment, nystagmus, and infantile retinopathy with a conspicuous maculopathy). The mechanism by which the biochemical abnormalities cause retinal disease has not been defined. Cobalamin C methylmalonic aciduria and homocystinuria is a partly treatable metabolic cause of nystagmus and maculopathy characterized by large atrophic macular patches. Retinal findings are characterized by large atrophic macular patches. Dietary supplementation with the essential amino acid methionine has restored rod photoreceptor activity in one infant.538

Infantile nystagmus is the most common form of nystagmus in infants and children. Our understanding of infantile nystagmus has evolved to incorporate two new concepts: (1) most individuals with infantile nystagmus have a primary disturbance of the anterior visual pathways, and (2) the nystagmus waveform in idiopathic cases is indistinguishable from the waveform seen in patients with sensory visual loss. The recognition that infantile nystagmus is often associated with a primary visual deficit fueled speculation that the presence of a primary visual disturbance may be a prerequisite for the development of infantile nystagmus. Partly on the basis of this uncertainty, the clinical pendulum swung toward obtaining electrophysiological studies in more children with infantile nystagmus. However, it has been clearly demonstrated that many individuals with infantile nystagmus have no ocular or electrophysiological abnormalities that are detectable using currently available methodology. This is not to say that the recognized genetic defects cannot involve the sensory visual system but only that their effects fall below the present threshold for electrophysiologic detection. We believe that routine electrophysiological testing is not mandatory in the diagnostic evaluation of infantile nystagmus. When the ocular examination reveals no structural abnormalities, the four clinical signs of congenital retinal dystrophy (photophobia, paradoxical pupil, myopia, oculodigital reflex) serve to facilitate the identification of patients who are likely to have a congenital retinal dystrophy and thereby render the routine electrophysiological investigation of every child with infantile nystagmus unnecessary. Figure 8.17 is a clinical algorithm to assist in the differential diagnosis of horizontal nystagmus in children.

Idiopathic Infantile Nystagmus Confirm with: • good visual acuity (20/40-20/70) • normal ocular examination • normal ERG • positive family history

No

Spasmus Nutans

Normal

Congenital Suprasellar Tumor (chiasmal glioma, craniopharyngioma)

Abnormal

MR Scan

• Low amplitude, high frequency “ocular shiver” • May be intermittent, monocular, or asymmetrical • Head nodding • Variable torticollis

Fig. 8.17 Differential diagnosis of horizontal nystagmus in children

• Optic nerve hypoplasia • Achromatopsia • Leber’s congenital amaurosis • Congenital stationary night blindness • Congenital cataracts • Cone-rod or rod-cone dystrophy

• Aniridia

Infantile Nystagmus (of visual sensory origin) • Albinism

Yes

Photophobia? High myopia? Paradoxical pupil? Oculodigital reflex?

• Horizontal pendular or jerk nystagmus • Increased intensity in side gaze • Right beating in right gaze, left-beating in left gaze • Stays horizontal in upgaze • Dampens with convergence • No oscillopsia

Manifest-Latent Nystagmus

• Better VA under binocular conditions

• Usually associated with congenital esotropia or amblyopia

• Low amplitude, horizontal jerk nystagmus • Fast phase beats toward abduction in the fixating eye

Horizontal Nystagmus in Children

Neurological Nystagmus • Leigh disease • Pelizeus-Merzbacher disease • Joubert syndrome • Infantile neuroaxonal dysrophy • Down Syndrome • Hypothyroidism • Maple syrup urine disease • Nutritional Nystagmus

(seizures, hypotonia, developmental delay), or systemic anomalies

Associated neurological signs

References

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Chapter 9

Torticollis and Head Oscillations

Introduction Children with visual or neurological disorders can exhibit abnormal head postures (torticollis) or rhythmic movements of the head (oscillations). Torticollis is not a diagnosis, but a sign of an underlying disorder.128 Although technically defined as a contraction, often spasmodic, of the muscles of the neck,128 for the purposes of differential diagnosis, most causes of abnormal head position (spasmodic or otherwise) are generally included under the umbrella term torticollis. The neuro-ophthalmologic evaluation of torticollis is simplified by the frequent association of a head tilt with contralateral superior oblique palsy.162 While many ophthalmologists see a predominance of patients with superior oblique palsy (or at least diagnose them as such), a slight majority in the general pediatric population probably have congenital muscular torticollis.162 When strabismus and nystagmus are absent, the differential diagnosis includes a long list of ocular and systemic conditions. Head oscillations in children often signify spasmus nutans or congenital nystagmus; however, an awareness of other rare causes is necessary to provide a complete evaluation. Abnormal head movements are less likely to be overlooked by parents than abnormal head positions. Although we use the descriptive terms head shaking and head nodding, many children display a combination of horizontal and vertical oscillations, and some (especially those with spasmus nutans) show complex elliptical head oscillations when viewing objects of interest. The term head tremor has the advantage of being directionally nonspecific, but it connotes a rapid, small-amplitude head movement (as seen in benign essential tremor) that differs from the slower, larger-amplitude oscillations seen in children with neurological disease. This chapter focuses on the distinctive clinical manifestations of the neurological and systemic conditions that lead to torticollis, head oscillations, or both. It includes extensive discussion of common conditions and brief mention of rare disorders that warrant consideration once common conditions are excluded. Although these disorders are dichotomized into visual or neurologic for purposes of classification, the reader will appreciate that neurologic disease underlies many of the

visual disorders that lead to torticollis. Although the term ocular torticollis is commonly used to describe anomalous head positions that result from visual input, many of these disorders are ultimately neurological in origin.211 Other forms of abnormal head movement (head thrusting, myoclonus, tics, and habit spasms) are covered in Chap. 7 in the context of their associated neuro-ophthalmologic findings.

Torticollis Torticollis, derived from the Latin tortus (twisted) and collum (neck), is defined as “a contracted state of the cervical muscles, producing twisting of the neck and an unnatural position of the head.”72 In clinical practice, torticollis refers to any abnormal head tilt, face turn, or vertical position of the head. Also known as “wryneck” or “caput obstipum,” torticollis was first alluded to by Hippocrates (c. 500 BC) and later detailed by Plutarch (356 to 232 BC).122 Throughout medical history, treatments for torticollis have ranged from elaborate splints and traction techniques to tenotomy of the neck muscles. In 1873, Cuignet described torticollis as a manifestation of misalignment of the eyes.75 Head posture is maintained anatomically by the vertebral column supporting the head and the muscles of the neck and shoulders (the sternocleidomastoid, thoracic, and cervical semispinalis muscles).211 An erect head posture is not maintained by these muscles, unless the brain has the ability to recognize the position of the head in relation to the body and to the pull of gravity. This information is supplied primarily by labyrinthine and vestibular reflexes, the proprioceptive impulses from the cervical muscles, by visual input from the two eyes, and by integrative cortical centers for balance in the brain.16,67 Abnormal head positions involve rotation of the head around one of the three primary axes: the vertical axis for horizontal head positioning, the horizontal axis for chin elevation and depression, and the anterior–posterior axis for head tilting toward the shoulder.211 Many patients utilize a

M.C. Brodsky, Pediatric Neuro-Ophthalmology, DOI 10.1007/978-0-387-69069-8_9, © Springer Science+Business Media, LLC 2010

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head position that involves simultaneous rotation around two or more axes (Fig. 9.1). This situation may reflect the fact that it is physically difficult to tilt the head without turning it somewhat in the opposite direction or lowering the chin, or it may represent a more precise compensation to some of the conditions discussed in the following section. Rarely, the entire head can be retracted or pushed forward with respect to the median axis of the body.

Ocular Torticollis Most ocular disorders that result in torticollis reflect a disturbance of neural output from the ocular motor nerves or the vestibular system or a disturbance of input from the afferent visual pathways. The abnormal head position may serve to restore single binocular vision (in the case of incomitant strabismus) or improve visual acuity (in the case of nystagmus).43 Alternatively, it may develop as a primitive tonus response to unequal visual input to the two eyes (in the case of dissociated vertical divergence, DVD) or to unequal visual input to the two sides of the visual field (in congenital homonymous hemianopia).24 Children with infantile esotropia take a head turn to “cross-fixate” with either eye in adduction.73,139 In this setting, it is not known whether this head turn simply serves to damp the latent nystagmus or whether both the esotropia and the latent nystagmus are parallel manifestations of a central tonus imbalance caused by unequal visual input to the two eyes.

9 Torticollis and Head Oscillations

Most commonly, binocular misalignment causes diplopia, which leads to compensatory adjustment to a new head posture that provides the perceptual reward of stable single binocular vision.211 In children with incomitant strabismus, the finding of an anomalous head position is a good prognostic sign that usually signifies the preservation of fusion. In this setting, the disappearance of torticollis may signify the onset of amblyopia and the need for occlusion therapy.210 Primitive visuo-vestibular reflexes also use binocular visual input to maintain vertical orientation.27 When congenital strabismus disrupts binocularity, these reflexes lead to compensatory head postures and additional ocular misalignment. Although it is often said that torticollis that is compensatory for strabismus begins around the sixth month of life, several reports have documented incomitant strabismus with compensatory torticollis in the first month of life.29,153 Central vestibular disorders (at the prenuclear level) can produce ocular misalignment, torsion, and torticollis that are not compensatory for binocular vision, as in the ocular tilt reaction. Gamio81 has observed that head tilting can alter the magnitude of paretic horizontal strabismus in some patients. She attributes this phenomenon to monocular adaptations in the vestibulo-ocular reflex (VOR), which reduces asymmetrical movement of retinal images during head motion and the resulting retinal image disparity.213 Most forms of ocular torticollis (Table 9.1) are associated with a distinct constellation of clinical and neuroimaging abnormalities that allow definitive diagnosis of the underlying condition. Once the specific cause of the ocular torticollis is established, strabismus surgery has a high rate of success in eliminating the abnormal head position.131

Table 9.1 Ocular Torticollis Head tilt Head turn Superior oblique palsy Plagiocephaly (synostotic) Spasmus nutans

Congenital nystagmus Dissociated vertical divergence Lens subluxation Infantile esotropia Fig. 9.1 Child with ocular torticollis in costume for Halloween. Note head tilt and simultaneous head turn

Incomitant strabismus Congenital nystagmus Congenital homonymous hemianopia Horizontal gaze palsies or gaze deviation Macular heterotopia

Cortical Visual Insufficiency Congenital ocular motor apraxia Uncorrected hyperopia

Vertical head position A or V pattern Congenital nystagmus with null point Congenital nystagmus with A or V pattern Congenital ptosis (unilateral or bilateral) Noncomitant strabismus (e.g., Brown Oblique astigmatism-Cortical visual loss-syndrome) Vertical gaze palsies or tonic gaze deviation Overlooking Opisthotonus

Torticollis

Head Tilts Incomitant Strabismus Any vertical extraocular muscle paresis may necessitate a compensatory head tilt to achieve binocular vision.34 Isolated vertical muscle weakness resulting from disease involving the neuromuscular junction or the muscle itself can lead to similar findings. Head tilting is often the salient clinical feature of an isolated oblique muscle palsy, whereas a head tilt that occurs in conjunction with an abnormal vertical head position often signifies an isolated vertical rectus muscle palsy. Most studies have found superior oblique palsy to be the most common single cause of a head tilt.134,162,168,202,211 The long intracranial course of the fourth cranial nerve, which innervates the superior oblique muscle, renders it particularly susceptible to injury from head trauma. Unilateral superior oblique paresis produces excyclodeviation and a hyperdeviation of the involved eye. Patients with uncomplicated unilateral superior oblique palsy tilt their heads contralateral to the side of the injured nerve to restore single binocular vision. This compensatory head posture causes the otolith apparatus to increase innervation to the extorters (inferior oblique muscle and inferior rectus muscle) of the involved eye and decrease innervation to the intorters (superior rectus muscle and superior oblique muscle), thus minimizing the mechanical advantage of the superior rectus muscle (an elevator) over the paretic superior oblique muscle (a depressor). However, tilting the head ipsilaterally to the side of the injured nerve causes the otolith apparatus to stimulate the intorters (the superior rectus muscle and superior oblique muscle) and inhibit the extorters (the inferior rectus muscle and inferior oblique muscle) of the involved eye, which provides a mechanical advantage to the superior rectus muscle over the paretic superior oblique muscle, resulting in worsening of the hyperdeviation.135 Because the head tilt recruits physiologic otolithic innervation to compensate for vertical misalignment of the eyes, and because supine positioning eliminates otolithic input, parents report that the head tilt is absent when the child lies down or sleeps. Because the hyperdeviation increases in adduction, children with superior oblique palsy often have a head turn in the direction of the tilt to position the paretic eye in abduction.162 In rare cases, the head turn can predominate. The patient with superior oblique palsy tilts his/her head to eliminate the vertical deviation rather than the torsional deviation, which can be overcome by adaptive mechanisms, including sensory cyclofusion, as well as other psychological-experiential and physiological-sensory adaptations.99,206 (Placing a prism in front of either eye of a patient with superior oblique palsy to match the vertical deviation eliminates

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the vertical deviation and causes the head tilt to resolve, despite persistence of the monocular extorsion.)206 Occasionally, children with superior oblique palsy seem unable to adapt to a monocular cyclotropia, in which case the cyclotropia (without an accompanying vertical deviation) can be the exclusive source of the torticollis.206 Children whose head tilt disappears on covering the paretic eye and persists when the nonparetic eye is covered probably fall into this group. Because binocular vision is disrupted when either eye is covered and symptoms of hypertropia are thus eliminated, only cyclotropia could explain the persistence of the head tilt when the sound eye is covered.206 Under binocular conditions, such a child would assume a compensatory head tilt to the opposite shoulder when the involved eye fixates and would have no compensatory head posture when the uninvolved eye fixates.131,205,206 These children may have difficulty adapting to acquired monocular torsion in a dominant eye. Alternatively, the observation that monocular extorsion produces a stereoscopic tilt of binocular visual world toward the extorted eye23 makes it is possible that some of these children may be adapting their head positions to their tilted sense of visual vertical. Some children with superior oblique palsy maintain a contralateral head tilt even though a manifest vertical strabismus exists and fusion is absent in the preferred head position.206 It has been speculated that, in such children, a long-standing head tilt may persist on a habitual basis; it may be secondary to unilateral contracture of the neck muscles, or it may serve to provide anomalous fusion on the basis of anomalous retinal correspondence.206 It is more likely, however, that these children have either DVD or the ocular tilt reaction that was misdiagnosed as superior oblique palsy. It is said that a child with superior oblique palsy rarely tilts the head toward the side of the hypertropic eye (reportedly to maximize separation of diplopic images).131,206 However, the finding of a paradoxical head tilt should again lead one to consider the possibility of DVD, which can be associated with a head tilt toward or away from the side of the hypertropic eye.48 Reversal of a head tilt following surgery for superior oblique palsy may indicate a masked bilateral superior oblique palsy or a simple surgical overcorrection of the hyperdeviation (which produces a reversal of the Bielschowsky Head Tilt test that is indistinguishable from masked bilateral superior oblique palsy).186 Congenital and acquired superior oblique palsies differ with respect to their clinical manifestations and their underlying etiologies. In acquired palsies, the head position is marked, a noncomitant deviation is present, intermittent diplopia is common, and there is no facial asymmetry, except in longstanding deviations.207 In contrast, congenital superior oblique palsy is often associated with milder torticollis that has persisted since infancy (evident in old photographs),163 together with facial asymmetry (see Chap. 6).212 Contrary to the prevailing

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dogma that children with superior oblique palsy do not have sufficient head control until 6 months of age to maintain a compensatory head tilt for fusion, we have seen an infant who showed a head and body tilt starting in the first month of life.29 In the absence of head control, this infant allowed gravity to passively tilt her head and body in the compensatory direction to optimize utricular input for vertical fusion. At 6 months of age, her motor control enabled her to maintain a head tilt while maintaining her trunk in the neutral position. Thus, the onset of a unidirectional head tilt within the first few months of life should not be considered diagnostic of congenital muscular torticollis. Large vertical fusional vergence amplitudes are also highly characteristic of congenital or long-standing superior oblique palsy.207 In contradistinction to congenital muscular torticollis, the head tilt associated with congenital superior oblique palsy resolves in the supine position, usually resolves with monocular patching, and exhibits no limitation to passive rotation in the opposite direction.207 Recognition of these features is crucial in establishing the diagnosis of congenital fourth nerve palsy, because spread of comitance may develop over many years, obscuring the characteristic ocular motility pattern. Many patients with congenital superior oblique palsy and torticollis deny diplopia, but some present with acute vertical diplopia when they lose control of their deviation. Unlike patients who acquire superior oblique palsy from an injury to the trochlear nerve, many patients with congenital superior oblique palsy are found at surgery to have lax, misdirected, or absent superior oblique tendons.172 It is unclear whether such cases of congenital superior oblique palsy result from congenitally absent trochlear innervation or a primary dysgenesis of the superior oblique muscle. Polymorphisms in this homeobox-containing ARIX gene may be responsible for some cases of congenital superior oblique palsy.121 A head tilt or turn can produce facial asymmetry, with an appearance of facial compression or reduced facial mass, ipsilateral to the tilt or turn in torticollis from a wide variety of causes.94 Because a head tilt or turn from any cause can eventuate in facial asymmetry (termed deformational plagiocephaly), this facial asymmetry in undiagnosed torticollis cannot be used to suggest an ocular cause. Bone, muscle, fat, and skin are all living tissues that undergo continuous turnover and remodeling throughout life (similar to the increasing arm length of tennis players on the side of the stroke arm).132 Gravity may also play a role in the tilt of the tip of the nose toward the side of the head tilt (pointing directly to the ground in the preferred head position). The complete facial asymmetries are three dimensional, requiring several different views to fully appreciate.94 Greenberg and Pollard94 found that the nasal tip tends to point toward a head tilt, but away from a turn.212 In superior oblique palsy, the head tilt and turn are commonly in the same direction, producing opposing forces in directing the nasal tip deviation. Thus, in

9 Torticollis and Head Oscillations

patients with superior oblique palsy who have nasal tip deviation away from the torticollis, the head turn may be more causally significant than the tilt. Although deformational plagiocephaly has been attributed to abnormal sleep positioning,88 disappearance of the head tilt in the supine position belies this hypothesis.170 It has been reported that visual field deficits can be associated with deformational plagiocephaly, although neither the laterality nor the severity of skull deformity is predictive of these visual field defects.189

Synostotic Plagiocephaly Patients with synostotic plagiocephaly have premature fusion of the coronal suture on one side of the skull.8,65 This cranial abnormality leads to ipsilateral forehead and orbital retrusion, contralateral forehead protrusion, orbital and lateral canthal dystopia, and contralateral zygomatic and occipital flattening65 (Fig. 9.2). Affected infants manifest unilateral superior oblique dysfunction and tilt their head contralateral to the side of the retruded orbit.8,65,80 In synostotic plagiocephaly, wherein malpositioning of the trochlea associated with an osseous (i.e., musculoskeletal) abnormality leads to superior oblique tendon laxity and signs and symptoms of superior oblique palsy. Weakness of the superior oblique muscle results from a desagittalization and laxity of the superior oblique tendon within the retruded orbit (Fig. 9.3), as well as excyclorotation of the extraocular muscles. The secondary form of plagiocephaly (deformational) results from the asymmetrical effects of congenital muscular torticollis on craniofacial growth. Thus, unlike deformational plagiocephaly, which can gradually result from congenital superior oblique palsy, synostotic plagiocephaly can be the cause of the palsy.80

Fig. 9.2 Infant with right synostotic plagiocephaly. Note retrusion of right forehead and orbit, elevated right superior orbital rim, widened right palpebral fissure, left forehead protrusion, and head tilt to left

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Torticollis

The high-frequency nystagmus that characterizes achromatopsia resembles that of spasmus nutans but is conjugate rather than asymmetrical.92 The compensatory nature of the head oscillations in spasmus nutans is discussed below. While the cause of the associated torticollis remains speculative, Gottlob et al91 believe that it may serve to directionalize the visually compensatory head nodding to its optimal trajectory.

Fig. 9.3 Relationship between inferior oblique muscle and superior oblique tendon in synostotic plagiocephaly. View from below depicts right orbit on left-hand side of page. Desagittalization of superior oblique tendon occurs due to retruded right orbit and right trochlea relative to inferior orbital rim

Spasmus Nutans Nystagmus accompanied by head oscillations and torticollis in an infant or young child is highly suggestive of spasmus nutans. In 1906, Still193 rhapsodically summarized the sensation of observing a child with spasmus nutans: “Hardly less striking than this rhythmic unsteadiness of the head is the curious way the child has of looking at objects out of the corner of his eyes with the head slightly averted and the face turned slightly downwards, reminding one of the behavior of the Beaver in The Hunting of the Snark, for as you may remember, ‘Whenever the butcher was by, The Beaver kept looking the opposite way And appeared unaccountably shy.’

The other feature which attracts attention is the exceedingly fine rapid nystagmus which is peculiar in being so much more marked in one eye than the other, that it may appear to be actually limited to one eye, a point which the mother herself has usually noticed.” The appearance of the nystagmus alone in spasmus nutans is fairly distinct, in that it resembles an ocular shiver that may be so fine and rapid as to be barely visible.91 It may be horizontal, vertical, or torsional in direction.107 The clinical appearance of spasmus nutans differs from that of infantile nystagmus in that spasmus nutans is often asymmetrical and may actually be monocular.45,90 It also differs in its usual time of onset (4 months to a year in spasmus nutans versus 2 or 3 months of age in congenital nystagmus).45 Although usually a benign, self-limited entity, MR imaging is warranted in children with spasmus nutans, because children with congenital suprasellar tumors may present with an identical constellation of findings.90,159 Neurodegenerative disorders188 and congenital retinal dystrophies92,138 may also rarely masquerade as spasmus nutans.

Infantile Nystagmus Children with infantile nystagmus occasionally utilize a head tilt to damp their nystagmus. In this setting, a careful search for an underlying cyclovertical muscle palsy should be undertaken before attributing the head tilt to a torsional null position. Infantile nystagmus with a torsional null position should increase in intensity when the patient’s head is straightened or tilted to the opposite side. Strabismus surgery is remarkably effective in treating head tilts in patients with infantile nystagmus.58,191,208 These procedures involve transposing the horizontal, vertical, or oblique muscles to rotate the eyes in the direction of the head tilt to produce a contradirectional tilt of the visual world that drives the patient to tilt the head back toward vertical to realign it with the perceived visual world. However, it has not been established whether this procedure works by correcting a pre-existing visual tilt (which could determine the null position of the nystagmus) or by creating a new tilt of the subjective visual vertical (akin to an ocular tilt reaction) that must be compensated. The fact that patients rarely complain of subjective tilt after this procedure argues in favor of the former possibility. We examined one infant with oculocutaneous albinism, who would tilt her head 90 degrees when viewing a horizontally rotating optokinetic drum, then rotate her head in lockstep with any rotation of the spinning drum. This adaptation presumably allowed her to optimize vision by using her intact vertical optokinetic system.

Benign Paroxysmal Torticollis of Infancy In 1969, Snyder190 described 12 infants with paroxysmal head tilts that lasted from 10 min to 2 days. In some infants, the torticollis was accompanied with vomiting, pallor, and agitation. When the torticollis resolved, the infants appeared normal until the next attack. After a period of months to years, the attacks subsided. Subsequent reports have shown a female predominance and a tendency for the attacks to occur upon awakening.

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Paroxysmal torticollis of infancy is considered to be a migraine equivalent that primarily affects the vestibular system.167 It is characterized by recurrent episodes of head tilt secondary to cervical dystonia. Attacks are often accompanied by vomiting, pallor, and ataxia, settling spontaneously within hours or days. Episodes begin within the first 12 months of life and resolve by 5 years.82 Older children may complain of headache or vertigo during the attack. Later in life, some children develop benign paroxysmal vertigo, which may be a migraine variant. Affected children often have a strong family history of migraine headache. An infant with an episodic torticollis, complete interval recovery, a suggestive past history, and a family history of migraines need not be subjected to invasive and expensive diagnostic studies. Benign paroxysmal torticollis of infancy has been linked to the CACNA1A mutation, which is thought to affect cerebellar output.82

Dissociated Vertical Divergence DVD is a common cause of head tilt in children.26 DVD occurs in the setting of infantile strabismus and is characterized by hyperdeviation of either eye when it is mechanically occluded or cortically suppressed.20 The head tilt that accompanies DVD illustrates the role of visuo-vestibular input into postural orientation. Just as the labyrinths are balance organs that calibrate graviceptive input to maintain vertical orientation, the two eyes are balance organs that modulate visual luminance input.27 Bilateral labyrinthine and visual input are yoked together in the central vestibular system to establish ocular and postural orientation.27 DVD corresponds to the dorsal light reflex in lower, lateral-eyed animals.20 In nature, vertical orientation is associated with equal luminance input from the sky to the two laterally placed eyes. When an overhead light is shined down from one side of a goldfish, the fish therefore tilts toward the light because unequal luminance input to the two laterally placed eyes evokes a tilt toward the light (Fig. 9.4).93,204 In the vertically stabilized fish, shining a light from one side elicits a compensatory vertical divergence of the eyes (that strives to realign the interpupillary axis with reference to the perceived vertical).93 When cortical binocular vision fails to develop in infancy, an atavistic resurgence of the dorsal light reflex manifests as DVD.20 It is, therefore, not surprising that some patients with uncorrected infantile esotropia, and others with DVD, maintain a head tilt toward the preferred eye (Fig. 9.4).54,139 This head tilt, which corresponds to the dorsal light reflex in fish, is not compensatory for binocular vision (as evidenced by the fact that it persists despite manifest vertical misalignment).54,139 As such, strabismus surgery to restore vertical

9 Torticollis and Head Oscillations

Fig. 9.4 Clinical algorithm for the differential diagnosis of DVDassociated head tilts. Used with permission from Brodsky et al26

alignment does not improve this head tilt, but torsional surgery can be used to alter the tilted subjective visual vertical and thereby eliminate the head tilt. Some patients with DVD maintain a head tilt toward the side of the hyperdeviating eye. This head tilt is compensatory for binocular vision, because it recruits otolithic innervation to neutralize the oblique muscle innervation that causes DVD.20,21,26 For example, DVD with hyperdeviation of the left eye results from simultaneous innervation to the right superior oblique muscles and inferior oblique muscles.100 A head tilt to the right activates otolithic innervation to the right superior oblique and left inferior oblique muscles and thereby increases the left hyperdeviation. A head tilt to the left recruits otolithic innervation to neutralize this cyclovertical divergence (Fig. 11).21,26,162 Thus, a head tilt to the side of the hyperdeviating eye can serve as a compensatory means of recruiting otolithic innervation to control a hyperdeviation (Fig. 11). This recruitment of otolithic innervation explains Jampolsky’s observation that a normal Bielschowsky Head Tilt Test response in DVD is characterized by a hyperdeviation of either eye that increases or becomes manifest when the head is tilted to the opposite side.115 In this setting, strabismus surgery to restore vertical alignment eliminates the associated head tilt.184 In DVD, a superior rectus contracture can also develop in a chronically hyperdeviating eye, causing a compensatory head tilt toward the side of the fixing eye.116 In this setting, superior rectus recession can eliminate the head tilt (as predicted by preoperative prism placement). Various mechanisms by which DVD are known to be associated with a head tilt are summarized in Fig. 12.26 The neutral head position maintained by most patients with DVD may therefore represent a compromise position between two opposing drives.26 On the one hand, a head tilt toward the side of the fixing eye that is necessary to reestablish vertical orientation increases the hyperdeviation of the contralateral eye. On the other hand, a head tilt toward the side of the hyperdeviating eye that is necessary to minimize

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Torticollis

the DVD-associated hyperdeviation disrupts vertical orientation. To the extent that there is little binocular vision and an asymmetric DVD, one might expect the drive for vertical orientation to override, resulting in a head tilt toward the side of the fixing eye (i.e., one that is driven by a human dorsal light reflex and noncompensatory for binocular vision). Alternatively, a strong potential for fusion and stereopsis would cause the drive for binocular vision to override, resulting in a head tilt toward the side of the hyperdeviating eye (which is compensatory for binocular vision).

Ocular Tilt Reaction The primary role of the otolithic (static) vestibular system is to maintain vertical orientation. In the ocular tilt reaction, unilateral injury to an otolith or its central pathways produces a tilt of the subjective visual vertical, necessitating a compensatory tilt of the head, torsional position of the eyes, and interpupillary axis to a new position that the central nervous system erroneously computes as vertical.16,28,66 Thus, injury to central graviceptive pathways from the left otolith produces greater right utricular output (as would occur physiologically with a right head tilt), causing the patient to perceive the world as tilted to the left). The ocular tilt reaction is a compensatory righting reflex consisting of head tilt, ipsiversive torsion of the eyes, and vertical divergence to restore vertical orientation (Fig. 9.5). In this setting, the head would be tilted to the left (to align the head with the perceived vertical), the upper poles of the eyes would be torsionally rotated to the left, and the right eye would be higher than the left eye (as if the horizontal axis between the two pupils also tilted to the left). In the ocular tilt reaction, the head tilt is usually asymptomatic, because the patient perceives the tilted head and body as realigning with vertical, and not as tilted. Many patients with this condition have undoubtedly been misdiagnosed as having superior oblique palsy. In the ocular tilt reaction, however, the head tilt is not compensatory for vertical diplopia (but rather for a tilted sense of vertical). The distinction between these two disorders is facilitated by examining for subjective and objective torsion in both eyes. In the ocular tilt reaction, there is intorsion of the higher eye and extorsion of the lower eye on Double Maddox Rod testing and fundus examination, while in superior oblique palsy, these same tests show extorsion of the higher eye.70 In the ocular tilt reaction, this binocular torsion disappears in the supine position,169 where the utricles behave as if they are functionally deafferented.25 While the Bielschowsky Head Tilt test is generally negative in skew deviation, it can occasionally simulate the pattern seen in superior oblique

Fig. 9.5 Ocular tilt reaction. (a) Physiologic ocular tilt reaction in a motorcycle rider. (b) Physiologic (left) versus pathological (right) ocular tilt reaction. With permission from Brodsky et al28

palsy.7,70,182 Acute vascular brainstem stroke is the most common cause of the ocular tilt reaction in adults,16,66 whereas posterior fossa tumors seem the most common cause in childhood.28 Rare causes such as polyarteritis nodosa have also been reported.175

Photophobia, Epiphora, and Torticollis Torticollis can be a presenting sign of a posterior fossa tumor.13,127,197 Marmor et al145 described three young children with photophobia, epiphora, and torticollis who were found to have posterior fossa tumors. In one child, the symptoms improved following surgical resection. Posterior fossa tumors could theoretically cause torticollis by irritation of the vestibular nuclear complex, dural stretch, tonsillar herniation, cyclovertical muscle paresis, or any combination thereof.145 In all probability, these conditions are attributable to some combination of the ocular tilt reaction, with regional compression of the trigeminal nerve.

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Down Syndrome The torticollis in Down syndrome is usually musculoskeletal in origin. Down syndrome is one of several genetic syndromes (along with Morquio syndrome, mucopolysaccharidosis, and osteogenesis imperfecta) in which torticollis may be a manifestation of cerebral spine instability resulting from laxity of cervical ligaments or malformed vertebral bodies.14 Caution is therefore advised to avoid hyperextension of the neck when administering eyedrops.161 Children with Down syndrome and infantile esotropia may utilize a head tilt to restore horizontal ocular alignment.143 Lueder et al143 described six such patients without DVD in whom the head tilt resolved following horizontal strabismus surgery. How unilateral utricular stimulation influences horizontal misalignment, and why this phenomenon has been observed primarily in children with Down syndrome, is unknown. In our experience, children with Down syndrome may have esotropia with primary superior oblique overaction and A-pattern, necessitating a chin-up position for fusion in downgaze.

Spasmodic Torticollis Spasmodic torticollis refers to a dystonia of the facial and cervical muscles resulting from neurological disease or medications affecting the basal ganglia.31,50 This diagnosis should be considered if dystonia in the face or limbs is present. Spasmodic torticollis associated with neurological disease has been successfully treated with botulinum toxin therapy and with selective surgical peripheral denervation of the sternocleidomastoid and splenius capitus muscle.18 Spasmodic torticollis in children may occur as an idiosyncratic reaction following a first dose of phenothiazine or haloperido1.77 In this setting, it may be accompanied by other dystonic reactions, including trismus, opisthotonos, and oculogyric crises.129 Drug-induced spasmodic torticollis resolves promptly when the child is treated with anticholinesterase medications (e.g., Cogentin). Spasmodic torticollis is uncommon in children except when drug induced.77 The highest frequency of drug-induced dystonia and oculogyric crises occurs in children under 15 years of age.129 Spasmodic torticollis may rarely occur as a familial condition.83 Paroxysmal dystonia in infancy is a condition that usually has its onset in the first months of life. Motor symptoms are characterized by torsion of the neck or trunk, opisthotonos, hypertonus of the upper limbs with flexion or extension of the arms and hyperpronation of the wrist, and no disturbance of consciousness.3 The attacks usually last several minutes and occur with a frequency ranging from several times a day to once a month. This entity differs from benign paroxysmal torticollis in infancy in that the trunk and arms are also involved, and no autonomic symptoms are detected.3 The attacks spontaneously remit in most cases.

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Paroxysmal choreoathetosis is a rare disorder with onset between 1 and 2 years of age. It consists of paroxysmal episodes of abnormal posturing and choreoathetoid movements that may include torticollis and facial grimacing. The child is conscious and often uncomfortable during the episode.174 These children are otherwise in good health and neurologically normal between attacks.177 The disorder can be familial or sporadic. The episodes occur several times a month, but may vary in frequency from several times a day to several times a year. They last for 5 min to an hour and often appear to be related to excitement or fatigue.177 These transient episodes do not appear to be epileptiform or migrainous in nature. Central nervous system pathology unrelated to the visual system should also be considered in patients with enigmatic torticollis (Table 9.2). Causes include syringomyelia and spinal cord tumors,127,197 arteriovenous fistula,10 as well as cervical epidural abscess with osteomyelitis,147 and Arnold-Chiari malformation.14,77 Torticollis associated with hyperactive tendon reflexes, ankle clonus, or extensor plantar responses suggests a cervical spinal cord disturbance and is an indication for MR imaging of the cervical spine.77 Head tilting has been described in the infectious disease literature as a rare manifestation of nuchal rigidity in patients with acute bacterial meningitis;146 however, no neuroophthalmologic examinations were performed to rule out the possibility of superior oblique palsy. Given the strong association between acute bacterial meningitis and cranial nerve palsies, an inflammatory superior oblique palsy must be the primary diagnostic consideration in the child with acute bacterial meningitis and an unexplained head tilt.

Head Turns Some head turns in children are physiological and purposeful. For example, one young girl took a large head turn when looking through a microscope monocularly so that she could use her nose to block her other eye because she did not know how to squint.178a Because visual head turns are compensatory (contraversive to the eye position in the orbits), while neurological head turns often produce an oculocephalic synkinesis with the head and eyes deviated in the same direction, it is important to document whether the head turn is ipsiversive or contraversive to the position of the eyes in the orbit. Visual disturbances may produce a head turn in several different ways (Table 9.1).

Incomitant Strabismus A head turn is often used to restore binocular single vision in patients with incomitant paralytic or restrictive strabismus. A patient who assumes an abnormal head posture for visually related reasons does so at least partly to frontalize their field of

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Torticollis Table 9.2 Nonocular torticollis Neurologic Musculoskeletal Paroxysmal torticollis of infancy Photophobia, epiphora, torticollis Idiopathic torsion dystonia Idiopathic torsion dystonia Ocular tilt reaction Spasmodic torticollis Syringomyelia Spinal cord tumor Meningitis Arteriovenous fistula Chiari malformation Ocular tilt reaction Benign paroxysmal torticollis of infancy Paroxysmal dystonia in infancy Paroxysmal choreoathetosis

Systemic

Congenital muscular torticollis

Unilateral deafness

Congenital deformities of the cervical spine

Compensation for pain

Klippel-Feil anomaly

Arthritis

Occipitocervical synostosis

Mastoiditis Gastroesophogeal Reflux (Sandifer syndrome) Grisel syndrome Psychiatric Nasopharyngeal Torticollis Organic aciduria

vision relative to their body.211 For example, a child with a sixth nerve palsy prefers to turn his or her head toward the affected side to realign the eyes, despite the fact that ocular alignment could also be obtained without a head turn by shifting the head and trunk laterally together while maintaining fixation in the direction opposite to that of the paresis.5 In children with Duane syndrome and esotropia, optical correction of hyperopia can significantly reduce a head turn, sometimes obviating the need for surgery.124,180 A head turn can be the salient clinical sign in patients with incomitant vertical strabismus who have good alignment in one lateral field of gaze. A head turn can occasionally overshadow a head tilt in unilateral superior oblique muscle palsy. Nystagmus Head turns are utilized by patients with congenital or manifest-latent nystagmus to move the eyes into a null zone, where the nystagmus is reduced and optimal visual acuity is achieved. In these disorders, it is critical to have the child fixate on the smallest recognizable object to elicit the full extent of the head turn. At times, a subtle nystagmus may not be visible unless the optic disc is viewed with a direct ophthalmoscope. Stevens and Hertle192 found that children with congenital nystagmus

and anomalous head postures have better mean visual acuities than those without anomalous head positions. In this light, the presence of an anomalous head position in a child with congenital nystagmus correlates with good vision and can be considered a positive prognostic sign. Children with unilateral microphthalmos, unilateral aphakia, or other conditions associated with congenital visual loss often develop manifest latent nystagmus with a large face turn toward the better-seeing eye. Similarly, the child with congenital esotropia and manifest latent nystagmus often turn his/her head to damp the nystagmus by placing the preferred eye in adduction. In spasmus nutans, head turns may function to directionalize the head oscillations to the necessary trajectory to improve vision.91

Congenital Homonymous Hemianopia Children with congenital homonymous hemianopia often turn their heads toward the hemianopic field while maintaining fixation on objects of interest.111,211 As this maneuver does not change the position of the intact visual field in space, its etiology remains a matter of some speculation. Children with congenital homonymous hemianopia are generally unaware of their abnormal head posture and are unable to explain why they maintain it. In patients with acquired homonymous hemianopia, a head turn does not manifest unless the causative hemispheric injury occurs in infancy.171 Most proposed explanations have assumed that torticollis must serve a compensatory function for visual orientation or navigation. For example, it has been suggested that the head turn may be an adaptive response to frontalize the visual world relative to the body, permitting the child to use saccades to increase the effective visual field during ambulation,69,171 or it may serve to minimize a subclinical nystagmus that is damped in one lateral field of gaze.87 Brodsky proposed that this form of torticollis may represent a nonpurposeful postural tonus imbalance of hemispheric origin, whereby early loss of visual input from one field directly increases neck muscle tonus on one side.24 Mechanistically, a postural tonus would circumvent any element of will or choice on the part of the individual; the head simply goes where the neck muscles pull it. Because these children are often also exotropic, it has been suggested that the development of exotropia may be an adaptive mechanism to expand their limited visual field.89 It is noteworthy, however, that the exotropic eye is frequently on the side of the intact visual field. However, Hoyt and Good111 have argued that the exotropia seen in children with congenital homonymous hemianopia could well be an epiphenomenon rather than a visual adaptation. Because an exotropia of either side serves to expand the functioning visual field, strabismus surgery may be contraindicated in these patients. Other ocular disorders have also been documented to produce head turns in children. The combination of a large

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convergent or divergent ocular deviation and limited ocular movements necessitates a head turn to direct the preferred eye toward the object of fixation.211 Head turns may also be seen in children with horizontal gaze palsy or gaze deviations without strabismus. Children with retinopathy of prematurity and macular heterotopia may take a head turn to fixate eccentrically with the better-seeing eye.134 Childrenwith nystagmus blockage syndrome also turn their heads to foveate objects of interest while utilizing excessive convergence.134

Seizures Involuntary head turning is a common feature of focal motor seizures.140 Certain associated features may help to clinically localize the seizure focus. If the patient remains conscious during the episode, then the head turning is usually away from the side of the seizure focus, and the seizure focus is usually frontal.148,198,214,215 A contralateral seizure focus is also likely when patients show a sustained, unnatural, lateral positioning of their head and eyes.214,215 In patients who are unconscious, whose seizures generalize, or who show milder deviations of the head and eyes, about half manifest an ipsiversive movement of the head.84,164 The site of the seizure focus may be localized to any lobe, but frontal and temporal are the most common.140

Cortical Visual Insufficiency Children with cortical visual insufficiency often display an oculocephalic dyskinesia characterized by horizontal conjugate gaze deviation with a large ipsiversive head turn.24a It is often difficult to determine whether a seizure focus or a postural tonus imbalance from asymmetrical hemispheric injury is driving these large head turns. In some case, these children appear to be trying to look back behind their bodies. In this setting, it is especially difficult to determine whether a homonymous hemianopia is present, especially when exotropia coexists. The pathophysiologic basis and the prognosis for spontaneous improvement remain to be determined.

Congenital Ocular Motor Apraxia As detailed in Chap. 7, children with congenital ocular motor apraxia are unable to generate volitional horizontal saccades and compensate by large head turns to fixate on peripheral objects of interest. Curiously, infants with congenital ocular

9 Torticollis and Head Oscillations

motor apraxia may intermittently jerk or shake their heads when fixating stationary objects.

Vertical Head Positions Visual input has been shown to influence vertical head position, with darkness producing increased extension of the neck.183 Most abnormal vertical head postures occur in children with congenital ptosis, A- or V-pattern horizontal strabismus, restrictive vertical strabismus, or incomitant vertical strabismus (Table 9.1).6 Children with unilateral congenital ptosis raise the chin to obtain binocular vision, whereas those with bilateral congenital ptosis raise the chin to see. While chronic head tilts and head turns can both produce facial asymmetry, no facial boney remodeling from vertical head postures has been recognized. Children with congenital fibrosis syndrome may have a combination of bilateral ptosis and fixed downgaze, each necessitating a chin-up position to compensate for their restrictive strabismus.62,134 Children with tonic upgaze or downgaze may maintain vertical head positions that are compensatory for vision (i.e., chin down with tonic upgaze) (Fig. 8.16) or ipsiversive when the eye and head positions are both neurologically driven (as seen in some patients with cerebral palsy). Patients with bilateral superior oblique palsy notoriously maintain a chin-down position, even when they are orthotropic in primary position. This compensatory head-down position probably serves to reduce binocular extorsion and to provide a larger working window of single binocular vision. In the setting of either A- or V-pattern strabismus or vertical restrictive strabismus, the chin-up or chin-down position places the eyes in a position of minimal deviation to establish some degree of binocularity.211 Stuart and Burian stated that “convergence” of the visual axes on downgaze and divergence on upgaze are normal physiologic variants, producing the so-called physiologic V- pattern.195 Havertape and Cruz102 have noted that some patients with high hyperopia maintain a chin-down head position for fixation without the spectacle correction in place. This abnormal head position was eliminated under monocular conditions and by having them wear the full refractive correction. They postulated that, because of a normal physiologic V-pattern, a chin-down position allows these children to maintain increased accommodation in an elevated ocular position without the development of an esodeviation. Some children with infantile nystagmus have a vertical null zone, necessitating a chin-up or chin-down position. Infantile nystagmus patients with even small A- or V-pattern may utilize a vertical head position to create a large exophoria, which enables them to increase convergence tone and improve visual acuity. Therefore, it is critical in the child with infantile nys-

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tagmus to search for an associated exophoria in the preferred field of gaze before concluding that the vertical head position results from a vertical null position, because the appropriate surgical management varies according to the underlying condition. Infants with congenital stationary night blindness may present with tonic downgaze and a chin up position to damp an upbeating nystagmus.189a Conversely, infants with congenital downbeat nystagmus may maintain a chin up posture to access their vertical null position (Fig 8.15).19a Rarely, the two problems coexist, as exemplified by the following case: A 5-year-old girl had been followed since infancy with congenital nystagmus and a marked chin-down position. Numerous examinations showed that the intensity of the nystagmus dampened in upgaze and increased in downgaze. In addition, she had a V-pattern with orthophoria in upgaze and esotropia in downgaze. The child was treated with bilateral superior rectus recessions and inferior rectus resections with lateral transpositions of the inferior rectus muscles. This procedure transferred the null zone to primary gaze and eliminated the V- pattern. Vertical head positions are also seen in children with vertical gaze palsy or vertical gaze deviations who must assume an abnormal head position to fixate. Rarely, children with retinal or optic nerve disease associated with altitudinal visual field defects may assume chin-up or chin-down positions,55 reflecting a postural tonus imbalance analogous to the head turn in congenital homonymous hemianopia. Children with overlooking may display tonic upgaze and dystonic chin-up positions, suggesting either that disturbed retinal input can alter postural tonus or that central neurologic dysfunction can contribute to this phenomenon.56 Conversely, premature children with tonic downgaze may maintain a chin-up position to view objects of interest. In children with severe neurological disease, opisthotonus (opistho = behind) may produce hyperextension of the neck, with flexion of the upper limbs and extension of the lower limbs in response to sensory stimuli in children with severe neurological disease.39 This condition may improve with intrathecal baclofen.

Refractive Causes of Torticollis Ocular refractive errors can lead to anomalous head positions that serve to improve vision (Table 9.1). In point of fact, these cases are exceptionally rare. In 1866, Javal reported that he could no longer see clearly through his astigmatic spectacles when he tilted his head either to the right or left and concluded that ocular torsion (now termed the static ocular counterroll) had occurred.119 Kushner found compensation for refractive errors to be a rare cause of abnormal head posture (found in 1 of 188 patients).134 Patients with bilat-

eral oblique astigmatism may tilt their head to directionalize the astigmatic blur with respect to the vertical meridian.36,134,180,211 Patients with cylindrical lenses may tilt the head to one side to counterroll the eyes into alignment with the axis of the cylinder in the spectacles.74 Undercorrected myopia may cause a patient to elevate the chin or turn the head to gain increased strength from the spectacle lenses.74,75,211 Undercorrected or overcorrected hyperopia may cause patients to adopt a head turn to look through the periphery of the lenses. Patients with anisomyopia and the “heavy eye” syndrome may have a head tilt toward the side of the more myopic eye.149 An 8-year-old girl with homocystinuria and bilateral ectopia lentis was reported to utilize a head tilt to recenter one of the crystalline lenses and obtain phakic vision.133 Although rare, these conditions should be included in the differential diagnosis of enigmatic torticollis. Rubin and Wagner described a patient who maintained a 45-degree head turn that disappeared after correction of an astigmatic refractive error in the right eye.180 They postulated that the patient was using the lid fissures to create a stenopeic slit effect. They also noted that patients with Duane syndrome often have a reduction of head turn after correction of hyperopia. Other reports of patients with anomalous head postures may also be referable to refractive errors.105,136 We saw an idiopathic unilateral head turn disappear in a young girl following placement of −1.50 spectacle lenses for both eyes, perhaps because blur was now induced when looking through the corners of the lenses.

Neuromuscular Causes of Torticollis Congenital Muscular Torticollis Congenital muscular torticollis is diagnosed in an infant or young child with a unilateral head tilt associated with limited rotation of the head to the opposite side (Fig. 9.6).108 It is differentiated from the more common head tilt associated with superior oblique palsy by the absence of associated vertical strabismus and by the palpable restriction to passive rotatory motion to the opposite side. Congenital muscular torticollis has been subdivided into three groups.113,144,201 Soon after birth, a mass appears in the belly of the sternocleidomastoid muscle (SCM) (fibromatosis colli), and the patient develops a head tilt to the side of the involved muscle.53,122 After several months, the mass or tumor disappears as signs of facial asymmetry become more evident (Fig. 9.5). In most cases, the head tilt subsequently resolves, and the facial asymmetry normalizes over the first year of life, with or without physical therapy.53 When the head tilt persists, the affected SCM is found to be hard and tight to palpation.113

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Fig. 9.6 Five-month old girl with congenital muscular torticollis. Note facial asymmetry (deformational plagiocephaly)

This is the most common presentation. Group 2, known as MT (muscular torticollis), consists of torticollis with tightness of the SCM but no palpable tumor. 40,68,106 The last group, Group 3 (also known as POST), is a postural torticollis without a mass or tightness of the SCM.41 Facial asymmetry (termed “facial scoliosis” in the older literature) is generally regarded as a ubiquitous finding in children whose congenital muscular torticollis fails to resolve spontaneously. It is considered to be an inevitable consequence of a permanent oblique head posture of long duration.110 As the neck and facial bones assume larger proportions, the fibrotic SCM fails to elongate normally, producing pathological changes of the face and skull. The eyebrow on the side of the shortened muscle tends to slope downward, and the portion of the face below the level of the eye becomes shorter and wider on the affected side than the corresponding normal side (Fig. 9.5). The frontal eminence is flattened on the affected side, and there is a well-marked bulge in the occipital region, while on the other side, the eminence is unduly prominent and the occipital region is rather flat. The vault of the skull is “thrown back” on the affected side and “pushed forward” on the opposite side, resulting in “deformational plagiocephaly.” Facial asymmetry progressively increases as growth continues and the cervical curve continues. It often resolves following early surgical intervention and, in some older children, shows a gradual reversal following surgical repair.32,113,142 The etiology of congenital muscular torticollis is controversial. Ho et al106 found that there was a 53% rate of firstborn children affected and a higher incidence of traumatic delivery in those with congenital muscular torticollis. These data support the concept of intrauterine crowding (from a

9 Torticollis and Head Oscillations

small uterus in the firstborn) and malposition, which could lead to more difficult, traumatic deliveries. Venous compression on the neck may also contribute. For reasons that are unclear, the incidence of torticollis associated with positional (deformational) plagiocephaly appears to be increasing.57 Congenital muscular torticollis is frequently associated with a history of some obstetrical difficulty.110 Histologically, it is characterized by contracture of the SCM, without osseous deformity, local inflammation, or primary neural abnormality.33 Excisional biopsies of the tumor have shown a hard, white, fibrous lesion that resembles a fibroma with no evidence of hematoma or injury.141 The sternal head of the muscle is almost completely replaced by fibrous tissue. Sarnet and Morrissy185 suggested that the separate arterial supply of the sternal head predisposes to ischemia, focal myopathy, and fibrosis, while the grouped atrophy in the clavicular head was consistent with the combination of secondary entrapment neuropathy of the spinal accessory nerve resulting from its passage through a myopathic sternal head on its way to the clavicular head. An association of congenital muscular torticollis with congenital hip dysplasia seems well- established. Hummer and MacEwen114 retrospectively reviewed records from 70 children with congenital muscular torticollis and found congenital dislocation of the hip in 5% and congenital subluxation of the hip in 15%. There was no statistically significant relationship between the side of the torticollis and the side of the hip dysplasia. Interestingly, Busch and Westin33 found congenital hip dislocation or dysplasia in 9 of 36 patients, which always involved the hip ipsilateral to the tight cervical muscles. Clinical and neuroradiographic examination of the hip joints is now considered a part of the routine evaluation of congenital muscular torticollis. Conservative treatment of congenital muscular torticollis consists of passive tilting of the head in the direction opposite the deformity, rearrangement of the crib to encourage the infant to lie on the affected side, and special neck braces in some cases.33 Approximately 80% of infants respond to conservative measures and do not require surgical release.33,37 Canale et al37 found that an exercise program is more likely to be successful when the restriction of motion is less than 30 degrees and there is little or no facial asymmetry. Approximately 50–70% of sternocleidomastoid tumors resolve spontaneously during the first year of life with minimal residual deficits. Physical therapy with manual stretching exercises is helpful for cases associated with restriction. Results of treatment with botulinum injection have been mixed at best.49 For resistant cases, surgical lengthening of the affected muscle is indicated. Beyond 1 year of age, congenital muscular torticollis does not generally respond to conservative measures. Previous surgical treatment of congenital muscular torticollis consisted of surgical transection of the contractured SCM, which often produced unsightly clavicular prominence

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and neck asymmetry.33,110 Bipolar release (i.e., complete release of the mastoid and clavicular attachments) combined with Z plasty of the sternal head has been recommended to avoid this complication.33,37 Musculoskeletal torticollis is rarely be a secondary manifestation of cervical skeletal abnormalities, such as occipitocervical synostosis, Klippel–Feil syndrome, scoliosis, basilar impression, atlanto-axial displacement, Sprengel’s deformity, Grisel’s syndrome (chronic atlanto-axial subluxation resulting from inflammation), and congenital subluxations of cervical disks, clavicle fractures, and brachial plexus injury (Table 9.2).9,14,105,173,180,196

Systemic Causes of Torticollis Torticollis is rarely auditory, gastrointestinal, rheumatologic, or psychiatric in origin (Table 9.2). An intermittent unilateral face turn in infancy may be the presenting sign of unilateral deafness.209 An extremely large, intermittent head tilt can be a sign of gastrointestinal disease.165 Sandifer syndrome is a rare disorder in which a child with hiatal hernia and gastroesophageal reflux takes a large head tilt to prevent regurgitation.210 Children with Sandifer syndrome typically have a history of vomiting and are thin. Compensation for pain may necessitate an abnormal head position in a variety of other conditions such as cervical arthritis or mastoiditis.209 Psychiatric patients with no neurologic or systemic disease occasionally assume large head tilts for no apparent reason.105

Head Nodding with Nystagmus In children with head nodding and nystagmus, the pathogenetic interrelationship between the ocular and cervical oscillations depends on the underlying condition. To understand how these oscillations interrelate under pathological circumstances, one must first understand the role of the VOR under normal conditions. In normal individuals, the VOR causes any movement of the head to be accompanied by eye movements that are equal in velocity and opposite in direction to that of the head.151 This reflex serves to stabilize the position of the eyes in space so that the direction of gaze remains constant during head movements. Thus, in children with nystagmus, head nodding would not be expected to change the waveform of nystagmus, because the head movements would be countered by the VOR, leaving the nystagmus to determine the position of the eyes.97 It is now clear, however, that this rule cannot be applied to individuals with congenital nystagmus, because head or total body movements can produce a dynamic shift in the null position (see Chap. 8) and thereby modify the congenital nystagmus waveform.61 The change in the overall congenital nystagmus waveform induced by vestibular stimulation is often misconstrued as evidence of an underlying deficit in the VOR in individuals with congenital nystagmus. In the child with nystagmus, head oscillations could function to improve vision only if (1) the VOR gain was inherently abnormal, (2) a normal VOR gain was somehow actively suppressed by the head movements, or (3) activation of a normal VOR could somehow “override” the nystagmus. Regardless of any clinically apparent effects of head oscillations

Head Oscillations Rhythmical oscillations of the head were once termed head nystagmus. In current usage, a nonsaccadic oscillation of the eyes is designated as nystagmus, while a similar oscillation of the head is often referred to as a tremor.60 However, head nodding can be conceptually viewed as a form of “head nystagmus,” because it represents a central disorder of the cephalomotor control system.38 Its neuro-ophthalmologic intrigue lies primarily in its association with pediatric nystagmus, where it may be compensatory (i.e., serving to reduce the intensity of nystagmus and improve vision) or noncompensatory (i.e., a centrally driven oscillation similar to the nystagmus itself). Several distinct forms of head nodding can be observed in children (Table 9.3).63 Some are benign, while others provide a decisive clinical clue to a potentially life-threatening neurological or systemic disorder that may be treatable.63 Our rudimentary understanding of the phenomenology of head nodding is exceeded by our ability to identify the underlying neurological or systemic disorders that produce it.

Table 9.3 Head nodding in children: Differential diagnosis Neurological disorders Visual disorders Systemic disorders Spasmus nutans Congenital nystagmus Bobble-headed doll syndrome

Neurodegenerative, metabolic, and multisystem genetic diseases Cerebellar disease Infantile spasms Congenital ocular motor apraxia Opsoclonus/ Myoclonus Autism Benign essential tremor

Blindness Intermittent esotropia Infantile esotropia

Aortic regurgitation Acute metabolic abnormalities (Hypomagnesemia, hypocalcemia, uremia, thyrotoxicosis)

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on the overall intensity of congenital nystagmus, compensatory head movements would have to prolong foveation time to improve vision.38,60

9 Torticollis and Head Oscillations

sively in spasmus nutans) could be construed as a predictive neurodevelopmental sign that the nystagmus would eventually resolve. Whether the eventual disappearance of spasmus nutans requires active suppression or it represents recovery of maturation ocular stabilization systems is unclear.

Spasmus Nutans Spasmus nutans is the most common condition associated with head nodding in children.45 The head nodding of spasmus nutans consists of a combination of true (anteroposterior) head nodding and lateral shaking of the head in an unpredictable pattern.107,193 It becomes prominent when the child inspects an object of interest and it seems to increase with the complexity of the fixation target.91,95 Gresty and colleagues95,96 were the first to describe simultaneous eye and head movement recordings in three children with spasmus nutans in whom head nodding abolished the nystagmus, activated normal VORs, and suppressed the nystagmus. These children had better vision when they nodded their heads. Gresty and colleagues concluded that the head nodding was an operant-conditioned phenomenon that served to suppress the nystagmus and improve visual acuity, and not a separate pathological phenomenon. Gottlob et al91 analyzed simultaneous head and eye movement recordings in 35 children with spasmus nutans. In 21 of these patients, the fine, fast dissociated nystagmus changed during head nodding to larger and slower symmetrical eye movements, with both eyes oscillating in phase at the same amplitude and 180 degrees out of phase to the head movements (see Fig. 8.8). The ocular oscillations during head nodding corresponded to a normal VOR. These investigators concurred with Gresty and colleagues95,96 that head nodding in spasmus nutans is an adaptive strategy to improve vision rather than an involuntary movement of pathological origin. Head nodding in spasmus nutans must therefore reduce or abolish the nystagmus through a mechanism that functions independently of the VOR or through stimulation of the powerful VOR to override the nystagmus.198 Gottlob et al91 also found that passive horizontal shaking of the patient’s head by the examiner suppressed mainly the horizontal nystagmus, whereas passive vertical shaking suppressed mainly the vertical nystagmus. This finding suggests that the principle direction of the head nodding in spasmus nutans may be dictated by the trajectory of the nystagmus. The associated head tilt in spasmus nutans may help directionalize the head nodding to most effectively suppress the nystagmus.91 Because children with spasmus nutans often utilize rapid elliptical or “figure eight” head movements when viewing objects of interest, the mechanism by which these head movements serve to improve vision may be more complex. Gresty and Halmagyi97 questioned whether a child’s ability to cancel nystagmus and improve vision by shaking the head (as seen almost exclu-

Infantile Nystagmus Approximately 10% of individuals with infantile nystagmus display a rapid, horizontal, pendular shaking of the head.79,160 According to Jan et al117, this head shaking occurs in bursts of 5–30 s and only during intense visual fixation. It occurs only with visual activity and does not involve any other part of the body. Head nodding in infantile nystagmus is a subconscious act that ceases when it is called to the individual’s attention and cannot be willfully reactivated.117 Many of the early conclusions drawn from studies pertaining to the interrelationship of infantile nystagmus and head shaking were based on clinical observations regarding the overall waveform of the nystagmus without objective documentation of the effect of head shaking on foveation periods. For many years, head shaking in infantile nystagmus has been thought to be compensatory in nature.46 This idea was attractive, because it seemed consistent with the clinical observation that the head nodding increased noticeably during periods of fatigue, anxiety, and intense curiosity, when the intensity of the nystagmus also increased.117 Electro-oculographic studies claiming to show that the VOR was defective in infantile nystagmus (see Chap. 8) seemed to provide a pathophysiological basis for the notion that head oscillations could stabilize the position of the eyes in space without being neutralized by a normal VOR. These early studies were inherently flawed either in premise or implementation. Some investigators provided only verbal descriptions of infantile nystagmus in which the head oscillations appeared to be equal and opposite to the ongoing eye movements (with a VOR gain somehow reduced to zero) or in which the head oscillations seemed to cancel the ocular oscillations by a central mechanism, as in spasmus nutans, without providing simultaneous eye and head movement recordings to support these claims.96,97 One report contained simultaneous head and eye movement recordings, but showed jerky head movements of approximately 30 degrees that were supposedly compensating for a nystagmus of approximately 7 degrees.150 In another case, eye movement recordings showed convergent nystagmus (which is consistent with spasmus nutans but not with infantile nystagmus) and head movements that canceled the nystagmus.198 As with smooth pursuit, the sustained vestibular input from head nodding produces a dynamic shift in the null zone, which changes the overall waveform of the nystagmus. The failure

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to recognize the significance of this observation has contributed to the conclusion that the VOR is inherently defective in infantile nystagmus. As discussed in Chap. 8, this myth has now been largely dispelled.38,61,98 Unlike the head nodding in spasmus nutans, however, electro-oculographic recordings in infantile nystagmus have shown that the associated head oscillations do not contribute to an improvement in vision. On the contrary, it is now believed to be an involuntary cephalomotor tremor that presumably shares a common pathogenic origin with the nystagmus.60 Electro-oculographic recordings of infantile nystagmus have shown that, during foveation periods, the position of gaze remains stable during head rotation despite the superimposed oscillations of infantile nystagmus. With rare exceptions, the VOR is preserved, and electro-oculographic recordings show no flattening of foveation periods.38,60,140 These findings are consistent with the fact that older children and adults are often aware of their intermittent head shaking and do not believe it helps them see.60 Carl et al38 documented an exception to this rule in a patient who showed true compensation of infantile nystagmus by the head movements. This patient suppressed his VOR gain, and improvement occurred only during foveation periods. Simultaneous eye and head movement recordings showed that the foveation periods were not flat when the head was still, but they became flat when the head movements occurred. Four other individuals who were studied showed no improvement in foveation periods during head shaking. Dell’Osso and Daroff60 have stressed that most individuals with congenital nystagmus have flat foveation periods and can therefore achieve no visual benefit from shaking their heads.60 From both a theoretical and an evidentiary standpoint, however, head nodding in infantile nystagmus is almost never visually adaptive. Head nodding in infantile nystagmus can also be asso ciated with a fine-amplitude nystagmus in several congenital retinal dystrophies (achromatopsia, blue-cone monochromatism, congenital stationary night blindness), producing a clinical appearance that may mimic spasmus nutans.92,138

Neurodegenerative Disorders, Metabolic Defects, and Genetic Syndromes Pelizaeus-Merzbacher disease may be associated with intermittent shaking movements of the head and a rapid, irregular, often asymmetric pendular nystagmus.1 Children with 3-methylglutaconic aciduria and neurological signs of Behr syndrome may display head nodding, nystagmus, and optic atrophy.187 Dhir et al64 described two siblings with reduced visual acuity, nystagmus, hypopigmentation of the maculae, head nodding, dysarthria, and other neuromuscular coordination resulting from

histidinemia. Reports from the Japanese literature have described a newly recognized condition in boys characterized by ataxic diplegia, mental retardation, horizontal pendular nystagmus, head nodding, and abnormal auditory brainstem responses.2 Head nodding and nystagmus can occasionally be seen in multisystem genetic disorders.71,157

Head Nodding without Nystagmus Bobble-Headed Doll Syndrome Children with large third ventricular cysts or tumors that are associated with obstructive hydrocephalus occasionally develop a to-and-fro bobbing or nodding of the head and trunk. This 1to 3-Hz anterior–posterior movement is named for its resemblance to the movement of a doll whose weighted head is mounted on a coiled spring.11 This disorder can be distinguished from benign familial tremor by its slower rate, its invariable association with hydrocephalus, and the child’s ability to volitionally inhibit it.63 With rare exceptions, it is unique to children, with an average age of 7 years at diagnosis.120 The head nodding of the bobble-headed doll syndrome is a slow (1–3 Hz) anteroposterior movement that disappears with sleep and in the lying position, that can be suppressed or decreased at will, or that decreases during voluntary head motion or activity.63,200 The head nodding may be accompanied by a synchronous gentle rocking of the trunk or movement of the hands.158 The cause of the head and trunk movements is unclear. Rapidly progressive hydrocephalus is not associated with the bobble-headed doll syndrome. Similarly, the classic setting sun sign of infantile hydrocephalus has not been reported in conjunction with the bobble-headed doll syndrome, although it is related to third ventricular dilatation and periaqueductal dysfunction. The bobble-headed doll syndrome seems to signify a slowly progressive hydrocephalus, while the setting sun sign is a sensitive sign of rapidly progressive hydrocephalus or shunt blockage in shuntdependent hydrocephalus.63 Most children with bobble-headed doll syndrome have been found to have a cyst or mass in or near the anterior part of the third ventricle.120 Most of the remaining cases have been found to have hydrocephalus secondary to aqueductal stenosis or, rarely, ventricular shunt obstruction,59 suggesting a slow dilation of the third ventricle as the possible common denominator. Some children with bobble-headed doll syndrome harbor, a subclinical nystagmus, and the head nodding may actually contribute to an improvement in vision.85 It has therefore been suggested that the head nodding in the bobbleheaded doll syndrome may share a common pathogenesis

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(compression of the floor of the third ventricle) with the head nodding in spasmus nutans-associated suprasellar tumors.85 In some children, the head bobbing precedes other signs or symptoms of elevated intracranial pressure by as much as 6 months.200 Associated neurological and endocrinological abnormalities are common. Apart from a large head size, neurological findings may include abnormal pyramidal-tract findings, ataxia or intention tremor of the trunk, and optic disc pallor – which may reflect compression of the optic nerves, chiasm, or tract, depending on the underlying cause.200 Endocrinological abnormalities may also be present, including diabetes insipidus, precocious puberty, and advanced bone age.200 Resolution or improvement of the tremor following surgical removal of the cyst or tumor is noted in some patients.120

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can occur several times a day then cease spontaneously for a week or two, affected children may be misdiagnosed as having epilepsy, psychogenic disturbances, tics, or paroxysmal choreoathetosis.158 The high frequency of benign essential tremor (5 to 1.5 cps) distinguishes it from the bobble-headed doll syndrome. Unlike the bobble-headed doll syndrome, in which the head movements are inhibited by activity, benign essential tremor persists or worsens with activity.200 Ingestion of small amounts of alcohol (one drink) abates the tremor, whereas ingestion of larger volumes exacerbates it. Treatment with propanolol effectively abolishes the tremor. Autopsy studies of the basal ganglia and other structures have failed to detect any pathological abnormality.176

Paroxysmal Dystonic Head Tremor Cerebellar Disease Midline cerebellar lesions may give rise to a slow, (3 to 4 cps) predominantly anteroposterior oscillation of the head (titubation) which may simulate the bobble-headed doll syndrome.44,200 However, cerebellar head tremors are accompanied by other cerebellar signs, such as truncal ataxia and motor incoordination, as well as cerebellar eye signs (ocular dysmetria, impaired pursuits, gaze-evoked nystagmus, impaired VOR suppression).47 Kalyanaraman et al123 described three related children with head nodding and nystagmus associated with a cerebrocerebellar degeneration of unclear etiology. Idiopathic torsion dystonia is characterized by twisting and repetitive movements and postures that are not attributed to exogenous factors (e.g., trauma, neuroleptics) or other neurologic disorders (e.g., Wilson’s disease, Parkinson’s disease). Age at onset of idiopathic torsion dystonia ranges from early childhood to the eighth decade, and almost any skeletal muscle may be involved. When idiopathic torsion dystonia begins in childhood, it is likely to start in a limb and then spread to other body regions.19

Benign Essential Tremor Benign essential tremor is a hereditary, monosymptomatic condition in which an intermittent, involuntary, high-frequency tremor affects the head and hands. Although it more commonly develops during later childhood or adolescence, it may appear at as early as 2 years of age. The head movements may precede the hand movements by several years. Benign essential tremor may initially manifest as shuddering or shivering attacks in which the head flexes and turns along with other body movements.203 Because these brief shuddering attacks

Paroxysmal dystonic head tremor is a rare, nonfamilial disorder characterized by attacks of horizontal head tremor (frequency 5–8 Hz).77,178 The attacks last 1–30 min and cannot be suppressed. They begin in adolescence, but some children may have an associated head tilt that predates the onset of the tremor by 5–10 years.77 Neuroimaging studies are negative. The condition is nonprogressive, and its cause is unknown. Daily clonazepam reduces the frequency and severity of attacks.77

Autism Autistic children may display rocking of the head and trunk along with other motor stereotypes (hand flapping and spinning), sensory stereotypes, and impaired communication and socialization. Necropsy studies implicate severe Purkinje cell loss in the posterior cerebellar vermis and cerebellar hemispheres as a neuroanatomical correlate of autism.52 This abnormality is reflected on theMR imaging as either hypoplasia or hyperplasia of the cerebellar vermis, causing previous quantitative MR estimates of the mean posterior cerebellar size to fall within the normal range. However, the MR imaging shows increased total brain volume attributable to generalized enlargement of gray and white matter cerebral volumes, but not cerebellar volumes.51,103 Current theories focus on autism as a disorder of connectivity, particularly involving the association cortex.152

Infantile Spasms Infantile spasms may manifest with nodding attacks that occur in isolation or together with mental retardation, myoclonic jerks, or various neurological deficits.76,154 Morimoto

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Head Oscillations

et al154 described such nodding attacks in a 2-year-old boy whose nodding disappeared immediately following surgical resection of a right temporal astrocytoma.

movements tend to be slow and rhythmical with boredom and fatigue and become faster and irregular with stress or excitement.117,118

Congenital Ocular Motor Apraxia

Intermittent Esotropia

We have observed infants with congenital ocular motor apraxia who, in addition to head thrusting, show intermittent head nodding during fixation of a nonmoving object. This nodding may persist at an age when the head thrusting has resolved. We assume it somehow serves to fine-tune or recalibrate the fixation mechanism in this disorder.

Neurologically normal children have been described as having intermittent esotropia without nystagmus and intermittent head nodding that manifested only when the eyes were straight.125,181 The head movements cease with the spontaneous onset of esotropia or with the occlusion of either eye. “During head stabilization by the examiner, affected children often develop a manifest esotropia.” These reports suggest that the head nodding can somehow facilitate horizontal ocular alignment. Infantile esotropia is rarely associated with head nodding and nystagmus. Brodsky and Wright30 described three patients with infantile esotropia, fine torsional nystagmus, and head oscillations that varied from shaking to nodding during periods of visual attention. Strabismus surgery restored ocular alignment and eliminated the head oscillations. It was unclear whether the head oscillations were casually related to the infantile esotropia, to the associated nystagmus, or both. Other infants with infantile esotropia may exhibit features of spasmus nutans that do not appear to be compensatory for binocular alignment.179

Opsoclonus/Myoclonus Severe myoclonus associated with opsoclonus can cause incessant, rapid, irregular head movements. Kinsbourne126 described wobbling, titubation, and rapid, irregular jerking movements of the head in three of six young children with acute postviral myoclonic encephalopathy associated with opsoclonus. The associated myoclonus distinguishes this disorder from other causes of head nodding. In the absence of an underlying neuroblastoma, the illness may resolve over weeks to months, although the course is protracted and recovery incomplete in some children.140

Visual Disorders Blindness Jan has reviewed the numerous abnormal head movements in visually impaired children. Head oscillations are among the sophisticated adaptations that blind children develop to interact more effectively with their physical surroundings. Head oscillations in the visually impaired child may appear as stereotyped, purposeless movements to the examiner, if their numerous adaptive functions go unrecognized. Children with tunnel vision may make side-to-side oscillating head movements when walking in order to scan the environment. Many blind children use their hearing to avoid obstacles with surprising efficiency.86 Jan118 has noted that, in the corridors of schools for the blind, it is not uncommon to see children walking with their heads slowly turning from side to side, while making clicking or chirping noises, in order to use their “radar systems.” The rhythmical front-to-back or sideto-side rocking movements of the head or trunk seen in blind children may start as a response to understimulation or overstimulation and later become a habit. These self-stimulating

Otological Abnormalities Labyrinthine Fistula

118

“Head nystagmus” was alluded to in the older literature as a sign of labyrinthine fistula.60 Despite the recent flurry of interest in this controversial condition, its association with head shaking seems to have disappeared.15,35,109,130

Systemic Disorders Aortic Regurgitation Patients with severe aortic regurgitation may display a bobbing motion of the head and a jarring motion of the body with each systole due to a widened arterial pulse pressure (de Musset sign).194 The head bobbing of aortic regurgitation is accompanied by a high-pitched, decrescendo, diastolic murmur along the left sternal border. Originally considered a

460

sign of syphilitic aortitis, de Musset sign rarely develops in children with Marfan syndrome.

Endocrine and Metabolic Disturbances A gross tremor of the head and hands may occur in endocrine and metabolic disturbances such as hypomagnesemia,78 hypocalcemia (including hypoparathyroidism), uremia, and thyrotoxicosis.158 These findings may also be seen in untreated phenylketonuria and in citrullinemia.158

Nasopharyngeal Disorders Torticollis has been described under the rubric “nasopharyngeal torticollis” in many acute and chronic upper respiratory infections, including pharyngitis, tonsillitis, sinusitis, and otitis media.128 The SCM on the affected side is frequently in painful spasm, and the underlying cervical lymph nodes are usually enlarged.128

Organic Acidurias Torticollis may be seen in dystonic metabolic conditions, such as gluteric aciduria, that are accompanied by severe motor and language disability.137

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References 148. McLaghlan RS. The significance of head and eye turning in seizures. Neurology. 1987;37:1617–1619. 149. Mein J, Harcourt B. Diagnosis and Management of Ocular Motility Disorders. Oxford: Blackwell Scientific; 1986. 150. Metz HS, Jampolsky A, O’Meara DM. Congenital ocular nystagmus and nystagmoid head movements. Am J Ophthalmol. 1974;74:1131–1133. 151. Miller NR, ed. Walsh and Hoyt’s Clinical Neuro-ophthalmology, II. 4th ed. Baltimore: Williams and Wilkins; 1985:893–897 152. Minshaw NJ, Williams DL. The new neurobiology of autism. Cortex, connectivity, and neuronal organization. Arch Neurol. 2007;64:945–950 153. Mocan MC, Wright KW, Salvador MG. Evidence of binocular fusion in a 3-week-old infant with transient abducens nerve paresis. J AAPOS. 2007;11:199–200. 154. Morimoto K, Abekura M, Nil Y, et al. Nodding attacks (infantile spasms) associated with temporal lobe astrocytoma – case report. Neurol Med Chir. 1989;29:610–613. 155. Morris HH, et al. The lateralizing significance of versive head and eye movements during epileptic seizures. Neurology. 1986;36:606–611. 156. Mount LA, Reback S. Familial paroxysmal choreoathetosis. Arch Neurol Psychiatry (Chicago). 1940;44:841–847. 157. Murayama K, Greenwood RS, Rao KW, et al. Neurological aspects of del (1q) syndrome. Am J Hum Genet. 1991;40:488–492. 158. Nelhaus G. Abnormal head movements of young children. Dev Med Child Neurol. 1983;25:384–398. 159. Newman SA. Spasmus nutans. Or is it? Surv Ophthalmol. 1990;34:453–456 160. Norn MS. Congenital idiopathic nystagmus. Incidence and occupational prognosis. Ophthalmology. 1964;42:889. 161. Nucci P, de Pellegrin M, Brancato R. Atlantoaxial dislocation related to instilling eyedrops in a patient with Down’s syndrome. Am J Ophthalmol. 1996;122:908–910. 162. Nucci P, Kushner BJ, Serafina M, et al. A multi-disciplinary study of the ocular, orthopedic, and neurologic causes of abnormal head postures in children. Am J Ophthalmol. 2005;140:65–68. 163. Nutt AB. Abnormal head posture. Br Orthop J. 1963;20:18–28. 164. Ochs R, Gloor P, Quesney F, et al. Does head-turning during a seizure have lateralizing or localizing significance? Neurology. 1984;34:884–890. 165. O’Donnell JJ, Howard RO. Torticollis associated with hiatus hernia (Sandifer’s syndrome). Am J Ophthalmol. 1971;71:1134–1137. 166. Osterberg G. On spasmus nutans. Acta Ophthalmol. 1937;15:457–467. 167. Parker W. Migraine and the vestibular system in childhood and adolescence. Am J Otol. 1989;10:364–371. 168. Parks MM. Isolated cyclovertical muscle palsy. Arch Ophthalmol. 1958;60:1027–1035. 169. Parulekar MV, Dai S, Buncic JR, et al. Head position-dependent changes in ocular torsion and vertical misalignment in skew deviation. Arch Ophthalmol. 2008;126:899–905. 170. Paysse EA, Coats DK, Plager DA. Facial asymmetry and tendon laxity in superior oblique palsy. J Pediatr Ophthalmol Strabismus. 1995;32:158–161. 171. Paysse EA, Coats DK. Anomalous head posture with early-onset homonymous hemianopia. J AAPOS. 1997;1:209–213. 172. Plager DA. Tendon laxity in superior oblique palsy. Ophthalmology. 1992;99:1032–1038. 173. Plagiocephaly and torticollis in young infants. Lancet. 1986;2:789– 790 [Editorial] 174. Prensky AL. An approach to the child with paroxysmal phenomenon with emphasis on nonepileptic disorders. In: Dodson WE, Pellock JM, eds. Pediatric Epilepsy: Diagnosis and Therapy. New York: Demos Publications; 1993:63–80. 175. Ragge NK, Harris CM, Dillon MJ, et al. Ocular tilt reaction due to a mesencephalic lesion in juvenile polyarteritis nodosa. Am J Ophthalmol. 2003;135:249–251.

463 176. Rajput AH, Rozdilsky B, Ang L, et al. Clinicopathologic observations in essential tremor: Report of six cases. Neurology. 1991;41: 1422–1424. 177. Richards RN, Barnett HJ. Paroxysmal dystonic choreoathetosis. Neurology. 1968;18:461–469. 178. Rivest J, Marsden CD. Trunk and head tremor as isolated manifestations of dystonia. Mov Disord. 1990;5:60–65. 178a. Romano P. Editorial. Binoc Vis Q. 1997;12:85. 179. Rose KM, Havertape SA, Cruz OA. Development of spasmus nutans after initial diagnosis of infantile esotropia. Am Orthop J. 1999;49:193–195. 180. Rubin SE, Wagner RS. Ocular torticollis. Surv Ophthalmol. 1986;30:366–376. 181. Rubin SE, Slavin ML. Head nodding associated with intermittent esotropia. J Pediatr Ophthalmol Strabismus. 1990;27:250–251. 182. Safran AB, Rossilion B. Why should Bielschowsky Head Tilt Test be negative in patients with skew deviation? Mechanism and significance. Trans 25th Eur Strabis Assoc Mtg. Lisse, Netherlands: Aeolus Press; 1999 183. Salem OH, Preston CB. Head posture and deprivation of visual stimuli. Am Orthop J. 2002;52:95–103. 184. Santiago AP, Rosenbaum AL. Dissociated vertical deviation and head tilts. J AAPOS. 1998;2:5–13. 185. Sarnet HB, Morrissy RT. Idiopathic torticollis: sternocleidomastoid myopathy and accessory neuropathy. Muscle Nerve. 1981; 4:374. 186. Saunders RA, Roberts EL. Abnormal head posture in patients with fourth cranial nerve palsy. Am Orthop J. 1995;45:24–33. 187. Scheffer RN, Zlotogora J, Elpeleg ON, et al. Behr’s syndrome and 3-methylglutaconic aciduria. Am J Ophthalmol. 1992;114: 494–497. 188. Sedwick LA, Burde RM, Hodges FJ. Leigh’s subacute necrotizing encephalomyelitis manifesting as spasmus nutans. Ophthalmology. 1990;102:1046–1048. 189. Siatkowski RM, Fortney AC, Nazir SA. Visual field defects in deformational posterior plagiocephaly. JAAPOS. 2005;9:274–278. 189a. Simonsz HJ, Florijn R, Bergen AAB, Kamermans M. Night blindness associated with transient tonic downgaze. Strabismus. 2009, In press. 190. Snyder CH. Paroxysmal torticollis of infancy: A possible form of labyrinthitis. AJDC. 1969;117:458–460. 191. Spielmann A. Pediatric nystagmus and strabismus. Curr Opin Ophthalmol. 1990;1:621–626. 192. Stevens DJ, Hertel RW. Relationships between visual acuity and anomalous head posture in patients with congenital nystagmus. J Pediatr Ophthalmol Strabismus. 2003;40:259–264. 193. Still GF. Head nodding with nystagmus in infants. Lancet. 1906;2:207–209. 194. Stone J. Syphilis and the cardiovascular system. In: Schlant RC, Alexander RW, eds. The Heart. 8th ed. New York: McGraw-Hill; 1994:1949–1952. 195. Stuart JA, Burian HM. Changes in horizontal heterophoria with elevation and depression of gaze. Am J Ophthalmol. 1962;53:274–279. 196. Suchowersky O, Calne DB. Non-dystonic causes of torticollis. Adv Neurol. 1988;50:501–508. 197. Taboas-Perez RA, Rivera-Reyes L. Head tilt: A revisit to an old sign of posterior fossa tumors. Bol Asoc Med PR. 1984;76(2):62–65. 198. Taylor D. Disorders of head and eye movements in children. Trans Ophthalmol Soc UK. 1980;100:489–494. 199. Thurston SE, Leigh RJ, Osorio I. Epileptic gaze deviation and nystagmus. Neurology. 1985;35:1518–1521. 200. Tomasovic JA, Nellhaus G, Moe PG. The bobble-headed doll syndrome: an early sign of hydrocephalus. Two new cases and a review of the literature. Dev Med Child Neurol. 1975;17:777–792 201. Twee TD. Congenital muscular torticollis: current concepts and review of treatment. Curr Opin Pediatr. 2006;18:26–29.

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Chapter 10

Neuro-Ophthalmologic Manifestations of Neurodegenerative Disease in Childhood

Introduction Neurodegenerative disorders in children pose a unique diagnostic challenge. Unlike many genetic syndromes, the clinical manifestations of childhood neurodegenerative diseases are often nonspecific and show considerable overlap. Pathognomonic clinical signs are rare. Many of these conditions are uncommon, and extensive clinical experience is generally lacking, even in tertiary referral centers. To further complicate matters, these children often present in the early stages of their illness, when evidence of progression is questionable and motor or cognitive impairment is relatively mild. It is only with extended observation that both clinical and neuroimaging abnormalities evolve to suggest a limited set of diagnostic possibilities. These children usually require repeated observation by a multidisciplinary team of neurologists, neuroimaging specialists, neuro-ophthalmologists, and geneticists before a specific diagnosis is established.199 Children with neurodegenerative diseases often present with a combination of motor and intellectual impairment. Although the definitive diagnosis of many of these disorders is made by testing for biochemical or genetic abnormalities, the differential diagnosis is based on the child’s physiognomy, systemic and neurological findings, neuro-ophthalmologic abnormalities, and the results of neuroimaging studies. The neuro-ophthalmologist is often called upon to look for ocular motility or retinal signs that suggest a specific diagnosis so that ancillary investigations can be directed appropriately. It is inappropriate to investigate every child with developmental delay for neurodegenerative disease, and the complex interplay between development and degeneration may make the choice of which patients to be investigated, a difficult one. In this setting, visual system abnormalities may be among the most quantifiable and reproducible clinical features, and therefore figure prominently in the diagnostic decision-making process. In some circumstances, visual system abnormalities are the presenting sign of a neurodegenerative disease. The neuro-ophthalmological features of these conditions may include optic atrophy, retinal degeneration, nystagmus, ophthalmoplegia and other motility disturbances, and cortical

visual loss. In particular, the later-onset abnormalities (i.e., occurring after 5 years of age) may present with visual loss or the new onset of strabismus, ophthalmoplegia with ptosis, or nystagmus. A traditional framework for categorizing neurodegenerative diseases is to divide them into disorders that involve primarily gray matter and those that involve primarily white matter. This classification system is useful primarily as a clinical and neuroimaging tool to aid in differential diagnosis. The definitive classification system for neurodegenerative disorders has yet to be established, and it appears that grouping diseases by the effected subcellular organelle (i.e., lysosomal, mitochondrial, and peroxisomal diseases) will eventually be supplanted by a genetic classification system. In this chapter, a combination of traditional and subcellular organelle classification systems will be used. The classification of each neurodegenerative disease under these systems is summarized in Table 10.1. The primary involvement of gray versus white matter in neurodegenerative disease is often reflected in the early neurological abnormalities. Gray matter diseases present with intellectual deterioration, seizures, and involuntary movement disorders. Neuro-ophthalmologic abnormalities, when present, are dominated by retinal degeneration and supranuclear ocular motor disturbances (Table 10.2). White matter diseases usually begin with spasticity and optic atrophy. However, gray matter disorders may eventually spread to involve white matter and vice versa, and many neurodegenerative disorders involve both gray and white matter primarily. Immaturity and poor motor control make behavioral evaluation of vision difficult in children with neurodegenerative disease. Accurate assessment of vision can be confounded by the child’s ambiguous response to visual stimuli. In this context, ancillary testing in the form of visual physiology and neuroimaging investigations may provide critical objective information.142 Electroretinography (ERG) is most likely to be abnormal in gray matter diseases, whereas the visual evoked potential (VEP) may provide early evidence of optic atrophy (Table 10.3) or intracranial white matter tract disturbance.

M.C. Brodsky, Pediatric Neuro-Ophthalmology, DOI 10.1007/978-0-387-69069-8_10, © Springer Science+Business Media, LLC 2010

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Table 10.1. Classification systems of neurodegenerative diseases of childhood Classification by organelle/biochemical defect Mitochondrial encephalomyelopathies CPEO (Kearns-Sayre syndrome) MELAS MERRF Leigh disease

Peroxisomal disorders

Lysosomal storage diseases

Aminoacidopathies

Metal metabolism

X-linked adrenoleukodystrophy Refsum disease Peroxisomal biogenesis disorders (Zellweger syndrome, infantile Refsum disease, neonatal adrenoleuko-dystrophy)

Gangliosidoses (GM1) Tay-Sachs (GM2) disease Sandhoff disease Fabry disease Gaucher disease Niemann-Pick disease Farber disease Krabbe disease Metachromatic leukodystrophy Mucopolysaccharidoses Mucolipidoses Glycoproteinoses

Maple syrup urine disease Homocystinuria Organic acid disorders (methylmalonic) acidemia, propionic acidemia)

Wilson disease PKAN/NBI

Classification by gray versus white matter involvement Primarily gray matter involvement

Primarily white matter involvement

Mixed gray and white involvement

Zellweger syndorme Metachromatic leukodystrophy Neuronal ceroid lipofuscinosis Adrenoleukodystrophy Alexander disease Tay-Sachs (GM2 type 1 disease) Leigh disease Canavan disease Niemann-Pick disease Pelizaeus-Merzbacher disease Gaucher disease Krabbe disease Mucopolysaccharidoses Vanishing white matter disease Sialidosis PKAN/NBI Wilson disease CPEO, chronic progressive external ophthalmoloplegia; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; MERRF, myoclonic epilepsy associated with ragged red fibers; PKAN/NBI, pantothenate kinase-associated neurodegeneration/neurodegeneration with brain iron accumulation.

Neuroimaging findings are frequently nonspecific in neurodegenerative disorders of childhood. The presence of megelencephaly suggests Canavan disease or Alexander disease. Symmetrical changes suggesting edema in the basal ganglia or brainstem are characteristic of Leigh disease. Extensive bioccipital or bifrontal white matter edema with peripheral enhancement is characteristic of X-linked adrenoleukodystrophy with active demyelination. Although rarely diagnostic alone, neuroimaging of children with neurodegenerative diseases can narrow the differential diagnosis and direct genetic or biochemical investigations. Magnetic resonance (MR) imaging is particularly valuable in differentiating white matter from gray matter disease. These studies should be interpreted by an experienced observer because, even early in the course of gray matter disease, the cerebral white matter may show decreased volume because of Wallerian degeneration, and some white matter disorders have an inflammatory component that can cause a contiguous mass effect on adjacent gray matter. White matter disorders such as adrenoleukodystrophy (ALD) and Alexander disease may show hypodensity (decreased attenuation) of central white matter on computed tomography (CT) scanning or prolonged T1 and T2 relaxation times on MR imaging (producing low signal on T1-weighted images and high signal on T2-weighted images) before any

atrophy is apparent. The site of early white matter involvement may provide additional diagnostic information. Neuroimaging specialists divide cerebral white matter into central and peripheral zones. Peripheral white matter is that which immediately underlies the cortex. Because these fibers follow the cortical gyri, they appear in the shape of a “U” on axial imaging of the brain. Disorders in which the abnormality is limited to white matter should undergo careful scrutiny of these subcortical “U fibers” because symmetrical involvement in a macrocephalic patient is strongly suggestive of Alexander disease. Bilateral symmetric peripheral white matter disease in a child who is not microcephalic should raise suspicion of galactosemia.17 Early involvement of deep white matter suggests a different group of disorders. Deep white matter involvement combined with thalamic involvement suggests Krabbe disease, whereas deep white matter involvement combined with corticospinal tracts involvement suggests peroxisomal disorders. A paucity of myelin without evidence of inflammation or injury to myelin is characteristic of Pelizaeus– Merzbacher disease.17 Gray matter disease may involve either cortical gray matter or deep gray matter nuclei. Gray matter diseases of the cortex include neuronal ceroid lipofuscinosis, gangliosidoses, and peroxisomal disorders. The MR abnormalities that suggest a peroxisomal disorder include focal migrational derangements

Neuronal Disease

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Table 10.2. Neurodegenerative conditions associated with prominent ocular motility manifestations Disease

Dominant clinical feature

Metabolic defect

Diagnostic test

Pelizaeus-Merzbacher disease

Horizontal jerk nystagmus, head tremor, delayed development Ataxia, defective saccadic initiation, strabismus, erratic vertical movements, immune deficiency Ataxia, ophthalmoplegia, nystagmus, seizures, weight loss Ptosis, external ophthalmoplegia, pigmentary retinopathy, cardiac conduction defects Retinal degeneration, internuclear ophthalmoplegia, malabsorption of fat, ataxia Early-onset ataxia, dysarthria, cognitive impairment, cerebellar atrophy Later-onset ataxia, peripheral neuropathy, ovarian failure

Unknown Unknown, possible

Tigroid appears to myelin stain on CNS tissue

Unknown, possible cellular repair deficiency

Low IgA

Multiple energy pathway abnormalities, including cytochrome c oxidase Mitochondrial DNA

Enzyme assay on fibroblasts

Apo B transport protein deficiency

Serum lipid profile, liver biopsy

Low coenzyme Q levels

Genetic testing for apratoxin mutation

Elevated α-fetoprotein

Genetic testing for senatoxin mutation

Hepatosplenomegaly, developmental regression, saccadic initiation failure type 3, head thrusting, supranuclear horizontal gaze palsy, "fixed" estropia (type 2) Hepatosplenomegaly, ataxia, athetosis, impaired vertical saccades (downward more affected)

Deficient glucocerebrosidase

Enzyme assay on peripheral leukocytes and fibroblasts

Abnormal esterification of cholesterol, leading to accumulation of sphingomyelin

Skin fibroblasts, molecular testing

Ataxia telangiectasia

Leigh disease Kearns-Sayre syndrome Abetalipoproteinemia

Ataxia with ocular motor apraxia type 1 (AOA1) Ataxia with ocular motor apraxia type 2 (AOA2) Gaucher disease type III

Niemann-Pick type C

DNA analysis on leukocytes

CNS, central nervous system.

combined with hypomyelination, dysmyelination, or demyelination. In addition, the peroxisomal disorders tend to affect the posterior limb of the internal capsule, cerebellar white matter, and brainstem tracts. When the cerebral hemispheres are affected, the occipital white matter may be more severely involved posteriorly. Careful inspection of the subcortical U fibers, gray matter, and the splenium of the corpus callosum may help differentiate this pattern in peroxisomal disorders from other conditions such as occipital region infarction or the mitochondrial encephalomyelopathies. The peroxisomal disorders spare the subcortical U fibers and gray matter and preferentially involve the splenium of the corpus callosum. The mitochondrial encephalomyelopathies show combined involvement of deep gray matter nuclei and peripheral white matter.19,328 Other conditions causing primarily cortical gray matter disease early on include the mucopolysaccharidoses (MPS) and lipid storage disorders. The differential diagnosis of deep gray matter involvement depends on which nuclei are principally involved. The thalamus is involved early in Krabbe disease and also in the GM2 gangliosidoses. Globus pallidus involvement is seen in Canavan disease, Kearns–Sayre syndrome (KSS), methylmalonic and propionic acidemia, and maple syrup urine disease.17 Involvement of the putamen and caudate (striatal disease) is compatible with Leigh disease; (MELAS)

syndrome; and Wilson disease. Hypointensity of the globus pallidus on T2-weighted MR imaging suggests the diagnosis of Hallervorden–Spatz disease.17

Neuronal Disease Neuronal Ceroid Lipofuscinosis The neuronal ceroid lipofuscinoses (NCLs) are a group of disorders with common features, but with enough distinctions to warrant subclassification. The NCLs are inherited in an autosomal recessive manner with the exception of the adult form, which may be dominant or recessive.36,352 The overall incidence is estimated at 1 in 100,000 births, but is approximately ten times higher in the Scandinavian population.342 All forms of NCL eventually manifest in intellectual and gross motor deterioration, seizures, and visual loss from retinal degeneration and optic atrophy with an abnormal ERG (Fig. 10.1).162,240 Neuroimaging reveals evidence of combined white and gray matter atrophy that is most pronounced in the cerebral hemispheres and the brainstem (Fig. 10.2).257,320 Cardiac problems are common, especially in the late stage of the disease.154 Several lines

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Table 10.3. Neurodegenerative diseases with optic atrophy as a prominent feature Disease

Dominant clinical feature

Metabolic defect

Diagnostic test

Adrenoleukodystrophy Neonatal – Peroxisomal biogenesis defects X-linked adrenoleukodystrophy

White matter degeneration in infancy

Peroxisomal disorder (multiple)

White matter degeneration in childhood Peroxisomal disorder (single) (ages 5 to 15) White matter degeneration, severe, infancy Early spasticity, blindness, intellectual deterioration Seizures, gross motor deterioration, kinky hair Hypotonia, peripheral neuropathy dementia Severe white matter degeneration,

Peroxisomal disorder (single)

Very long-chain fatty acids in serum and cultured skin fibro-blasts, molecular testing N-Acetyl aspartic acid in urine, enzyme assay on fibroblasts

Intellectual and motor deterioration, vision loss Ocular motor abnormalities, head tremor Ataxia, ocular motor abnormalities, spontaneous remissions

Neuronal accumulation of lipo-fuscin PLP

Canavan disease Krabbe disease Menke disease Metachromatic leukodystrophy Alexander disease Neuronal ceroid lipofuscinosis Pelizaeus-Merzbacher disease Leigh disease

Asparto-acylase deficiency Galactocerebrosidase, β-galactosidase Abnormal copper metabolism Arylsulfatase-A deficiency GFAP

Enzyme assay on white blood cells, fibroblasts; confirm with gene testing Low serum copper and ceruloplasmin gene testing Urine for sulfatide enzyme assay on fibroblasts and white blood cells Clinical and neuro-progressive megaencephaly Clinical and neuro-imaging, molecular testing Skin, conjunctiva, white blood cells; molecular testing for CLN mutations Clinical and neuro-imaging

Multiple energy metabolism Fibroblasts defects, Fibroblasts cytochrome c oxidase deficiency PKAN Spasticity, dystonia, intellectual Iron storage abnormality, Molecular testing for PANK2 mutation deterioration PANK2 mutation GFAP, glial fibrillary acidic protein; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; MERRF, myoclonic epilepsy with ragged red fibers; PKAN, pantothenate kinase-associated neurodegeneration; PLP, proteolipid protein. * Many degenerative syndromes have optic atrophy as a late consequence of retinal degeneration or diffuse neuronal loss (e.g., spinocerebellar degenerations, MELAS); these diseases are not included in this table.

of evidence point to functions for the CLN genes in the endosomal–lysosomal system and suggest neuron-specific roles for these proteins.69 Current classification of the NCLs distinguishes eight different disorders, which often encompass clinical heterogeneity.127 Six genes, PPT1, TPP1, CLN3, CLN5, CLN6, and CLN8, are known to be associated with NCL. Two genes, CLN1 and

CLN2, encode for lysosomal proteases palmitoyl protein thioesterase 1 (PPT1) and tripeptidyl peptidase 1 (TPP1), respectively.125 Lysosomal membrane proteins of currently unknown function are encoded for by CLN3, CLN5, CLN6, and CLN8. Most cases of juvenile-onset NCL are caused by mutations in CLN3, which maps to chromosome 16p21.161 The most common is a 1.02 kb deletion that is present on

Fig. 10.1 Neuronal ceroid lipofuscinosis. Funduscopic appearance. (a) Note optic atrophy and attenuation of retinal arterioles. (b) Dull appearance of macula, with rippling of internal limiting membrane. Courtesy of Stephen P. Christiansen, M.D.

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skills are severely affected, myoclonic seizures develop, and death occurs by 4 years of age. The ERG is of low amplitude and ultimately becomes flat,142 reflecting severe retinal degeneration. Cataracts may also be seen in this condition.22 Optic atrophy ensues with progression of disease. CLN1 on chromosome 11p32, encoding PPT1, is the gene most often mutated in this subtype.

Late Infantile (Jansky–Bielschowsky Disease) These children undergo a similar pattern of deterioration as those with the infantile form, but they gain more skills by the time of onset (age 2–4 years), which makes the degenerative aspect of the disease more apparent. The retinal degeneration is most visible in the macula, but the entire retina is involved as reflected by extinction of the ERG early in the disease.153 CLN2 on chromosome 11p15, encoding TPP1, is the gene most often mutated in this subtype.

Fig. 10.2 Neuronal ceroid lipofuscinosis. T1-weighted MR image shows diffuse atrophy of cortical gray matter combined with diffuse thinning of cerebral white matter. Hypointense area is seen in occipital lobe, possibly representing lipofuscin storage material (arrow)

approximately 85% of disease chromosomes.216 Juvenile phenotypes have also been observed following mutations in the CLN1 and CLN2 genes.127 The primary biochemical defect in these disorders is yet to be ascertained, and there is no treatment available.65 The diagnosis of an NCL is often based on assay of enzyme activity and/or molecular genetic testing and, in some instances, on clinical findings and electron microscopy of biopsied tissues as discussed below.27,352 The diagnostic testing strategy in a proband depends on the age of onset. The clinical subtypes correlate with particular mutations and their corresponding enzymatic defects. Two lysosomal enzymes, palmitoyl-protein thioesterase 1 (PPT1), which is encoded by the gene PPT1, and tripeptidyl-peptidase 1 (TPP1), which is encoded by the gene TPP1, have been identified as deficient in the neuronal ceroid-lipofuscinosis in white blood cells, fibroblasts, and chorionic villi. Assays of the enzymatic activity of PPT1 and TPP-1 are clinically available. Molecular genetic testing of the PPT1, CLN3, CLN5, CLN6, and CLN8 genes is available on a clinical basis.352

Infantile NCL (Santavuori-Haltia Disease) Neurological deterioration with severe visual loss occurs between 8 months and 1½ years.273 Intellectual and gross motor

Juvenile NCL (Batten Disease) Visual complaints may be the presenting feature of this disease, occurring between 4 and 10 years of age.292 “Overlooking” is a common behavior in children with NCL.311 The child demonstrating this phenomenon appears to look over the top of the object of regard. This strategy has been noted in children with loss of central vision from damage to the papulomacular bundle.130 Early in the course of the disease, retinal abnormalities may be limited to a striking attenuation of retinal arterioles. As the disease progresses, optic atrophy becomes evident and macular abnormalities develop, including a subtle discoloration and rippling of the internal limiting membrane (Fig. 10.1). A coarse pigment granularity or bull’s-eye maculopathy may also develop. At first, the b wave of the ERG is selectively attenuated, but progression of the disease leads to extinction of both the a and the b waves. The VEP becomes increasingly abnormal as optic atrophy ensues. The CLN3 mutation is most commonly present in this subtype, but molecular genetic testing of PPT1 should be performed if a CLN3 mutation is not found. Visual problems are usually the presenting symptom. By the time these children come to medical attention, visual acuity is often 20/400 or less. Curiously, these children do not generally complain of difficulty seeing despite the fact that they have not yet developed dementia. Over time, they develop seizures and Parkinsonism, with dysarthria and slow speech. Angry outbursts and depression are common. Myoclonus is seem mainly in other forms of NCL.2a The following case description illustrates the evolution of visual and neurological dysfunction in juvenile NCL. A boy had a normal prenatal and neonatal course. He walked at 8–9

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months of age and appeared to have normal vision in early childhood. He went to the Head Start Program at age 4 and did well, by the parent’s account. At age 5, the child complained of everything being out of focus. His school performance declined, and he had difficulties with coordination. Over the next year, he developed staring spells and tremors. He was first seen by us at age 11. At that time, his IQ measured 64. His visual acuity was 20/20 in each eye, but the fundus examination showed a pigmentary maculopathy. The neurological examination was remarkable for hyperreflexia and difficulties with tests of coordination. The ERG was unrecordable under either scotopic or photopic conditions. The metabolic screen (including very long-chain fatty acids [VLCFA]) for storage diseases was negative; however, electron microscopy of white blood cells showed irregularly shaped, variably sized, dense, osmiophilic granular bodies. Tubular inclusions were commonly seen in several mononuclear cells. Electrophysiological testing may facilitate the early diagnosis of Batten disease, and ERG typically demonstrates an electronegative waveform under both scotopic and photopic conditions. The most suggestive ERG feature of Batten disease is a markedly reduced b:a ratio in the single flash photopic ERG, with additional a-wave delay. An electronegative maximal response is consistent with the inner retinal localization of the gene product for CLN3.66 However, the diagnosis of Batten disease is now confirmed by molecular analysis of the CLN3 gene, with most disease alleles having the common 1.02 kb deletion.65 CLN3, on chromosome 16p11-12, encodes battinin, a 438 amino acid residue protein. Neuropathologically, JNCL is associated with widespread neuronal degeneration, including retinal atrophy and massive loss of brain substance, and accumulation of intracellular lipopigments.38 Despite the abnormal electroretinogram, it has recently been proposed that the primary site of neural injury may involve the lateral geniculate nucleus with retrograde degeneration.38 Retinal degeneration may be caused by an accumulation of storage material in the ganglion cell layer, which may represent a primary microglial defect,252 or an upstream insult to the lateral geniculate nucleus producing primary optic atrophy and a retrograde retinal degeneration.345 It is unknown whether the associated reactive gliosis precedes or is triggered by neuronal loss.38 Brain biopsy shows enlargement of most neurons, with eccentric nuclei and peripheral displacement of the Nissl substance. The neuronal cytoplasm is filled with granular material that stains pale gray with Sudan black, orange with oil red O, and intensely red or purple with PAS. The neuronal granular material shows a bright yellow autofluorescence. With hematoxylin and eosin, the granules stain pale yellow, resembling lipofuscin. Electron microscopy (EM) of the tissue examined has shown these granules to be cytosomes with curvilinear profiles (Fig. 10.3).25,208 Before genetic testing was available, demonstration of these characteristic findings

Fig. 10.3 Electron microscopy of neuron demonstrating characteristic “fingerprint” profile. Courtesy of Gerald A. Fishman, M.D.

on electron microscopy was the standard confirmation of diagnosis in all forms of this disease. Tissue for examination was generally obtained via biopsy of conjunctiva, rectum, skin, or muscle.47,162,163 In some cases, the diagnosis can be established by examining the white blood cell buffy coat and finding: (1) vacuolated lymphocytes or azurophilic hypergranulated neutrophils on light microscopy, or (2) membrane-bound intracellular inclusions and fingerprint profiles on electron microscopy.162,208 An animal model with ultrastructural similarities to NCL may improve our molecular understanding of this condition.44

Lysosomal Diseases Gangliosidoses The sphingolipidoses, mucopolysaccharidosis, mucolipidoses, glycogen storage diseases, glycoproteinoses, and other storage diseases are the result of an abnormal accumulation of metabolic products within lysosomes. This accumulation is due to a relative deficiency in the activity of hydrolytic enzymes that may be absent or mutated to less effective forms or lacking in activator proteins.306 As with most other degenerative diseases, the categorization of the gangliosidosis by eponym has been replaced by a system based on biochemistry. The gangliosides are classified by the system of Svennerholm, in which the letter G refers to ganglioside, the number of sialic groups are referred to by M (mono), D (di), or T (trisials), and the number of hexosides

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Lysosomal Diseases

in the molecule is given by the subscript 1, 2, or 3 (tetrahexose sides are 1, trihexoside 2, and dihexosides 3).304 These biochemical categories are then further divided on the basis of age of onset and clinical features. GM2 gangliosides have the most prominent visual system involvement, with rare cases of GM1 reported with a cherry red spot.95

GM2 Type I (Tay–Sachs Disease) Tay–Sachs disease, which is the most common of the gangliosidosis, constitutes over 90% of cases of GM2 gangliosidoses and remains the prototype of the neuronal lysosomal lipid storage disorders.171,342 This autosomal recessively inherited deficiency of hexosaminidase A causes accumulation of GM2 ganglioside in the neurons of the central nervous system (CNS) and retinal ganglion cells. In the gangliosidoses, ophthalmoscopy typically shows a macular cherry red spot (Fig. 10.4) that results from the accumulation of opaque gangliosides in the retinal ganglion cell layer surrounding the fovea, causing the retina to become turbid with a milky white discoloration188,232 and the normal choroidal circulation to be visible through the ganglion cell-free fovea.62 Other neurodegenerative diseases associated with a cherry red macula are summarized in Table 10.4. The onset is in the first few months of life, with blindness, seizures, spasticity, and an exaggerated acoustic response (i.e., a startle response to sound) in the first year of life. The cherry red macula sign may disappear as retinal ganglion cells are lost.70,183,232,241 ERG remains normal throughout the course of the disease.241 A variety of ocular motor disturbances have been described.168 Horizontal conjugate gaze deviations and horizontal strabismus are early features.

Fig. 10.4 Tay–Sachs disease. Bilateral macular cherry red spots

As the disease progresses, there is sequential loss of voluntary movements, pursuit and optokinetic responses, voluntary saccades, random short saccades, and vestibularly elicited eye movements. Tonic downward ocular deviation may be a persistent sign late in the disease.168 The diagnosis is usually made by finding low levels of hexaminidase A. Over 100 heterogenous mutations have been found to cause this condition, with the beta-hexaminidase a subunit mRNA often unstable or absent.342 There is no definitive treatment, and death usually occurs by age 4.171 A late-onset variant of Tay–Sachs disease, due to a partial defect of hexosaminidase A, usually presents in adulthood

Table 10.4. Pediatric neurodegenerative disorders associated with cherry-red macula*

Gangliosidosis GM1 Gangliosidosis GM2 Sialidosis

Niemann-Pick disease

Gaucher disease type II Subacute sclerosing panencephalitis Farber disease (disseminated lipogranulomatosis) Krabbe disease (rare) Metachromatic leukodystrophy (rare) *Adapted from Kivlin et al.183

Type 1 (Tay-Sachs disease) Type 2 (Sandhoff disease) Type 1 (Cherry-red spot myoclonus syndrome) Type 2 (Cherry-red spot dementia syndrome, Goldberg-Cotlier syndrome) Type A (Typical cherry-red spot) Type B (Crystalline macular halo) Type C (Variable faint opacification of perimacular area)

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but may also present in childhood.268 This form is more common in Ashkenazi Jews, and is characterized by a progressive course and variable clinical picture that includes ataxia, signs suggestive of motoneuron disease, and psychiatric symptoms.193 Affected patients do not develop cherry red spots but display a prominent and unique ocular motility disorder.268 Horizontal and vertical saccades may appear interrupted, stuttering, and multistep,268 and large saccades can stall in mid-flight, producing transient decelerations.193 CT scanning shows hyperdense areas in the thalamus, with white matter attenuation, a small cerebellum and brainstem, and ventricular dilation.343 Pathological examination of the brain reveals degeneration of cerebral white matter and atrophy of cerebellar hemispheres on gross examination. Neurons are distorted and ballooned and nuclei are displaced to the periphery of the cell. Glial cells are filled with large globules of glycolipid.306 Adult Tay–Sachs disease is associated with a distinct Gly-Ser mutation or seen in a compound heterozygote with the infantile Tay–Sachs mutation.342 GM2 ganglioside accumulates in large amounts in the CNS of patients with Tay–Sachs disease due to a failure of the deficient enzyme hexosaminidase A to cleave N-acetyl-hexosamine from accumulative molecule, thus blocking the normal metabolism of this lipid. The abnormal gene in Tay–Sachs disease is located on chromosome 15 and codes for the a chain of the enzyme.12 The diagnosis may be suspected on clinical grounds and is confirmed by assaying for the enzymatic activity of hexosaminidase A in leukocytes. Carrier screening and prenatal diagnosis of Tay–Sachs disease has been available for many years, and an analysis of the impact of the screening since 1974 indicates that the instances of laboratory error are extremely low. The identification of couples and pregnancies at risk has resulted in a dramatic decrease in the incidence of Tay–Sachs disease in the Jewish population.172

GM2 Type II (Sandhoff Disease) This condition has similar neuro-ophthalmologic findings to Tay–Sachs disease but differs by virtue of its involvement of visceral tissues. Hexosaminidase A and B activity are both abnormal. Affected children develop hepatosplenomegaly, renal abnormalities, and cardiomyopathy.35 Death occurs by 2–4 years of age. Biochemical detection of the enzymatic abnormality can be performed on fibroblasts or leukocytes.198

GM2 Type III These patients experience loss of vision later than those with GM2 types I and II. Ataxia develops between 2 and 6 years of age. Eye movement abnormalities, including pursuit deficit

and saccadic dysmetria, may be seen. Optic demyelination and atrophy are invariable, but rods, cones, and pigment epithelium remain unaffected. In GM2 type III, the ERG is normal, and the VEP is reduced or unrecordable.124,157 The normal ERG is important in distinguishing this type of gangliosidosis from NCL, which is associated with a severely reduced ERG.

Niemann–Pick Disease Niemann–Pick disease includes three disorders. The first two (Niemann–Pick disease A and B [NPA and NPB]) are caused by acid sphingomyelinase deficiency with secondary accumulation of sphingomyelin. Niemann–Pick disease, type C (NPC), which is a lipid-trafficking disorder, was grouped with NPA and NPB in 1961, before the molecular bases of these disorders were understood. NPC is now known to be identical with disorders previously designated as Niemann– Pick disease types D, E and F. In NPA, sphingomyelin accumulation occurs in both neural and visceral tissue, whereas type B has been characterized as causing visceral accumulation only. Patients with type A disease have a rapidly degenerative neurological course, usually leading to death before 4 years of age. The predominant ophthalmological feature is a classic cherry red spot in the retina. NPB is primarily nonneurologic, and patients with type B disease generally live longer than those with type A. However, patients with type B develop massive hepatosplenomegaly, bony changes, and diffuse pulmonary infiltration. These children develop a characteristic macular halo consisting of a discreet, white, crystalline-appearing ring surrounding the fovea of each eye.58 This halo masks macular circulation on fluorescein angiography. It was believed that patients with NPB did not develop cherry red spots at the macula, but a recent natural history study has found that this lesion is relatively common in NPB.211 Patients with NPC are not sphingomyelinase-deficient but have variable sphingomyelin accumulation. An isolate in patients of Nova Scotian descent was previously named Niemann–Pick disease type D but is now known to be allelic with NPC. Type C disease has also been termed juvenile dystonic lipidosis, the Neville–Lake syndrome and the DAF (downgaze palsy, ataxia– athetosis, and foamy macrophages) syndrome.61 This condition may present at any age from fetal life to adulthood. Neonatal presentations are dominated by visceral disease, and affected infants often succumb to liver or ventilatory failure. Later onset disease is characterized by an insidious neurologic deterioration characterized by progressive ataxia, dysphagia, dysarthria, dystonia and, eventually, dementia. Adult cases my masquerade as psychiatric diseases before the cerebellar and brainstem signs become prominent. Cataplexy occurs in about one quarter of patients, and sei-

Lysosomal Diseases

zures in about one half. Hepatosplenomegaly may also be present, but its absence does not rule out the diagnosis. Neuro-ophthalmological findings figure prominently in this disease and serve as a biosurrogate to monitor disease progression. Saccades are slower and smaller and occur with larger latencies. As a rule, vertical movements are more severely affected than horizontal movements and downgaze is more affected than upgaze.61,267,290 Many patients display loss of vertical saccades, impaired downgaze, and loss of the fast phase of optokinetic nystagmus (especially downward) in the presence of preserved doll’s eye movements. Diagonal saccades may show a curved trajectory, and a horizontal component may contaminate attempted vertical eye movements. As with other supranuclear neurodegenerative disorders, prominent blinking may occur when attempting to make saccades. Over time, horizontal saccadic abnormalities may ensue, with the development of head thrusts to compensate for the eye movement abnormality.235 Smooth pursuit movements remain fairly well-preserved.108 The biochemical abnormality in type C disease is abnormal trafficking of lipids in the endosomal–lysosomal system. This leads to the accumulation of unesterified cholesterol, particularly in peripheral tissues, and glycosphingolipids (glucosylceramide, GM1 and GM2 gangliosides), most markedly in the CNS. The diagnosis is made by demonstrating accumulation of free cholesterol in cultured fibroblasts using filipin staining; the secondary defect in cholesterol re-esterification in the ER that is catalyzed by ACAT can also be measured but is less reliable. This biochemical defect is caused by mutations in two distinct genes: NPC1, located on chromosome 18, and NPC 2 on chromosome 14. Ninety-five percent of cases of NPC are associated with mutations in NPC1. More than 250 mutations have been described in NPC1. A trial of cholesterol-lowering agents was ineffective in altering the clinical course of NPC242; more recently, a strategy aimed at reducing the accumulation of glycosphingolipids showed evidence of a modest benefit in stabilizing the disease.244 The primary endpoint of this study was the change in horizontal saccadic eye movement velocity.

Gaucher Disease Gaucher disease is the most common lysosomal storage disease.243 Gaucher disease is an autosomal recessive disorder associated with reduced activity of the lysosomal hydrolase glucocerebrosidase, which is encoded by an extensively characterized gene located in chromosome 1q21.193,243 All three clinically determined types of Gaucher disease have a defect in the catabolic enzyme glucocerebrosidase, resulting in excessive accumulation of a glycolipid glucocerebroside within macrophages in multiple organs.2 The characteristic

473

lysosomal accumulation of storage material can be appreciated in the form of “Gaucher” cells in most tissues. Diagnosis is usually established by assay of B-glucocere brosidase activity in peripheral leukocytes or skin fibroblasts.55 Type I is the most common type of Gaucher disease. It was originally termed nonneuronopathic because the brain and spinal cord are not primarily affected. More recent studies have shown an association of glucocerebrosidase mutations with parkinsonianism, and neuropathological changes in clinically type I Gaucher disease. Findings include hepatosplenomegaly, easy bruising, bone pain, fractures, and arthritis. It may present at any time from childhood to adulthood and may cause a pigmented bulbar conjunctival lesion, bringing the patient to ophthalmological attention. Affected infants may show a supranuclear horizontal and vertical saccadic palsy that is usually distinguishable from congenital ocular motor apraxia in that it is not present at birth and vertical saccades are also affected.61,132,338 Some may show a macular or perimacular atrophy of the retina.46 Clusters of foamy macrophages in the retina may form scattered discrete white spots in the posterior pole, especially along the inferior vascular arcades.59,117 Enzyme replacement therapy is proven to be safe and effective in the treatment of type 1 Gaucher disease,120 producing amelioration of hepatosplenomegaly and of hematologic manifestations within 6–12 months.120,225 However, bone disease improves more slowly, and neurologic complications do not reverse with this treatment.120 Types 2 and 3 are known as neuronopathic forms because they affect the CNS. The locus for both disorders maps to 1q21.300 Type 2 is the acute neuronopathic infantile form, which is characterized by ocular motor apraxia, strabismus, trismus, opisthotonus, and death typically by 2 years of age. Patients are usually normal at birth but develop hepatosplenomegaly, developmental regression, and growth arrest within a few months.300 A “fixed” esotropia and a supranuclear horizontal gaze palsy are frequently seen.104 The finding of fixed esotropia in a child with hepatosplenomegaly should therefore be considered a dire prognostic sign of type 2 Gaucher disease. Some patients develop a cherry red spot and optic atrophy.300,311 Because enzyme replacement therapy is expensive and does not ameliorate the neurologic symptoms,120,215,225 treatment is rarely given. Type 3 is the subacute juvenile neuronopathic form of Gaucher disease. It also affects the nervous system but tends to progress more slowly than type 2. It begins in the first decade with organomegaly and growth retardation, progressing to intellectual deterioration and seizures, sometimes characterized as a myoclonic dementia. Cranial nerve dysfunction and an isolated horizontal supranuclear gaze palsy may develop. Ocular motor involvement may range from isolated horizontal supranuclear gaze palsy to complete inability to generate voluntary or reflexive saccadic eye movements with substitution of compensatory blinks and head thrusts.243 Affected patients may display a selective

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horizontal saccadic initiation failure with loss of optokinetic quick phases,37 and horizontal saccades that are slower, smaller, and longer than normal.143 This ocular motor deficit may be accompanied by horizontal head thrusting and thereby simulate congenital ocular motor apraxia.61,243 Patients with Gaucher type 3 also have “upward looping” horizontal saccades with upward trajectories.61,243 While many disorders cause saccadic initiation failure, its presence in a patient with known Gaucher disease is widely considered to be diagnostic of type 3.143 The advent of enzyme replacement therapy has significantly changed the management of Gaucher disease but has made early and correct diagnosis imperative.143 In adult patients, slow saccades may be a prominent finding and may provide a therapeutic index during enzyme replacement therapy for this disorder.8,193,243,338 Substrate reduction therapy and chaperone-mediated enzyme reduction therapy are also being explored.120

Mucopolysaccharidoses The mucopolysaccharidoses are a heterogeneous group of disorders caused by widespread accumulation of intracellular and extracellular glycosaminoglycans (GAG) systemically and in ocular tissues. MPS are caused by reduction in the activity of specific lysosomal enzymes involved in the breakdown of GAG, which results in a wide spectrum of clinical phenotypes, ranging from disorders that are fatal in the first months of life to those compatible with a normal lifespan.13 The most obvious defects are intellectual and motor retardation, bone and joint deformities, and a typical coarse facies. Ocular signs include progressive corneal clouding and retinal degeneration varying with subgroups. The early clinical classification of MPS has been supplanted by a biochemical scheme: MPS1H (Hurler syndrome), MPS1S (Scheie syndrome), and MPS1HS (Hunter–Scheie syndrome); MPS2 (Hunter-severe and Hunter-mild) and MPS3 (Sanfilippo A, B, C); MPS4 (Morquio A, B); MPS5 (no longer used); MPS6 (Maroteaux-Lamy); MPS7 (Sly); and MPS8 (diferrante). Retinal degeneration is found in MPS1H, MPS1S, MPS2, MPS3, and MPS7. Although the diagnosis is confirmed by enzyme and genetic studies, screening includes examination of lymphocytes for vacuolated inclusions, a skeletal survey to look for boney changes, and screening for glycosaminoglycans in the urine.342 New treatments resulting in a longer lifespan and better intellectual function for many MPS patients have made the long-term ocular management of these patients crucial for optimum quality of life. Enzyme replacement therapy is now approved for use in Hurler’s, Hunter’s, and Maroteaux–Lamy syndromes. Although bone marrow transplantation and enzyme

replacement therapy improved the clinical prognosis, they do not arrest neurological deterioration.249 Bone marrow transplantation has produced corneal clearing in a small subset of patients,136,291,301,332 but most of them still have significant corneal clouding.13,68 Potentially promising therapeutic avenues in development include intrathecal enzyme replacement therapy and gene therapy, which has also been investigated in animal models.13

MPS1H (Hurler Syndrome) Children with this condition are normal at birth but begin to develop the characteristic coarse facies (Fig. 10.5) and corneal clouding within the first year of life. Distinct physical characteristics include frontal bossing, saddle nose, short neck, claw-shaped hands, oar-shaped ribs, and bullet-shaped phalanges. Mental retardation becomes obvious during the first few years of life. As motor development progresses, a peculiar stance and gait are noted due to lumbar lordosis, thoracic kyphosis, and flexion contractures at the elbows and knees.306 The abnormality is progressive, and survival beyond 10 years of age is rare. Bone marrow transplantation in younger patients and enzyme replacement therapy in older ones produces clinical improvement and longer survival; however, cognitive deficits continue to progress.349,350 Death usually results from cardiac failure. Corneal clouding, the predominant ophthalmological feature in this condition, starts at approximately 6 months of age and is not associated with photophobia or increased corneal diameter. However, these children frequently develop glaucoma and have retinal degeneration. ERG changes show a rod-cone degeneration, with the rod function more severely affected.49 Optic disc abnormalities may include papilledema, pseudopapilledema, and optic atrophy.28,29,67 Histopathologic examinations have shown that optic disk

Fig. 10.5 Hurler syndrome. Characteristic facial appearance includes frontal bossing, saddle nose, coarse features, and short neck

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Lysosomal Diseases

swelling may result from infiltration of the lamina cribrosa, leading to narrowing of the scleral canal and prelaminar axonal stasis (pseudopapilledema).28,29 Children with Hurler syndrome may also have papilledema secondary to hydrocephalus. Optic atrophy can be secondary to previous swelling or occur as a secondary effect to retinopathy.13,65 Although usually not required for the diagnosis of these conditions, ERG can provide valuable objective evidence of retinal function in patients with cloudy corneas. Gills et al123 described 21 patients with Hurler syndrome using the older classification. Subnormal ERGs were found in types I (MPS1H), II (MPS2), and III (MPS3). Visual electrophysiologic studies are recommended as part of the preoperative and postoperative evaluation for penetrating keratoplasty. With the advent of bone marrow transplantation and enzyme replacement therapy, the ERG and VEP have begun to play an increasing role in the quantification of visual pathway improvement or deterioration during treatment.13 When corneal transplantation or glaucoma surgery is contemplated, it is well to remember that many patients with mucopolysaccharidosis are at major anesthetic risk, and complications occur relatively frequently. For example, Hurler patients often have airway obstruction secondary to abnormal cervical vertebra, short neck, high epiglottis, and GAG infiltration of soft tissues, and these problems tend to increase with age. A fiberoptic endoscope may be required for intubation. Macrocephaly may result from intracranial mucopolysaccharide deposition, hydrocephalus, or a combination of the two.17 MR imaging shows white matter abnormalities, including focal and diffuse areas of prolonged T1 and T2 relaxation times, with focal lesions in the corpus collosum, basal ganglia, and cerebral white matter.179 Cerebral atrophy and white matter changes occur earliest in types I, II, III, and VII and may not be seen until the second decade of life in types IV and VI.189 Imaging of the spine in patients with Hurler syndrome is often indicated because spinal cord compression is a common and serious complication of the disease.17 Pathological changes from stored mucopolysaccharide occur in virtually every organ in this condition. The lysosomes of neurons are enlarged with material that resembles lipid. Electromicroscopy shows mucopolysaccharide granular inclusions in lysosomes in tissues throughout the body.262 The enzymatic defect in MPS1H is an absence of a l-iduronidase activity. Large quantities of dermatan sulfate and heparan sulfate accumulate because the a l-iduronic acid portions of these compounds are not cleaved. Clinical characteristics lead to suspicion of the diagnosis and are confirmed by assaying a l-iduronidase activity in leukocytes or cultured fibroblasts.137 Screening studies can be performed on urine assessing mucopolysaccharide content and dermatan sulfate and heparan sulfate. The gene for both Hurler and Scheie syndrome is on chromosome 4p16.342

MPS1S (Scheie Syndrome) These patients differ from MPH1H in that the CNS is relatively spared from the condition, corneal clouding is severe, and retinal degeneration may occur. Dermatan sulfate and heparan sulfate are excreted in the urine, and the enzymatic deficiency appears to be similar to MPH1H.346

MPS2 (Hunter Syndrome) Hunter syndrome is an X-linked recessive condition producing a phenotype that is similar to but milder than Hurler syndrome. Hunter syndrome has also been described in females who have mutations of the X chromosome.43 Corneal clouding is absent or mild, and pigmentary retinopathy and optic disk elevation have been reported.28,29 Patients with normal intellectual function may live for decades but eventually die of cardiac disease. Iduronate sulfatase activity is deficient, and this enzymatic abnormality can be assayed in leukocytes, fibroblasts, and hair roots.56 Progressive exophthalmos and hypertelorism has been reported in this condition.1 The gene for Hunter syndrome is on chromosome Xq28.342

MPS3 (Sanfilippo Syndrome) This subgroup has more severe psychomotor abnormalities, is hyperactive, and sleeps very little. In this context, the clinical diagnosis is usually established on the basis of a skull X-ray. These children show no corneal clouding, less severe physical changes than types I and II, and a later-onset retinal dystrophy. There are four enzymatic subgroups, inherited as autosomal recessive traits. ERG changes are more severe than in MPS1H, and examination of retinal pathology shows evidence of rodcone degeneration, with rod degeneration predominating.49 Characteristic coarse hair is a singular feature of MPS3A. The biochemical defects can be assayed in leukocytes or fibroblasts.137 The genes for Sanfillippo syndrome type A is located on 17q25.31, while those for type B are located on17q21 and 12q14.342

MPS4 (Morquio Syndrome) Children with Morquio syndrome are normal early in life but develop short stature and bone dysplasia at about 18 months of age. This subcategory is relatively mild when compared with the first three groups; however, progressive but mild intellectual deterioration occurs, and characteristic connective tissue abnormalities are noted. There is a characteristic abnormality of tooth enamel leading to discoloration and a rough surface. Corneal opacification is mild. Visual loss is not as severe as

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10 Neuro-Ophthalmologic Manifestations of Neurodegenerative Disease in Childhood

in MPS1H.75 However, progressive pseudoexophthalmos due to shallow orbits has been described in patients with Morquio174 and Hunter syndromes.1 Two different biochemical syndromes are classified as types A and B. The first is due to a deficiency of N-acetylgalactose-amine-six-sulfatase and the second is due to beta-galactosidase deficiency. These can be detected on the basis of enzyme assay of leukocytes or fibroblasts. The genes for type A is located on chromosome 16q24.3, while that for type B is located on chromosome 3p21.33.

MPS6 (Maroteaux–Lamy Syndrome) Children with this form of MPS have similar physical features to MPS1H. An important feature of Maroteaux–Lamy syndrome is hypoplasia of the odontoid process of the second vertebra, which places these children at risk for spinal cord compression during endotracheal intubation. Intellect may be normal, but skeletal deformities tend to be severe. Corneal clouding is present, and glaucoma may occur. Some children with MPS6 are deaf. The biochemical abnormality is a deficiency in N-acetyl-galactose-amine-four-sulfatase, which is the same enzyme as aryl sulfatase B. The diagnosis can be made by assaying enzyme activity in leukocytes or fibroblasts. These children die in their 20s from cardiac failure. The gene is located on chromosome 5q13–14.

MPS7 (Sls Syndrome) There is considerable phenotypic variation in this syndrome, but the onset may be in the neonatal period. Intellectual deficiency and motor abnormalities become obvious in the first 2 or 3 years of life. Corneal clouding has been reported in some cases. Dysostosis is a prominent feature, with notable expansion of the ribs and proximal humerus. The biochemical abnormality is a deficiency of beta glucuronidase. The gene for this enzyme is located on chromosome 7q21.11.

Sialidosis Sialidosis is due to a deficiency of a neuraminidase and occurs in two clinical forms. Individuals with type I sialidosis (cherry red spot myoclonus syndrome) are usually normal into adolescence, when they develop visual deterioration and myoclonus. A cherry red spot in the macula is virtually always present. The visual impairment may be progressive, and intellectual deterioration occurs. Cultured fibroblasts demonstrate a deficiency of a neuraminidase. A concomitant deficiency of beta galactosidase has been described. These

patients may have angiokeratoma corporis diffusum, which is also seen in Fabry disease and fucosidosis.306 Type II sialidosis has also been termed Goldberg–Cotlier syndrome and cherry red spot dementia syndrome; it is the same as mucolipidosis type I. Children become symptomatic between 8 and 15 years of age, with Hurler’s facies, decreased visual acuity, ataxia, myoclonus, mental retardation, corneal clouding, and cherry red spots.84,128 Enlarged viscera and vacuolated blood cells are not found.

Subacute Sclerosing Panencephalitis Subacute sclerosing panencephalitis (SSPE) is a chronic, degenerative disease of the CNS that occurs as a rare sequela of measles virus infection. First described by Dawson in 1933,78 it is still not known how the measles virus manages to survive dormant for many years and why it becomes active again and causes SSPE. Although it usually occurs in children who were infected prior to the age of 4, symptoms of SSPE do not develop for many years following the primary infection. Early signs are often subtle and include personality changes, behavioral abnormalities, and declining school performance (phase 1).91 Phase II begins with the onset of involuntary movements, usually an axial myoclonus. Phases III and IV of the disease are characterized by progressive neurological deterioration, severe EEG abnormalities and, usually, coma and death. Rare cases of prolonged survival, stabilization, and improvement have been noted.91,263,266 Neuro-ophthalmologic abnormalities are found in a large number of these patients and include cortical blindness, homonymous hemianopia, visual hallucinations, and impaired visual spatial function.30,114,265,271 Ocular motor abnormalities are also seen, including nystagmus, supranuclear palsies, and cranial nerve palsies.149,265 Retinal examination may show focal white retinal lesions in the posterior pole that cause loss of central vision. These may produce a cherry red spot appearance when they involve the macu1a.133,149,187,265 These white lesions resolve into areas of retinal pigment epithelium (RPE) atrophy with gliotic scarring of the retina and radiating retinal folds (Fig. 10.6). There is no evidence of vitreous inflammation during this process. Histopathologically, retinal necrosis is evident with minimal inflammation, and Cowdry type A and Cowdry type B intranuclear inclusions have been recovered from retinal tissue.111,115,187 Because the neuro-ophthalmologic findings may be the only clinical signs to accompany the behavioral changes early in the disease, recognition of the full spectrum of potential neuro-ophthalmologic dysfunction is important. EEG shows periodic complexes that become more frequent over time. The progression of MR changes shows a consistent pattern.

White Matter Disorders

477

Fig. 10.6 Subacute sclerosing panencephalitis. Note macular pigmentary changes and folds in internal limiting membrane. Courtesy of William F. Hoyt, M.D

The earliest pathologic finding is focal, high T2-intensity white matter changes followed by atrophic changes that lagged behind the white matter changes. In the advanced state, an almost total loss of white matter is evident, and the corpus callosum becomes thin.42 In the late stages, neuroimaging is nonspecific, with CT scanning showing diffuse atrophy and MR imaging showing patchy areas of prolonged relaxation time in the cerebral and cerebellar white matter.17

White Matter Disorders Neuroimaging, combined with genetic and molecular biological analysis, has revolutionized the workup and understanding of metabolic disease. The high MR contrast between myelinated white matter and demyelinated or unmyelinated white matter, and between normal and damaged gray matter, has led to discovery of new patterns of tissue involvement.18,321,323 New white matter disorders, such as vanishing white matter disease321,326 and megalencephalic leukoencephalopathy with subcortical cysts,324 continue to be identified. Abnormalities of white matter detected by MR imaging in metabolic disorders can be the result of many different processes, including inflammation, splitting (vacuolization) of myelin, and death of astrocytes or oligodendrocytes.18 For example, in Canavan disease and maple syrup urine disease, a splitting of myelin is assumed to be a toxic phenomenon because of abnormal metabolites.18 In X-linked adrenoleukodystrophy, myelin breakdown may be the result of its inherent instability or of triggering an inflammatory

microglial reaction.18 White matter injury in Tay–Sachs disease is attributed to a combination of hypomyelination, myelin loss secondary to axonal degeneration, and primary demyelination.322 In globoid cell leukodystrophy (Krabbe disease), the cytotoxic compound psychosine accumulates within oligodendrocytes after much of the brain has myelinated, causing cell death and breakdown of myelin sheaths maintained by the affected cells.18 In all of these disorders, MR imaging shows white matter that is extremely bright (hyperintense) when compared with gray matter on T2-weighted images and dark (hypointense) when compared with gray matter on T1-weighted images.18 Recently, a number of metabolic disorders called hypomyelinating disorders have been described, in which the principle finding is loss of myelin. In these disorders, white matter abnormalities are more subtle on MR imaging, being isointense to slightly hyperintense compared with gray matter on T1-weighted images and moderately hyperintense compared with gray matter on T2-weighted images. The prototypical hypomyelinating disease is Pelizaeus–Merzbacher disease. Other hypomyelination leukodystrophies include the Pelizaeus–Merzbacher-like disease (caused by mutations of GJA12 at chromosome 1q41–42), the 18q deletion syndrome (caused by deletion of the portio of the chromosome containing the gene for myelin basic protein, the other main structural protein of myelin), sialuria (also called Salla disease, caused by mutations of the SLC17A5 gene at 6q14– q15), hypomyelination with atrophy of the basal ganglia and cerebellum, trichothiodystrophy with photosensitivity, Cockayne’s syndrome, and hypomyelination with congenital cataracts.18,33

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Metachromatic Leukodystrophy Metachromatic leukodystrophy is an autosomal recessive disorder that is usually caused by mutations in the arylsulfatase A (ARSA) gene on chromosome 22q13.31. It is considered to be the most common white matter degeneration of childhood. Symptoms begin as a gait abnormality, usually in early childhood (1–2 years of age in the late infantile form and 5–10 years in the juvenile form). These children become progressively weak and, ultimately, bedridden and demented, with death usually occurring by age 10. A prominent feature of this condition is peripheral nerve involvement leading to decreased deep tendon reflexes.202,247 Neuro-ophthalmologic abnormalities include optic atrophy leading to delayed VEPs and strabismus.63,356 Rarely, nystagmus197 and a cherry red macula are seen.23 CT scanning reveals generalized atrophy and diffuse white matter lesions, with no enhancement after contrast.9,179 MR imaging demonstrates high-signal intensity lesions in the periventricular white matter on T2-weighted images.260 The peripheral white matter is spared until late in the disease179 (Fig. 10.7).

The condition is named for the appearance of the pathologically stored lipid material on light microscopy when stained with toluidine blue. Under these circumstances, the accumulated material stains brown or gold and demonstrates a birefringent character in samples of cerebral white matter.306 In addition to white matter involvement, some stored material is found in the cortex. The accumulation occurs in both neurons and glial cells. The condition also involves the deep cerebral nuclei and the spinal cord. The biochemical abnormality is an accumulation of sulfatides due to deficiency of arylsulfatase-a activity.303 The deficiency of this enzyme results in failure to break down and reutilize myelin. Several molecular forms of arylsulfatase-a exist and may account for the different phenotypes of metachromatic leukodystrophy.100 The enzyme activity can be assayed in urine or leukocytes. Ancillary studies may disclose elevated spinal fluid protein and a nonfunctioning gallbladder as assessed by cholecystogram.306 The heterozygous state (carriers) can be characterized by the enzymatic activity in white blood cells or fibroblasts.20 Late-onset forms of metachromatic leukodystrophy may respond to bone marrow transplantation.

Canavan Disease (Spongy Degeneration of Cerebral White Matter)

Fig. 10.7 Metachromatic leukodystrophy. This T2-weighted MR image shows prolongation of T2 relaxation time throughout cerebral white matter. Sparing of peripheral white matter (subcortical U fibers) is seen (arrow)

Canavan disease is an autosomal recessive disorder caused by aspartoacylase deficiency.302 This deficiency leads to increased concentration of N-acetylaspartic acid in brain and body fluids. The failure to hydrolyze N-acetylaspartic acid causes disruption of myelin, resulting in spongy degeneration of the white matter of the brain. The clinical features of the disease are hypotonia early in life, which changes to spasticity, macrocephaly, head lag, and progressive mental retardation. Although Canavan disease is panethnic, it is most prevalent in the Ashkenazi Jewish population. Infants with Canavan disease may appear normal in the first few months after birth, only to become progressively irritable and hypotonic, with poor head control. After 6 months of age, the triad of hypotonia, head lag, and megalencephaly should lead one to consider this leukodystrophy. Children with Canavan disease develop optic atrophy, but they are still able to see and recognize their surroundings.209,302 As optic atrophy develops and vision loss progresses, nystagmus may be seen. Canavan disease is inherited as an autosomal recessive trait, with a mutation in the gene that synthesizes aspartoacylase.209 High levels of urine N-acetylaspartic acid, often more than 50 times normal, are a specific test for the diagnosis of Canavan disease. CT or MR imaging of the head shows diffuse whitematter degeneration in Canavan disease.41 The aspartoacelylase gene has been cloned and localized to the short arm of chromosome 17 (17p13-ter).175,176 Aside from symptomatic

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management of seizures, preliminary results with gene therapy have shown some promise in managing Canavan disease.195 Clinical improvement in one patient following treatment with lithium citrate (which decreases whole-brain levels of N-acetyl aspartate in a rat genetic model of Canavan disease) suggests that this treatment may also hold promise.169 Dietary supplementation with acetate has recently been suggested as treatment for Canavan disease.57,204 The clinical diagnosis of Canavan disease rests on progressive neurologic deterioration in a child with megalencephaly, optic atrophy, and seizures. The clinical picture is of a quiet, apathetic, fair-haired baby with a drooping head.246 Hypotonia and lack of head control usually become evident between the ages of 3 and 9 months. As in children with Alexander disease, progressive megalencephaly develops. Megalencephaly, spasticity, mental and motor retardation, and optic atrophy, with parenchymal cerebral degeneration, end in a decerebrate state.246 Many die in infancy, but some survive into adolescence. Studies have shown that aspartoacylase deficiency causes N-acetylasparic acid to accumulate and damage cerebral myelin, with excess N-acetylaspartate in plasma and urine.209 Pathologically, Canavan disease is characterized by the finding of a spongiform degeneration of cerebral white matter. The pathologic sine qua non of Canavan disease is vacuolization of the deep cortical layers and subcortical white matter. As tissue is lost, the ventricles may become enlarged (Fig. 10.8). Myelin sheaths decrease in size and, in the later stage, axonal loss is noted. Cortical neurons appear

normal early in the course of the disease, but neuronal loss may be seen in long-standing cases.102 Canavan disease, like the other spongy myelopathies such as Kearns–Sayre syndrome and myoclonic epilepsy with ragged red fibers (MERRF), shows preferential involvement of the subcortical white matter on pathological studies. This distinguishes it from Krabbe disease and metachromatic leukodystrophy, which spare peripheral white matter until late in the disease.17 Unlike other spongiform myelopathies, Canavan disease does not show pathological involvement of gray matter. This condition was once thought to be a mitochondrial disorder because of its clinical similarities to other mitochondrial encephalomyopathies.283

Krabbe Disease Krabbe disease is an autosomal recessive disorder of sphingolipid metabolism that is caused by mutations in the galactosylceramide gene on chromosome 14q31.342 Prior to 6 months of age, infants display irritability, dysphagia, spasticity, mental deterioration, poor vision, and deafness, and generalized seizures. Intense optic atrophy ensues within the first months of life.45,141 On rare occasion, a cherry red spot has been reported.229 Patients generally die within the first few years of life. In terminal stages of this illness, the children are blind, deaf, and have opisthotonic posturing. CT shows periventricular hyperdensity52,101 that occurs concomitantly with decreased attenuation in white matter.17 MR imaging demonstrates white matter abnormalities in the form of nonspecific T1 and T2 prolongation in deep cerebral and cerebellar white matter, with a predilection for parietooccipital involvement (Fig. 10.9).16,98,342 Clumps of globoid and epithelioid cells and cerebral white matter are the characteristic pathological abnormality in Krabbe disease. Cortical atrophy and overall loss of brain mass may also be noted. The lipid accumulation in this disease is due to deficiency of the enzyme galactocerebroside beta galactosidase, which results in the storage of large amounts of galactocerebroside (galactosyl ceramide), which is toxic to oligodendroglial cells.306 Banked cord blood and bone marrow transplantation are effective treatments for infantile Krabbe disease, but only if given in the presymptomatic stage.

Pelizaeus–Merzbacher Disease Figure 10.8 Canavan disease. T2-weighted MR image shows diffuse increased signal intensity in deep white matter with multifocal round areas of higher signal intensity, suggesting vacuolar changes (arrow). Courtesy of Charles M. Glasier, M.D.

Pelizeus–Merzbacher disease is a rare X-chromosomal neurodegenerative disorder that affects primarily the white matter of the CNS and is caused by mutations of the proteolipid protein 1 gene (PLP1), which codes for proteolipid protein (PLP), one

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10 Neuro-Ophthalmologic Manifestations of Neurodegenerative Disease in Childhood

Fig. 10.9 Krabbe disease. T2-weighted MR image showing diffusely increased signal intensity in deep white matter. Courtesy of Charles M. Glasier, M.D.

of the major structural proteins of myelin.18 Point mutations have been found in 10–25% of cases, but most affected patients have duplications of the gene,159,287 which has been mapped to Xq21.1.207 Duplication of the PLP gene, probably results in the accumulation of PLP within the oligodendrocytes, with resultant impaired cell function, and early oligodendrocyte death, resulting in impaired myelin formation. A rare autosomal recessive form of Pelizaeus-Merzbacher-like disease caused by GJA12 mutations can be present in girls.18,144a Clinically, the syndrome presents with nystagmus, hypotonia, progressive spastic quadriparesis of varying degrees, ataxia, and developmental delay associated with diffuse leukoencephalopathy.281,298 Carrier females may or may not manifest symptoms.207 The pathological hallmark is patchy demyelination with preservation of islands of normal myelin, resulting in a tigroid appearance of stained sections of white matter on light microscopy. Pelizaeus–Merzbacher disease has its onset in the first few months of life, beginning with nystagmus310 and head tremor and progressing to ataxia, limb tremor, and choreoathetosis. Trobe et al314 have described distinctive electro-oculographic characteristics of nystagmus in this condition, consisting of an elliptical pendular nystagmus that may be superimposed or interposed with upbeat nystagmus.314 Early in the course of this disease, nystagmus may be associated with head nodding and may simulate spasmus nutans. Patients may have saccadic dysmetria and other cerebellar signs such as truncal titubation.193 Optic atrophy and seizures occur later. Intellectual function is relatively preserved, but a mild dementia may occur. Most of these patients die in the second decade of life or during early adulthood, and most are male. A connatal form is more severe with death in the first few years of life.276

Fig. 10.10 Pelizaeus–Merzbacher disease. This T2 MR image in 7-year-old child shows severe loss of myelin. Myelin should appear dark in image. Courtesy of A. James Barkovich, M.D.

Neuroimaging in Pelizaeus–Merzbacher disease shows a lack of myelination without evidence of a white matter destructive process (Fig. 10.10).17,284,294,327 The finding of white matter abnormalities in a child thought to have spasmus nutans should raise suspicion of this disorder.

Cockayne Syndrome Cockayne syndrome is an autosomal recessive disorder related to the transcription-coupled repair pathway.88 It is a progressive neurological disorder characterized in infancy by growth failure (cachectic dwarfism), deficient neurological development, progressive retinal degeneration, and sensitivity to sunlight without propensity to cancer.88 It is also characterized by premature aging, dementia, worsening vision and hearing, endocrinopathies, progressive spasticity, ataxia, peripheral neuropathy, weakness, osteopenia, kyphosis, and joint contractures.258 Two genes for Cockayne syndrome have been identified.206,295,315,316 Complementation groups on a gene on chromosome 5q12 account for 20% of cases, while those on a gene on chromosome 10q11 account for 80% of cases.258 Type I, the “classical” type, has an onset in the postnatal period, while type II, the “severe” type, occurs before birth and usually results in death by 6 or 7 years.233

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The earliest evidence of this condition is often a photosensitive dermatitis in the first few months of life, followed by growth retardation, bony abnormalities, and a characteristic facial appearance in the first few years. Progressive cerebellar dysfunction and motor deterioration ensue. The facies is distinctive, with sunken eyes and cheeks, decreased tearing and corneal scarring, miotic pupils, sharp nose, jutting chin, thin lips, inadequate salivation, and dental caries.258 Cataracts, pigmentary retinopathy, and optic atrophy contribute to the visual loss.117,145 ERG shows variable degrees of reduction of scotopic and photopic responses, which seem to parallel the fundus changes and the age of the patient.196 A CT shows calcifications in basal ganglia and dentate nucleus of the cerebellum along with cerebral atrophy.80 MR imaging demonstrates delayed myelination and T2 prolongation in periventricular white matter, basal ganglia, and dentate.80 The subcortical U fibers may be involved early, but more often they are preserved until later.17,74 Some children have been noted to have normal-pressure hydrocephalus and have benefitted from shunting.107 Neuropathologic changes resemble those of Pelizaeus– Merzbacher disease, showing patches of nonmyelination with preserved islands of normal myelin. In addition, globus pallidus and cerebellum may show calcifications. No biochemical abnormality has yet been identified for this syndrome, and diagnosis is made on clinical grounds.

Alexander Disease Alexander disease is a leukodystrophy that usually presents in infancy with megalencephaly, dementia, spasticity, and seizures.7 However, it may also present in later childhood and, rarely, in adulthood,280,341 when its progression may be confused with multiple sclerosis.147 Characteristic pathologic findings include accumulation of Rosenthal fibers throughout the cerebral white matter, with striking demyelination and cavitation of the frontal lobes but relative sparing of the cerebellum.7,11,82,170,254 It has been postulated that Rosenthal fibers form as a consequence of a metabolic disturbance of astrocytes that in turn leads to the degradation of excessive amounts of glial filaments.87 Most cases have been shown to be due to mutations in the gene encoding glial fibrillary acidic (GFAP) protein.164 This sporadic neurodegenerative disorder occurs in an infantile and a juvenile form. The infantile form begins in the first year of life, with intellectual and motor retardation, spasticity, seizures, and progressive megalencephaly without hydrocephalus. The head enlargement is progressive, and hydrocephalus may be superimposed in later stages.107 The prominent neuro-ophthalmologic feature in the infantile form is optic atrophy. The juvenile form is rare and has

its onset between 7 and 14 years of age. Bulbar or pseudobulbar dysfunction occurs, including difficulty swallowing, abnormal speech, nystagmus, ptosis, facial diplegia, and atrophy of the tongue. Mentation appears to be normal.126 The possibility of an adult form has been suggested with a clinical picture resembling multiple sclerosis. On pathological examination of the brain, the characteristic finding is refractile cyanophilic bodies related to astrocytes around blood vessels. These occur throughout gray and white matter and in the optic nerves and tracts.270 Loss of myelin is marked in the infantile cases. The brainstem may be predominantly involved in the juvenile form. Neuroimaging studies show abnormalities in the white matter beginning in the frontal areas and gradually proceeding posteriorly. CT scanning shows low-density lesions in the frontal lobes with contrast enhancement near the tips of the frontal horns.99 MR imaging shows a similar pattern of abnormality, with prolonged T1 and T2 relaxation times progressing from anterior to posterior white matter. Peripheral white matter is affected early.17,236 The clinical diagnosis of Alexander disease is not straightforward because there is no biochemical or genetic marker for this disease. Although mutations in the gene for GFAP have been suggested as a cause of infantile and juvenile variants of this disorder,31,40 other primary causes must be eliminated, and a final diagnosis is made by finding demyelination with an abundance of Rosenthal fibers on biopsy or at cerebral autopsy. There is also controversy surrounding whether Alexander disease represents a distinct nosologic entity. Its characteristic Rosenthal fibers are found around some intracranial cysts, in hemimegalencephaly, and in some astrocytic tumors. There is some evidence that they represent a reaction to metabolic stress and that they are not specific to any single disease entity. Nevertheless, they present more diffusely and in larger numbers in cases termed Alexander disease.146 There is no specific therapy for this condition.

Sjögren–Larsson Syndrome Sjögren–Larsson syndrome is an autosomal-recessive neurocutaneous disorder with a prevalence of less than 0.4 per 100,000 population.351 Originally described in 1957 by Sjögren and Larsson, this white matter disease comprises the clinical triad of spastic diplegia or tetraplegia, mental retardation, and ichthyosis.288 It is caused by disturbed lipid metabolism due to a deficiency of the microsomal fatty aldehyde dehydrogenase (FALDH) enzyme, which catalyzes the oxidation of many different medium and long-chain fatty aldehydes into fatty acids. Therefore, FALDH deficiency results in the accumulation of fatty alcohols and fatty aldehydes in body tissues.113 In addition to their neurologic symptoms,

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most patients suffer from photophobia and subnormal visual acuity. A crystalline maculopathy, in which crystalline dots are scattered throughout the perifovea within the inner retinal layers, develops in early childhood. These crystals should be specifically sought in the child who presents with icthyosis, as they are present whenever the enzyme deficiency is found. Optical coherence tomography (OCT) shows focal hyperreflectivities in the perifoveal ganglion cell and inner plexiform layers, together with a cystic foveal atrophy that is not visible ophthalmoscopically.113 MR imaging shows an arrest in myelination, signal abnormalities involving periventricular white matter, and mild ventricular enlargement.351

Cerebrotendinous Xanthomatosis Cerebrotendinous xanthomatosis is a rare autosomal lipid storage disease resulting from deficiency of the mitochondrial enzyme sterol 27-hydroxylase, resulting in a reduced production of cholic acid and particularly chenodeoxycholic acid, and leading to accumulation of cholestanol and cholesterol in many tissues.330 Cerebrotendinous xanthomatosis is an important form of neurodegeneration that should be suspected in children who have chronic diarrhea.330,331 These children have bilateral cataracts, which develop after the first few years of life, and are therefore not accompanied by nystagmus.73 Over time, these children suffer mental deterioration, pyramidal tract dysfunction, and cerebellar ataxia.330 They eventually develop a neurologic picture that resembles multiple sclerosis. Cerebral atrophy and deep cerebellar white matter lesions are found on MR imaging.32,155 In addition to developing bilateral cataracts, some patients show clinical signs of optic neuropathy.73 Chronic elevation of bile acids and cholestanol produce these neurologic abnormalities. It is critical to look for cataracts in the child with chronic diarrhea, because identification and treatment of this syndrome can prevent these neurologic complications. Early treatment with chenodeoxycholic acid stabilizes the condition.330

Peroxisomal Disorders Peroxisomes are subcellular organelles that were first recognized in 1954 in the proximal tubule of the kidney. They are found in all eukaryotic species and in almost every cell. The name was chosen because these organelles produce and reduce hydrogen peroxide. They also contain enzymes needed for the oxidation of amino and dicarboxylic acids. In this process, H2O2 is formed and then detoxified by catalase, another peroxisomal enzyme.93,245 In 1973, Goldfischer129 discovered that peroxisomes were absent in liver and renal tubular

epithelial cells of patients with Zellweger syndrome. Various peroxisomal functions were found to be absent. A specific biomarker for screening patients was first identified in 1984,226 and the first gene defect was identified in 1992.285 Thus, the major clinical syndromes attributable to peroxisomal biogenesis disorders (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondrodysplasia punctata) were all described before the biochemical and molecular mechanisms of peroxisomal dysfunction were understood.296 Inherited diseases of peroxisomes are divided into the peroxisomal biogenesis disorders, in which a mutation in one or more of the 12 peroxisomal assembly genes (PEX genes) results in a virtual absence of peroxisomes and a generalized loss in all peroxisomal function (e.g., the cerebrohepatorenal [Zellweger] syndrome, the infantile form of Refsum disease, the neonatal form of ALD, the rhizomelic type of chondrodysplasia punctata, and hyper-pipecolic acidemia), and those in which only a single peroxisomal function is impaired (e.g., X-linked adrenoleukodystrophy [ALD], the adult form of Refsum disease, and pseudorhizomelic chondrodysplasia).110,296,342 Abnormal retinal pigmentation occurs in Zellweger syndrome, neonatal ALD, hyper-pipecolic acidemia, and infantile Refsum disease. These children may have abnormal ERGs early in the course of the disease. Optic disc pallor has been reported in Zellweger syndrome, neonatal ALD, and hyperpipecolic acidemia.48,250 MR imaging studies in children with peroxisomal disorders have shown the following general abnormalities: (1) neuronal migrational disturbances in combination with hypomyelination, dysmyelination, or demyelination; (2) symmetrical demyelination of the posterior limb of the internal capsule, cerebellar white matter, and brainstem tracts with a variable affection of the cerebral hemispheres; and (3) symmetrical demyelination – exhibiting two zones: the first starting in the occipital area and spreading outward and forward, and the second involving the brainstem tracts.17,328 Biochemical studies performed on blood and urine are used to screen for the perioxisomal biogenesis disorders.296 DNA testing is possible for all of the disorders but is more challenging for Zellweger syndrome, which can be associated with 12 different PBX genes.296 Current treatment is mainly supportive, consisting of treating seizures, providing hearing aids, treating ocular disorders, and addressing other developmental needs. However, some therapeutic interventions have been successful in these patients. A diet low in phytanic acid has been successful in the treatment of adult Refsum disease. Oral bile acid administration has improved hepatobiiloary function in some infants with Zellweger syndrome. Newer experimental therapies directed at peroxisomal proliferation hold promise for more directed therapy.212,344

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Zellweger Syndrome Zellweger hepatorenal syndrome is an autosomal recessive disease characterized by unique facies, failure to thrive, and visual impairment. The characteristic craniofacial features include a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large anterior fontanel.296 Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. There is absence of neonatal and deep tendon reflexes and little spontaneous movement.296 The eyes may demonstrate corneal clouding, cataracts, glaucoma, optic atrophy, and retinal anomalies, with extinguished ERG waveforms. Homozygotes also have characteristic lens abnormalities consisting of a dense cortex producing a cortical-nuclear interface that is visible at the slit lamp through a dilated pupil. Hittner et al153 have shown that the heterozygous parents of four infants with Zellweger syndrome had lens changes consisting of curvilinear condensations in the cortical region in the same location as the lens changes in the homozygous state. The liver is enlarged, and there are renal cysts. Bone stippling is seen at the patella and in other bones in about 50% of patients.296 Although most children die within the first year of life, a later-onset form is recognized in which there is some degree of psychomotor development, with development of head control, independent walking, and speech.296 These patients tend to have sensorineural hearing loss and retinitis pigmentosa, leading to the initial diagnosis of Usher syndrome or even Leber congenital amaurosis.296 The characteristic neuronal migration abnormalities are easily demonstrated by MR imaging.328 These include periventricular neuronal heterotopias, pachygyria, and polymicrogyria.347 In some children, a leukodystrophy develops, with degeneration of myelin in the CNS, loss of acquired skills, and development of spasticity.296 The gross pathologic abnormalities relate to neuronal migration abnormalities and polymicrogyri. Microscopically, there is evidence of gliosis and accumulation of lipids; however, unlike storage diseases, the lipid droplets in Zellweger syndrome are in the astrocytic cytoplasm rather than in macrophages.3 The severe lack of myelin noted histologically in the brains of these infants may be due to a combination of disturbed myelination and accelerated demyelination.4 The combination of neuronal and white matter disease is reflected in retinal ganglion cell abnormality and optic atrophy. Zellweger syndrome is caused by mutations in the PXE complementation genes, with 12 genes known to cause variants of the condition.296 Defects in the PXE gene impair peroxisome assembly and multiple metabolic pathways confined to this organelle, providing the biochemical bases of the peroxisome biogenesis disorders.296 Zellweger cerebrohepatorenal syndrome is a severe form of diffuse peroxisomal deficiency.

Initially, the syndrome was attributed to the absence of or a decrease in the number of peroxisomes; however, peroxisomal membrane ghosts have now been identified in cells, indicating that Zellweger syndrome and other conditions like it may in fact be due to peroxisomal assembly abnormalities.274 Plasma levels of VLCFAs, pipecolic acid, phytanic acid, and bile acid intermediates are all elevated in this syndrome.

Adrenoleukodystrophy Adrenoleukodystrophy (ALD) is an X-linked disorder with a wide spectrum of phenotypes, varying from the rapidly progressive, childhood-onset, predominantly cerebral form to the more slowly evolving subtypes characterized by adrenomyeloneuropathy or Addison disease.221 The common pathophysiological feature in all forms is the accumulation of C26:0 and C24:0 VLCFA in the CNS and other tissues owing to their impaired degradation as a consequence of perixosomal dysfunction.286 The gene for ALD has been mapped to Xq28.214 It encodes for a peroxisomal membrane component termed the ALD protein, which belongs to the class of adenosine triphosphate-binding cassette proteins.150 The deficiency of a single peroxisomal function in X-linked ALD differs from neonatal ALD, in which there is impairment of multiple peroxisomal functions, including deficiencies in very long chain fatty acid (VLCFA) oxidation by phytanic acid oxidase and plasmalogen synthesizing enzymes.277 X-linked ALD presents at an average age of 7 years. Initial manifestations include increased skin pigmentation, decreased school performance, and “dementia-type” changes in memory and emotional expression. Motor disturbances may be prominent, with a stiff-legged spastic gait. Visual disturbances are common and, occasionally, they occur early. Homonymous hemianopia,275 visual agnosia, decreased visual acuity, strabismus, selective reading dysfunction, and cerebral blindness have all been reported. Optic atrophy eventually develops.184,191,312,355 The childhood form may manifest with emotional lability and hyperactivity, leading to the diagnosis of attention-deficit hyperactivity disorder.105,224,299 Cognitive decline, poor school performance, and visual loss typically follow. Rarely, visual loss can be the presenting symptom of the disease. Other neurological deficits include hearing loss, progressive ataxia, and spastic quadriparesis. Children may have skin hyperpigmentation due to adrenal dysfunction and adrenal deficiency can be lethal. Hypoadrenalism,158 and hypogonadism105 may also complicate the clinical course.230 The disease is fatal if untreated.192 Infants with ALD (neonatal form) have severe hypotonia and seizures at birth, and later they exhibit growth and mental retardation. Other neurological features include macrocephaly, large fontanels, nystagmus, optic atrophy, pigmentary retinopathy, and abnormal vision and hearing. Most children die

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before 5 years of age. A few have survived until age 10. Other phenotypes include the rapidly progressive childhood form, the adolescent form, and the adult cerebral forms (adrenomyelopathy, which presents as slowly progressive paraparesis in adults, and Addison disease without neurologic manifestations).223 These phenotypes are frequently misdiagnosed, respectively, as attention-deficit hyperactivity disorder, multiple sclerosis, or idiopathic Addison disease. About 50% of female carriers develop a spastic paraparesis secondary to myelopathic changes similar to adrenomyeloneuropathy, often leading to the misdiagnosis of multiple sclerosis. The biochemical hallmark of ALD is excess VLCFA, which can be measured in cultured skin fibroblasts, white cells, red blood phospholipids, or total plasma lipids. The concentration of C26:0 is elevated to approximately five times normal. Assays of long chain fatty acids in plasma, cultured chorion villus cells and amniocytes, and mutation analysis permit presymptomatic and prenatal diagnosis, as well as carrier identification. The timely use of these assays is essential for genetic counseling and therapy. Early diagnosis and treatment can prevent overt Addison’s disease and significantly reduce the frequency of the severe childhood cerebral phenotype. A promising new method for mass newborn screening has been developed. When implemented, it should have a profound effect on the diagnosis and management of X-linked ALD. Studies of choroinic villus sampling or amniocentesis now permit accurate prenatal identification of affected male fetuses. The finding of normal cognitive function in neurologically and radiologically normal boys with X-linked adrenoleukodystrophy suggests that prevention and timely institution of therapy can potentially preserve cognitive function.71 The plasma VLCFA assay is the recommended diagnostic procedure in males.222 Plasma VLCFA levels are increased on the day of birth. Electrophysiological findings in two cases of neonatal ALD were reported by Verma et al333 One child was examined at age 1 year and the other at age 3½ years. Neither child demonstrated visual following responses, and both had severe seizures and long-tract signs. Both had nonrecordable or extremely diminished ERG responses and no consistent, identifiable positivity in VEP responses except for the right eye of the 1-year-old child, which showed a delayed positive wave with a mean latency of 137 ms. Ophthalmological examination of the younger patient showed normal media, normally reactive pupils, full extraocular movements, intermittent fine jerk nystagmus on horizontal gaze, and unremarkable fundi other than mild temporal pallor in each eye. The older child had sluggishly reactive pupils, pendular nystagmus, clear media, bilateral optic atrophy, and retinitis pigmentosa, suggesting a degeneration of photoreceptors and an accumulation of lipids in the ganglion cells. Battaglia et al24 have studied the EEG, ERG, and flash VEP in 14 boys with X-linked ALD and in two siblings of

affected boys. These siblings had adrenocortical deficiency but were neurologically normal. All 14 affected boys had EEG abnormalities characterized by irregular, large-amplitude, slow activity. Similar EEG findings were seen in the two siblings of affected patients. The ERG was normal in all cases. The VEP was abnormal in four of 12 cases. The recording deteriorated over a short time frame in two cases and was low or unrecordable when first measured in two others. The VEPs in two siblings were normal.24 Detection of the carrier state of X-linked ALD by VEP has been reported.217 Neuroimaging studies are normal prior to the onset of symptoms.71 X-linked ALD classically involves the occipital white matter bilaterally. Areas of active demyelination may show intense contrast enhancement at the periphery of the lesions. These lesions are usually symmetric and may affect the posterior occipital region most severely. White matter lesions in the occipital region also characteristically involve the splenium of the corpus callosum early on. Occipital U fibers are relatively spared (Fig. 10.11). With time, the lesions extend forward to involve the lateral and medial geniculate bodies, the thalamus, and posterior limb of the internal capsule bilaterally. Cerebellar and brainstem white matter are relatively spared. Lesions are usually symmetric and may affect the posterior occipital region most severely, with the anterior occipital region affected to a lesser extent.328 Pathologically disordered neuronal migration, including pachygyria and polymicrogyria, is the most striking abnormality.342

Fig. 10.11 Adrenoleukodystrophy. This T2-weighted MR image shows symmetrical hyperintense hemispheric lesions primarily involving occipital white matter (arrow)

Basal Ganglia Disease

Patients who show early evidence of cerebral involvement should be considered for hematopoietic stem cell transplantation (HSCT).248 HSCT is not recommended for asymptomatic patients with normal MRI findings because half of them never develop the cerebral forms of X-linked ALD. Neurologically asymptomatic boys who are identified by screening at-risk relatives of known patients or those with idiopathic Addison disease have the best chance of benefitting from HSCT.224 While Lorenzo’s oil therapy does not alter the progression after the onset of cerebral disease, recent data suggest that it may significantly reduce the risk of developing cerebral disease.225

Basal Ganglia Disease Pantothenate Kinase-Associated Neurodegeneration Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden–Spatz syndrome,139 is a rare, autosomal recessive, childhood-onset neurodegenerative disorder associated with brain iron accumulation.92 Most patients have mutations in the pantothenate kinase 2 (PANK2) gene.342 The most common clinical features include occurrence at a young age (generally after early childhood); a motor disorder, mainly of the extrapyramidal type characterized by dystonic postures, muscular rigidity, and involuntary movements of choreoathetoid or tremulous type, but with findings suggestive of corticospinal tract dysfunction as well; mental changes indicative of dementia; and a relentless progressive course extending over several years and leading to death in early adulthood.89 A rapidly progressive earlyonset childhood type, a slowly progressive early-onset type, and a late-onset childhood type have all been described.307 Neuro-ophthalmologic abnormalities include Adie’s-like pupils, hypometric and slowed vertical saccades, and saccadic pursuit movements.92 Poor convergence and square wave jerks are also occasionally found. Peripheral pigmentary retinopathy is common, and electroretinography is often abnormal even in the absence of optic atrophy.92 The basic pathophysiology of PKAN remains unknown; however, its clinical manifestations, recessive genetic transmission, and characteristic iron deposition in the globus pallidus and substantia nigra seen on neuroimaging establish the diagnosis. The typical clinical findings include an onset in early childhood of motor disorders of an extrapyramidal type, characterized by dystonic posturing, difficulty walking, and muscular rigidity. As the disease progresses, involuntary movements of a choreoathetoid type appear along with progressive intellectual deterioration. Most patients die in early adulthood. Although optic atrophy is rare in this condition and in other degenerations of the extrapyramidal system,92 it

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has been described as the presenting symptom in Hallervorden– Spatz disease.51,353 Retinitis pigmentosa has been described in some children.89,305 Although the metabolic abnormality in Hallervorden–Spatz syndrome is unknown, it likely involves abnormal iron binding within the basal ganglia. Iron may play a role in modulating dopamine binding to postsynaptic receptors, and abnormal iron storage may interrupt these mechanisms, as well as disrupting oxidation and peroxidation reactions, leading to cellular damage within the basal ganglia.305 Iron deposition in conjunction with destruction of the globus pallidus gives rise to the characteristic “eye-of-thetiger” sign on MR imaging.26 MR imaging may show abnormalities early in the course of this disease144, characterized by an overall low signal on T2-weighted images in the globus pallidus and substantia nigra, with a central zone of high signal within the globus pallidus26,135,253 (Fig. 10.12). The classic “eye of the tiger sign” is present once symmetrical T2 hyperintensity develops, superimposed upon the hypointense background, presumably due to gliosis.261 In some cases, the appearance of these abnormalities precedes the onset of clinical symptoms.135,144 The MR pattern of PKAN is not the characteristic of other extrapyramidal-type movement disorders, such as Parkinson disease, Wilson disease, and Leigh disease, thus allowing a fairly confident diagnosis

Fig. 10.12 Pantothene kinase-associated neurodegeneration (PKAN). Axial T2-weighted MR image shows markedly “eye-of-the-tiger sign” caused by hypointense signal in inferior globus pallidus bilaterally (arrow). Courtesy of A. James Barkovich, M.D

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when this imaging pattern is seen in a child with characteristic clinical findings. However in some cases, distinguishing PKAN from neuronal ceroid lipofuscinosis can be difficult, and it has been suggested that PKAN is a form of neuronal ceroid lipofuscinosis. Vacuoulated lymphocytes, when examined by electron microscopy, may contain abnormal cytosomes, including fingerprint, granular, and multilaminated bodies.308,361 The characteristics of the observed materials suggest the presence of ceroid lipofuscin, a substance that accumulates in neuronal ceroid lipofuscinosis. The striking rust-brown pigmentation obvious on gross examination of the globus pallidus and the zona reticulata of the substantia nigra, documented in the original descriptions, continues to be the outstanding neuropathologic characteristic of PKAN. Staining of fresh brain confirms increased iron content in pigmented areas.138,139 There is no specific treatment for this condition.

Wilson Disease The symptoms of Wilson disease are caused by an abnormal accumulation of copper, primarily in the liver but subsequently in many other organs, including the CNS. This disease is inherited in an autosomal recessive fashion and is due to the presence of an abnormal protein in the liver that binds copper much more strongly than liver proteins in normal individuals. The copper-storing capacity is exceeded, and unbound copper increases in the circulation, with deposition in other tissues. The defect is in a copper-transporting ATPase on chromosome 13q14.3.193 Although patients are usually diagnosed in the second and third decade, they may become symptomatic as early as 5 years of age. It is estimated that 40% present with liver disease, 40% with neurologic symptoms, and 20% with psychiatric disturbances.342 Patients who are diagnosed in adolescence and in later life more often have neurological signs predominating such as loss of fine motor skills, progressive clumsiness, and dysarthria. The principal ophthalmological sign in Wilson disease is the Kayser–Fleischer ring. Ophthalmologists are frequently asked by internal medicine and pediatrician consultants to examine patients with liver disease or unexplained neurological degeneration for Kayser–Fleischer rings, as this establishes the diagnosis of Wilson disease. A slit lamp examination is required for this evaluation although advanced Kayser–Fleischer rings can be seen by the naked eye. These rings reflect copper deposition in Descemet’s membrane, leading to a brownish-green discoloration of the membrane, seen most easily near the limbus of the cornea. Patients with Wilson disease may also have “sunflower cataracts.” Neuroophthalmologic features of Wilson disease include supranu-

clear gaze palsies, difficulty initiating saccades, cogwheel pursuit, slow vertical saccades, gaze distractibility, lid opening apraxia,178 and oculogyric crisis.182,190,193,194 In general, pursuits are more affected than saccades, and vertical movements are more affected than horizontal ones.160 Vertical smooth pursuit movements tend to be particularly affected, with vertical optokinetic responses and horizontal smooth pursuit less often affected.160 The laboratory confirmation of Wilson disease includes serum levels of ceruloplasmin (less than 20 mg/dL) and increased urinary excretion of copper (greater than 100 mg/24 h). Treatment of the condition includes a low-copper diet and d-penicillamine (a chelator of copper) in conjunction with zinc, which increases urinary excretion. Trientine can be used as a substitute for penicillamine D. The CNS damage in Wilson disease is associated with increased tissue copper content. Copper interferes with cellular metabolism and enzymatic activity, leading to cellular death. Toxic levels of copper are found throughout the brain in this disease; however, the main pathological findings are in the basal ganglia, thalamus, and brainstem. These changes include degeneration of neurons, increased numbers of astrocytes with neurofibrillary plaques and tangles and, ultimately, spongy degeneration and cavitation of the structures. Several studies have shown good correlation between neurological features and MR abnormalities in Wilson disease. The correlation is particularly good with moderate to advanced disease, whereas asymptomatic patients with biochemically proven Wilson disease have no MR imaging findings.5,205 Most symptomatic patients demonstrate lesions of the putamen. The characteristic lesion is a peripheral high signal area on T2-weighted imaging surrounding a central area of low signal. Pathological correlation of this finding has not been clarified. Patients with MR abnormalities limited to the putamen usually show dystonia. Patients with involvement of the putamen and caudate may show parkinsonian features as do patients with abnormal MR findings in the substantia nigra. MR imaging also shows hyperintense signal abnormalities in the lenticular nucleus, dentate nucleus, white matter, cerebellum and brainstem, along with areas of cerebral atrophy.121,160,357 However, eye movement abnormalities may be present even when no neuroimaging abnormalities are present.160

Aminoacidopathies and Other Biochemical Defects Maple Syrup Urine Disease Maple syrup urine disease is caused by defects in the branched chain a-keto-acid dehydrogenase (BCKD) complex.342 The enzymatic defect is one of oxidative decarboxylation of

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Aminoacidopathies and Other Biochemical Defects

the ketoacids of these amino acids and can be demonstrated in leukocytes. This disease is named after the smell of urine that contains increased amounts of the three branched-chain amino acids valine, leucine, and isoleucine. It is genetically heterogenous, with gene loci found on three different chromosomes (E1a on chromosome 19q31, E1b on chromosome 6q14, and E2 on chromosome 1p31).342 This disease becomes manifest in the neonatal period with difficulties in feeding, hypoglycemia, metabolic acidosis, and a severe, progressive neurological deterioration. Supranuclear gaze palsies are frequent findings in this condition, including paralysis and paresis of upward gaze201,359 or a combination of vertical and horizontal gaze palsies.54,278 Ptosis is also frequently seen, and nystagmus commonly accompanies the recovery phase after the institution of dietary measures. This nystagmus frequently occurs in bursts, and associated bursts of flutter-like movement of the eyelids may also occur in the recovery phase.85,278,359 Untreated patients die within the first few months of life. Treatment consists of a diet limited in the branched-chain amino acids, and this can arrest the progressive deterioration of the condition. There are several variants of this condition, one of which shows responsiveness to supplementation with vitamin B1 (thiamine).234

Homocystinuria The classical type of homocystinuria is caused by an inborn error of metabolism involving methionine metabolism. Clinical features of the untreated condition involve progressive intellectual deficiency, tall stature, arachnodactyly, malar flush, fair hair, and dislocated lenses. Affected patients are also at an increased risk of thromboembolic episodes, often involving the cerebral vasculature and sometimes brought on by anesthesia.227 Several enzymatic deficiencies may result

in a similar phenotype. Type I homocystinuria (classic) is due to the deficiency of cystathionine-b synthetase and results in high blood levels of homocystine and methionine. Neuro-ophthalmological abnormalities such as visual field defects, papilledema, and optic atrophy may arise from cerebral thromboembolic events. Another type of homocystinuria associated with remethylation problems in the homocysteine-to-methionine cycle that uses vitamin B12 and folate as cofactors (e.g., the maculopathy and retinopathy of cobalamin C methylmalonic aciduria and homocystinuria)317 is detailed in Chap. 4. Patients with the early-onset form of this disease develop progressive retinal disease, eventually leading to atrophic macular lesions and optic atrophy with peripheral bone spicule pigmentation.121 The clinical features of this form of homocystinuria are detailed in Chap. 4.

Abetalipoproteinemia Abetalipoproteinemia is an autosomal recessive disorder characterized by the complete absence of apolipoprotein B, causing malabsorption of all fat-soluble vitamins, including A, D, E, and K. It was first described by Bassen and Kornzweig in a patient with atypical retinitis pigmentosa, malformed erythrocytes, ataxia, and intestinal malabsorption that had led to the misdiagnosis of celiac disease.21,255 It is caused by mutations in the microsomal triglyceride transfer protein gene.354 The most prominent ophthalmological finding in abetalipoproteinemia is a pigmentary retinal degeneration (Fig. 10.13). A clinicopathologic correlation in a patient with abetalipoproteinemia dying of unrelated causes showed that the pigmentary retinal degeneration was accompanied by loss of photoreceptors in the posterior pole, loss or attenuation of pigment epithelium, excessive accumulation of lipofuscin in

Fig. 10.13 Kearns–Sayre syndrome. Note bilateral retinal pigmentary changes and discrete ring of peripapillary pigment atrophy OD. (a) Right retina. (b) Left retina

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the submacular pigment epithelium, and invasion of the retina by macrophage-like pigment and cells.64 Retinal degeneration is associated with waxy pallor of the optic disc, narrowing of the retinal vessels, and clump or spot retinal pigment epithelium pigmentation rather than the bone corpuscle pigmentation usually seen in retinitis pigmentosa.116 Abetalipoproteinemia may also be complicated by subretinal neovascularization associated with retinal angioid streaks.90 Ocular motor abnormalities are also prominent. Yee et al358 first described an unusual form of internuclear ophthalmoplegia in which the adducting rather than the abducting eye showed nystagmus on sidegaze. Absence of adduction was accompanied by convergence insufficiency in these patients.167,358 Some patients may display angioid streaks radiating from the disc,165 producing a helicoid degeneration.354 Neurological abnormalities include loss of deep-tendon reflexes, followed by decreased distal lower extremity vibratory and proprioceptive senses and cerebellar signs such as dysmetria, ataxia, and spastic gait.255 Neuropathology reveals axonal degeneration of the spinocerebellar tracts and demyelination of the fasciculus cuneatus and gracilis.255 Total cholesterol levels are very low, and triglyceride levels are also very low, with little increase after ingestion of fat.255 There are no detectable plasma chylomicrons, very low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), or apolipoprotein B (apo B), the major structural apolipoprotein of these lipoproteins.255 An abnormality of LDLs or b lipoproteins, established the biochemical hallmark of this disease.272 Apo B is absent in the plasma of patients with abetalipoproteinemia, and it was thought that a molecular defect in the apo B gene may be responsible for this condition; however, the apo B gene was proven to be normal in genetic studies.186 Rather, a protein responsible for intracellular assembly and secretion of apo B-containing lipoproteins has been found to be deficient in abetalipoproteinemia.177,348 This defect leads to deficient fat absorption from the intestine, interfering with the absorption of all fat-soluble vitamins. The defect profoundly affects the metabolism of vitamin E, which relies on this lipoprotein not only for absorption from the intestine but also for transport to peripheral tissues from the liver.186 Vitamin E acts as a free radical scavenger and prevents oxidative injury to membrane lipids.289 Vitamin E deficiency has been implicated in retinal changes in abetalipoproteinemia. Oral vitamin E supplementation can prevent both the retinopathy of abetalipoproteinemia269 and other neurologic sequelae.177,228,255 Vitamin A and K supplements can adequately increase the plasma and tissue levels of these vitamins; however, very large oral doses of vitamin E are required to achieve adequate tissue levels of vitamin E. The recommended dosage is 150–200 mg/kg/day. Adults may require up to 20,000 mg/day (the recommended dietary allowance for normal people for vitamin E is 15 mg/day).

Children with pigmentary retinopathy and neurological degeneration and infants with malabsorption or failure to thrive should be screened for abetalipoproteinemia by performing a plasma cholesterol level. A level lower than 1.5 mmol/L (60 mg/dL) is suspicious for abetalipoproteinemia. Most patients who have very low cholesterol do not have abetalipoproteinemia but do have one of the more common syndromes, such as familial hypobetalipoproteinemia. Treatment with high doses of vitamin E can retard or halt progression of the neurological disease and, possibly, the retinal disease.269 Hypobetalipoproteinemia, a different disease, can be a phenocopy for abetalipoproteinemia.309 All cases of abetalipoproteinemia reported so far are due to mutations in the MTP gene, which encodes the microsomal triglyceride transfer protein (an 894 amino acid protein that is a component of a protein complex involved in the early stages of lipidation of apo B in liver and intestine). Most of these mutations result in truncated proteins devoid of function, but some missense mutations have been reported to be associated with a milder form of the disease.309

Mitochondrial Encephalomyelopathies Mitochondrial encephalomyelopathies are relatively common neurometabolic disorders of childhood.76 Several neurodegenerative syndromes are caused by disorders of mitochondrial metabolism in children.79 These abnormalities produce defects in the energy cycle of susceptible cells, causing abnormal function and, ultimately, death of the cell. Nerve tissue and striated muscle are most commonly affected. The conditions included in this group of disorders are Alper disease, Menke disease, Leigh disease, and mitochondrial depletion syndrome (MDS), all manifesting their abnormalities in early childhood. A group of disorders with progressive neurological symptoms occurring later in life include chronic progressive external ophthalmoplegia (CPEO), KSS, MELAS, and myoclonic epilepsy with ragged red fibers (MERRF). Except for the syndrome of neurogenic weakness, ataxia, and retinitis pigmentosa (NARP) that can present in childhood,181 the fine or granular pigmentary retinopathy that accompanies these disorders differs from the bone-spicule pigmentation of retinitis pigmentosa. Several unique features of mitochondrial functioning account for the genetic and clinical features of these syndromes. The mitochondrial encephalomyopathies have only recently begun to be understood on a molecular level, and a detailed classification system has yet to be worked out.156 A thorough understanding of these conditions is made difficult by the complexity of mitochondrial energy metabolism, which is controlled by both nuclear DNA and mitochondrial DNA (mtDNA) and by the characteristics of

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mitochondrial inheritance and deterioration of mitochondrial function with aging.134,340 Mitochondria are the major supplier of adenosine triphosphate for cellular energy metabolism. The mitochondrial metabolism itself can be disturbed in any of four major steps.19 The complexity of the interplay between these steps of mitochondrial metabolism and other cellular functions can be illustrated by the fact that abnormalities of the different steps in the mitochondrial energy chain can result in the same phenotype, whereas identical genetic defects can cause different phenotypic expression.134,156,318,319,340 The complexity of mitochondrial diseases becomes more readily apparent when one considers that the circular mtDNA containing 16,500 base pairs works in concert with nuclear DNA to build and execute the energy-producing function of the subcellular organelle. Each circular mtDNA has 37 genes encoding 22 transfer RNAs, two ribosomal RNAs, and 13 proteins essential to oxidative phosphorylation. Nuclear DNA encodes for 56 subunits of the mitochondrial electron transport chain, and the expression of the mtDNA genes requires replication, transcription, and translation, most of which is encoded by nuclear DNA. Nuclear mutations have been found to be responsible for a number of recessive mitochondrial disorders. Oxidative phosphorylation alone requires hundreds of nuclear, mitochondrial, and cytoplasmic genes.19 Mitochondria are the only subcellular organelles to have their own DNA, and this DNA differs from nuclear DNA in several important ways. First, it is circular and has no enterons (the noncoding sequences common to nuclear DNA). The genetic code used by mtDNA is also different from the nuclear DNA code. Mitochondria divide in a manner similar to the budding of bacteria. On cell division, mitochondria are randomly divided into each daughter cell. During fertilization, the human sperm cytoplasm has very few mitochondria and does not contribute significantly to the mitochondrial content of the zygote; therefore, all offspring inherit the female parent’s mitochondrial genotype. While nuclear DNA is inherited in a Mendelian fashion, mtDNA is entirely maternally inherited. The mitochondrial function is not controlled exclusively by the mtDNA present in the organelle, but rather, most mitochondrial functions are still under the control of nuclear DNA. However, mtDNA encodes for 13 components of the electron transport chain, most importantly, complex I, III, IV, and V. Ribosomal and transfer RNA are also encoded by the mtDNA. Abnormalities in these RNAs produce multiple defects in oxidative phosphorylation. Mitochondrial disorders are caused by mutations of nuclear or mtDNA-encoded genes involved in oxidative phosphorylation.134 Because mitochondria are present in many of our organs and play a key role in energy metabolism, mitochondrial encephalomyopathies often present as

multisystem disorders that may manifest with neurologic, cardiac, endocrine, gastrointestinal, hepatic, renal, and/or hematologic involvement.86,134,339 The clinical recognition of mitochondrial disorders as a group is impeded by the enormous variability in their phenotypic expression.134 There are hundreds of mitochondria per cell and thousands of copies of mtDNA, which leads to a mixture of normal mtDNA and mutant DNA, a phenomenon called heteroplasmy. Furthermore, a cell may drift toward the expression of more normal or more mutant DNA with cell replication, a phenomenon called mitotic segregation. Whether a cell’s energy metabolism reflects the abnormal DNA present in a cell may be influenced by a threshold effect in which a certain percentage of abnormal DNA is required before energy metabolism is affected. Finally, the degree to which a particular cell depends on mitochondrial energy metabolism may vary, thus explaining why muscle, brain, and heart, with their very high energy demands, may be particularly vulnerable to these abnormalities.

Chronic Progressive External Ophthalmoplegia (CPEO) Chronic progressive external ophthalmoplegia has been divided into many subsets according to clinical findings. The most well known of the syndromes considered to be a subset of CPEO is Kearns–Sayre syndrome. Its unique phenotype not withstanding, Kearns–Sayre syndrome may be one particular manifestation of a larger group of abnormalities, all caused by deletions of mtDNA. These deletions lead to similar biochemical abnormalities that produce clinical syndromes that differ because of the phenomena previously noted. MtDNA deletions of varying sizes have been demonstrated in patients with CPEO, but to date, no correlation between the size of the deletion and the severity of symptomatology has been described. Most cases of mitochondrial disease associated with CPEO arise sporadically.34 In sporadic cases, it is likely that the rearrangements occurred during embryogenesis. Autosomal recessive and autosomal dominant inheritance have also been demonstrated, implicating nuclear DNA abnormalities.134 Confirmation of the diagnosis usually requires fresh muscle biopsy for histopathological examination (using cytochrome oxidase stain with electron microscopy to look for “parking lot” inclusions) and Southern blot analysis to look for deletions. MtDNA analysis of skeletal muscle tissue of some CPEO patients reveals rearrangements of segments of mtDNA in the form of deletions and duplications. Largescale mtDNA rearrangements are commonly found in CPEO and Kearns–Sayre syndrome. These rearrangements have been found in over 90% of Kearns–Sayre syndrome patients,

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compared with about 50% of CPEO patients.34 Patients are typically heteroplasmic for these rearrangements, and the mutant mtDNA accounts for 20–90% of the total skeletal muscle mtDNA. Kearns–Sayre syndrome patients typically have a greater percentage of mutant mtDNA in their tissues than patients with less severe CPEO syndromes.34 More than 90% of patients with Kearns–Sayre syndrome and about 50% of patients with CPEO have a single large deletion in mtDNA. Blood mtDNA analysis is usually normal. Patients with mtDNA deletions present as sporadic cases, whereas other patients with CPEO show a maternal pattern of inheritance in which mtDNA point mutations are found.334,335 Large-scale deletions resulting in CPEO are almost always heteroplasmic – the more tissue with the deletions (i.e., the greater the degree of heteroplasmy), the more likely the phenotype will be severe (i.e., more toward the Kearns–Sayre syndrome phenotype than the simple CPEO).14 The risk of developing a severe phenotype (i.e., additional CNS symptoms with neurological manifestations) is higher when the age of onset is before age 9 and lower when the onset is after age 20.14 Complete Kearns–Sayre syndrome is characterized by onset of clinical abnormalities in the first or second decade of life, with progressive ptosis and external ophthalmoplegia. A characteristic retinal abnormality occurs in patients with Kearns–Sayre syndrome, consisting of widespread salt-andpepper retinal pigment epithelial mottling, seen most strikingly in the macula, together with a discrete halo associated with peripapillary pigmentary atrophy118 (Fig. 10.13). Cardiac conduction defects due to degeneration of the HIS Purkinje system begin with a partial block but lead to a complete heart block with or without an associated cardiomyopathy. The cerebrospinal fluid (CSF) protein is found to be elevated to greater than 100 mg/dL, and many patients demonstrate cerebellar ataxia. A history must be obtained regarding other symptoms or signs of mitochondrial disease, including ptosis, deafness, weakness, ataxia, malabsorption syndromes, palpitations, syncope, respiratory insufficiency, diabetes, and tetany.34 Routine laboratory testing for mitochondrial disease is limited. Serum lactate elevation, especially after exercise, is a variable finding in patients with CPEO, MELAS, and Leigh syndrome. Neuroimaging is mandatory to rule out associated CNS lesions, with diffusion-weighted imaging and spectroscopy MRI sometimes providing supportive information. CSF analysis may reveal high lactate levels and elevated protein. Skeletal muscle biopsies (with examination by a laboratory that is equipped for mitochondrial analysis to perform enzymatic assays to measure biochemical deficiencies) can be examined to look for ragged red fibers. Genetic analysis is best performed on skeletal muscle biopsies, especially if rearrangements of mtDNA are suspected. Point mutations in mtDNA can be detected using polymerase chain reaction

amplification techniques on whole blood samples or any tissue that contains mitochondria. Avoiding agents that might stress mitochondrial energy production is a nonspecific recommendation with no confirmed benefit. Current criteria for diagnosis include two obligatory features: early-onset CPEO (prior to age 20) and retinal pigmentary degeneration, plus one of the following three: heart block, CSF protein greater than 100 mg/dL, or cerebellar syndrome.77 However, a large number of systemic, neurologic, and laboratory abnormalities have been noted in Kearns–Sayre syndrome (Table 10.6). The use of systemic corticosteroid therapy in these patients can precipitate hyperglycemic acidotic coma and death.15 The characteristic MR imaging abnormalities in CPEO include abnormal hyperintensities in the deep gray matter nuclei (particularly the thalamus and globus pallidus) on T2-weighted images and patchy white matter involvement.19,72,81,94,173,179,231 The white matter involvement is predominantly peripheral with early involvement of the subcortical U fibers sparing of the periventricular fibers (Fig. 10.14). Other disorders involving myelin, such as lysosomal disorders and peroxisomal abnormalities, tend to spare this subcortical myelin and affect the older central myelin first.17 The finding of little or no reduction in extraocular muscle volume may help distinguish CPEO from the other forms of ophthalmoplegia, such as congenital fibrosis syndrome.238 The brain ultimately undergoes a spongy degeneration affecting both gray and white matter, and these patients may eventually become demented. Muscle biopsy shows ragged red fibers as it does in patients with the other mitochondrial encephalomyopathies.

Leigh Subacute Necrotizing Encephalomyelopathy Leigh disease is probably the most severe manifestation of mitochondrial encephalomyelopathy.342 Onset is often within the first year of life but may rarely develop in later childhood or adulthood. Affected children exhibit hypotonia, loss of verbal and motor milestones, a waxing and waning course of vomiting, weight loss, stupor, and seizures. The striking resemblance to the pathological abnormalities of thiamine deficiency (Wernicke encephalopathy) led to the early suggestion that Leigh disease is secondary to an inborn error of thiamine metabolism. However, a variety of energy metabolism abnormalities have been found, all of which impair mitochondrial DNA production.180 Children with Leigh disease may develop a variety of unusual brainstem motility abnormalities, including horizontal gaze palsies, internuclear ophthalmoplegia, dorsal midbrain syndrome, and a condition initially resembling spasmus

Mitochondrial Encephalomyelopathies

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Fig. 10.14 Kearns–Sayre syndrome. (a) This MR image shows abnormally high signal intensity in globus pallidus bilaterally (arrow). (b) At higher level, increased signal intensity in peripheral white matter, including subcortical U fibers is evident (arrow), while periventricular white matter is spared. Courtesy of A. James Barkovich, M.D.

nutans.279 Although primarily a gray matter disease, white matter is eventually involved, and optic atrophy may develop late in the course of the disease. A characteristic symmetrical pattern of neuroimaging abnormalities is now known to be highly characteristic for Leigh disease. MR imaging shows prolonged T1 and T2 relaxation times in the basal ganglia, periaqueductal region, and cerebral peduncles. Involvement of cerebral white matter may also occur17,213 (Fig. 10.15). Serum and CSF lactate levels may be elevated. Proton spectroscopy may be useful in delineating Leigh disease from other diseases primarily affecting basal ganglia as it is the only disorder to date to show elevated lactate levels in these areas by this study.83 The clinical features of Leigh disease may be caused by several biochemical defects, including pyruvate dehydrogenase deficiency (X-linked inheritance), COX deficiency (autosomal recessive), and OXPHOS deficiency (mtDNA mutations). Most Leigh disease results from nuclear gene defects.256 Approximately 20% of patients with Leigh disease have the T-to-G or T-to-C mtDNA mutation at np8993, within the ATPase 6 gene of complex V of the electron transport chain. A third of patients with NARP carry the Leigh mutation and present with variable combinations of ataxia, seizures, sensory neuropathy, dementia, and retinitis pigmentosa.181,237 Heteroplasmic levels greater than 90% are seen

Fig. 10.15 Leigh disease. T2-weighted MR image shows increased signal intensity in lentiform nuclei (large arrows) and medial thalamic nuclei (small arrows) bilaterally. Courtesy of Charles M. Glasier, M.D.

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with the classic Leigh disease presentation, whereas lower levels of heteroplasmy are associated with the NARP (neurologic weakness, ataxia, and retinitis pigmentosa) phenotype. Other mutations reported in association with the Leigh disease phenotype include the A324G MELAS mutation as well as the A8344G MERRF mutation256 and G1544T tRNAval, deletions and depletions of mtDNA levels.134

Mitochondrial Encephalomyelopathy and Stroke-Like Episodes (MELAS) MELAS is the mitochondrial disease that is most consistently associated with retrochiasmal visual loss.34 MELAS is characterized by recurrent abrupt attacks of headache, vomiting, focal and generalized seizures, and focal neurologic symptoms and signs lasting hours to days. There is a posterior cerebral predilection for damage, and visual disturbances have been reported in more than half of patients. It is not uncommon for patients with MELAS to have CPEO, pigmentary retinopathy, or optic atrophy.34 The hallmark of this syndrome is the occurrence of strokelike episodes that result in hemiparesis, hemianopia, or cortical blindness. Focal or generalized seizures, recurrent migrainelike headaches, vomiting, short stature, hearing loss, and muscle weakness are common. The syndrome usually develops during childhood and has a relapsing and remitting course, with strokelike episodes separated by periods of variable resolution that results in progressive neurologic dysfunction and dementia. Initial symptoms of MELAS begin in early childhood and include headache (which may be indistinguishable from complicated migraine), vomiting, seizures, and reversible neurological deficits, including visual disturbances.152 The recovery following the strokelike events may be surprisingly good, but recurrences of neurologic deficits occur, ultimately leaving patients with hemiparesis, hemianopia, or complete blindness. Patients with otherwise characteristic MELAS syndrome may have ptosis and external ophthalmoplegia suggestive of CPEO.97 Angiographic studies have failed to demonstrate significant vascular occlusions, leading to the hypothesis that these are metabolic strokes caused by an area of brain exceeding its respiratory ability rather than by thromboembolism. MR imaging studies in this condition show edema in affected areas that are not restricted to specific vascular distributions.210 Patients with MELAS have been described as showing parietooccipital hypodensity on CT scanning and T2 prolongation on MR.19 On pathologic examination, spongiform changes are primarily in the gray matter. Neuroimaging studies demonstrate radiolucent areas on CT scans and areas of hyperintense signal on T2-weighted MRI.50 These lesions predominantly involve the cortex and subcortical white matter, may cross the boundaries of the

major arterial territories, and are more common in parietooccipital regions than in other regions. These lesions may appear transitory because as the initial lesions resolve, new and often adjacent lesions appear. A point mutation in mitochondrial transfer RNA at position 3,243 can be identified in most patients with this syndrome.131 The resulting biochemical abnormalities include decreased respiratory activity in complexes I, III, and IV. There are no clinical differences between patients who have the point mutation in mtDNA and those with MELAS syndrome who do not have the mutation.131 This finding illustrates the heterogeneity of mitochondrial energy metabolism abnormalities noted earlier. Prenatal diagnosis for MELAS syndrome is now possible.39

Myoclonic Epilepsy and Ragged Red Fibers (MERRF) This relatively uncommon condition consists of myoclonic epilepsy, generalized epilepsy, ataxia, proximate weakness, fatigability, spasticity, sensory loss, dysarthria, optic atrophy, and dementia.134 Onset can occur at any age and is variable even within families. Muscle biopsy shows ragged red fibers seen in the other conditions. Myoclonus is usually the presenting symptom and is often precipitated by noise, photic stimulation, or action. Epilepsy and ataxia soon follow. Myopathy is generally subclinical or mild. Optic atrophy may develop; however, there is no ophthalmoplegia or retinal abnormality in this disease. Biochemical aberrations may include elevations of serum pyruvate or pyruvate and lactate and reduced activities of complexes I and IV.134 This condition has a point mutation in mitochondrial transfer RNA encoded by a mutation of mtDNA at the 8344 nucleotide pair. The most common mutation is the heteroplasmic mtDNA A8344G mutation, which is present in both muscle and blood.140 However, other mutations within the same tRNA gene, t8356C and G8363C, are also found in association with this phenotype.239

Mitochondrial Depletion Syndrome Mitochondrial depletion syndrome (MDS) typically manifests as neonatal or infantile-onset fatal lactic acidosis with severe hypotonia and progressive liver failure.134 mtDNA levels are typically reduced to less than 5% of normal.219 MDS is a common cause of lactic acidosis presenting in infancy.339 In one study of children with hypotonia, weakness, and developmental delay, 10% were found to have MDS.203 Other features may include seizures, ophthalmoplegia, renal Fanconi syndrome, congestive heart failure, and cataracts. CNS signs and symptoms may be present in 20% of patients. The clinical course is fatal, with death by 1 year of age.134

Horizons

Congenital Disorders of Glycosylation The carbohydrate-deficient glycoprotein syndromes are a group of lysosomal storage disorders in which there is a defective glycosylation of secretory, lysosomal, and membrane-bound proteins.166,185 Because the function of glycoproteins include transport and membrane receptor proteins, glycoprotein hormones, complement factors, immunoglobulins, and other enzymes, abnormalities in their synthesis manifests in a broad range of systemic effects.342 These syndromes usually become apparent in the early neonatal periods, with failure to thrive and multisystem organ failure, especially involving the liver and heart. In addition to the neonatal onset, clinical features of carbohydrate-deficient glycoprotein syndromes include the lower motor-neuron impairment of the legs more than the arms, subcutaneous fat pads, strabismus, and retinitis pigmentosa. Neuroimaging typically shows enlargement of the cisterna magna with brainstem and cerebellar hypoplasia.6 Ophthalmologic features are common and include strabismus, nystagmus, and a retinal degeneration with severely diminished scotopic ERG waveform.10 Less common findings include congenital cataract, retinochoroidal coloboma, glaucoma, and retinitis pigmentosa.220 The most common form, type 1a, produces prominent neurologic dysfunction in infancy. Patients with carbohydrate-deficient glycoprotein syndrome 1a can present with panting tachypnea, a nystagmus resembling ocular flutter,293 and a slowly progressive pigmentary retinopathy resembling what is seen in mitochondrial disease.109,293

Horizons Ongoing identification of gene-causing mutations in combination with newer MR imaging techniques such as diffusion tensor imaging and proton spectroscopy, are being applied to genetic metabolic disorders to differentiate hypometabolic disorders from cystic degeneration and myelin vacuolization.329 Several new potential therapies are currently under investigation. Most of these therapies (enzyme replacement therapy, gene therapy, bone marrow transplantation, neural stem cell therapy, molecular or pharmacological chaperone therapy), are designed to restore enzyme activity.297 Others (substrate deprivation, metabolic bypass therapy) do not restore enzyme activity, but are designed to reduce levels of the compounds that accumulate in lysosomes. CNS diseases, which are proving to be the most refractory to treatment, will probably require a combination of therapeutic approaches to reverse or halt their devastating effects. Bone marrow and stem cell transplantation require the need for an immunologically-matched healthy bone marrow

493

donor.297 Blood (mesenchymal cells) and brain (neural stem cells) provide the two major sources of stem cells. Although stem cells have been shown to spread through the brain in mice, it is unclear whether the number of cells necessary to make replace a deficient enzyme cells numbers can be delivered in humans. It is anticipated that stem cells could be genetically manipulated before transplantation to increase production of the missing enzyme.297 Enzyme replacement therapy involves replacement of the defective enzyme with a functional enzyme molecule that has been manufactured in the laboratory.297 Although it has shown efficacy in treating several disorders including Gaucher disease type 1, mucopolysaccharidosis, Fabry disease, Pompe disease, it does not work well for diseases primarily involving the CNS because the enzymes do not easily cross the blood–brain barrier.297 Gene therapy introduces a functional version of the gene that is mutated in affected individuals to replace or augment its function.119,297 The gene can be introduced as free DNA, in a lipid coat (liposome), or as part of a viral vector. At present, viral delivery is the most common approach. Viral delivery requires modification of a specific virus so that it cannot cause disease and then having it carry the gene for the missing enzyme to the brain or other target organ. This promising therapy is currently limited by a number of real and potential difficulties. These include: (1) the inherent difficulty of creating effective vectors, especially for gene delivery to non-dividing cells within the brain, (2) the need to introduce the gene into a large number of cells to have a clinical effect; (3) the potential for an oncogenic event as a result of the random insertion of the gene into the host cell chromosomes; and (4) the extensive review processes now needed for all gene therapy trials.119,297 Gene therapy is being currently researched as a treatment for numerous disorders, including Canavan disease.119,297 Molecular chaperone therapy provides a new and novel therapeutic approach for the treatment of neurodegenerative diseases.200,297 When a protein or enzyme is misfolded because of a genetic mutation and is unable to adopt the correct functional shape,200,297 it is destroyed within the cell, leading to decreased amounts of enzyme that gets transported from the endoplasmic reticulum to the lysosome, and therefore reduced enzyme activity.200,297 Pharmacological chaperones are small molecules that bind to and stabilize the functional form or three-dimensional shape of a misfolded protein in a cell, allowing it to be efficiently trafficked from the endoplasmic reticulum and distributed to the lysosome in the cell, which increases enzyme activity and cellular function and reduces the stress of the abnormal substrate on cells.200,297 Substrate deprivation (also called substrate synthesis inhibition, substrate reduction, and substrate balancing) utilizes molecular inhibitors to decrease the production of the molecule that typically accumulates to high levels in persons with lysosomal storage diseases.297 For example, children with Tay–

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Sachs disease accumulate high levels of GM2 which causes brain cells to die. in brain cells; this accumulation causes the brain cells to die.297 Decreasing the synthesis of GM2, which is the substrate for the missing enzyme, should decrease cell death and moderate the course of the disease. The inhibitor miglustat (Zavesca®) has undergone clinical trials in children with juvenile GM2 Tay–Sachs and Sandhoff disease and children under the age of 2 years with Tay–Sachs disease or Sandhoff disease with no clear benefit,240,297 but showed modest benefit in stabilizing Niemann–Pick type C disease.244 Metabolic bypass therapy is a theoretical approach that would introduce special chemicals called activators to increase the synthesis or activity of alternative lysosomal enzymes that could then degrade larger-than-normal amounts of a substrate like GM2 and partially bypass the need for the defective enzyme.297

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Chapter 11

Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

Introduction Advances in genetics and neuroimaging have revolutionized the diagnosis of intracranial disease in children. An integrated approach to these diseases has also emerged from the proliferation of multidisciplinary clinics and programs combining expertise in pediatric neurology, neurosurgery, neuropathology, neuroradiology, neuro-oncology, and neuro-ophthalmology. The role of genetic defects is increasingly recognized in many intracranial disorders, and basic research elucidates their pathogenesis at the molecular level. Refinement in neurosurgical management continues to advance the treatment of these disorders, while preventative and therapeutic measures will arise from molecular genetic research. Recent documentation of increased cancer risk in children exposed to multiple computed tomographic (CT) scans has emphasized the need to order diagnostic magnetic resonance (MR) imaging if possible.112 This chapter provides dedicated discussion on the intracranial disorders of neuro-ophthalmologic consequence in children.

The Phakomatoses van der Hoeve,901 a Dutch ophthalmologist, first used the term “phakoma” to describe retinal astrocytic hamartomas in tuberous sclerosis and myelinated retinal nerve fibers in neurofibromatosis. Noting that the retinal astrocytic hamartomas resembled dried lentils (“phaki”), he assumed that tuberous sclerosis and neurofibromatosis were related conditions and coined the term “phakomatosis” as an umbrella term to describe congenital disorders that produce benign growths in the central nervous system (CNS).828 He later expanded this concept to include other conditions characterized by CNS, cutaneous, and often ocular involvement,828 but never specified that the skin or central nervous system had to be involved.99

In its present usage, phakomatosis is a loosely defined and somewhat arbitrary term that has evolved to include a heterogeneous group of multisystem disorders that share a predisposition to develop hamartomas within the CNS, often in association with cutaneous, ocular, or visceral lesions.73 Approximately 20–30 disorders have been classified as phakomatoses, and some patients display features found in more than one phakomatosis. All of these diseases are congenital in origin, but their inheritance patterns vary, and some do not appear to be genetically transmitted.99 Borchert99 and Parsa671 have argued that application of the term phakomatosis should ideally be limited to tuberous sclerosis, NF1, NF2, von Hippel Lindau disease, and ataxia telangectasia because these conditions share mutations in tumor suppressor genes, and patients with these diseases have a higher frequency of malignancies.293,479 Consistent with Knudson’s “two-hit hypothesis,” germline mutations in responsible genes result in increased susceptibility to tumor formation following the development of a secondary somatic mutation and loss of heterozygosity. In contrast, neither hamartomas nor heredity is clearly involved in Wyburn–Mason syndrome or Sturge–Weber syndrome, and neither Wyburn–Mason syndrome nor von Hippel–Lindau syndrome produces cutaneous findings. The phakomatoses (both definite and arguable) of neuro-ophthalmologic significance are discussed below.

Neurofibromatosis (NF1) von Recklinghausen neurofibromatosis (NF1) is an autosomal dominant disorder that affects numerous organ systems, including the eye.520,734,871 It is one of several autosomal diseases that are associated with advanced paternal age. NF1 has no clear predilection for race or sex. It has an incidence of approximately one in 3,000, making it the most common phakomatosis.317,412,871 NF1 is essentially fully penetrant, but there is considerable variation in the intrafamilial and inter-

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familial features of the disease. Only 50% of patients have affected relatives,805 and NF1 is said to have one of the highest mutation rates in humans.871 The responsible gene for NF1 is located in the pericentromeric region of the long arm of chromosome 17 and encodes a 2818 amino acid.44,871 It functions as a tumor suppressor gene,708 and expression of the gene product, neurofibromin, is predominantly restricted to neuronal tissue in adults.414 Pathological mutations range from single nucleotide substitutions dispersed throughout the gene to large-scale genomic deletions, sometimes including the entire gene. Part of the protein encoded by neurofibromin shows high sequence homology with the GTPase activator protein (GAP) family of proteins that interact with ras proteins to regulate cell growth and differentiation and act as negative regulators of neurotrophin-mediated signaling. The mammalian target of rapamycin (mTOR) pathway is aberrantly activated in NF1deficient primary cells and in human tumors.222,439 This activation is mediated by the phosphorylation and inactivation of the TSC2-encoded protein tuberin. Tumor cell lines derived from NF1 patients are highly sensitive to rapamycin; an increased level of mTOR pathways activation is reported in human NF1-associated pilocytic astrocytomas.293 Deletions of the entire gene are associated with a more severe phenotype, including a high frequency of mental retardation and severe learning difficulties.485 The numerous dysgenetic, hamartomatous, and neoplastic lesions that arise in NF1 have been attributed to a disturbance in neural crest migration brought about by the NF1 mutation, causing abnormal aggregations of Schwann cells or melanoblast precursors occur during the migratory phase of neural crest development.96 Because many of the disparate findings in NF1 relate to a common neural crest origin, Bolande96 once termed NF1 “the quintessential neurocristopathy” to encapsulate the fact that malignancies of neural crest-derived cells, such as malignant schwannoma, occur more commonly in NF1 patients.96,871 However, many features of NF1, such as short stature, intellectual impairment, macrocephaly, speech impediment, pseudoarthrosis, and malignancies of non-neural crest origin (e.g., myelogenous leukemia, rhabdomyosarcoma) cannot be reconciled with a neural crest origin.871 NF1 is a progressive condition with variable complications occurring over the time course of the disease. Café au lait spots, pseudoarthrosis, and externally visible plexiform neurofibromas can generally be identified during infancy. Freckling, optic gliomas, and severe scoliosis occur in the first decade of life. Pseudarthrosis occurs in 5% of patients and usually involves the distal one-third of the tibia and fibula.848 The cardinal pathologic features of NF1 are the café au lait spots of the skin and a variety of neural hamartomas, known collectively as neurofibromas, that develop in the peripheral, autonomic, and central nervous system.96,731,732,735

Café au lait spots are pigmented macules of the skin that result from aggregation of heavily pigmented melanoblasts in the basal layers of the epidermis.96 They are present in the majority of children with NF1 at birth and become prominent by the end of the first decade of life. Children with NF1 may also have diffuse skin hyperpigmentation or innumerable freckles. Axillary freckling in NF1 tends to be congenital, whereas diffuse freckling or freckling at points of friction (e.g., inguinal or other intertriginous zones) is often acquired.708 Peripheral neurofibromas are a hallmark of NF1.588 They arise from cells in the peripheral nerve sheath and contain a mixture of cell types such as Schwann cells, fibroblasts, mast cells, and vascular elements.96,548,588 The proportion and growth pattern of these constituents account for the morphologic differences so that plexiform neurofibromas, pure schwannomas, and neuromas are described.96 Neurofibromas occurring as subcutaneous nodules near the terminations of peripheral nerves in the dermis comprise the most conspicuous feature of neurofibromatosis, but neurofibromas may also arise within the central and autonomic nervous systems.96 Cutaneous neurofibromas develop toward the end of the first decade, just before puberty. They are initially sessile but often become pedunculated.708 Enlarging neurofibromas may produce intense pruritis that may respond to mast cell stabilizers. The histology of neurofibromas is typically hypocellular, and the cytology is indolent.96 However, if a skin neurofibroma is being constantly traumatized by friction with clothing, it is generally recommended that it be removed, because of the potential risk of malignant transformation.708 NF1 patients have a 10% lifetime risk of developing malignant peripheral nerve sheath tumor or neurofibrosarcoma, which usually arises within a neurofibroma as an aggressive and often fatal malignancy.281,890 Malignant peripheral nerve sheath tumors usually arise with preexisting plexiform or a focal subcutaneous neurofibromas, whereas cutaneous neurofibromas do not become malignant.281 However, large patches of cutaneous hyperpigmentation in patients with neurofibromatosis tend to overlie these large plexiform neuromas, which have an unusually high incidence of degeneration to neurofibrosarcomas. When the hyperpigmentation overlying a plexiform neurofibroma extends to midline, it may signify underlying spinal cord involvement.708 Although multiple cell types (i.e., Schwann cells, mast cells, perineural cells, fibroblasts, and endothelial cells) are found in neurofibromas,733 Schwann cells are proposed to be the true tumorigenic cell population.476,750,764 Diffuse plexiform neurofibromas are usually congenital or appear in early childhood, whereas nodular lesions develop later in life.484,916 Cutaneous involvement of the face is relatively uncommon in NF1, but plexiform neurofibroma of the upper lid tends to be associated with ipsilateral dysgenesis of the globe and orbit. Plexiform neurofibroma of the upper lid classically produces

The Phakomatoses

the “swan neck” or “lazy S” deformity (Fig. 11.1). Approximately 50% of children with plexiform lid neurofibromas have congenital glaucoma which occurs only in association with orbitofacial involvement.615a In addition to congenital glaucoma and buphthalmos, children with plexiform neurofibroma of the upper eyelid may have ipsilateral orbital enlargement, ipsilateral sphenoid dysplasia (absence of the sphenoid wing and anterior clinoid, with or without pulsating exophthalmos), and progressive facial hemihypertrophy (Francois syndrome) (Fig. 11.2).43,408 These changes may be associated with prolapse of the temporal lobe into the orbit or lateral expansion of the middle cranial fossa (termed orbitotemporal neurofibromatosis).425 The plexiform neurofibroma is congen-

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ital in origin but may not be evident at birth until it grows to a size that causes cosmetic disfigurement.658 Although surgical debulking has historically been the treatment for plexiform neurofibomas, targeted biologically based treatments are now under investigation.658 Some children with NF1 have buphthalmos in the absence of congenital glaucoma.431 Weiner931 and Hoyt and Billson408 have suggested that buphthalmos in neurofibromatosis sometimes represents a generalized hyperplasia of the orbit and its contents (i.e., an expression of regional gigantism) rather than a consequence of uncontrolled intraocular pressure. Some children also display congenital iris ectropion secondary to endothelialization of iris, with the iris adherent to Schwalbe’s line. Choroidal ganglioneuroma has also been reported in this setting.819 Prior to neuroimaging, the combination of unilateral proptosis and poor vision in such cases was often incorrectly attributed to orbital optic glioma. When correctly diagnosed, this constellation of findings signifies a unilateral process. The most common ocular feature of neurofibromatosis is Lisch nodules of the iris.551,552,708,871 Lisch nodules are tan to brown, avascular, dome-shaped lumps in the anterior iris (Fig. 11.3). Pathologically, they have been considered to be

Fig. 11.1 Neurofibromatosis-1. Plexiform neurofibroma of left eyelid in child with NF1 who had ipsilateral glaucoma and absence of sphenoid wing

Fig. 11.2 Francois syndrome. This child had orbital dystopia with a plexiform neurofibroma, buphthalmos, high myopia, congenital glaucoma, and absence of the sphenoid wing

Fig. 11.3 Neurofibromatosis-1. Lisch nodules on surface of iris may be few (a) or numerous (b)

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melanocytic hamartomas with a compact plaque of spindle cells overlying a loose stromal accumulation of melanocytes.439 More recently, Richetta et al738 found that Lisch nodules are composed of pigmented cells, fibroblast-like cells, and mast cells similar to neurofibromas. In blue and green irides, they appear pale to medium brown with feathery margins; in dark brown irides, they are cream colored, domeshaped, and extremely well defined (Fig. 11.1).708 When present in young children, they tend to be glassy and translucent in appearance.944 Ragge et al710 combined data from six large studies of Lisch nodules in different age groups, and found that the prevalence of Lisch nodules in neurofibromatosis gradually increases to about 50% at age 5 years, 75% at age 15 years, and 95–100% of adults over age 30.710 Despite the absence of Lisch nodules in many young children, the diagnosis of neurofibromatosis can usually be established on the basis of other criteria.641 Unlike neurofibromas, there is no acceleration in the rate of appearance of Lisch nodules associated with puberty.534 Lisch nodules are highly suggestive, but not pathognomonic, of NF1, as they have been rarely reported to occur in patients with segmental neurofibromatosis,934 NF2,174 and Cushing disease.106 The major neuro-ophthalmologic manifestations in children with NF1 are proptosis, optic disc swelling, optic atrophy, ptosis, strabismus, and amblyopia. Pulsatile proptosis may occur when the sphenoid wing is absent, and only the dura separates the brain and orbit. Enophthalmos may also be seen occasionally in this setting. Nonpulsatile proptosis occurs most commonly with ipsilateral orbital optic glioma but may also result from a localized or plexiform orbital neurofibroma.602 When optic disc swelling is accompanied by ipsilateral proptosis, the causative lesion is usually an orbital optic glioma. Optic disc swelling without proptosis may herald hydrocephalus secondary to hypothalamic/chiasmal glioma extending into the third ventricle, hydrocephalus associated with aqueductal stenosis, an intracranial arachnoid cyst, a spinal ependymoma, or some other NF1associated spinal tumor. Optic atrophy may occur primarily with optic glioma or pursuant to prolonged optic disc swelling from any of the above-mentioned causes. Ptosis in NF1 is usually S-shaped and associated with an upper lid plexiform neurofibroma. Strabismus and amblyopia may result from nonaxial proptosis because of orbital optic glioma, or from visual deprivation when a plexiform neurofibroma of the lids or buphthalmos are present. Caucasians with neurofibromatosis frequently have choroidal pigment hamartomas in the posterior pole, which tend to be flat and hyperpigmented or silvery gray. These easily overlooked lesions are probably the next most common ocular finding in neurofibromatosis following Lisch nodules. Choroidal and ciliary body neurofibromas are well recognized but uncommon manifestations of NF1.240 Although myelinated nerve fibers are said to be more

common in children with neurofibromatosis, this association may be fortuitous. The reported association between enlargement of the corneal nerves and neurofibromatosis is equally dubious, with previously described cases possibly occurring in patients with a multiple endocrine neoplasia syndrome.602 Yasunari et al960 found bright, patchy choroidal lesions in 100% of NF1 patients, a frequency that exceeded that of Lisch nodules (76%) and plexiform neurofibroma (29%). Primary retinal involvement is more common in NF2, but may occasionally occur in NF1. Several reports of retinal dialysis and detachment adjacent to a peripheral astrocytic hamartoma in children with NF1 suggest that unlike the visually benign astrocytic hamartomas of tuberous sclerosis, NF1-associated astrocytic hamartomas are more likely to produce retinal traction, dialysis, and ultimately detachment.240,575 Retinal vascular disease is another occasional finding.240,611 Children with NF1 have been described with bilateral capillary hemangiomatosis240 as well as retinal vascular occlusive disease,611 which may be similar in etiology to the vascular ischemic manifestations that have been described in the aortic, cerebral, and renal vasculature.784 Retinal vascular abnormalities have now been recognized in NF1. Muci-Mendoza et al451,621 described a distinctive microvascular abnormality in 12 of 37% of patients with NF1. In ten cases, the abnormality was subtle, consisting of tortuosity and a corkscrew appearance of a second- or thirdorder venule or a tributary of a major retinal vein. Two cases had more striking vascular abnormalities, with a venovenous anastomosis and an extensive arteriovenous malformation (AVM) coexisting with an epiretinal membrane. Certain features on magnetic resonance (MR) imaging are highly suggestive of NF1 (Figs. 11.4 and 11.5).708 These include (1) bilateral optic gliomas; (2) tubular expansion with lengthening and kinking of one or both optic nerves; (3) a double-intensity signal to the orbital optic nerve, with a bright outer signal on T2-weighted images corresponding to the perineural tumor and the dark central core corresponding to the optic nerve194,418,798; (4) chiasmal glioma extending into both optic tracts; and (5) high-signal intensity foci in the brain parenchyma on T2-weighted images, especially in the globus pallidus, basal ganglia, and cerebellar white matter.250 By far the most common abnormality detected on MR imaging in patients with NF1 is foci of increased signal on T2-weighted images (Fig. 11.6). These lesions are seen most commonly in the basal ganglia, internal capsule, brainstem, and cerebellum.694 They are typically small and may be solitary, multiple, or confluent. They tend to increase in number in early childhood and then regress later in childhood, which suggests that they may represent age-related abnormalities in myelination.808 They tend to disappear with age and have no known clinical significance.252,423,707,828

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Fig. 11.4 Distinctive MR imaging characteristics of orbital optic glioma in NF1. (a) T1-weighted axial MR image of left orbital glioma. Fusiform area of low intensity (closed arrow) surrounds central core of high signal intensity. An arachnoid cyst (open arrow) occupies left anterior temporal fossa. Note that peripheral (outer) tumor signal is isointense to CSF contained within arachnoid cyst. Tumor is kinked posteriorly. (b) T1-weighted MR image of right orbital glioma showing linear enlargement of right optic nerve with circumferential zone of low signal intensity (closed arrow) surrounding central core of higher signal intensity. Open arrow denotes CSF within arachnoid cyst that is hypointense to brain on T1-weighted images. (c) T1-weighted coronal MR image of left orbital glioma. There is marked enlargement of optic

nerve with ring of low signal intensity (dark arrow) surrounding core of higher signal intensity. Large area of low signal intensity inferior and lateral to optic nerve (white arrow) corresponds to anterior extent of arachnoid cyst. (d) T2-weighted axial MR image through superior aspect of both optic gliomas. In left orbit, there is donut-shaped area of high signal intensity (dark arrow) surrounding inner circle of low signal intensity. Image represents tangential cut through superior aspect of upwardly kinked tumor. In right orbit, linear area of high signal intensity surrounds central core of low signal intensity. Note that outer signal within both tumors remains isointense to CSF (Open arrow denotes CSF in arachnoid cyst that is hyperintense to brain on T2-weighted images.)116

The most common intracranial tumor in NF1 is optic pathway glioma.536 The prevalence of optic pathway glioma on CT scanning in neurofibromatosis has been estimated to be 15%.532 Optic gliomas are typically WHO grade I pilocytic astrocytomas arising within the optic pathway and hypothalamus.527,672 In a child with NF1, the finding of hypertelorism heralds the presence of optic glioma.938 Visual evoked potential screening provides correlative information415,463,952 but offers no clear advantage to routine clinical screening.824

Parsa et al showed that optic gliomas can undergo spontaneous regression.674 According to Parsa and Givrad,672 tumor suppressor genes encode proteins that serve to control cell proliferation. These proteins induce cells that multiply in an abnormal way to either slip into senescence or undergo apoptosis. When heterozygous mutations occur in genes, the resulting haploinsufficiency of expressed proteins can allow the occasional replicating cell in normal tissues to undergo proliferation for an otherwise longer period before being brought under control. Thus, hamartomas such as gliomas

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Fig. 11.5 Chiasmal glioma. (a) Axial MR imaging shows diffuse enlargement of the orbital and intracranial optic nerves. (b) Coronal MR image shows bilobed chiasm. (c) Axial MR imaging shows posterior tumor extension along the optic tracts. (d) Another case showing hyperintense signal corresponding to more severe tumor involvement of the optic tracts

can occasionally grow in infancy and during the first decade of life, but their growth potential decreases dramatically thereafter. Decreased proliferative activity is a feature of older glial tumors, and, over time, the apoptotic processes may lead to eventual spontaneous regression of these juvenile pilocytic tumors.141,674 Once diagnosed, optic pathway tumor progression is uncommon in children with NF1.792 Although the prognosis is better in patients with NF1, even in isolated cases, this tumor is characterized by early rapid enlargement in the prediagnostic phase, followed by stagnation or diminution.792 In one study, no child found to have a tumor confined to the optic

nerve by neuroimaging screening developed decreased vision or other evidence of progression.537 Because orbital optic gliomas without chiasmal involvement do not “grow backward” and extend into the chiasm, surgical removal of an optic nerve glioma, particularly the intracranial portion, to prevent “spread” to the chiasm is unnecessary.540 However, all patients with chiasmal involvement need clinical and endocrinologic evaluation at initial presentation and on subsequent followup to monitor for the onset of precocious puberty. As optic nerve gliomas in childhood are rare, if ever, malignant, biopsy or surgical resection is rarely necessary.970 Surgical excision or debulking carries a significant risk of iatrogenic visual loss.

The Phakomatoses

Fig. 11.6 Multiple focal hyperintense lesions in the midbrain of a child with NF1

Surgical excision of tumors that have led to proptotic eyes without functional vision should be reserved for cosmetic purposes or to treat complications of exposed globes. Optic pathway gliomas occasionally appear to behave aggressively in young patients, with local expansion resulting in progressive clinical findings. This enlargement may correspond to a brief period of transient neoplasia before the control of cellular proliferation is reasserted or to accumulation of extracellular mucosubstance.672,673 No reports have documented spontaneous malignant transformation of a WHO grade I pilocytic astrocytomain in this location.672,673 Chiasmal/hypothalamic gliomas are associated with a higher probability of visual loss.38 These children also develop more complications such as hydrocephalus and precocious puberty.542 Involvement of the optic radiations signals a more aggressive optic pathway glioma in patients with NF1.543 Aggressive chiasmal/hypothalamic NF1-associated tumors have been found on biopsy to represent high-grade astrocytomas or difficult-to-classify gliomas or have other worrisome indices, such as high proliferative indices.542 Chemotherapy or en bloc resection are occasionally used in this setting.459 Despite significant advances in pediatric neurooncology,539,657 no highly effective treatment exists for anterior visual pathway gliomas, whether associated with NF or not.337,673,824,855,879 No correlation with long-term outcomes in terms of improvement of clinical symptomatology or progression-free period or survival has been demonstrated. Several authors have

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reported similar visual outcomes in observed and treated patients with anterior visual pathway gliomas.337,879 Even when tumor reduction occurs with chemotherapy, visual function is often unchanged.657 Moreover, mutagenic chemotherapy carries a risk of toxicity, infection, and secondary tumor development. Vincristine and carboplatin have been the most frequently employed agents.824 Vincristine has potential neurotoxicity and can cause an optic neuropathy.823 The addition of etoposide to the chemotherapy regimen has been suggested to increase progression-free rates, but results for isolated visual gliomas are not reported, and acoustic toxicity remains a concern.576 Any purported treatment effect must also take into account the natural propensity of these tumors for spontaneous regression.149,360,666,674,785 Radiotherapy is no longer generally employed in younger children because of the vulnerability of the immature nervous system to therapeutic doses, as well as the potential risk for inducing secondary malignancies many years later. There is evidence that NF patients are unusually sensitive to the potential mutagenic effects of radiotherapy, making it even less desirable in this group.658 Radiotherapy can lead to secondary malignancies or cerebrovascular disease with moyamoya in patients with NF1.430 In the future, stereotactic radiotherapy may be more promising, but secondary tumors remain a concern.568,824 Children with NF1 also display a variety of disparate CNS manifestations unrelated to tumor formation. Headaches are particularly common in patients with NF1. Intellectual impairment, learning disability, or hyperactivity is seen in approximately 40% of children with NF1. Macrocephaly is common and does not seem to correlate with intellectual performance, seizures, or electroencephalographic abnormalities.602,731 Although the presence of unidentified bright objects (UBOs) that appear hyperintense on T2-weighted MR imaging multiple hyperintense T2-weighted lesions have been suggested to correlate with learning disabilities,273,905 recent studies have failed to confirm a convincing relationship.266,300,695,845 Macrocephaly in NF1 is associated with abnormal development of both gray and white matter in the brain.845 Aqueductal stenosis can result from tumor compression or, more commonly, from a structural alteration of the aqueduct rather than tumor compression.602 Hydrocephalus due to aqueductal stenosis is an uncommon complication of NF1 that results from periaqueductal proliferation of subependymal glial cells or from a Chiari 1 malformation.2,374 Brainstem and cerebellar gliomas are independently associated with neurofibromatosis and deemed to have a more favorable overall prognosis than their sporadic counterparts.90,149,291,538,614,697,910 Brainstem gliomas can be distinguished from (UBOs) because they exhibit focal or diffuse brainstem enhancement, demonstrate mass effect, and may enhance with gadolinium.86

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

NF1-associated tumors are less aggressive than non NF1 brainstem tumors, and are more often localized to the medulla than the pons.86,614 On histologic examination, they are identical to pilocytic astrocytomas found elsewhere in the body.195,538,707 However, in many cases their behavior is even more indolent than what would be expected for typical low-grade gliomas. They remain quiescent for years without adjuvant therapy, raising the question of whether they are more appropriately classified as glial hamartomas.697 It is equally possible, however, that aggressive screening of NF1 patients probably reveals these lesions when they are small and not causing symptomatology, while non-NF1 gliomas are not discovered until the patient has a larger tumor with clinical symptomatology. These tumors may appear as a diffuse area of brainstem enlargement in association with increased signal on T2-weighted images, a focal enhancing nodule with or without associated cystic areas, and periaqueductal gliomas that manifest with late-onset aqueductal stenosis.697 Although most cases do not require surgical intervention,86,538,697 some patients require shunting for hydrocephalus.86 As with optic gliomas, some NF1-associated brainstem gliomas regress spontaneously. Cerebrovascular abnormalities have been reported in 2.5% of children with NF1 and include stenosis or occlusion of the internal carotid and cerebral arteries, aneurysm, and moyamoya disease.756 Intracranial arachnoid cysts may also occur.116,211,270,574 Seizures are more common in NF1 and may occur without a structural lesion.602 Patients with NF1 may also have malformations of cortical development such as cortical dysplasia, pachygyria, and polymicrogyria.40 In both NF1 and NF2, isolated ocular motor nerve palsies may arise from schwannomas involving the ocular motor nerves in NF1.124 Unilateral superior oblique palsy has been reported both from cranial nerve involvement and from mechanical retrodisplacement of the trochlea by orbital plexiform neurofibroma.165 Cognitive disability is another common problem in children with NF1. Children with NF1 have a lower mean IQ (86–94), with particular deficits in visual spatial skills, nonverbal long-term memory, executive functions, and attention.88,490,491,531 It has been suggested that cognitive and motor deficits in children with NF1 are related to hyperintensities on T2-weighted MR imaging of the brain, but some studies have failed to confirm this relationship. Unlike the focal hyperintense T2-weighted lesions in NF1, the cognitive impairment does not improve into adulthood.300,414,636 The IQ is typically in the low-average range, but mental retardation is uncommon.300,414 Cognitive deficits are wide ranging in NF1 and are often the most significant cause of lifetime morbidity in this population.236,414,655 Studies using mouse models for NF1 have shown that increased RAS/ERK signaling is primarily responsible for the neuronal plasticity deficits as

well as the spatial learning and attention deficits of these mice.205,371,491,535 Inactivation of RAS in the NF1+/− mouse model ameliorates cognitive deficits, raising exciting possibilities for the development of specific therapy in patients.414,491 Finally, patients with NF1 have a life expectancy of about 15 fewer years when compared with the general population with malignancies (brain tumors and malignant peripheral nerve sheath tumors) and cerebrovascular disease contributing disproportionately to mortality.414,714,835,973

Neurofibromatosis 2 (NF2) The hallmark of NF2 (formerly known as central neurofibromatosis) is the presence of bilateral vestibular schwannomas (a more accurate term than acoustic neuroma because the tumors are composed of Schwann cells and arise predominantly from the superior branch of the vestibular nerve).299,684,708,875 NF2 has an incidence of about one in 25,000 births and an annual incidence of one in 2,355,000.286 The diagnosis can also be made if there is a first-degree relative with NF2 together with either a unilateral eighth nerve mass or any two of the following: neurofibroma, meningioma, glioma, schwannoma, or posterior subcapsular or capsular lens opacity of adolescent onset.627 Patients with NF2 tend to develop acoustic and visual pathway tumors arising from neural coverings (meningiomas, schwannomas, ependymomas), in contrast to the neural or astrocytic tumors that typify NF1.708,727 Café au lait spots and skin neurofibromas may develop but tend to be fewer in number, and Lisch nodules are absent.510,708 The main features that distinguish NF2 from NF1 are bilateral vestibular schwannomas, cutaneous schwannomas, spinal schwannomas, lack of Lisch nodules (with rare exceptions), fewer café au lait spots, and the presence of juvenile-onset cataracts.708 Bilateral hearing loss is the most common presenting symptom.450 The average age of onset of hearing loss in NF2 is in the teens or twenties, but the age at presentation (or detection) is highly variable.708 The genetic defect that produces NF2 has been localized to the long arm of chromosome 22.758 The NF2 gene lies on chromosome 22q11.2 and has 17 coding exons.299 The gene encodes a 595 amino acid protein known as merlin (or schwannomin),757,882 which is widely expressed in Schwann cells, meningeal cells, peripheral nerves, and the lens.187,398 Merlin is structurally related to other proteins that link the actin cytoskeleton to cell surface glycoproteins that control growth and cellular remodeling.887 The NF2 gene functions as a tumor suppressor and regulator of Schwann cell and leptomeningeal cell proliferation. Inactivating NF2 mutations and the loss of merlin expression

The Phakomatoses

have been detected in sporadic meningiomas, schwannomas, and mesothelioma, as well as in NF2-associated tumors.801 The precise mechanisms underlying tumor formation in NF2 have not been determined, but it is likely that merlin interacts with multiple intercellular signaling pathways to maintain growth suppression.312 Merlin also stabilizes physical junctions between cells and promotes contact-dependent growth inhibition of cells.618 Loss of merlin through mutation impairs this inhibitory process, leading to cell proliferation. The subset of glial cells with epithelial features (Schwann cells, ependymal cells, and Muller cells) may be particularly sensitive to the loss of the NF2 gene.584 Inactivation of the NF2 gene can be detected in the vast majority of sporadic schwannomas and in about 50–60% of sporadic meningiomas.299,427,517 A genotype–phenotype correlation has been described in NF2.67,287 In general, patients with constitutional nonsense or frameshift NF2 mutations have a more severe form of the disease (as indicated by more tumors, younger age at onset of NF2 symptoms, a higher prevalence of cataracts, and a higher prevalence of retinal abnormalities), whereas patients with missense mutations, large deletions, or somatic mosaicism have milder disease (as indicated by fewer tumors, older age at onset of NF2 symptoms, and a lower prevalence of cataracts and retinal abnormalities).67,287,302 Among patients with constitutional splice-site NF2 mutations, mutations in 5¢ exons are associated with more severe disease than are mutations in 3¢ exons.67,477 The spectrum of ocular and neuro-ophthalmological manifestations in NF2 has recently received widespread attention.727,736 Kaiser-Kupfer et al444 described juvenile posterior subcapsular cataracts in children with NF2 and noted that they were not a feature of NF1. These characteristic “posterior subcapsular cataracts” are actually central posterior cortical opacities that extend posteriorly to the lens capsule.104,108 Some children with NF2 also have cortical cataracts near the lens equator.444,460 The genetic sequence that codes for the beta-crystalline component of the human lens has also been localized to chromosome 22, which raises the possibility that these juvenile cataracts may result from a structural defect in this protein.398 Landau et al510 were the first to recognize the association of combined retinal pigment epithelial hamartoma with NF2. Numerous reports of this association have followed.354,460 Dossetor et al260 reviewed the two previous reports of optic disc glioma along with an additional case and found that all three documented cases occurred in patients with NF2. The finding of an optic disc glioma is also highly suggestive of NF2.260 Good et al described multiple epiretinal glial opacities in a child with NF2.355 Kaye et al 460 and Landau and Yasargil 512 found epiretinal membranes in most patients with NF2 and suggested that these preretinal opacities may be the most common ocular finding in NF2. Some patients exhibit choroidal hyper-

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fluorescence of the posterior pole.303 While some neuro-ophthalmologic overlap exists, associated visual system tumors and hamartomas in NF2 tend to primarily involve the retina and optic disc (Fig. 11.7), while those of NF1 tend to primarily involve the optic nerve and uveal tract.708,727 Other optic disc anomalies associated with NF2 include the morning glory disc anomaly134 (Fig. 2.8) and pseudopapilledema due to a prepapillary gliotic membrane.555 Combined hamartomas can also deform the optic disc.709 Intracranial tumors may give rise to papilledema, and schwannomas of the ocular motor nerves may produce cranial nerve palsies. Optic nerve sheath meningiomas in children should prompt medical evaluation for NF2 (Fig. 11.8).216,460 The strong association of optic nerve sheath meningiomas with NF2 parallels the association of optic nerve glioma with NF1. These meningiomas behave in a more invasive and aggressive manner than their adult counterparts as evidenced by the intraocular extension of an optic nerve sheath meningioma in a 13-year-old girl with NF2 described by Cibis et al184 Bosch et al102 found that optic nerve sheath meningiomas were found in approximately 27% of consecutive patients with NF2. Conversely, NF2 is concomitantly diagnosed in 28% of pediatric patients with primary optic nerve sheath meningiomas.515 Clinical variability is seen in NF2, with two distinct phenotypic subtypes identified. The severe form is characterized by young age at onset, rapid progression of hearing loss, and multiple associated tumors. The mild form occurs at an older age and shows slower deterioration of hearing and few associated tumors.670 While adults with NF2 usually present with symptoms associated with vestibular schwannoma, the disease presentation is quite different in children. Evans and colleagues reported that 61 of 334 patients (18%) with NF2 presented with symptoms at younger than 15 years of age, and only 26 (43%) had clinical features associated with vestibular schwannoma.286 Children with NF2 often first come to medical attention because of ocular, subtle skin, or neurological problems.579,761 The significance of these problems is realized only when they later present with classical symptoms due to bilateral vestibular schwannoma or other intracranial tumors.761 In one study,101 initial symptoms for patients with early-onset NF2 consisted mainly of visual problems and lower motor neuron weakness as opposed to eighth nerve impairment in late-onset disease. In this study, symptom onset at a young age was a significant risk factor for marked disease progression. Because presymptomatic testing improves the clinical outcome of the disease, NF2 patients and their families should be managed at specialty treatment centers. Relatives of affected individuals should be initially screened at birth because ocular abnormalities are already present. Because vestibular schwan-

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Fig. 11.7 Neurofibromatosis-2. (a) Lesion resembling epiretinal membrane with macular pucker. (b) Combined hamartoma of retina and retinal pigment epithelium (CHRPE). (c) Milder variant of

(CHRPE). (d) Bizarre retinochoroidal defect resembling a coloboma. With permission from Rettele et al727

nomas develop later, the first MR scan can be performed at 10–12 years of age.282 Medical evaluation of the child with NF2 includes a detailed family history, with examination of first-degree relatives, slit lamp examination, audiogram, and MR imaging of the brain and spinal cord. Genetic evaluation with consideration of chromosome analysis and molecular genetic testing should take place. Children and affected relatives should be warned not to swim without supervision as several deaths from drowning have been reported in patients with NF2.708,965a Although vestibular schwannomas may be detected on neuroimaging in children with NF2, they often remain asymptomatic until young adulthood.27 Bilateral vestibular schwannomas develop in 95% of patients with NF2.284,298,834 They are more lobular than sporadic vestibular schwannomas and have meningoepithelial cell proliferation and axons that are trapped within the tumor.298 “Collision tumors” may occur where small tumors grow close together (Fig. 11.8).298 While decreased vision secondary to a retinal

or optic nerve lesion may not be amenable to treatment, some children show visual improvement following treatment of cataract, exposure or neurotrophic keratopathy, strabismus, or amblyopia. Because many children with NF2 eventually become deaf, even moderate degrees of visual loss can be devastating, and attempts at visual rehabilitation may have a significant positive impact on their future independence and quality of life. In all but a few cases, vestibular schwannoma arise from the vestibular part of the nerve. Because schwannomas tend to grow off a single fascicle, however, small schwannomas can often be resected while preserving the nerve. At times, they can even preserve the involved nerve while compressing other nerves. Consequently, surgeons can sometimes preserve hearing when these tumors are resected in the early stages. In most cases, however, total removal of the tumor is often difficult because of the multilobulated lesions, risk of facial nerve damage, and the concomitant hazards of corneal ulceration and disfigurement.282 Surgery in the later stages

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Fig. 11.8 Neurofibromatosis-2. (a) Coronal MR image shows kissing schwannomas. (b) Axial T1-weighted gadolinium enhanced images above the level of the lateral ventricles shows two right convexity meningioma

and a parasagittal meningioma. With permission from Rettele et al.727 (c) Axial orbital MR image showing large optic nerve sheath meningioma in another patient with NF2 (Courtesy of James J. Garrity, M.D.)

nearly always results in total deafness in the affected ear and loss of cochlear function.298 Bilateral schwannomas can develop on other cranial nerves, including the oculomotor and trigeminal nerves, but they rarely require surgical intervention.282,293 The association of unilateral schwannoma with posterior subcapsular cataracts should also raise supicion of NF2.103 Spinal tumors, including schwannomas and meningiomas, are detected in about 90% of individuals with NF2 on neuroimaging, but only 30% of spinal extramedullary tumors are symptomatic.298,580 Cutaneous tumors, including café au lait patches and pigmented plaque-like lesions (that are usually schwannomas but, occasionally, neurofibromas), may also occur.282

Tuberous Sclerosis Tuberous sclerosis complex is a multisystem genetic disorder with no racial or sexual predilection.828 It has an autosomal dominant pattern of inheritance,793 but the rate of spontaneous mutation approaches 60%, and many affected individuals have no family history of the disorder.828 As with neurofibromatosis, tuberous sclerosis has been associated with advanced paternal age. Linkage analysis has demonstrated that the tuberous sclerosis complex is genetically heterogeneous,449 with about half of mutations at a site on chromosome 9q34 that codes for the protein hamartin (TSC1),321 and the remaining half at

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a site on chromosome 16p13 that codes for the protein tuberin (TSC2) near the locus for adult polycystic kidney disease.588,698 Mutations in TSC1 or TSC2 can be identified in 60–80% of patients with tuberous sclerosis.220,441 Among familial cases of tuberous sclerosis, about half show linkage to the TSC1 gene and half to the TSC2 gene.720 However, sporadic cases are four times more likely to be caused by TSC2 than TSC1 mutations.441,504 Patients with TSC2 mutations also have worse disease than those with TSC1 mutations.220,793 They may also have renal cysts due to deletions or duplications of the PKD7 gene.489 Thus, TSC2 mutations tend to generate a more severe phenotype, but not a different one, than TSC1 mutations.793 Somatic mosaicism for mutations is also a known phenomenon. Within the cytoplasm, hamartin and tuberin associate to form a heterodimer that acts as a critical regulator of cell cycle progression by way of inhibition of the mTOR pathway.864 Under normal circumstances, the hamartin/tuberin suppressor complex is disrupted in response to growth factors and nutrients, which enables increased activation of mTOR to regulate cell proliferation and organ size.793 In TSC, mutations of TSC1 and TSC2 result in failure to inactivate mTOR and unregulated cell growth. Subependymal giant cell astrocytomas demonstrate biallelic inactivation of TSC1 or TSC2, supporting the concept that loss of function of the tuberin/hamartin complex underlies tumorigenesis.172 Bycontrast, cortical tubers do not consistently harbor two mutations, suggesting that haploinsufficiency at the TSC1 or TSC2 locus may lead to tuber formation.432 Diagnostic criteria for tuberous sclerosis were last revised in 1998.743 Affected patients exhibit a variable constellation of neurologic, cutaneous, visceral, and retinal lesions.212 Although tuberous sclerosis was originally defined by the classic clinical triad of adenoma sebaceum, epilepsy, and mental retardation, the complete triad occurs in less than one-third of cases diagnosed by modern criteria; and some patients with tuberous sclerosis have none of the three classic features.388,793 Gomez353 divided the diagnostic criteria of tuberous sclerosis into primary criteria (adenoma sebaceum, ungual fibroma, cerebral cortical tuber, subependymal nodule, fibrous forehead plaque) and secondary features (infantile spasms, hypopigmented macules, shagreen patch, retinal hamartoma, bilateral renal cysts or angiomyolipomas, cardiac rhabdomyoma, a first-degree relative with tuberous sclerosis). The diagnosis of tuberous sclerosis, according to this classification, can be established when a patient exhibits one primary criterion or two or more secondary criteria.744 Diagnostic neuroimaging criteria have also been established. A definitive diagnosis of tuberous sclerosis can be assigned when CT scanning or MR imaging demonstrate multiple subependymal nodules (especially with calcification) or

when multiple cortical abnormalities with calcification and subcortical white matter edema are present.828 A presumptive diagnosis can be established when there is (1) an intraventricular tumor consistent with a subependymal giant cell astrocytoma, (2) focal wedge-shaped calcifications in the cerebral or cerebellar cortex, or (3) multiple cortical/subcortical foci of edema.828 DNA testing is useful in confirming the diagnosis of tuberous sclerosis, in ruling out a causative mutation in the parents, and for prenatal diagnosis.448,793 Systemic manifestations involve primarily skin and viscera. Adenoma sebaceum are angiofibromas that occur in a butterfly distribution over the nose and cheeks (Fig. 11.9). The rash eventually develops in 80–90% of cases and is pathognomonic for tuberous sclerosis.943 However, it is typically absent in children younger than 2 years of age, which may delay the diagnosis. When it develops late in the first decade of life, it is sometimes mistaken for prepubertal acne. Other cutaneous lesions include ash-leaf spots (Fitzpatrick patches), which are whitish hypopigmented lesions seen best with ultraviolet light, confetti-like macules, ungual or periungual fibromas (Fig. 11.9), and pedunculated skin growths on the neck (Molluscum pendulum).793 The light is selectively absorbed by skin melanin, causing the hypopigmented lesions to stand out more conspicuously. Histopathologically, ash-leaf spots contain a normal number of melanocytes, but the melanosomes are smaller and contain subnormal amounts of melanin. Shagreen patches (yellowish plaques located on the eyelids or lumbosacral regions) are also characteristic of the syndrome (Fig. 11.9). Some children also have café au lait spots and nevi. Visceral involvement may include renal cysts, renal angiomyolipomas, cardiac rhabdomyomas, and cystic lesions of the lungs pulmonary lymphangiomatosis, which can be life threatening. The skeletal system is affected in 40% of patients, with sclerotic areas occurring in the calvarium and the spine and with phalangeal cysts in the hands and feet.943 The shortened life span in some patients with tuberous sclerosis is attributable to a combination of causes, including status epilepticus, renal failure from extensive angiomyolipomas, cardiac failure, pulmonary complications from lung involvement, and hydrocephalus or hemorrhage from intraventricular lesions or their surgical complications.793,828 The most common ocular manifestation of tuberous sclerosis is the astrocytic hamartoma (the original “phakoma” of van der Hoeve, which is present in most cases but is easily overlooked) (Fig. 11.9).901 These angiogliomatous hamartomas may appear early in infancy809 as flat, translucent, noncalcified superficial retinal lesions that have a slushy appearance reminiscent of cotton in water. These lesions are sometimes vascularized and, rarely, are associated with vitreous hemorrhage or seeding.34,36,299,493 Because they arise

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Fig. 11.9 Tuberous sclerosis. (a) Adenoma sebaceum. (b) Retinal astrocytic hamartomas. (c) Subungual fibromas. (d) Transillumination of subungual fibromas (All courtesy of William F. Hoyt, M.D)

from the retinal nerve fiber layer, they are usually situated near the optic disc. Over time, they calcify and enlarge into raised tumors with a “mulberry-like” appearance that resemble optic disc drusen in consistency but are much larger. They rarely compromise vision (unless they are situated in the macula or a vitreous hemorrhage occurs), and the importance of their recognition lies primarily in establishing the diagnosis of tuberous sclerosis. However, these lesions must be distinguished from the rare solitary retinal astrocytoma that is not associated with phakomatosis, prominently vascular, and causes severe intraocular damage.28 Retinal astrocytic hamartomas show a characteristic profile on ocular coherence tomography (OCT), which may facilitate the diagnosis. These include a gradual transition from a normal ret-

ina into an optically hyperreflective mass with retinal disorganization, characteristic “moth-eaten” spaces, and posterior shadowing.815 Although these lesions only rarely enlarge, Shields et al817 documented visual loss secondary to massive enlargement of astrocytomas of the retina and optic disc in four patients with tuberous sclerosis. Elevation of one optic disc can result when an astrocytic hamartoma is situated on the surface of the optic disc.334,818 Small, calcified astrocytic hamartomas of the optic disc may be impossible to distinguish from disc drusen. Uncalcified astrocytic optic disc hamartomas appear as a focal elevated mass of whitish, gray, or yellowish tissue that obscures visualization of the underlying disc. Rarely, an optic disc tuber may be localized within the substance of the optic disc.135

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Brodsky and Safar135 described an intrinsic optic disc tuber that slowly enlarged over 10 years without compromising vision (Fig 3.16). Retinal astrocytic hamartomas may be confused with a variety of other retinal lesions caused by retinoblastoma, toxoplasmosis, and toxocara. Fluorescein angiography shows a prominent network of fine blood vessels in the superficial portion of the mass during the venous phase and intense late staining of the tumor.334,818 Approximately one-third of children with tuberous sclerosis have discrete achromic patches in the peripheral retina that are analogous to ash-leaf spots. These white lesions that can be focal, linear, circular, or “paint brush” in configuration are often dismissed as peripheral chorioretinal scars. CNS lesions of tuberous sclerosis include cortical tubers, subependymal nodules, and giant cell astrocytomas.108,588 Tubers have no known malignant potential, so it is important to differentiate these masses from neoplastic processes. Cortical and subcortical tubers can be found in 70% of individuals with tuberous sclerosis.358 They represent regions of cortical dysplasia that may result from aberrant neuronal migration during embryogenesis.588 These brain lesions are almost always benign hamartomas. They have been variously described as low-grade benign neoplasms, clusters of heterotopic neurons within the white matter, and regions of gliosis or abnormal myelin (destruction/dysplasia).78,95,828 The cortical/subcortical tuber appears to represent a cluster of abnormal neurons whose migration has been perturbed. The lesion is centered on the gyrus and consists of giant cells which can resemble neurons or astrocytes.96,507 Myelin is decreased in the tuber, and dense fibrillary gliosis is present.96 These hamartomas occur in two prominent locations: on the surface, as superficial cerebral cortical “tubers” and as deep subependymal nodules. The cortical tubers are typically large and pale compared with the surrounding normal gyri.828 They lack the normal six-layered lamination of cortical gray matter and may contain giant neurons.787 On CT scanning, they appear as an enlarged gyrus with a central hypodensity. They show a central hyperintensity on T2-weighted imaging (termed a “gyral core”) and a central hypointensity surrounded by a hyperintense rim (termed a “sulcal island”) on T1-weighted imaging (Fig. 11.10).95,107,828 In young infants, the signal pattern of tubers is often reversed (i.e., the lesions are bright on T1-weighted images and darker on T2-weighted images).96 Clinically, cortical tubers are associated with seizures (which are often the presenting sign of tuberous sclerosis) and mental retardation. The seizures often manifest as infantile spasms, which consist of sudden flexion and extension movements of the extremities that may occur numerous times daily and evolve into grand mal seizures as the child becomes older. Mental retardation, once thought to be an invariable association, is present in only 60% of cases.943 Ninety-five percent of tubers are multiple, and 90% occur in the frontal

lobes.405 However, solitary tubers are occasionally detected on MR imaging in the absence of other clinical or neuroimaging signs of tuberous sclerosis.251 Overall, approximately 80% of patients with tuberous sclerosis have epilepsy, and approximately 65% have intellectual disabililty.353,530 In general, the severity of neurological symptoms correlates with the tuber count,358 with increased tuber burden and infantile spasms are associated with an increased risk of developmental delay. Contrary to accepted dogma, however, mental retardation is not invariable in patients with tuberous sclerosis and infantile spasms.349 Newer neuroimaging techniques such as diffusion tensor imaging and positron emission tomography (PET) scanning have provided a more accurate assessment of the epileptogenic zone and improved identification of patients who would benefit from surgery for epilepsy.550 Subependymal nodules are usually asymptomatic. They are usually located along the lateral borders of the ventricles in the striothalamic groove between the caudate nucleus and the thalamus (Fig. 11.10).828 They are sharply circumscribed, do not spread through the periventricular tissue, and are covered by intact ependyma. They may be calcified or uncalcified and, as with retinal lesions, their degree of calcification increases with age.902 Because of their mixed signal characteristics, the nodules are more easily visualized on CT than on MR imaging.828 These subependymal nodules may give rise to subependymal giant cell astrocytomas in 5–15% of individuals with tuberous sclerosis.876 This transition tends to occur within the first two decades of life. In the infant with seizures, the heterotopic gray matter of periventricular nodular heterotopia can easily be mistaken for subependymal nodules.530 However, the subependymal nodules of tuberous sclerosis are usually smaller, fewer, inhomogenous, and calcified, with signal intensity resembling white matter.530 The distinction between subependymal nodules and giant cell astrocytoma is one of size and position rather than of histology.261 Bender and Yunis78 have suggested that the same cellular components are present in all the parenchymal brain lesions, that they represent a combination of both neuronal and astrocytic features, and that they result from disordered migration and differentiation. Although histologically benign and slow growing, giant cell astrocytomas cause major visual and neurological morbidity by enlarging to obstruct the foramina of Monro, leading to hydrocephalus, chronic papilledema and, eventually, optic atrophy.261 Because of their intraventricular location, surgical morbidity is common and gross total resection may not be possible.348 The recently described mTOR upregulation in tuberous sclerosis-associated visceral tumors has led to treatment trials with the antibiotic rapamycin (also called sacrolimus).793 Preliminary results indicate that oral rapamycin therapy may induce regression of brain astrocytomas associated with tuberous sclerosis.65,147

The Phakomatoses

Fig. 11.10 Tuberous sclerosis. (a) MR image in infant demonstrating multiple subependymal nodules and cortical tubers. (b) MR image in older child demonstrating giant cell astrocytoma with associated

Sturge–Weber Syndrome Encephalotrigeminal angiomatosis is a misleading label for Sturge–Weber syndrome because it fails to reflect the underlying neuropathology as we now understand it. The term angioma refers to a mass of plump endothelial cells with high mitotic activity. An angioma involves capillaries that

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hydrocephalus. (c) CT scan shows characteristic multiple nodular calcific lesions in subependymal regions. (d) MR image showing multiple cortical tubers. (Upper figures courtesy of Charles M. Glasier, M.D.)

are actively proliferating and that appear histopathologically as a tumor.147 A typical facial hemangioma in children is the capillary hemangioma, which is not present at birth and which proliferates before it involutes. This lesion differs from the port-wine stain or nevus flammeus of Sturge–Weber that is present at birth and consists of a venous dilatation with no capillary proliferation.65,147

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The port-wine color of the facial lesion is due to the presence of deoxygenated blood within the vascular spaces. Although some have attributed the venous malformation of Sturge–Weber to a congenital deficiency of sympathetic autonomic innervation to the involved venous bed,765,833,918,957 a chronic sympathetic deficit would produce constriction rather than dilatation of vessels. It is now believed that any decreased nerve density in these lesions is secondary to the presence of ecstatic vessels.671 The adjective encephalotrigeminal is also inaccurate because the location of the port-wine stain may coincidentally have a dermatomal distribution but is in no way dictated by trigeminal innervation. The facial telangiectasia is primarily unilateral, but it may cross the midline slightly and extend to involve the mucosa of the hard palate and the linings of the paranasal sinus along with the conjunctiva, episclera, and choroid of the ipsilateral eye.828,856 Glaucoma involves the eye on the affected side in at least 30% of cases and may lead to buphthalmos, anisometropia, and amblyopia if present in the first 2 years of life.182,424 Although glaucoma in Sturge–Weber syndrome is generally attributed to elevated episcleral venous pressure, isolated trabeculodysgenesis may play a dominant role in infant eyes.182,424,856 Sturge–Weber syndrome is nonhereditary, and medical management involves laser therapy for treatment of the nevus flammeus and medical and/or surgical treatment of seizures and glaucoma. Most children with facial port-wine stains do not have ocular or pial involvement (i.e., no Sturge–Weber syndrome). Those who develop glaucoma almost invariably have involvement of both the upper and mid face.70 The intracranial lesion of Sturge–Weber syndrome is a leptomeningeal vascular malformation that is similar to and ipsilateral to the facial lesion.828 It typically overlies the occipitoparietal region but may extend anteriorly in some children. This leptomeningeal malformation lies along the surface of the brain in the subarachnoid space between the pia and the arachnoid membrane but does not involve the brain itself (Fig. 11.11). Over time, the underlying cerebral cortex becomes dysfunctional, progressively atrophic, and calcified.828 As unilateral cerebral atrophy occurs, the skull develops asymmetrically, and the calvarium thickens on the side of the lesion with increased diploic space, increased pneumatization of the paranasal sinuses, elevation of the petrous ridge, and elevation of the lesser wing of the sphenoid.828 Neuro-ophthalmologic complications in Sturge–Weber syndrome are generally limited to homonymous hemianopia from occipital lobe involvement, positive visual phenomena due to seizures, and glaucomatous optic atrophy. Strabismus and anisometropic amblyopia are also common in children with glaucoma and buphthalmos. Seizures in Sturge–Weber syndrome are often difficult to control with medication. Bilateral intracranial involvement,

although rare, is associated with seizure onset at an earlier age and with seizures that are more difficult to control.640 The presence of seizure activity in the first year of life seems to be predictive of a poor outcome.640 Surgical lobectomy or hemispherectomy with resection of the involved cortex in children with intractable seizures has produced encouraging results.245,640,828 Genetic studies have documented a possible role of fibronectin expression in this condition.196,245 Infants with Sturge–Weber syndrome are often neurologically intact at birth, but there is a high incidence of focal or generalized seizure activity that usually begins in the first year of life.828 Focal neurological deficits, such as spastic hemiparesis with or without atrophy or hemianopia, or mental retardation are thought to be secondary to atrophy of the involved cortex.20 CT scanning shows the three Cs: cerebral atrophy, calvarial thickening, and cortical calcifications (Fig. 11.11).828 The MR imaging often shows superficial enhancement of the cerebral hemispheres. Although the leptomeningeal malformation alone is sufficient to establish the diagnosis,20,213 it is important to distinguish this vascular lesion from the meningoepithelial angiomatosis that occurs in some patients with neurofibromatosis. Unlike the leptomeningeal malformation of Sturge–Weber syndrome, meningoepithelial angiomatosis tends to be more focal and infiltrative into the underlying brain.828 Parsa671 has provided a unifying explanation for the Sturge–Weber syndrome, emphasizing that it is not necessary to invoke an embryonic injury to multiple tissue layers derived from the neural crest. According to Parsa, cortical venous or dural sinus dysplasia during embryogenesis can secondarily affect various sites via disruption of normal cephalic hemodynamics, producing port-wine stains, and in more severe cases, the full Sturge–Weber syndrome. Whenever bridging veins from cerebral cortex to dural sinuses are thrombosed or absent, impaired cortical drainage results in leptomeningeal thickening. Centripetal (inward) drainage occurs via deep medullary and subependymal cerebral veins with collateral development. Centripetal drainage also increases cavernous sinus pressure, which is then transmitted to orbital circulation via emissary veins. MR imaging shows thickening of the choroidal plexus in direct proportion to the lack or dysplasia of choroidal veins.365,849 Because venous drainage is poor, the metabolic activity of the underlying cortex becomes increasingly dysfunctional.671 Neuronal death and calcification occurs in the middle layers of neurons in the cerebral cortex, subcortical white matter, and in local blood vessels, causing seizures. Because scalp and orbital veins are emissary (valveless) in nature, the associated dural sinus aplasia can also impede cutaneous drainage as a result of the inability of scalp emissary veins to drain into the dural venous sinus.

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Fig. 11.11 Sturge–Weber Syndrome (a) Noncontrast axial CT scan demonstrating dense cortical calcifications. (b) T1-weighted gadoliniumenhanced demonstrating enhancing leptomeningeal vascular malformation and mild cerebral hemiatrophy. Courtesy of Charles M. Glasier, M.D.

(c) Coronal MR imaging shows prominent enlarged draining veins in the right occipital lobe. (d) Axial T1-weighted axial MR image shows leptomeningeal enhancement, prominent draining veins within the right temporal lobe, and choroidal thickening and enhancement in the right eye

According to Parsa,671 as orbital veins are also emissary in nature, increased cavernous sinus pressure is transmitted to orbital blood flow, to ophthalmic and facial veins and, eventually, to the external jugular vein, resulting in orbital and periorbital venous ectasia and upper facial port-wine stains. Cerebral venous flow affecting the pterygoid plexus produces port-wine stains in the lower portion of the face. When both the upper and lower eyelids are involved, conjunctival and epscleral tissues also demonstrate vascular dilatory changes. High tissue pressure could also produce hypertrophy (thickening of the skin overlying the port-wine stain, buphthalmos) as well as demyelination of cutaneous

nerves with eventual atrophy. Dilation and expansion of the choriocapillaris obscures the deeper and also the expanded choroid, giving rise to the so-called tomato-catsup fundus, and to dilated, tortuous conjunctival vessels.

von Hippel–Lindau Disease von Hippel–Lindau disease is a familial disorder with an autosomal dominant pattern of inheritance.631 There is no racial or gender predilection. The syndrome is caused by

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germinal mutations in the VHL gene, located in 3p26.800 This gene encodes for a protein that is mainly located in the cytoplasm but that can be shuttled to the nucleus. This protein has been implicated in a variety of functions at the transcriptional and posttranscriptional level.443 This protein seems to regulate the transcription of hypoxia-inducible genes by altering the stability of their mRNA. Unless a cell is oxygen deprived, the VHL protein normally shuts down the release of these factors. Therefore, pVHL inactivation results in overexpression of hypoxia-inducible mRNAs, including vascular endothelial growth factor.482 This is concordant with the high vascularization of VHL-related tumors. Angiogenesis inhibitors, including antibodies directed against VEGF and small-molecule inhibitors of VEGF receptors, are currently being employed in a number of clinical trials for clear cell renal carcinoma and hemangioblastomas.559,620 Unlike neurofibromatosis and tuberous sclerosis, von Hippel–Lindau disease has a low spontaneous mutation rate. Most affected children have inherited the disease, and other family members should be screened for the disease.293,561,562,850 Affected patients develop a variety of ocular, CNS, and visceral tumors, including retinal angiomatosis, CNA hemangioblastoma (50%), renal cell carcinoma (22%), pheochromocytoma (approximately 14%), and epididymal cystadenoma.383,561,562,629,630,631 The retinal lesions tend to become symptomatic earlier than the CNS lesions, which tend to become symptomatic earlier than the visceral tumors.383,413,602 Cysts of the lungs, kidneys, bones, pancreas, adrenal glands, and omentum have also been described. CNS malformations include hemangioblastomas and endolymphatic sac tumors.152 CNS hemangiomas are found in approximately 50% of gene carriers and differ from sporadic hemangioblastoma in their tendency for multiple occurrence and their tendency to develop at a younger age.631 Approximately 75% are cystic versus solid, and 75% develop intracranially versus intraspinally.631,781 Most intracranial hemangioblastomas are located within the cerebellum and often in the midline.602 Neuroimaging generally reveals a cystic lesion with a strongly enhancing mural nodule.293 Cerebellar hemangioblastomas generally present in the mid-thirties with signs of increased intracranial pressure (headache, nausea, vomiting) and, less commonly, signs of cerebellar dysfunction (ataxia, clumsiness, nystagmus).413 A small number of patients with von Hippel–Lindau syndrome have a syrinx of the brainstem, spinal cord, or both.631 The associated polycythemia in some cases probably relates to the extremely high levels of erythropoietin found within the hemangioblastoma tumor cyst.404 The characteristic ocular lesion is the retinal capillary hemangioblastoma, which is generally detected within the second or third decade of life. This vascular tumor is a reddish retinal mass supplied by a single, dilated, tortuous feeder artery extending from the optic disc to the tumor and drained

by a similarly engorged vein extending from the tumor back to the disc (Fig. 11.12). Retinal capillary hemangiomas tend to develop in the temporal periphery or midperipheral retina, may be single or multiple, and are bilateral in approximately half of cases.949,950 Occasionally, exudative hemangiomas may be situated within the disc substance (Fig. 11.12) and simulate neuroretinitis or juxtapapillary choroidal neovascularization.333 These posterior tumors differ from the peripheral ones in that they typically lack the dilated feeder vessels.631 Retinal capillary hemangioblastomas are histopathologically identical to cerebellar hemangioblastomas, showing an extensive network of capillaries with intertwined plump stromal cells. Their capillaries are fenestrated, explaining their proclivity to cause massive retinal exudation that, if left untreated, may lead to total exudative retinal detachment and permanent visual loss. The exudative retinopathy in this condition may be mistaken for Coats disease if the underlying hemangioma is not recognized. These retinal angiomas are treatable with a combination of retinal cryotherapy or laser photoablation, depending upon their size and location, but careful followup is mandatory because they tend to recur. Solitary capillary hemangiomas, which may be seen in older adults with no other signs of von Hippel–Lindau disease and no evidence of familial involvement, generally lack the markedly dilated and tortuous feeder vessels but otherwise resemble those of von Hippel–Lindau syndrome.816 The finding of optic neuropathy or proptosis warrants imaging to look for hemangioblastoma of the optic nerve or chiasm in the child with von Hippel–Lindau syndrome.594 In one case, photodynamic therapy was successful in the treatment of retinal hemangioblastoma.33 Retinal examination can often provide confirmation of the disorder long before CNS hemangiomas develop. de Jong et al228 found that twin retinal vessels provide a reliable retinal marker for von Hippel–Lindau disease. Unlike normal retinal arterioles and venules, twin vessels are separated by less than one venule width and run a parallel and sometimes overlapping course. In children with a family history of von Hippel–Lindau disease, a careful search should be made for incipient retinal lesions that are most frequently located in the equatorial or pre-equatorial retina. Incipient lesions resemble diabetic microaneurysms and are not associated with dilation of the major vascular channels leading to and from them.438 Aside from their obvious diagnostic significance, incipient lesions can be easily photocoagulated and obliterated.438 Genotype–phenotype correlations have been established. For example, families with the VHL gene without pheochromocytomas (classified as type 1) typically have germline von Hippel–Lindau deletions or protein-truncating mutations, while families with von Hippel–Lindau disease in which one or more family members exhibit pheochromocytomas (classified as type 2) typically have germline missense mutations.

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Fig. 11.12 von Hippel–Lindau disease. The capillary hemangioma may be subtle overlying the retina (a; arrow) or optic disc (b) and (c) Figures courtesy of William F. Hoyt, M.D. (d) Giant capillary hemangioma of the optic disc (Courtesy of Jose Pulido, M.D)

Families with von Hippel–Lindau disease type 2 can be further classified into those in which some members are affected by renal carcinoma (in addition to their ocular, cerebellar, and renal lesions; type 2B), and those in which renal carcinoma is very rare (type 2A). Types 1 and 2B are the most common subtypes and appear to show a similar susceptibility to ocular angiomatosis.175,214,928 The von Hippel–Lindau disease 2A phenotype suggests the presence of a specific mutation (T505C) in the VHL gene, which is associated with a negligible risk for renal cell carcinoma. Patients with complete deletions of VHL protein have the lowest prevalence of ocular disease (14.5% compared to 37.2% in the overall group with amino acid substitutions, protein-truncating mutations, and complete deletions) and the most favorable visual prognosis. However, genotype category appears to have no correlation with the unilaterality or bilaterality of ocular disease or with the number or extent of peripheral retinal capillary hemangiomas.949 Huson et al 413 have suggested that patients carrying the diagnosis and those at risk should undergo an annual retinal examination starting at 5 years of age and biennial neuroimaging of the head, spine, and abdomen and urinary

vanillylmandelic acid (VMA) and meta-adrenaline testing starting at age 10, because life-threatening CNS and visceral tumors can remain clinically occult for long periods.383 No pathologic difference exists between sporadic and von Hippel– Lindau-associated hemangioblastomas, and both are believed to result from identical mutations of the VHL gene.293 However, patients who have von Hippel–Lindau disease typically develop neurologic symptoms at an earlier age and are more likely to harbor multiple cerebellar lesions.199,825

Ataxia Telangiectasia Ataxia telangiectasia is a rare autosomal recessive neurocutaneous disease characterized by combinations of telangiectasia of the skin and eye, cerebellar ataxia, various immune deficiencies, frequent sinus and pulmonary infections, and a predilection to develop malignancies. Linkage analysis has localized a gene for ataxia telangiectasia to chromosome region 11q22–11q23, but more than one gene locus may be present.336

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Ataxia telangiectasia is classified with the “breakage syndromes,” which are diseases with a high frequency of chromosome breaks and rearrangement and an elevated risk of leukemia and other neoplasms. Cutaneous telangiectasias are most often first noted in the conjunctiva, then in the malar area, ears, palate, and across the bridge of the nose. The conjunctival telangiectasia is generally confined to the area of the palpebral fissure. Mottled hypopigmented and hyperpigmented skin regions may also be seen. The major neurological findings arise from characteristic progressive degeneration of the cerebellar cortex, which is readily demonstrable on neuroimaging. Progressive cerebellar ataxia usually develops by the time the affected child begins walking. In contrast, the telangiectatic lesions develop later, usually around 3–7 years of age. The ataxia is followed by progressive neurological deterioration that leaves the patients in a wheelchair. Dysarthria, choreoathetosis, myoclonic jerks, and endocrine abnormalities usually develop.

The characteristic ophthalmologic finding is bilateral bulbar conjunctival telangiectasis, which becomes apparent during childhood (Fig. 11.13). The telangiectatic conjunctival vessels are confined to the area of the palpebral fissure, have numerous sausage-shaped aneurysmal dilatations, and take frequent abrupt turns. Patients later develop abnormalities in ocular motility disturbances described as ocular motor apraxia, because of defective saccadic initiation. Head thrusts may be less conspicuous or absent, however. Nystagmus and other cerebellar eye signs may also be present. Some patients have developed periodic alternating nystagmus.847 In one prospective study of 58 patients with ataxia telangiectasia,292 strabismus was found in 38% (with esodeviation most common), apraxia of horizontal gaze was present in 30%, hypometric saccades were evident in 76%, pursuit abnormalities were present in 63%, and nystagmus was seen in 29%. Interestingly, accommodation was also deficient in the 54 patients in whom it was measured.

Fig. 11.13 Ataxia telangiectasia. (a and b) Conjunctival telangiectasia consisting of dilated vessels confined to the palpebral fissure. Courtesy of William F. Hoyt, M.D. (b) T1 weighted MR scan shows diffuse atrophy of cerebellum

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The most important neuropathologic abnormality in ataxia telangiectasia is cerebellar degeneration, with reduced number of Purkinje, granular, and basket cells in the cerebellar cortex, and neurons in the vermian and deep cerebellar nuclei. MR is the preferred neuroimaging modality and typically shows vermian atrophy with an enlarged fourth ventricle and cisterna magna.290 A lesser degree of cerebellar hemispheric atrophy may also be present (Fig. 11.13).290,777 Patients develop a variety of immunological abnormalities that include defective cellular and humoral immunity. The thymus is absent or rudimentary. Patients are prone to frequent sinopulmonary infections, skin infections, and T-cell lymphoproliferative disorders (lymphomas and leukemias). Persistent elevated levels of alpha fetoprotein are present in almost all patients.739 Pulmonary failure due to frequent infections and resulting bronchiectasis is the most common cause of death. Aicardi et al4 described a slowly progressive syndrome that mimics ataxia telangiectasia by showing indistinguishable neurological signs (ocular motor apraxia, spinocerebellar degeneration, choreoathetosis) but with a later onset and with no associated telangiectasia or multisystemic involvement. They excluded other causes of supranuclear ophthalmoplegia, such as Gaucher disease, Niemann–Pick disease, and Huntington disease, by clinical features, family history and, when appropriate, by enzymatic and skin biopsy studies. They suggested that this syndrome represents an unusual form of spinocerebellar degeneration. These patients do not have head thrusts, but saccadic dysfunction and convergence abnormalities are common.467 Patients have slowly progressive ataxia and show cerebellar atrophy on neuroimaging. This condition is due to a mutation in MRE11, a gene also involved in the cellular repair response to double-stranded DNA breaks.136,467

Linear Nevus Sebaceous Syndrome In 1963, Feuerstein and Mims described two patients with a neurocutaneous disorder consisting of the triad of a midline facial skin lesion (linear sebaceous nevus of Jadassohn), seizures, and mental retardation.304,509 Affected children display a nondermatomal linear pigmented nevus that is elevated and plaquelike in appearance and is present at birth (Fig. 11.14).304 Since its original description, numerous descriptions of associated ophthalmological findings have been reported,145,457,509 and its underlying brain malformation has been more clearly defined.167 Linear sebaceous nevus syndrome is now recognized as one of several “coloboma syndromes” with multisystem involvement. In addition to optic disc coloboma, a variety of other optic disc anomalies, including optic nerve hypoplasia457

and peripapillary staphyloma,145 may be present (Fig. 11.14). This syndrome should be included in the differential diagnosis of conjunctival and corneal dermoids, along with Goldenhar syndrome and encephalocranial lipomatosis (discussed later). Other ocular choristomas, such as choroidal osteoma, have also been described.509 A variety of ophthalmological findings have been noted, including lid colobomas, ptosis, and Coats disease.145 These children generally have severe neurological impairment, with seizures and severe mental retardation as the predominant neurological findings. Neuroimaging has shown that most of these children have hemimegalencephaly, which accounts for their poor neurological prognosis.167

Klippel–Trenauney–Weber Syndrome Klippel–Trenauney–Weber syndrome is a rare congenital angiodysplasia consisting of cutaneous vascular malformations, varicosities, and boney and soft tissue hypertrophy of the involved parts that appear in childhood on the affected side (Fig. 11.15).146,638 Only one side of the body is usually affected, but occasionally, both sides are involved.638 The upper extremity is affected in 60% of cases, the lower extremity in 30%, and the head and trunk exclusively in the remaining 10%.638 While hypertrophy is the most common abnormality of bone and soft tissue, atrophy may also occur. This condition is inherited as an autosomal dominant trait with variable expressivity. Ocular and neurological abnormalities are more common when the cutaneous vascular malformations involve the face.146 According to Parsa,671 its pathophysiology is similar to that of Sturge–Weber syndrome. However, while only atrophy develops in Sturge–Weber syndrome, preferential involvement of the lower extremities (where gravity cannot assist in venous drainage) in Klippel– Trenauney–Weber syndrome, leads to elevation of tissue pressure, impedance of lymphatic flow, with secondary limb hypertrophy. Unlike in Sturge–Weber, seizures, and mental retardation may occur but are infrequent. A number of intracranial vascular malformations, including leptomeningeal vascular malformations, AVMs, and aplasia of the internal carotid artery have been described.638 Hemimegalencephaly has also been described in several patients with Klippel–Trenauney– Weber syndrome.146,577 One child had ipsilateral facial hypertrophy and high myopia, suggesting an overgrowth syndrome involving both brain and eye.146 Neuro-ophthalmologic abnormalities in Klippel– Trenauney–Weber syndrome include optic disc anomalies, which include tilted disc with telangectatic vessels,638 optic nerve hypoplasia,715 optic nerve sheath meningioma840 and orbital optic nerve enlargement in the absence of visual

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Fig. 11.14 Linear nevus sebaceous syndrome. (a) Elevated verrucous, pigmented, plaque-like lesions covering right side of the face in linear distribution. Note characteristic midline lesion on forehead. (b) Left optic disc demonstrating peripapillary excavation and temporal optic disc pallor. No macular structures are identifiable. (c) Hemimegalence phaly. T2-weighted axial MR image demonstrating enlargement of the posterior portion of right cerebral hemisphere, dilatation of occipital

horn of right lateral ventricle, and parieto-occipital cortical dysplasia, as evidenced by the increased signal intensity relative to contralateral hemisphere. (d) Right: T1-weighted coronal MR image through level of occipital horns, demonstrating enlargement of right hemisphere and lateral ventricle, with absence of posterior periventricular white matter. With permission from Brodsky et al133

dysfunction,356 Homer syndrome,638 ptosis,638 afferent pupillary defect638; strabismus,638 and nystagmus.146 Additional ophthalmological findings include conjunctival retinal and peripapillary choroidal varicosities (Fig. 11.15),121 choroidal angiomas, orbital varices iris colobomas, iris heterochromia,

strabismus, ptosis, and enophthalmos.146 Glaucoma occurs but with less frequency than in Sturge–Weber syndrome.356 Although this disorder shares cutaneous features with Sturge–Weber syndrome, the relationship, if any, between the two disorders is not known.

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Fig. 11.15 Klippel–Trenauney–Weber syndrome. (a) Facial photograph showing bilateral port wine stain. (b–d) Optic disc photographs in glaucomatous right eye over 14-year period, demonstrating progressive

cupping of right optic disc and evolution of “hemorrhoidal” circumpapillary choroidal varices. With permission from Brodsky et al121

Brain Tumors

combination with chemotherapy and radiation therapy can be curative in patients with primitive neuroectodermal tumors and ependymomas.391 Childhood brain tumors differ considerably from the adult variety in incidence, location, histology, morphology, and natural history. Common adult tumors such as meningiomas, schwannomas, pituitary tumors, and metastasis are rare in children. The predilection of adult neoplasms to affect the cerebral hemispheres differs markedly from childhood tumors, wherein approximately 50% of tumors in children older than 1 year are infratentorial. In one study,447 simple signal characteristics on diffusion weighted imaging correlate well with tumor grades in the pediatric population. Perinatal tumors are most often teratomas or tumors of neuroepithelial origin (astrocytoma, glioma, medulloblastoma, choroid plexus papilloma).421

Primary brain tumors are the most common solid neoplasms in children and are second only to leukemia in overall frequency during childhood.36,45,675,694 Brain tumors are the most common cause of cancer-related death and the second most common form of cancer in children.391 Recent advances in neuroimaging (higher resolution, diffusionweighted imaging, newer endoscopes and their surgical implementation to decrease complications) have led to greater survival and decreased morbidity in pediatric brain tumor patients.391 Our understanding of the molecular mechanisms involved in the pediatric brain tumors has also advanced. 796 Surgery alone can be curative in a number of tumors, such as pilocytic astrocytomas, craniopharyngiomas, and choroid plexus tumors.391 Surgery in

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There is concern that children with CNS tumors should be diagnosed sooner after the onset of symptoms.571 Although there is no real evidence that early diagnosis changes life expectancy, smaller tumors can be surgically resected with fewer complications, and gross total resection of several pediatric tumors has been linked to improved outcomes.571 There are several reasons why the diagnosis of a brain tumor can take several months from the onset of symptoms. Headache from migraines in children is at least 1,000 times more prevalent than headache caused by brain tumor. Furthermore, headaches from either increased intracranial pressure or migraine are associated with nausea and vomiting, and both can produce nocturnal distress.571 Finally, the ophthalmoscope (and the ophthalmologist) may be underutilized, so that papilledema is not detected in its early stages.571 Brain tumors often present with visual symptoms and/or educational problems or behavioral problems.945 The vast majority of children with brain tumors have additional neurological symptoms. Symptoms are often nonspecific, depending not only upon the localization of the tumor but the age of the child.728 Pediatric intracranial tumors may present with raised intracranial pressure, motor and visual system abnormalities, weight loss, macrocephaly, growth failure, or precocious puberty.945 Relevant initial history should inquire about early morning vomiting, poor balance (or wobbliness in an infant), motor dysfunction, disturbed vigilance, disturbed eye motility, and a change in growth or weight.728 In addition to neurologic assessment, a carefully taken history with questions about visual symptoms and or educational and behavioral difficulties is helpful in establishing the need for neuroimaging or other diagnostic evaluation. In a review of 200 consecutive children with brain tumors,945 the most frequent presenting complaint was headache (41%). Visual difficulties were noted in 10% and educational or behavioral problems in 10%. Additional neurologic signs were present in almost all cases, and 38% had papilledema. Approximately half of patients presenting with headache had visual complaints. The most common visual symptoms were diplopia (43%) and blurred vision (39%).945 Within the pediatric age group, the distribution of brain tumors differs between infants and older children. Although posterior fossa tumors are generally more common than supratentorial tumors in children, supratentorial tumors (suprasellar gliomas, teratomas, primitive neuroectodermal tumors, choroid-plexus tumors) predominate in infants. In the first 6 months of life, the tumors are more commonly supratentorial than infratentorial; in the second 6 months of life, the incidence is about equal in both locations, and thereafter, a posterior fossa predominance emerges. The younger the child, the more likely the tumor is to be supratentorial. Brain tumors in infants have protean clinical manifestations that include irritability, listlessness, lethargy, vomiting,

failure to thrive, and hydrocephalus with increasing head circumference and bulging fontanelles.7,20,340,403 Focal neurologic deficits are generally absent because of the immaturity of the brain and the expansile nature of the cranium. Increased intracranial pressure is caused by obstruction of the ventricular system by the mass or, less commonly, by the sheer bulk of a supratentorial mass without ventricular obstruction.705 Vomiting is the most common presenting symptom of infants with brain tumors (as in all age groups). It may result from increased intracranial pressure or from neoplastic involvement of the floor of the fourth ventricle, where the vomiting center is located. In the absence of papilledema, such children may initially be misdiagnosed as having gastrointestinal disease. Infants with cerebral hemispheric tumors and hemiparesis may be misdiagnosed as having static encephalopathy with hemiparetic cerebral palsy. Seizures are most commonly partial, with elementary symptoms with or without generalization, but infantile spasms may occur. In some infants with brain tumors, infantile spasms show a favorable response to adrenocorticotrophic hormone (ACTH) therapy prior to diagnosis of the tumors.760 Infants with midline tumors may show failure to thrive, endocrine dysfunction, and visual disorders. The diencephalic syndrome of Russell may also be found. This is characterized by profound failure to thrive despite good appetite. Affected children are alert and energetic despite severe emaciation. If the tumor involves the chiasm, decreased vision and nystagmus may be present. Older children are more likely to show localizing neurological findings (cranial nerve palsy, hemiparesis, clumsiness, ataxia) and often present with recurrent headaches, nausea, vomiting, and visual complaints, which may be ascribed to nonspecific causes, delaying the diagnosis of underlying hydrocephalus and associated tumor. Tumors in the region of the hypothalamus often cause endocrine dysfunction (decreased appetite, failure to thrive), bitemporal hemianopia, or abnormal eye movements (seesaw nystagmus, spasmus nutans-like syndrome). Seizures are generally less common in children with posterior fossa tumors than in children with supratentorial tumors. In a study involving 3,291 children with brain tumors,343 supratentorial tumors were associated with seizures in 22% of children younger than 14 years of age and in 68% of older teenagers. Among children with infratentorial tumors, the prevalence of seizures was approximately 6% in all age groups. The tumor location with the highest incidence of seizures was the superficial cerebrum, with seizures occurring in more than 40% of cases.343 Headaches occur very frequently in children with brain tumors and are commonly, but not exclusively, associated with increased intracranial pressure.

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A significant portion of the clinical signs and symptoms in children with brain tumors involves the visual system, either due to direct involvement of related structures in the neoplastic process or due to the mass effect of the tumor with associated hydrocephalus or secondary compression, deformation, or parenchymal shifts. Occasionally, children present initially to an ophthalmologist with visual signs and symptoms. Neuro-ophthalmologic evaluation is also a significant component of the clinical followup of these children. Signs and symptoms of brain tumors can be nonlocalizing, falsely localizing, or localizing. Tumors are the most common cause of noncommunicating hydrocephalus (obstruction of cerebrospinal fluid [CSF] flow within the ventricular system) in children. The associated increased intracranial pressure gives rise to most of the nonlocalizing signs that include headache, papilledema, and sixth nerve palsy. This constellation of signs and symptoms does not provide specific clues regarding the tumor location. Falsely localizing signs are exemplified by the presence of bitemporal hemianopia in a child with posterior fossa tumor. The field defect results not from direct chiasmal infiltration but rather from compression by an enlarged third ventricle due to tumor-associated hydrocephalus. Once nonlocalizing and falsely localizing signs are excluded, the remaining symptoms and signs are generally related to the location of the tumor. The presence of alternating skew on lateral gaze in a child with brain tumor suggests a lesion in the lower brainstem or the cerebellum, such as a cystic cerebellar tumor or Chiari malformation.409,942 Acute changes in intracranial pressure associated with brain tumors may cause a variety of herniation syndromes characterized by displacement of brain tissue, either downward or, less commonly, upward. These syndromes include uncal, transtentorial, and falcial herniation. Uncal herniation results when a lateralized tumor in the frontal or temporal lobe causes a shift of structures through the tentorial notch into the midbrain. Pupillary-involving oculomotor palsy results from entrapment of the nerve by the herniated uncus on the free edge of the tentorium. Downward displacement of the cerebellar tonsils may result in compression of the medulla. Early signs of tonsilar herniation may include head tilt and a stiff neck, presumably arising from irritation of the cervical roots by the herniated mass. Although children with posterior fossa tumors often develop paralytic strabismus, some may present with acute comitant esotropia.942 Therefore, the finding of comitancy in acute esotropia is no guarantee that there is no underlying intracranial mass. Acute comitant esotropia that does not fit the classic profile of accommodative esotropia should prompt a search for other neuro-ophthalmologic signs, such as papilledema or nystagmus. The failure to fuse despite satis-

factory postoperative ocular alignment in this setting should also raise concern about an underlying brain tumor.942 Acute comitant esotropia may also occur in the setting of a Chiari malformation.409 Associated gaze-evoked nystagmus or downbeat nystagmus in such a child should suggest this possibility. Acute comitant esotropia in children may also follow minor head trauma or be cryptogenic, and such cases generally lack associated neurologic findings, such as papilledema or nystagmus.186 Children with posterior fossa tumors rarely develop spasm of the near reflex221 or signs and symptoms reminiscent of myasthenia gravis.711,853 When successful treatment of brain tumors produces resolution of cranial nerve palsies, many patients are left with a comitant strabismus from longstanding disruption of fusion or from secondary extraocular muscle contracture.110 Conversely, brain tumors can produce cranial nerve palsies in children with preexisting strabismus. This possibility should be considered when a longstanding comitant strabismus is complicated by diplopia, incomitance, or other signs of extraocular muscle weakness. Functional imaging techniques such as MR spectroscopy, perfusion imaging, diffusion imaging, and diffusion tensor imaging are increasingly used in the diagnosis and treatment of brain tumors in children.908 However, estimate of tumor size remains the primary imaging endpoint in the evaluation of response to treatment.908 Clinical outcome, measured not only by survival rates but also by the effects of disease and therapy on quality of life, has improved over the past two decades for some tumor types, most notably medulloblastoma and cerebellar astrocytoma.36,656

Suprasellar Tumors Suprasellar tumors in children include optic pathway gliomas, craniopharyngiomas, germinomas, pituitary adenomas, and others.1a,521,763 Due to the proximity of these tumors to the various structures that comprise the anterior visual pathway, these tumors have a high propensity to cause various neuroophthalmologic symptoms and signs. These include optic atrophy, chiasmal syndrome, papilledema, spasmus nutans, seesaw nystagmus, and bobble-headed doll syndrome. Frisén and Jensen319 have recently found the optic chiasm to be surprisingly robust. Using sensitive perimetric techniques, they found an elevation of 6 mm necessary to produce a visual field defect in 50% of patients, and an additional elevation of 5 mm necessary to produce a visual field defect in 90% of patients.319 In adults with chiasmal syndrome, the findings of symptomatic visual loss, younger age, unilateral optic disc pallor, a relative afferent pupillary defect, and an absolute or complete visual defect, especially one worse inferiorly, is

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suggestive of something other than pituitary tumor.587 However, these guidelines cannot be loosely applied to children, who tend to present with visual loss more readily from pituitary adenoma.519,926 The clinical and neuroimaging features of suprasellar tumors in the pediatric age group are detailed in Chap. 4.

Pituitary Adenomas Most pediatric pituitary adenomas present after the onset of puberty with frequent headaches, changes in visual acuity, and, in girls, menstrual dysfunction. Most are secretory, with prolactinomas being most common.519,596,803,804,925 Children younger than 17 years of age may be diagnosed during evaluations for delayed puberty.740 Pituitary adenomas in the prepubertal period may be more likely to exhibit extrasellar extension or invasiveness.313,519,652 Pituitary adenomas in children may present with more severe visual loss and a have a greater likelihood of producing optic atrophy prior to presentation.519,926 Visual improvement after surgical decompression for pituitary adenomas in children may not be as high for children as in adults and may be more likely to be associated with optic atrophy.569,857,925 Octreotide, a synthetic somatostatin analog, can rapidly improve visual function in some patients with both secreting and nonsecreting pituitary macroadenomas that compress the anterior visual pathways.

Rathke Cleft Cysts Rathke cleft cysts are benign epithelial lined intrasellar cysts that are believed to arise from remnants of Rathke’s pouch endoderm or neuroepithelium.506,821,964 They are small, asymptomatic, and reported to occur in 2–33% of routine autopsies.699 The most common presenting symptoms are visual impairment, hypothalamic dysfunction, hypopituitarism, and headache.278 Rathke cleft cysts are usually diagnosed in adults, and are frequently asymptomatic in childhood.278,911 MR imaging shows signal variability from hypointensity to hyperintensity on T1-weighted images, and hypointense T2-weighted images, with no enhancement of the cyst wall, no calcification, no solid matter in the cyst, and a “ledge sign” from the constraining effects of the posterior diaphragma sella.475 Rathke cleft cyst must be distinguished from craniopharyngioma and pituitary adenoma. It is thought that craniopharyngioma and Rathke’s cleft cysts have a common origin from the remnants of Rathke’s pouch but with a different histologic differentiation. Rathke cleft cysts are generally intrasellar but may show suprasellar extension. In contrast,

craniopharyngioma appears as a mixed cystic and solid suprasellar tumor. Rarely, chiasmal compression and optic atrophy can result, and surgical resection can produce improvement in the associated visual field defects.699 Rathke cleft cysts require a less aggressive treatment, have a lower incidence of recurrence, and a better visual prognosis. Visual defects, endocrine dysfunction, and headaches improve or resolve with treatment. Transsphenoidal drainage of the cyst with partial excision of the wall is generally effective.596 Rathke cleft cyst must also be distinguished from lymphocytic infundibulo-neurohypophysitis, which produces thickening of the pituitary infundibulum and the pituitary gland, and has been reported to cause recurrent optic neuropathy in a 13-year-old boy.13

Arachnoid Cysts Arachnoid cysts comprise approximately 1% of nontraumatic intracranial masses.32,937 These cysts consist of clear fluid enclosed in reduplicated layers of arachnoid.726 Their MR signal characteristics are identical to those of cerebrospinal fluid.32 They may originate from maldevelopment of the leptomeninges in the prenatal or early postnatal period.496,726 The most common location for arachnoid cysts is in the middle cranial fossa, where they are generally asymptomatic.726 Aside from the well-known association of large arachnoid cysts with papilledema, obstruction of the cerebrospinal fluid pathway, or intracystic or subdural hematoma24 isolated cranial nerve palsies involving the oculomotor nerve,63,157,416,529 trochlear,645 and abducens nerve,581,772 have been reported. Symptomatic patients are generally treated with cystoperitoneal shunting. This procedure produces resolution of headaches, diplopia, and papilledema, but does not reverse head enlargement, mental retardation, or behavioral problems.24

Cavernous Sinus Lesions Though rare in children, cavernous sinus lesions can represent a life-threatening condition.522 The finding of single or multiple nontraumatic ocular motor nerve palsies with ocular motor synkinesis, facial pain, or other trigeminal involvement suggests localization to the cavernous sinus. Lesions affecting the cavernous sinus in children include meningioma,939 lymphoma,171,446,518,773,799 rhabdomyosarcoma,522 giant aneurysm,322,469,648 and thrombosis.668 In cases of painful ophthalmoplegia, the diagnosis of Tolosa–Hunt syndrome should also be considered.233,866,962

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Hemispheric Tumors Hemispheric Astrocytomas Astrocytomas are the most common supratentorial tumors in childhood, constituting approximately 30% of such tumors. There is no gender predilection. Most cases in children are benign, but more malignant grades (e.g., glioblastoma multiforme) can occasionally occur. In general, the duration of symptoms before diagnosis is longer with supratentorial than with infratentorial astrocytomas. Supratentorial tumors are often large at the time of presentation.81,590 The clinical signs of cerebral hemispheric astrocytomas are generally determined by the tumor location. Signs and symptoms of increased intracranial pressure, seizures, and focal neurologic deficits predominate. Headaches may be focal or diffuse; persistent focal headaches may have a localizing value. Seizures are relatively common, presenting abnormalities of hemispheric tumors, ranging in incidence from 30 to 60% of cases. It should be emphasized, however, that the incidence of tumors in children with epilepsy is quite low in general. They tend to occur more frequently in the slow-growing astrocytoma than in the rapidly growing glioblastoma multiforme and, in this respect, can be considered a good prognostic sign. Seizures are more likely when tumors involve the sensory-motor strips of the cortex or the temporal lobes. Ataxia may be present with tumors of the frontal lobes or thalamus, presumably due to involvement of the frontopontine pathway, and this may lead to the incorrect diagnostic suspicion of a posterior fossa process. Neuro-ophthalmologic abnormalities may arise from direct involvement of the geniculostriate pathways or from hydrocephalus. Visual field abnormalities and papilledema are the most common neuro-ophthalmologic signs. Involvement of the frontal gaze center causes an inability to look volitionally to the contralateral side while retaining reflexive eye movements to that side. If the lesion is irritative rather than paralytic (as in tumor-associated seizure activity), there may be tonic conjugate deviation of the eyes toward the side contralateral to the lesion. Tumors involving the deep parieto-occipital regions may be associated with defects in conjugate horizontal pursuit to the side of the lesion in association with contralateral homonymous hemianopia. Therefore, deep parietal tumors often produce loss of horizontal optokinetic responses toward the side of the lesion, while occipital tumors do not (Cogan’s rule).191 Cerebral astrocytomas may appear on CT scanning as solid, with a central necrotic area, or cystic, with an enhancing mural nodule. The tumors are typically found deep within the cerebral hemispheres but can occur in the centrum semiovale or cortex. It is usually impossible to differ-

entiate benign from malignant astrocytomas of the cerebrum with MR imaging, although low-grade tumors tend to be homogeneous, whereas higher-grade tumors show considerable heterogeneity. No definitive MR criteria exist to differentiate cerebral astrocytomas from ependymomas or oligodendrioglioma. The best prognosis is attained by patients with benign cystic astrocytomas resembling their infratentorial counterparts.590 These can be cured by total excision and may show prolonged symptom-free survival, even after subtotal resection. The therapeutic role of radiation in these tumors is under debate. In contrast, children with glioblastoma multiforme or anaplastic astrocytoma require radiation and, potentially, chemotherapy.264

Gangliogliomas and Ganglioneuromas These tumors differ from most CNS tumors in that both neuronal and glial elements are involved in the neoplastic process. They are labeled as gangliogliomas when the glial elements predominate and as ganglioneuromas when the neuronal elements predominate. There is no gender predilection.830,858 These tumors are slow growing and frequently present in the second decade of life or beyond with a long history of focal neurological deficits. The specific clinical manifestations depend on the location of the tumor. If the motor cortex or the temporal lobe is affected, patients present with a long history of focal seizures.861 If the occipital lobe is affected, homonymous hemianopia may result. The treatment is surgical resection.

Supratentorial Ependymomas Supratentorial ependymomas are histologically identical to their infratentorial counterparts and tend to peak in incidence between the ages of 1 and 5 years. There is a slight male preponderance. The presenting clinical features depend upon the location of the tumor, with focal seizures and signs and symptoms of increased intracranial pressure being most common.277,351

Primitive Neuroectodermal Tumors Primitive neuroectodermal tumors (PNETs) are a group of highly malignant tumors found primarily in the cerebral hemispheres of children and young adults. They represent a pathologic quagmire in that there is considerable confusion regarding their differentiation on pathologic grounds from

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other neuroectodermal tumors, such as neuroblastomas, medulloblastomas, and pinealoblastomas. They are uncommon and occur most often in children under 5 years of age. In general, the duration of symptoms to diagnosis is short, with an average of 3 months.325,874 PNETs are sharply delineated from surrounding brain tissue and are cystic, with hemorrhagic features on gross inspection. Microscopically, they are highly cellular tumors composed of very poorly differentiated small cells (90–95%) with a high nuclear-to-cytoplasmic ratio. Focal areas of differentiation along neural or glial lines and a prominent mesenchymal component may be present. Their cell of origin is impossible to identify with certainty, but ultrastructural studies show resemblance to the developing cortical plate of the fetus, suggesting an origin from primitive undifferentiated neuroectoderm of the cerebrum. The clinical presentation depends upon the location and growth rate of the tumor. The most common presentations include signs and symptoms of increased intracranial pressure, seizures, and long tract signs. Strikingly, some children may be relatively asymptomatic despite a huge tumor mass and may be spared severe neurological symptoms and signs (with the exception of papilledema and an inappropriate affect) until death.194 Motor deficits such as hemiparesis or paraparesis are common. Visual field abnormalities and papilledema are the most common neuro-ophthalmologic findings. MR imaging reveals a sharply defined tumor due to relative lack of edema and the presence of enhancement.306 Because the tumors sometimes show extensive calcification, CT scanning without contrast may be a useful adjunct to MR imaging. Although aggressive treatment with surgery, radiation, and chemotherapy has been attempted, the prognosis remains poor irrespective of treatment modality. The average 5-year survival is, at best, 20%.

Posterior Fossa Tumors Medulloblastoma Medulloblastomas are otherwise known as the PNETs of the posterior fossa.318 They are the most common posterior fossa tumor in childhood, comprising approximately 40% of all such tumors.170,395 The incidence peaks around 5 years of age. Boys are affected somewhat more frequently than girls in most series. Children are usually diagnosed shortly after the onset of symptoms. Cushing’s217 description of the clinical course of a child with cerebellar medulloblastoma provides a graphic portrait of this disease: “A pre-adolescent child

previously in good health begins to complain of headaches or of suboccipital discomfort and to have occasional attacks of vomiting without preliminary nausea, usually on first arising in the morning. Attendance at school meanwhile may continue, but the teacher soon notices that the child is listless, inattentive, and the character of his work noticeably falls off. Ere long it is apparent that there is some unwanted clumsiness in movement and awkwardness in gait. The mother may find that the child quickly outgrows its caps and she thinks the head enlarges unduly fast. In course of time it is noticed, at home or in school, that the child’s sight is impaired; or a beginning squint of one eye may be detected, even in the absence of any complaint of double vision. The family doctor, who has previously suspected some gastrointestinal disorder, may then have the eye grounds examined and, to the surprise and shock of everyone, a choked disc is found. Three or four months, on the average, have elapsed, and at about this stage of the malady, many cases come under hospital care.” The most common presenting symptoms are nausea, vomiting, and headaches due to increased intracranial pressure.675 This arises as the tumor grows and impinges on the roof of the fourth ventricle, causing obstruction to CSF flow. Vomiting is the most common presenting sign of cerebellar tumors and may also arise independently of intracranial pressure by direct tumor pressure on the area postrema (vomiting center), located near the inferior aspect of the fourth ventricle. Other abnormalities include papilledema, diplopia, and nystagmus. Unilateral and bilateral internuclear ophthalmoplegia have been reported, arising either from brainstem neoplastic infiltration or compression.26 In addition, older children and adults may initially present with ataxia, while infants may initially present with increasing head size due to hydrocephalus. Most medulloblastomas are located in the midline of the cerebellum. They are considered to be congenital in nature, deriving from remnants of the fetal external granular layer of the cerebellum or the medullary velum. Medulloblastomas are highly cellular tumors composed of primitive, undifferentiated, small, round cells with abundant mitoses. Homer– Wright pseudorosettes are typically found. They are highly malignant tumors, showing local invasiveness as well as a high tendency, perhaps more than any other tumor, to seed the subarachnoid space. Extraneural metastasis to bone, lymph nodes, or viscera may arise as a result of tumor manipulation or shunting. The putative congenital origin of medulloblastoma has led some authors to use Collins’ rule to predict its course.94 This rule predicts that the period of risk for recurrence of a tumor of embryonal origin after treatment is the patient’s age at the time of diagnosis plus 9 months. CT scanning classically reveals a well-defined, hyperdense tumor of the vermis. Isolated hemispheric involvement is rare in children.774 The hyperdensity of the tumor arises from its

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Fig. 11.16 Cerebellar medulloblastoma. (a) Sagittal T1-weighted MR image shows mass with lower intensity than brain parenchyma (arrowheads). Mass occupies fourth ventricle. (b) Axial T1-weighted image shows mass filling of fourth ventricle (arrowheads). (c) Coronal

T1-weighted MR image shows uniform tumor enhancement (arrows). (d) Sagittal T1-weighted MR image of same patient after treatment consisting of surgical excision, radiation, and chemotherapy

composition by small, round cells with a high nuclear-to-cytoplasmic ratio. The tumor enhances diffusely with contrast. Unlike cerebellar astrocytomas, cysts are uncommonly seen, and unlike cerebellar ependymomas, calcification is seen in less than 10% of cases. The MR appearance is variable and nonspecific (Fig. 11.16). The T2-weighted are hypointense or isointense to gray matter,595 which reflects the tumor composition of increased nuclear-to-cytoplasmic ratio and, hence, reduced water content. The heterogeneity of the MR signal results from cysts and calcification within the tumor mass. The management is complex and includes various combinations of surgical excision, irradiation, and chemotherapy.285 However, in comparison with all malignant brain tumors, the outlook has improved most dramatically for children with medulloblastomas. This is largely due to the use of craniospinal rather than local radiotherapy, with the addition of

chemotherapy in selected patients. Because leptomeningeal dissemination is common, a staging workup of the neuroaxis is now advocated for guiding postoperative management.241 Through continued refinement in chemotherapy and radiotherapy, both progression-free survival and overall survival have improved to 80%.675

Cerebellar Astrocytoma Astrocytomas are the most common brain tumors in children. They tend to occur in various locations, both infratentorially and supratentorially. Cerebellar astrocytomas may occur anywhere in the cerebellum, including the vermis, the hemispheres, or both. Cerebellar astrocytomas show no gender predilection and tend to develop in a slightly older age group than medulloblastomas,

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generally peaking in incidence in the latter half of the first decade.227,328 The early presentation of affected children consists of early morning headaches and vomiting due to increased intracranial pressure. Vomiting generally occurs in the morning and may occur without nausea. After vomiting, the child may feel well for the rest of the day, with a repeat performance the following morning. Because the symptoms are recurrent, the child may undergo gastrointestinal evaluation before a correct diagnosis is finally made. As the tumor enlarges, the headaches become persistent. Neurologic symptoms may help predict the location of the tumor. The child with a midline cerebellar tumor presents with truncal ataxia, whereas the child with cerebellar hemispheric tumor shows appendicular signs (e.g., dysdiadochokinesia, dysmetria). Children may show apathy, irritability, and neck stiffness and pain and may develop attacks of unconsciousness (so-called “cerebellar fits”). Because of the insidious nature of the symptoms, some children have few or no complaints until late in the disease, despite the presence of a large tumor, with papilledema as the only abnormal finding. The average duration of symptoms before diagnosis is approximately 18 months, compared with only 5 months in medulloblastoma. The most common neuro-ophthalmologic abnormalities are papilledema, diplopia, and nystagmus. Coarse nystagmus to the side of the lesion is of localizing value and should be distinguished from vestibular nystagmus, which is directed to the side opposite the lesion. The presence of a sixth nerve palsy may be a false localizing sign indicating increased intracranial pressure or may signal neoplastic invasion of the brainstem, the latter usually accompanied by hyperreflexia and Babinski responses. Children may have torticollis if brainstem involvement results in fourth nerve palsy. Cerebellar astrocytomas are generally noninvasive, welldemarcated tumors.790 Mitoses are conspicuously absent and, when present, suggest a malignant astrocytoma. Approxi mately 80% of cerebellar astrocytomas are cystic, showing either a large cyst with a solid mural nodule or multiple smaller cysts. Microscopic or gross calcification is present in up to 25% of cases. At least two histologic types exist. The most common form (termed the juvenile variety) consists of areas of compact, fibrillated cells with abundant Rosenthal fibers alternating with loose spongy areas composed of microcysts. Rosenthal fibers are eosinophilic, beaded, or cigarshaped swellings of astrocytes that represent a benign degenerative process. The second type is a diffuse form, consisting of fibrillated stellate or piloid cells, identical to that encountered in cerebral astrocytomas. The juvenile form has a considerably better prognosis than the diffuse form. Early recurrence and poor survival is also associated with brainstem invasion and onset before 4 years of age.

The presence on CT scanning of a low-density mass, typically within the cerebellar hemispheres, often with a cystic component, is suggestive of a cerebellar astrocytoma. The presence of an enhancing nodule on CT scanning adjacent to the cyst is a compelling evidence of the diagnosis. On MR imaging, the tumor signal is nearly always hypointense to the surrounding cerebellum on T1-weighted imaging and hyperintense and generally homogenous in appearance on proton density and T2-weighted imaging (Fig. 11.17). Cerebellar astrocytomas have the best overall prognosis of any childhood brain tumor.860 The preferred treatment of cerebellar astrocytomas is complete surgical resection.514,894 If this is accomplished, the 10-year survival rate exceeds 90%. If only incomplete excision is possible due to the invasion of critical surrounding brainstem parenchyma, patients may be observed expectantly for tumor progression before radiotherapy is considered.

Ependymoma Intracranial ependymomas, which account for about 12% of pediatric brain tumors, may arise from any region of the ventricular system, but most childhood ependymomas are located in the posterior fossa.893 The average age at diagnosis is 5 or 6 years.741 Unlike medulloblastomas, the diagnosis is usually delayed as a result of the insidious onset of symptoms.207 Posterior fossa ependymomas arise from differentiated ependymal cells that line the roof, floor, or lateral recesses of the fourth ventricle. Most are solid in nature, but some are very soft and deformable. Therefore, in contrast with most other brain tumors that grow as steadily enlarging masses, ependymomas can wrap themselves around various structures in their vicinity and become quite adherent to the adjacent brain. They also have a tendency to exit through the foramina of Magendie and Luschka into the subarachnoid space.558 In general, posterior fossa ependymomas present with signs and symptoms of increased intracranial pressure (due to obstruction of the fourth ventricle) and unsteady gait.487,893 The growth characteristics of these tumors render them more likely to present with neuro-ophthalmologic manifestations than other posterior fossa tumors. Invasion of the cerebellum, brainstem, or cerebellopontine angle produce corresponding neurological abnormalities that include nystagmus, ocular motor nerve palsies, and internuclear ophthalmoplegia. Brodsky and Boop125 described a 3-year-old boy with unilateral Duane syndrome who was found to have a large ependymoma that was compressing the floor of the fourth ventricle.

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Fig. 11.17 (a) Sagittal MR image shows large cystic cerebellar mass. Note enhancing portion inferiorly. (b) Axial scan shows involvement of left cerebellar hemisphere and midline structures. Note enhancing mural nodules (arrow)

Torticollis may result from the involvement of the trochlear nerve or may accompany neck pain and stiffness from encroachment of the tumor on the upper cervical nerve roots. Spinal cord ependymomas are a well-recognized but readily overlooked cause of papilledema.578 Ependymomas are cellular tumors with a regular histologic pattern. Ependymal rosettes are diagnostic and are composed of tumor cells lined around a central lumen. Perivascular pseudorosettes are common, and cilia may be present. Two grades of ependymomas are recognized: a benign or differentiated ependymoma and a malignant or anaplastic variety. The anaplastic variety has typical features of ependymomas but also has pleomorphism, necrosis, increased cellularity, mitoses, and giant cells. Anaplastic ependymomas are more common in the supratentorial regions. A posterior fossa ependymoma appears on CT scanning as a hyperdense or isodense fourth ventricular mass with punctate calcifications, small cysts, and moderate enhancement with contrast. Extension of the mass through the fourth ventricular foramina or the foramen magnum further supports the diagnosis. The MR imaging signals may be heterogeneous or homogenous, depending on the presence of calcification, hemorrhage, or cysts (Fig. 11.18).841 Posterior fossa ependymomas are quite difficult to surgically excise in their entirety and have a high recurrence rate after surgery.386 Although gross total resection has been widely accepted as an important prognostic factor,589 many children experience recurrence despite gross total resection,352,837 and only slightly more than half of children are

long-term survivors of this cancer. This is compounded by the tendency of the tumor to seed the CSF pathways, including the spinal subarachnoid space. While radiation therapy is standard for cases in which the tumor communicates with the ventricular system, it has deleterious effects on the developing brain, producing neurocognitive defects that may be mitigated by conformal radiotherapy.589,675 A neuro-ophthalmologic syndrome of visual impairment with mutism may follow posterior fossa surgery in children.545 Following suboccipital craniotomy (usually for removal of medulloblastoma or ependymoma), these children become withdrawn without verbal output and exhibit impaired visual behavior mimicking cortical visual loss. These children fail to blink to a threat or follow objects.545 Pupillary activity remains normal and retinal examination reveals only papilledema. Neuroimaging discloses no lesions of the retrogeniculate pathway. The prognosis for visual recovery is excellent and parallels the return of normal speech. The mechanism is unclear.545

Brainstem Tumors Brainstem gliomas represent about 15% of pediatric CNS tumors.428 The mean age at diagnosis is 7–9 years, with no gender predilection.541 Diffuse gliomas are the most commonly encountered brainstem tumor, accounting for 58–75% of all tumors.9,276 Children with diffuse brainstem gliomas

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Fig. 11.18 Posterior fossa ependymoma. (a) Sagittal and (b) coronal MR images show extension of tumor through fourth ventricular foramina. (c) Note extension of tumor anteriorly (arrowheads). (d) MR imaging shows associated hydrocephalus

invariably have a rapidly progressive course. They often present acutely with multiple cranial nerve signs, ataxia, long tract signs, and cerebellar signs. Current management options for these tumors are limited to radiotherapy, with or without adjuvant chemotherapy. Systemic chemotherapy has been used, albeit with unproven efficacy. These tumors show a variable clinical presentation but a uniformly poor outcome by virtue of their location. The pons is the most common site of origin of brainstem gliomas, followed by the midbrain and the medulla.573,659 The prognosis is dismal.675 Most children die within 18 months of diagnosis, similar to the clinical course for glioblastoma multiforme.8,541 Brainstem tumors are suggested by the triad of long tract signs, cranial neuropathies, and ataxia. In addition, brainstem gliomas should be considered in the differential diagnosis of

an infant with failure to thrive who has facial paresis, absent cough reflex during suctioning, or a depressed gag reflex. The cranial nerves most commonly affected are the sixth and seventh nerves, and the two are often present together. The most common neuro-ophthalmologic symptom is diplopia due to involvement of the ocular motor nerves. Seesaw nystagmus in a patient with brainstem tumor localizes the tumor to the region of the diencephalon. The presence of a third or fourth cranial nerve palsy, diffuse ophthalmoplegia, the various features of Parinaud syndrome in any combination, or profound hydrocephalus suggests a mesencephalic component to the tumor. Occasionally, diffuse ophthalmoplegia due to mesencephalic involvement simulates myasthenia gravis clinically as well as by showing a false-positive response to Tensilon.123,711 Convergence palsy

Brain Tumors

may accompany midbrain tumors or tumors of the pineal region. Primary position upbeat nystagmus has been observed in tumors at the pontomesencephalic junction.884 Horizontal eye movement abnormalities (horizontal gaze paresis due to involvement of the abducens nuclei or the paramedian pontine reticular formation, internuclear ophthalmoplegia, one-and-a-half syndrome) are features of pontine involvement.192 Pontine horizontal gaze abnormalities may be associated with ipsilateral facial palsy and contralateral hemiparesis. Pontine gliomas have been reported to cause chronic isolated sixth nerve palsy.327 An associated sixth nerve palsy may also occasionally show spontaneous improvement. Asymmetry of the palate, absent gag reflex, atrophy of the tongue, and various other bulbar signs, including swallowing and feeding abnormalities, indicate medullary involvement. Vomiting, unaccompanied by headache, may occur due to direct infiltration of the emesis center in the medulla. Ataxia may result from direct cerebellar involvement or, more likely, from the compromise of cerebellar pathways passing through any of the cerebellar peduncles. Rarely, brainstem tumors have been associated with congenital ocular motor apraxia.968 In contrast with the cerebellar tumors discussed, hydrocephalus and signs and symptoms of increased intracranial pressure are quite uncommon in pontine glioma until late, despite significant enlargement of the brainstem and even bulging of the enlarged brainstem into the fourth ventricle. However, tectal and tegmental gliomas may present with headaches and increased intracranial pressure due to compression and obstruction of the sylvian aqueduct. Duration of symptoms until diagnosis varies widely, from several weeks to several years. Biopsy is seldom necessary because MR imaging is diagnostic.675 Although the natural

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history is one of inexorable progression, there are a few reports of brainstem tumors showing a remitting and exacerbating course.778 This presentation may be mistaken for a demyelinating or parainfectious disorder. Presumably, these remissions result from resolution of edema or necrosis in the area of the tumor. Most brainstem gliomas are fibrillary astrocytomas similar to those found in the cerebral hemispheres; only a small minority are pilocytic in nature. The tumor cells are seen to intermingle with neurons and nerve fibers on histopathologic examination, infiltrating along these structures rather than destroying them. This may explain the relative preservation of various neural functions in the brainstem despite apparent diffuse involvement of the brainstem structures. It is not unusual for the child with a pontine glioma to present initially to the ophthalmologist for evaluation of a horizontally incomitant esotropia or a face turn resulting from a sixth nerve palsy. If such a child has an initially negative neuroimaging study, reimaging for a possible pontine glioma is indicated if the palsy fails to completely resolve within 6 months. Brainstem tumors are much more easily identified with MR imaging than CT scanning (Fig. 11.19).57,154 CT scanning typically shows an expanded brainstem that is hypodense or isodense to the surrounding brainstem.87 MR imaging shows a brainstem mass that is hypointense on T1-weighted images and hyperintense on T2-weighted images. T2-weighted images are especially useful for detecting tumor infiltration into surrounding structures.307 Other characteristic findings include obscuration of the pons with no contrast enhancement, and engulfment of the basilar artery by tumor.257 Diffuse tumors enlarge the brainstem smoothly, without focal areas of exophytic growth, and have a worse prognosis.

Fig. 11.19 Brain stem glioma. (a) MR scan with gadolinium enhancement of largely medullary pontomedullary glioma. (b) Pontomedullary glioma mass

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The treatment of brainstem tumors by either surgery, radiotherapy, or chemotherapy alone or in various combinations has been generally ineffective.276,433,486 Long-term survival after gross total resection of some juvenile pilocytic astrocytomaa has been achieved, albeit with significant morbidity.465 Most of these tumors are infiltrative, malignant, intrinsic tumors that are not amenable to resection. Their diffuse nature is readily demonstrable on T2-weighted MR images, obviating the need for biopsy. The prognosis of brainstem gliomas is generally poor, with an average 5-year survival rate of approximately 10–30% and a median survival of less than a year. Particularly bad prognostic signs include: (1) history suggestive of onset before 6 months of age, (2) long tract signs, (3) ataxia, (4) a diffusely infiltrative lesion, and (5) involvement of two-thirds or more of the pons. Generally, pontine gliomas, which tend to be diffuse and infiltrative, have a poorer prognosis than mesencephalic or medullary gliomas. In contrast, low-grade tumors located in the medulla or midbrain, exophytic tumors, and those that are associated with neurofibromatosis are associated with improved survival.

Tumors of the Pineal Region Tumors of the pineal region are relatively rare but disproportionately important from the neuro-ophthalmologic standpoint by virtue of their location. Pineal region tumors are classified into those that are derived from the pineal gland parenchyma, those that are of germ cell origin, and those representing other histological types not related to the previous two.71,230,270,437 Pineal gland tumors include pineocytomas and pinealoblastomas.294 Germ cell tumors include germinomas, choriocarcinomas, embryonal cell carcinomas, endodermal sinus tumors, and teratomas.296,436 Tumors derived form contiguous structures include quadrigeminal plate gliomas, gangliogliomas, ganglioneuromas, and meningiomas. Dermoids and epidermoids as well as other tumors also occur in this region.694 The diversity of tumor histology reflects the diversity of anatomic sites from which the neoplasm may arise (e.g., pineal gland, brain parenchyma, dura). The most common tumors in this location are germ cell tumors, which arise from midline rests of multipotential germinal cells.294,437,959 Germ cell tumors thus occur primarily in the midline and are found in the pineal region, cistern, or both. Germinomas and teratomas are the least malignant and have the best overall prognosis. Teratomas consist of elements derived from all three germinal layers, usually present within the first 6 months of life and occasionally present at birth. Choriocarcinomas, embryonal carcinomas, and endodermal sinus tumors are more malignant tumors.

Germinomas represent at least 50% of all pineal region tumors. They are identical histologically to those found in the gonads, abdomen, and chest. Germinomas usually occur in the second decade of life and show slight male predominance. When germinomas occur in the suprasellar area, no gender predilection is noted. Microscopically, germinomas consist of two cell types, large vesicular cells and small cells resembling lymphocytes. Mitotic activity is confined to the larger cell type. Germinomas may contain elements of other germ cell tumors and are then referred to as mixed germ cell tumors. Children with tectal plate lesions usually present in a delayed fashion with symptoms and signs referable to hydrocephalus.865 The clinical presentation depends primarily upon the size of the tumor at the time of diagnosis.865 The most common presentations of tumors in this location are hydrocephalus due to compression of the sylvian aqueduct696 and the dorsal midbrain syndrome (Parinaud syndrome) due to compression of the dorsal mesencephalon.865 The dorsal midbrain syndrome manifests as lid retraction, pupillary light-near dissociation, impaired upward gaze, and convergence–retraction nystagmus. Visual loss, bitemporal hemianopia, diabetes insipidus, precocious puberty, and failure to thrive imply involvement of the anterior hypothalamus by a primary tumor in this location or a secondary to metastasis from the pineal region.521 After hydrocephalus is managed with third ventriculostomy, tectal tumors require close clinical and radiologic surveillance.865 Most larger tumors require surgical resection but are found to be histologically benign. The only significant predictor of future enlargement is lesion volume at the time of diagnosis. Pineal tumors are one of the few neuro-ophthalmologic causes of myopia, which can result from increased accommodative tone secondary to central disinhibition of the Edinger–Westphal nucleus. Multiple cranial nerve involvement as well as various brainstem syndromes suggest basilar or brainstem extension of the tumor. Less common neuroophthalmologic manifestations of tumors in this location have also been described, including skew deviation and bilateral superior oblique palsy due to compression of the decussating fourth cranial nerves. Pineal germinomas may also cause visual loss through direct seeding of the optic nerve or chiasm.566 The germ cell tumors often produce biological markers that are detectable in the blood or the CSF. Endodermal sinus tumors elaborate alpha-fetoprotein, choriocarcinomas produce the beta subunit of human chorionic gonadotropin, and embryonal carcinomas produce both markers.442 Germinomas and teratomas are generally devoid of markers. These markers are helpful in establishing the diagnosis and monitoring the treatment response (markers decrease or disappear) and tumor recurrence (markers re-emerge).

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Fig. 11.20 Pineal region tumors. (a) MR image shows pineal germinoma (arrowheads). (b) Glioma of quadrigeminal plate (arrow) causing aqueductal occlusion and hydrocephalus

The neuroimaging modality of choice for this region is contrast-enhanced MR imaging (Fig. 11.20)870; however, the histologic diagnosis is difficult to infer with neuroimaging alone. Germinomas tend to be well defined and to show homogeneous enhancement, while pinealoblastomas and pineocytomas tend to have a mixed signal on T1-weighted images, hyperintense signal on T2-weighted images, and variable enhancement. The definitive diagnosis is made only after tumor resection and histopathologic examination although the diagnosis can be inferred by neuroimaging if positive markers are also present. The treatment of pineal region tumors depends to a large measure on the tumor histology. Benign teratomas, dermoid cysts, and pineocytomas can be cured with surgery alone. Because of their exquisite chemosensitivity and radiosensitivity, pure germinomas are associated with at least an 80% long-term survival rate.345 The treatment of other germ cell tumors entails surgical debulking and shunting, if needed, followed by staging of the tumor. This is generally followed by chemotherapy and radiation. Reddy et al described two children who developed central fusion disruption following irradiation of probable pineal germinomas, and questioned whether neurons in the pineal area play an active role in modulating central fusion.718 However, nongerminoma germ cell tumors are largely neither radiosensitive nor chemosensitive and generally have a poor prognosis. The overall prognosis of affected patients depends on the histologic type and the extent of the tumor at diagnosis. Endoscopy for pineal region tumors is now used not only to biopsy tumors but also to perform a third ventriculostomy, thereby obviating the need for a shunt in some cases.391

Meningiomas Characteristic differences of childhood meningiomas compared to adulthood meningiomas include a slight predominance in males, a high frequency of intraventricular location, frequent cystic forms, and the common finding of dural attachment. While children can harbor malignant meningeal tumors, children with typical meningiomas and complete removal have a good prognosis. Malignant forms of meningioma are commonly radiation-induced meningiomas. These radiation-induced meningiomas show a female predominance and a short latency period, which seems directly related to the age at irradiation.164 Optic nerve sheath meningiomas in children tend to be more aggressive (Fig. 11.8), but histological review has not shown malignancy.14,183,330,453,917,953 While the diagnosis of optic nerve sheath meningioma in a child should promote a search for NF2,727 it is not known whether the association of NF2 confers a different prognosis for tumor growth.104 Nevertheless, the finding of NF2 may dictate a less aggressive approach to surgical excision. For non-NF2 patients, the earlier recommendation of exenteration may be tempered to excision of the optic nerve from chiasm to globe.330 The role of radiation therapy (with the potential for development of secondary radiationinduced tumors) has not been evaluated in children.330

Epidermoids and Dermoids These tumors occur relatively more frequently in the posterior fossa. As the name implies, epidermoids are derived from epidermal elements (squamous epithelium with keratin),

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while dermoids are derived from epidermal as well as dermal components (have additional pilosebaceous structures). They represent congenital rests of tissue that are retained intracranially due to incomplete separation of neuroectoderm from surface ectoderm during neural tube closure. The clinical presentation of these tumors varies with their location. The most common location of epidermoids is the cerebellopontine angle, followed by the pineal region, the suprasellar area, and the middle cranial fossa. Epidermoids in the cerebellopontine angle usually present with cranial neuropathies, suprasellar epidermoids tend to present with hydrocephalus, and middle cranial fossa epidermoids often present with aseptic meningitis secondary to leakage of epidermoid contents into the subarachnoid space. Dermoids are less common than epidermoids within the intracranial cavity and tend to occur in the posterior fossa (within the vermis or the fourth ventricle).

Gliomatosis Cerebri Gliomatosis cerebri is an uncommon primary brain tumor characterized by diffuse proliferation of neoplastic glial cells, with relative preservation of underlying brain architecture.472,903 The diagnosis is made through a combination of a predominantly diffuse, infiltrative lesion, and histologic findings.474 The exact origin of the tumor is unclear, but it may represent a clonal neoplasm stemming from a single cell.762 Patients present with headaches, seizures, and behavioral changes. Elevated intracranial pressure and papilledema are common and may even be the presenting features of the disease.215 The optic nerves may also be primarily involved.297 Children with gliomatosis cerebri may present with intractable epilepsy, corticospinal tract defects, and developmental delay,435 whereas both children and adults may present with progressive visual loss from infiltration of the anterior visual pathway by tumor cells.297,838 Because of the diffuse nature of this condition, CT scanning is often initially normal, but MR imaging usually suggests that diagnosis. MR imaging shows the involvement of more than one lobe, with high-intensity signal on T2-weighted and proton-density images, usually with no enhancement.922,923 Patients presenting with signs and symptoms of increased intracranial pressure may be thought to have idiopathic intracranial hypertension.605 Proton MR spectrospopy of gliomatosis cerebri shows markedly elevated levels of creatine–phosphocreatine (CR) and myo-inositol (Ins), a decreased level of N-acetylaspartate (NAA), and a moderately elevated level of cholinecontaining compounds (Cho), which help differentiate gliomatosis cerebri from low-grade glioma.326 Some patients present with ocular motor disturbances. Dexter et al243 described a 16-year-old girl who presented with

a third nerve palsy and progressed to bilateral involvement. A second case of a 12-year-old boy was described as having either right or both eye deviation to the right.703 There is no definitive treatment for gliomatosis cerebri, although radiotherapy and chemotherapy are usually given.210 Regardless of therapy, this condition is usually fatal.

Metastasis Unlike adult tumors, extracranial tumors rarely metastasize to the intracranial compartment in children. However, seeding of certain brain tumors in children occurs often along the CSF pathways, causing invasion of the leptomeninges.843 “Drop metastasis” to the spinal subarachnoid space and cauda equina can occur. Seeding and spinal drop metastasis occur most commonly in medulloblastoma (one-third of cases) but also occur in other tumors such as ependymomas, germinomas, pinealoblastomas, and anaplastic gliomas.

Complications of Treatment of Intracranial Tumors in Children One of the key concerns in the treatment of brain tumors in children is the adverse effect of irradiation on the developing brain. The glial and vascular endothelial cells are more radiosensitive than neurons, explaining the nature of the delayed brain response to radiation, namely, vascular occlusion. The parameters that increase the extent and likelihood of irradiation damage include younger age of the patient, deeper path of radiation, larger overall volume of brain irradiated, presence of hydrocephalus, and overall dose and fractionation of radiation administered. Reduced radiation dose is particularly necessary in very young children because of the immaturity of the brain and the predisposition to develop postirradiation vaso-occlusive disease. Concurrent administration of chemotherapy may potentiate the adverse effects of radiation on the brain. Trials of preradiation chemotherapy are now used in infants and young children to obviate or delay subsequent radiation therapy. One of the most significant delayed effects of radiation is a reduction of the level of cognitive function in both the neuropsychologic and intellectual spheres.346,513 A significant proportion of these children show a significant diminution in their IQ, which may appear many years after the conclusion of radiotherapy. Endocrine abnormalities and cranial neuropathies can result from cranial radiation. Secondary tumors may also arise near the site of irradiation. One particular presentation of postirradiation damage in children is moyamoya disease. Moyamoya, a Japanese word

Hydrocephalus

meaning “something hazy like a puff of cigarette smoke drifting in the air,” is a descriptive name applied to the angiographic finding of an abnormal network of collateral vessels at the base of the brain in the region of the basal ganglia. Most authors consider occlusive vasculopathy of the internal carotid artery and/or the proximal portion of the anterior or middle cerebral arteries to be the primary condition and the abnormal network of vessels to be a result of it. Moyamoya disease is a progressive disorder that has been described with basal meningitis, tumor, neurofibromatosis, atherosclerosis, connective tissue disease, sickle cell disease, Fanconi anemia, Down syndrome, and following radiation of the brain between 6 months and 12 years of age.647 Children with moyamoya disease usually present with recurrent transient cerebral ischemic attacks and infarctions (hemiplegia, paresthesia, seizures).831 Actions requiring hyperventilation, such as crying, running, and inflating balloons, are known to precipitate cerebral ischemia in patients with moyamoya disease. Neuro-ophthalmologic features of moyamoya disease are more common in children with moyamoya disease than in adults and usually arise from involvement of the posterior cerebral circulation. These include visual field defects (most commonly homonymous hemianopia), decreased visual acuity, blurred vision, episodic blindness, and scintillating scotomata.609 In one series of 178 patients,609 visual symptoms were found in 43 (24.1%) of cases. Children at risk of moyamoya disease who present with a suggestive history, such as scintillating scotomata or other transient visual disturbances, should undergo prompt evaluation because newer anastomotic procedures such as pial synangiosis (suturing a donor scalp artery directly to the pial surface to promote hemispheric vascularization) may forestall or prevent permanent visual loss.609,831

Hydrocephalus As a single or isolated condition, the incidence of hydrocephalus is approximately 1–1.5 per 1,000 births. Most of these cases are recognized before the children are 5 months of age and are considered congenital.232,713 Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from the cerebral ventricles to absorption into the systemic circulation.724 Hydrocephalus, in the broadest sense, denotes an increased amount of CSF in the cerebral ventricles as opposed to local fluid accumulation in subdural hygromas, arachnoid cysts, or in tissue defects (e.g., porencephalic cyst). It results from impaired CSF circulation, reabsorption, or rarely hypersecretion. Most of the CSF is produced in the ventricular system by the choroid plexus. The flow of CSF may be traced as it leaves the lateral ventricles passing through the foramina of

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Monro to the third ventricle, then through the sylvian aqueduct to the fourth ventricle. The CSF then exits the ventricular system by passing through the foramina of Magendie and Luschka into the cisterna magna and the basilar cistern. Most of the fluid then enters the cisternal system (suprasellar cistern, cistern of the lamina terminalis, ambient cistern, superior cerebellar cistern) which are part of the cerebral subarachnoid space. The remainder of the fluid enters the spinal subarachnoid space but also eventually flows into the cerebral subarachnoid space. The traditional concept states that the drainage of CSF occurs via absorption through the arachnoid villi, which are evaginations of the subarachnoid space into the lumina of the dural and cerebral venous sinuses.488 Alternate pathways of absorption including the cerebral lymphatics and perineural sheaths, are likely to predominate in infancy since the normal human infant has no arachnoid villi. Long ago, Welch and Friedman932 proposed the flow of CSF directly to the venous sinuses as a one-way valve mechanism (later shown by Tripathi to be mediated by a giant vesicular transport mechanism).880 A “minor outflow pathway” through the choroid plexus and the periventricular fenestrated venous capillaries into the deep venous channels may predominate in neonates and children under 2 years of age, possibly explaining the poor results obtained with endoscopic third ventriculostomy in this age group.644 When ventriculomegaly is discovered, a determination must be made as to whether it is progressive and whether it is causing neurologic compromise.553 The extent of ventricular enlargement as a result of increased CSF pressure depends partially on the age of the patient (and hence the distensibility of the ventricular system). Except for the rare occurrence of choroid plexus papilloma where CSF is overproduced,274 hydrocephalus generally results from impaired CSF flow and absorption (obstructive hydrocephalus). Impaired drainage may occur as a result of blockage in the ventricles, the cisterns, the cerebral convexities, or the arachnoid villi. In addition to ventriculomegaly, neuroimaging shows effacement of the sulci and gyri, and diminished extraaxial fluid against the undersurface of the skull. Thus, obstructive hydrocephalus is divided into communicating hydrocephalus, in which there is either extraventricular obstruction of CSF flow or diminished absorption of CSF, and noncommunicating hydrocephalus, in which the obstruction is within the ventricles, including the outlet foramina of the fourth ventricle. While MR imaging is the mainstay of diagnosis, other neuroimaging studies, such as CINE CSF flow studies, functional MRI, PET and SPECT studies, have been used to help evaluate patients with hydrocephalus.553 These studies have generally demonstrated hyperdynamic CSF flow and areas of decreased CSF flow and metabolism.553 Hydrocephalus is primarily caused by poor absorption or blockage of CSF circulation, and less than 0.5% of all cases

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are caused by overproduction of CSF (from choroid plexus papilloma). Many causative factors that result in diminished CSF absorption are recognized, including maternal malnutrition, toxins, infections (bacterial, viral, cytomegalovirus, and toxoplasmosis), and other acquired conditions (e.g., intraventricular hemorrhage, bacterial infections, trauma, tumors). Congenital malformations of the CNS sometimes affect CSF circulation, causing ventricular enlargement and increased intracranial pressure. Arnold–Chiari malformations, agenesis of the corpus callosum, cerebellar hypoplasia, Dandy–Walker malformations, and other cortical malformations are associated with hydrocephalus.713,842 In addition, microscopic changes and parenchymal destruction are common in all patients with hydrocephalus. If left untreated, the progressive ventricular enlargement causes displacement and an eventual decrease in the number and caliber of the microvasculature, resulting in decreased blood flow to the periventricular white matter. With time, the tissue destruction leads to porencephalic cysts, which are frequently seen as diffuse white matter loss and periventricular encephalomalacia.232,713 Several terms pertaining to hydrocephalus warrant clarification. Normal-pressure hydrocephalus is a form of hydrocephalus in which signs of progressive hydrocephalus exist despite the fact that the CSF pressure is within the normal range. It is most commonly encountered as a sequela of meningitis or perinatal asphyxia. Intermittent spikes of high pressure may be responsible, requiring intracranial pressure monitoring. The term arrested hydrocephalus describes a disorder in which the hydrocephalus has spontaneously resolved although some residual clinical signs may persist (e.g., enlarged head size or enlarged ventricles). The term hydrocephalus ex vacuo is used to describe the situation in which enlarged ventricles result from periventricular white matter destruction rather than actual hydrocephalus. Hydranencephaly refers to a situation in which most of the brain has been destroyed in utero and resorbed, being replaced by a CSF-filled sac. It should be emphasized that these mechanisms of ventricular dilation are not mutually exclusive. For example, long-standing hydrocephalus due to increased intracranial pressure eventually causes periventricular tissue damage and hemispheric atrophy. Conversely, hydranencephaly may become complicated by secondary impairment of CSF circulation, causing increased intracranial pressure.

Hydrocephalus due to CSF Overproduction Hydrocephalus secondary to CSF overproduction occurs exclusively in choroid plexus papilloma, a rare neoplasm accounting for 2–4% of childhood intracranial tumors. Although overproduction of CSF alone can produce hydrocephalus, the presence of hydrocephalus in choroid plexus

papillomas may actually result from the complex interaction of CSF overproduction and partial restriction of CSF flow.725 Nearly half of these tumors occur in the first decade of life, with many occurring in infancy. These papillomas occur in infants, most frequently in the lateral ventricles, occasionally in the third and, rarely, in the fourth ventricle. This distribution pattern is reversed in older patients. These papillomas can produce huge amounts of CSF and present during infancy with macrocephaly and signs of intracranial hypertension. The tumors most commonly originate within the trigones of the lateral ventricles. Resection of the tumor is often curative for the hydrocephalus.

Noncommunicating Hydrocephalus Noncommunicating hydrocephalus arises from a variety of lesions that cause blockage of CSF flow within the ventricular system at any level from the foramina of Monro to the foramina of Magendie and Luschka. Underlying disorders include tumors, aqueductal stenosis, aqueductal gliosis, arachnoid cysts, congenital anomalies, and isolated fourth ventricle. Tumors are the most common cause of this type of hydrocephalus.

Communicating Hydrocephalus Communicating hydrocephalus results from extraventricular obstruction of CSF flow or reabsorption. After the CSF exits the ventricular system through the foramina of the fourth ventricle, it enters the cisterna magna and basilar cisterns and then flows into the subarachnoid space. CSF drainage may be impaired within the cisterns or when the arachnoid villi are obstructed. Continuous intracranial pressure recordings may provide potentially misleading diagnostic information in this form of hydrocephalus.272 Causative disorders include intraventricular hemorrhage, meningitis, CSF seeding of tumor, cerebral venous sinus thrombosis, and normal-pressure hydrocephalus. From the neuro-ophthalmologic standpoint, noncommunicating hydrocephalus is much more likely to cause impaired upgaze and the various features of the dorsal midbrain syndrome than the communicating variety, with most of these cases being due to developmental or acquired aqueductal stenosis.859 One recent study of motility disturbances found that children with hydrocephalus that was surgically treated before 1 year of age are more likely to present with strabismus, motility defects, or torticollis. The etiology of hydrocephalus, number of shunt revisions, and ventricular size had little correlation with motility disturbances.25

Hydrocephalus

Common Causes of Hydrocephalus in Children In children, shunt malfunction, posterior fossa tumor, trauma, meningitis, and intracranial hemorrhage are frequent causes of acute hydrocephalus presentation.713,842 The common causes of hydrocephalus in the pediatric age group are summarized in Table 11.1 according to the age of onset.

Aqueductal Stenosis Normally, the sylvian aqueduct in the newborn measures 3 mm in length and an average of 0.5 mm in cross section. The cerebral aqueduct is the most common site of ventricular obstruction of CSF flow, being the longest and narrowest passage. Complete obstruction of the aqueduct is referred to as atresia, incomplete obstruction as stenosis. In aqueductal stenosis, focal narrowing generally occurs either at the level of the superior colliculi or the intercollicular sulcus. Aqueductal stenosis occurs as a developmental abnormality or an acquired lesion due to obstruction of the sylvian aqueduct most often by tumor (e.g., tumors of the pineal gland or midbrain).696 When the aqueduct is obstructed after perinatal hemorrhage, meningitis, or other inflammatory disorder, the term aqueductal gliosis is sometimes used. The developmental variety of aqueductal stenosis accounts for approximately 20% of cases of hydrocephalus. Less common causes of aqueductal stenosis or obstruction include systemic viral infections (e.g., mononucleosis,

Table 11.1 Common causes of hydrocephalus in the pediatric age group Before age 2 years Aqueduct stenosis Aqueductal gliosis (infection or hemorrhage) Chiari malformations (+/− myelomeningocele) Dandy–Walker malformation Perinatal asphyxia, hemorrhage (premature infants) Intrauterine infection Neonatal meningoencephalitis Congenital midline tumors Choroid plexus papilloma Vein of Galen malformation Congenital idiopathic After age 2 years Posterior fossa neoplasms Aqueductal stenosis, gliosis, obstruction Chiari I malformation Intracranial hemorrhage Intracranial infections Idiopathic

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mumps),206,643 intracranial toxoplasmosis,935 basilar dolichoectasia,109 and mesencephalic venous malformations.646 Nontumoral aqueductal stenosis may occur in patients with NF1.338 A rare X-linked, genetic syndrome combines the features of aqueductal stenosis with hydrocephalus, macrocephaly, adducted thumbs, spasticity, mental retardation, and cerebral malformations (usually agenesis of corpus callosum) caused by a mutation of L1CAM.807 This condition is usually diagnosed at birth or prenatally by ultrasound and is usually lethal.806 A rarer form of aqueductal stenosis inherited as an autosomal recessive disorder has also been described.64 The onset of symptoms in both aqueductal stenosis and gliosis is usually insidious. Patients may become symptomatic at any age from birth to adulthood.745 Neuroimaging shows dilation of the lateral and third ventricles but a normalsized fourth ventricle. Aqueductal stenosis is often accompanied by aqueductal forking or branching of the aqueductal channel. Developmental aqueductal stenosis may be associated with fusion of the quadrigeminal bodies, fusion of the oculomotor nuclei, peaking of the tectum, and spina bifida cystica and occulta. One rare cause of hydrocephalus due to obstruction of the sylvian aqueduct in children is an arteriovenous malformation involving the great vein of Galen (vein of Galen “aneurysm”) (Fig. 11.21).971 This malformation arises from a congenital connection between intracranial arteries (usually thalamoperforator, choroidal, and anterior cerebral arteries) and a vein in the region of the vein of Galen. This abnormal vascular communication produces aneurysmal dilatation of the short vein of Galen, located just behind the posterior wall of the third ventricle. The most common presenting symptom in children younger than 2 years of age is hydrocephalus. Neonates may present with congestive heart failure and loud intracranial bruits.

Tumors Tumors are the most common cause of noncommunicating hydrocephalus (obstruction of CSF flow within the ventricular system) in children. The sites of obstruction are most commonly those where the ventricular pathways are the narrowest: the foramina of Monro, the sylvian aqueduct, the fourth ventricle, and the foramina of Magendie and Luschka. The location and size of the tumor are significant determinants for the development of hydrocephalus; tumor size alone is less important. For example, large pontine gliomas are only infrequently associated with hydrocephalus, but tectal gliomas almost uniformly present with hydrocephalus. Tumors may also cause increased intracranial pressure by causing brain edema and swelling and by compression of the cerebral venous sinuses.

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Fig. 11.21 Vein of Galen malformation. (a) Cerebral angiography in 4-day-old female infant with a prenatal diagnosis of vein of Galen malformation. (b) CT scan in same infant

Intracranial Hemorrhage Intraventricular hemorrhage arising from the subependymal germinal matrix, with subsequent rupture into the lateral ventricle, is the most common variety of intracranial hemorrhages and is characteristic of premature infants. This form of hemorrhage usually arises postnatally, less commonly perinatally and, rarely, prenatally.913,914 The subependymal germinal matrix, a cellular structure located immediately ventrolateral to the lateral ventricle, is a source of cerebral neuroblasts between 10 and 20 weeks of gestation, as well as glioblasts (progenitors of cerebral oligodendroglia and astrocytes) in the third trimester. The numerous thin-walled blood vessels within the germinal matrix are a ready source of bleeding. The most common site of bleeding is just posterior to the foramen of Monro. The blood spreads from one or both lateral ventricles into the third and fourth ventricles and the basal cisterns. It enters the cerebral and spinal subarachnoid space, where it may incite an obliterative arachnoiditis within the basal cisterns with obstruction of CSF flow. Impaired CSF dynamics may also occur at the level of the sylvian aqueduct and the arachnoid villi. This form of intracranial hemorrhage is responsible for an increasing proportion of pediatric hydrocephalus as advances in neonatology enable us to salvage an increasing number of premature infants. Hydrocephalus is considered the main complication of intraventricular hemorrhage, with periventricular hemorrhagic infarction and germinal matrix destruction being additional common complications. The likelihood and rapidity of progression of hydrocephalus after intraventricular hemorrhage are directly related to the quantity of intraventricular blood.912 Large hemorrhages may lead to hydrocephalus within days, while smaller hemorrhages lead

to hydrocephalus over weeks. Acute obstructive hydrocephalus may arise from hematoma clogging the basal cisterns or the arachnoid villi. Later, an adhesive arachnoiditis develops that perpetuates the hydrocephalus long after the red blood cells break down. Another mechanism is organization of an intraventricular hematoma with reactive gliosis of the ventricular wall. The pathogenesis of germinal matrix hemorrhage and subsequent intraventricular hemorrhage in premature children is multifactorial and related to intravascular, vascular, and extravascular factors.913 Intravascular factors pertain to control of blood flow and pressure within the germinal matrix and include fluctuations of cerebral blood flow, abrupt increases or decreases of flow, increased cerebral venous pressure and, in some infants, disturbances of platelet function.Vascular factors pertain to the microcirculation of the germinal matrix and include vulnerability of the matrix vessels to ischemic injury. Extravascular factors include the mesenchymal and glial support for the germinal matrix vessels and the local fibrinolytic activity in the germinal matrix.913,914 The imaging procedure of choice to detect intraventricular hemorrhage in a premature infant is real-time cranial ultrasound scanning. The severity of intraventricular hemorrhage may be graded by ultrasound criteria. Grade I denotes a germinal matrix hemorrhage with intraventricular hemorrhage involving less than 10% of the ventricular area on parasagittal views, grade II involves 10–50% of that area, grade III involves greater than 50% of that area, and grade IV is associated with intraparenchymal extension.914 Periventricular leukomalacia is a frequent accompaniment of intraventricular hemorrhage in premature infants but is not causally related to the intraventricular hemorrhage.

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Hydrocephalus

Its co-occurrence in the same patient may complicate the clinical picture when hydrocephalus also exists, because both processes are characterized by enlarged ventricular size – in hydrocephalus, due to elevated CSF pressure, and in periventricular leukomalacia, due to hypoxic–ischemic injury to periventricular white matter. In full-term infants, intracranial hemorrhage occurs most frequently after trauma. Intraventricular hemorrhage is less common in full-term infants than in premature infants, and the incidence of hydrocephalus due to this complication is therefore much less in the full-term infant. It may arise from extension of a hemorrhagic cerebral infarction or a thalamic hemorrhage, vascular malformation, tumor, trauma, residual germinal matrix, or a choroid plexus hemorrhage.

disease. Lyme disease, a multisystem disease caused by Borrelia burgdorferi, a tick-borne spirochete, commonly affects children.76 The disorder causes various ophthalmic manifestations, including cranial neuropathies, iridocyclitis, vitritis, pars planitis, orbital myositis, keratitis, episcleritis, conjunctivitis, and optic neuritis.29 The disease may manifest as a meningitis, a meningoencephalitis, or an isolated cranial neuropathy. In some patients, the disorder may resemble idiopathic intracranial hypertension.76 AIDS also occurs in children and can present with increased intracranial pressure because of various underlying lesions (lymphomas, infections), but these intracranial lesions tend to be rarer in children with AIDS than in adults.702

Chiari Malformations Intracranial Infections Various infectious processes involving the intracranial compartment may result in hydrocephalus. Bacterial, viral, and fungal meningitis and various protozoan and parasitic infections of the brain may be associated with or followed by hydrocephalus. Brain abscesses occasionally cause hydrocephalus and/or homonymous hemianopia. Congenital infections of the CNS (congenital toxoplasmosis, cytomegalovirus, varicella, and herpes simplex virus) occasionally manifest with hydrocephalus. The hydrocephalus may result from more than one mechanism in any given infection. For instance, neurocysticercosis (infestation of the brain by the larval form of Taenia solium) may cause hydrocephalus through obstruction of the CSF pathways with cysts, leptomeningitis, or the mass effect and associated edema of intraparenchymal cysts.958 Intracranial hydatid cysts due to Echinococcus granulosus infection often manifest with signs and symptoms of hydrocephalus in endemic areas.278 Granulomatous meningitis (e.g., tuberculous meningitis) is more likely to cause hydrocephalus than bacterial meningitis, which is more likely to cause it than viral meningitis. Meningitis causes hydrocephalus acutely through a combination of blockage of the CSF pathways with purulent exudates and involvement of the arachnoid granulations in the infectious process. Cerebral abscesses and cerebral venous sinus thrombosis may complicate meningitis and contribute to the production of hydrocephalus. Later, fibrosis and scarring of the subarachnoid space block CSF outflow. Clogging of the arachnoid granulations with debris may play a role. Subclinical virus infections may cause “noninflammatory” aqueductal stenosis and hydrocephalus. Rarely, neurosarcoidosis may underlie the manifestation of hydrocephalus in children.930 Two other infectious diseases of the CNS associated with hydrocephalus are particularly noteworthy; AIDS and Lyme

Chiari malformations are characterized by herniation of the posterior fossa contents below the level of the foramen magnum. They are categorized into three types, and it is a common misconception that this classification is based on the degree of herniation.268 The different Chiari malformations do not represent different stages in the process of herniation; rather, they represent distinct malformations with different systemic associations. For example, the Chiari I malformation can be acquired, while Chiari II malformation is associated with myelomeningocele only, and Chiari III malformation is associated with encephaloceles, and Chiari IV is aplasia of the cerebellum. The treatment is generally directed at the posterior fossa pathology and includes decompression of the cervicomedullary junction, posterior decompressive procedures (e.g., opening of outlet foramina of the fourth ventricle, fourth ventricular shunting), and ventriculoperitoneal shunting. Generally, the major presenting symptoms of the Chiari malformations are occipital headache (particularly with cough and other Valsalva maneuvers), pain, dissociative sensory loss, and weakness.434 The signs and symptoms of Chiari malformations are largely a result of impaction of the posterior fossa contents at the foramen magnum, abnormal CSF dynamics at the craniocervical junction, and the associated hydrocephalus and syringomyelia.

Chiari I The Chiari I is now considered to be the most common Chiari malformation and an underrecognised cause of headaches in children.5a This malformation is characterized by protrusion of the cerebellar tonsils below the level of the foramen magnum (Fig. 11.22). It may be observed in several clinically different settings: (1) Some infants develop herniation of the

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

Fig. 11.22 Chiari I malformation. MR image shows that cerebellar tonsils extend 1 cm below level of foramen magnum

cerebellar tonsils as a result of intrauterine hydrocephalus. These cases are usually diagnosed with hydrocephalus in infancy or early childhood. (2) Some patients may have craniocervical dysgenesis (e.g., Klippel–Feil anomaly). This group often has concurrent platybasia and cervical vertebral abnormalities and usually presents during childhood with headaches when straining and with cranial nerve palsies. (3) Some patients may have acquired deformities of the foramen magnum (e.g., basilar invagination). They are generally asymptomatic during childhood but present during adulthood, with symptoms and signs similar to group 2 above. (4) Some patients develop Chiari I as a result of lumbo-peritoneal shunting and may show resolution of the abnormalities after shunt removal. An abnormality of mesodermal development results in reduced posterior fossa volume with downward impaction of a normal sized cerebellum in most cases of Chiari I malformation. In Chiari malformations, hydrocephalus generally results from lack of communication between the spinal subarachnoid space and the cranial subarachnoid space. The two subarachnoid compartments are separated by the impacted cerebellar tissue. Repetitive impaction of herniated cerebellar tissue with each beat of the heart creates a local increased intracranial pressure and a pressure wave in the spinal subarachnoid space and may lead to the development of syringo-

myelia. About 50% of patients with Chiari I malformation have concurrent syringomyelia. Symptoms of Chiari I may be intermittent and simulate those of multiple sclerosis. The diagnosis of Chiari I malformation should be suspected in any patient with occipital headaches with cough strain or sneeze, vertigo, oscillopsia, ataxia, disequilibrium, or dysphagia, especially if these symptoms coexist with other more characteristic symptoms of the disorder, such as upper cervical pain or weakness.794 Compression of neural structures at the level of the medulla rarely produce systemic hypertension, which may resolve after surgical decompression.667 Skeletal abnormalities of the cervical spine, including basilar impression, atlanto-occipital fusion, atlanto-axial assimilation, and Klippel–Feil syndrome, are also associated with a high incidence of Chiari malformation.846 Neuro-ophthalmologic abnormalities reported in Chiari I malformation include the various disorders associated with increased intracranial pressure (if it coexists). An acquired downbeat nystagmus is the classical neuro-ophthalmologic finding associated with Chiari I malformation, but other types of nystagmus may occur (discussed later). It should be noted that some of the abnormalities associated with Chiari I malformation may be intermittent, causing a diagnostic quandary. Intermittent abnormalities include symptoms of increased intracranial pressure,915 oscillopsia, and downbeat nystagmus.961 A case of convergence nystagmus has been reported in which the nystagmus was provoked by a Valsalva maneuver with neck flexion or extension; the nystagmus diminished on deep inspiration.619 Precipitation of nystagmus through Valsalva maneuver or neck movements suggests an intermittent rise in intracranial pressure as the cause, as was documented by intraventricular monitoring in one patient.915 Although downbeat nystagmus is the most common cause of oscillopsia in this disorder, oscillopsia can also occur in the absence of nystagmus.344 The various eye movement disorders in Chiari I malformation largely result from cerebellar ectopia and lower brainstem distortion. Periodic alternating nystagmus, which also localizes a lesion to the level of the foramen magnum,42 has been reported. Interestingly, seesaw nystagmus (which usually localizes to the diencephalon or parasellar region)972 and convergence retraction nystagmus (which localizes to the pretectal area of the midbrain) have also been described. Another case with signs localizing to the midbrain was reported by Cogan,190 who described a patient in whom neck extension regularly induced spasm of the near reflex and an exacerbation of the downbeat nystagmus that lasted several seconds after the head was returned to the primary position. Another patient with a Chiari I malformation and spasm of the near reflex has since been reported.221 Gaze-evoked nystagmus6 and rebound nystagmus854 may occur. Other neuroophthalmologic disorders include Horner syndrome (due to associated spinal cord syringomyelia),852 comitant strabismus,

Hydrocephalus

fourth nerve palsy, skew deviation, ocular dysmetria, ocular flutter, and various neuro-otologic abnormalities also occur.927 Acute comitant esotropia can be another presentation of Chiari I malformation. Ocular motor signs suggestive of this condition include an esotropia that is acquired after age 3, a distance deviation greater than the near deviation,692 A-pattern with bilateral superior oblique overaction, and nystagmus (particularly downbeat).409 Bixenman and Laguna92 described a 13-year-old girl who developed comitant esotropia who was successfully treated with strabismus surgery. Three years later, downbeat nystagmus developed, and Chiari I malformation was diagnosed with MR imaging. The nystagmus resolved, and the eyes remained aligned after neurosurgical decompression. Passo et al679 described a similar patient who was initially treated with strabismus surgery. After recurrence of esotropia and development of downbeat nystagmus, Chiari I malformation was diagnosed. In this patient, neurosurgical decompression of the posterior fossa restored ocular alignment and single binocular vision. On careful examination, other neurologic signs (downbeat nystagmus, headache, hydrocephalus) are often found.409 Subsequent case series have shown that suboccipital decompression often produces resolution of the esotropia.92,231,533,929 Although strabismus surgery initially restores horizontal alignment, recurrence of esotropia is common, and suboccipital decompression is often necessary for definitive treatment.692 In addition to comitant vertical strabismus, posterior fossa disease may also precipitate comitant strabismus that is purely horizontal. This prenuclear disorder is the horizontal analog of skew deviation. Like its vertical counterpart, horizontal skew deviation seems to be precipitated by a prenuclear perturbation of the ocular motor system.120 In light of recent reports, it would seem appropriate to expand our concept of skew deviation to include horizontal cases of acquired comitant esotropia that are increasingly recognized to accompany the Arnold–Chiari malformations and posterior fossa tumors in some children An association between Chiari malformations and idiopathic intracranial hypertension (IIH) has recently been recognized.178,501,904,907,915 Disturbed CSF movement at the foramen magnum, with increased resistance to outflow and venous flow abnormalities resulting in venous hypertension are likely to be contributory risk factors for the development of IIH in this setting.501 Decompressive surgery for Chiari I malformation may lead to IIH in children.288 Conversely, bony decompression of the posterior fossa may produce resolution of IIHwhen both conditions coexist.904 Surgical intervention could cause changes in CSF circulation due to postoperative scarring, or CSF inflammation due to blood reabsorption. This imbalance in CSF circulation may lead to changes in the turgor or the brain paren-

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chyma or an increase in resistance across the arachnoid villi leading to the postoperative development of IIH.288,501 Posterior cranial fossa decompression can produce clinical improvement in symptomatic patients.156 Lumboperitoneal shunting is well-recognized to result in Chiari malformations although these patients tend to be asymptomatic and rarely require treatment.181,246,440 Neuro-ophthalmologic symptoms and signs associated with Chiari I malformation often stabilize, improve, or resolve after suboccipital craniotomy.839,972

Chiari II The Chiari II malformation (also known as the Arnold–Chiari malformation) was until recently the most common of the Chiari malformations in the pediatric age group. However, the increased prevalence of in utero diagnosis (with ultrasound and alpha fetoprotein) leading to therapeutic abortion for Chiari II malformation, together with the increased clinical diagnosis of Chiari I with MR imaging, have rendered it less common than the Chiari I malformation. The Chiari II malformation is a highly complex malformation that is almost exclusively present in children with myelomeningocele. It can show any of the infratentorial features of Chiari I malformation, but it differs by involving supratentorial structures as well (Fig. 11.23). Ninety percent of cases of Chiari II malformation occur in association with myelomeningocele and hydrocephalus. Conversely, all patients with myelomeningocele and hydrocephalus harbor a Chiari II malformation. Patients with Chiari II malformation have a reduced cerebellar volume, weight, and cell content.237,275,382 The small cerebellar size has been blamed on mechanical compression secondary to crowding, which is presumed to lead to the secondary ischemic changes and parenchymal cerebellar loss.771 However, this reduction in cerebellar volume is not uniform: the hemispheres shrink, but the vermis can expand vertically.771 Vertical expansion of the cerebellar vermis is an important neuroimaging sign as patients who do not show vertical expansion have a small vermis and tend to show eye movement abnormalities, while those with vertical expansion do not.771 Patients are usually diagnosed at birth with myelomeningocele and develop hydrocephalus shortly after its repair. After the repair of the myelomeningocele, the clinical presentation to be expected from the underlying Chiari II malformation as well as the associated hydrocephalus, lower cranial nerve palsies, and syringomyelia, may differ according to the age of the child. Patients younger than 6 months tend to present with stridor, apnea, and/or dysphagia (feeding difficulty), while children older than 3 years of age tend to present with hemiparesis, quadriparesis, oscillopsia, nystagmus, or opisthotonos.74,401 Chiari II malformation accounts

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Fig. 11.23 Chiari II malformation. (a) Sagittal MR scan shows extension of cerebellar tonsils below level of foramen magnum (arrow) as well as tectal beaking (arrowheads). (b) Axial MR scan shows tectal beaking (arrowheads)

for approximately 40% of all hydrocephalic children, and hydrocephalus develops in approximately 85% of patients with myelomeningoceles.247 The cause of the myelomeningocele and associated Chiari II malformation is theorized to be lack of expression of carbohydrate molecules on the surface of neural cells in the developing neural tube.585 These surface molecules are required for neural tube closure as well as expansion of the central canal that eventually leads to formation of the cerebral ventricles. The absence or incorrect expression of these molecules leads to failure of closure of the posterior neuropore and failure of expansion of the cerebral ventricles, which in turn leads to the formation of an abnormally small posterior fossa. This causes the normally developing cerebellum to be squeezed out of the posterior fossa as it grows, getting indented in the process by the tentorium superiorly and the foramen magnum inferiorly. Hydrocephalus in Chiari II malformation is presumed to result from abnormal location of the foramina of the fourth ventricle below the foramen magnum and associated poor communication between the cerebral and lumbar subarachnoid space. Affected patients show a wide constellation of abnormalities that vary in severity. Mild cases show only minimal hindbrain abnormalities and may be confused with Chiari I malformation, but the concurrent myelomeningocele and supratentorial abnormalities are not features of Chiari I. The mesencephalic tectum is often distorted, being stretched posteriorly and inferiorly. This appears as tectal “beaking” on CT or MR scans and correlates with the clini-

cal degree of nystagmus.889 The pons, medulla, and cervical spinal cord are stretched inferiorly. There is a high incidence of associated syringomyelia, which may lead to the formation of a characteristic cervicomedullary kink. The cerebellum may extend anteriorly to encircle the brainstem. The cerebellar vermis usually herniates into the cervical spinal canal and may subsequently degenerate, leading in severe cases to nearly total absence of the cerebellum on neuroimaging. The fourth ventricle is usually small, lowlying, narrow, and vertically oriented. It may become encysted or isolated. Supratentorial abnormalities include an absent rostrum and an absent or hypoplastic splenium of the corpus callosum, prominent occipital horns, and abnormal gyral pattern in the medial aspect of the occipital lobes on MR imaging. Multiple surgical strategies exist for the management of symptomatic Chiari II malformation, with little consensus for optimal treatment at present.888 Placement of a properly functioning shunt can often obviate the need for boney hindbrain decompression.888 Early surgical intervention may prove life-sustaining in symptomatic Chiari II patients in which symptoms are referable to the medullary dysfunction.888 Neuro-ophthalmologic abnormalities described in Chiari II malformation include the various signs and symptoms related to the associated hydrocephalus, myelomeningocele, and syringomyelia.12,74,85,305,335 The associated downbeat nystagmus is typically worse in lateral gaze and worse with convergence.524 These patients have a propensity to develop A-pattern strabismus with superior oblique overaction,525,526

Hydrocephalus

547

probably representing a form of alternating skew deviation on lateral gaze.378,380 Pathological studies on patients with myelomeningocele and Chiari II malformation have shown disorganized brainstem nuclei,342 a feature that may explain the propensity of these children to show this type of skew deviation. Other reported abnormalities include internuclear ophthalmoplegia,27,635,951 defective smooth pursuit and optokinetic nystagmus, periodic alternating nystagmus,844 and periodic alternating gaze deviation.

Chiari III This is an exceedingly rare malformation in which the contents of the posterior fossa (cerebellum +/− brainstem) herniate through a cervical spina bifida cystica at the level of C1–C2. Hydrocephalus is a regular feature of this malformation.

The Dandy–Walker Malformation These disorders, called Dandy–Walker malformation, Dandy–Walker variant, and mega cisterna magna, are considered to represent a continuum of developmental anomalies and are collectively designated as the Dandy–Walker complex (Fig. 11.24).56 The Dandy–Walker malformation is classically characterized by the neuropathologic triad of (1) complete or partial agenesis of the cerebellar vermis, involving the cortex and deep cerebellar nuclei; (2) a greatly expanded, cystic, fourth ventricle; and (3) an enlarged posterior fossa with upward displacement of the lateral sinuses, tentorium, and torcula,56,523,653,678 and subsequently modified.155,877 An occipital encephalocele is also occasionallypresent.47,89 The Dandy–Walker malformation accounts for 2–4% of cases of hydrocephalus in children. The Dandy–Walker variant shows the above findings but with a normal-sized posterior fossa. It is more common than the true Dandy–Walker malformation and comprises about a third of posterior fossa malformations. Hydrocephalus is uncommon at birth but develops in 75% of cases by 3 months of age, and is present in 90% of patients at the time of diagnosis.47,653 The Dandy– Walker syndrome must be distinguished from mega cisterna magna (retrocerebellar arachnoid pouch), a cystic malformation wherein the posterior fossa is enlarged secondary to enlarged cisterna magna, but the cerebellar vermis and the fourth ventricle is normal. Most cases of the Dandy–Walker malformation are diagnosed in the first year of life, and most of these are diagnosed at birth. The major signs and symptoms are those of hydrocephalus as well as associated developmental delay and failure to thrive. Some features are more characteristic of Dandy–

Fig. 11.24 Dandy–Walker cyst. MR image shows replacement of most of posterior fossa contents with large cyst. Note attenuation of brainstem

Walker malformation than other causes of hydrocephalus, such as a large occiput with a higher-than-normal inion and the predisposition of patients to have recurrent attacks of pallor, ataxia and, occasionally, sudden respiratory arrest. Hydrocephalus is infrequently present at birth but appears by 3 months of age in over 75% of patients. Some patients may remain asymptomatic throughout life, while others may require shunting.497 Dandy–Walker syndrome must be distinguished from arachnoid cysts of the fourth ventricular roof. Although the cerebellum is essential in adults for control of many aspects of ocular motility, eye movement abnormalities in children with Dandy–Walker syndrome are often mild or absent, suggesting that other parts of the brain may be capable of taking over these roles in the developing nervous system.523 Children with congenital cerebellar disorders such as Dandy–Walker malformation are said be less affected than adults with lesions at similar locations.375,483,523,598 Despite the large cerebellar defect, patients may show only mild saccadic dysmetria, and eye movements may be normal,523 perhaps reflecting preservation of the ponto-mesencephalic junction in these patients.572 Despite being addressed extensively in the literature, the Dandy–Walker malformation remains poorly understood.680 The disorder seems to the result of a genetic predisposition, because the recurrence rate for siblings is 6%.623 The Dandy–

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Walker malformation was originally thought to result from developmental occlusion of the exit foramina of the fourth ventricle (Magendie and Luschka) and hence classified as one of the causes of noncommunicating hydrocephalus. It is now known, however, that the foramina of the fourth ventricle are patent in many cases. More recently, this malformation has been attributed to a developmental insult to the embryonic fourth ventricle and cerebellum.55,56 Most often, the Dandy–Walker malformation occurs as an isolated finding with low risk of occurrence in subsequent siblings. The risk to siblings is higher when the malformation occurs with Mendelian disorders such as Warburg syndrome, Aicardi syndrome, or with various chromosomal anomalies such as duplications of 5p, 8p, and 8q and trisomy of chromosomes 9, 13, and 18. Dandy–Walker syndrome is the most common cerebellar malformation associated with the PHACE (Posterior fossa malformations, Hemangiomas, Arterial malformations, Coarcation of the Aorta and other cardiac defects, and Eye abnormalities) syndrome.188 Oculocutaneous hypopigmentation in a child with Dandy–Walker syndrome should suggest the diagnosis of Cross syndrome (oculocutaneous hypopigmentation resembling albinism, mental retardation, spastic tetraplegia, abnormalities of the tongue and gingivae, microdontia, and generalized osteoporosis). This rare autosomal disorder is often seen in children of consanguineous parents.528 The Dandy–Walker malformation may also be associated with hypoplasia of the corpus callosum, polymicrogyria, gray matter heterotopia, porencephaly, low-set ears, malformed pinna, polydactyly, syndactyly, Klippel–Feil syndrome, Cornelia de Lange syndrome, Sjögren–Larsson syndrome,308 and cleft palate. Doubling of the optic disc has been described in one patient with a Dandy–Walker cyst.651 Various cardiac anomalies have been reported, including ventricular septal defects, patent ductus arteriosus, tetralogy of Fallot, and atrial septal defect.653

Congenital, Genetic, and Sporadic Disorders In addition to the aforementioned major causes of hydrocephalus, hydrocephalus also occurs as a feature in numerous genetic, metabolic, neurodegenerative, and sporadic syndromes. In some syndromes, hydrocephalus is presumed to result from diminished venous outflow through the jugular foramena. Syndromes in which this is thought to be the underlying mechanism include craniosynostosis (Apert syndrome, Carpenter’s syndrome, Pfeiffer’s syndrome, Crouzon syndrome),632 achondroplasia,511 and Marshall–Smith syndrome (a syndrome of accelerated osseous maturation and CNS malformations).768 Other disorders occasionally reported to be associated with hydrocephalus include Walker–Warburg syndrome,160 osteopetrosis,810 gestational

cocaine exposure, Aicardi syndrome, ring chromosome 22, various phakomatoses, Meckel–Gruber syndrome, Goltz focal dermal hypoplasia,19 immotile cilia syndrome,239,967 and numerous others. The immotile cilia syndrome is an autosomal recessive disorder with variable clinical manifestations that include recurrent respiratory infections, situs inversus, and sterility characterized by live but immotile spermatozoa. It has been occasionally reported in association with hydrocephalus. The pathogenesis of the associated hydrocephalus has not been elucidated, but some investigators believe that dysmotility of the ependymal cilia lining the ventricular system adversely affects the CSF circulation, leading to hydrocephalus in some patients. In most of the aforementioned syndromes described, the other associated anomalies lead to the correct diagnosis, but the hydrocephalus should be treated in the usual expeditious manner.

Clinical Features of Hydrocephalus Symptoms of hydrocephalus generally depend on the cause, the rate of increase in intracranial pressure, and the age of the patient at the time of onset. The presenting clinical features of hydrocephalus are legion. Although most children present with the classic signs and symptoms of intracranial hypertension, some may present only with gradual intellectual deterioration, behavioral changes or signs that suggest brainstem compression from associated Chiari malformations or spinal cord dysfunction due to tethering or syringomyelia. The age at which hydrocephalus develops in relation to the status of the cranial sutures determines whether enlargement of the head is a presenting sign. Thus, the most notable clinical finding in hydrocephalus prior to the age of 2 years is a rapid rate of head growth. Frontal bossing, separated skull sutures, tense anterior fontanelle with occasional intercalate bones, dilated scalp veins, and sparse hair are present. In severe cases (usually aqueductal stenosis), remolding of the anterior fossa can significantly reduce orbital volume and lead to bilateral proptosis. Irritability, failure to thrive, poor feeding, projectile vomiting, lethargy, or developmental delay may be noted. After 2 years of age, the most common presenting signs and symptoms involve focal deficits resulting from the primary lesion or nonlocalizing ones associated with increased intracranial pressure. These usually appear before any significant change in head size. Head size shows significant progressive enlargement only if the hydrocephalic process started before functional suture closure (usually 2 years of age), in which case the hydrocephalus prevents suture fusion. Diffuse spasticity and occasional chronic “fisting” are also seen. A variety of endocrine

Hydrocephalus

abnormalities can be associated with chronic hydrocephalus, including precocious puberty and growth deficiency caused by chronic displacement and stretching of the pituitary stalk.681 Older children may report headaches before other signs and symptoms of elevated intracranial pressure become symptomatic. The neuro-ophthalmologic manifestations of hydrocephalus have been discussed in previous chapters and are summarized in Table 11.2.305,335,525,526,892 Children can present with various combinations of these findings, which may complicate the clinical picture. For example, a child may show poor vision due to both bilateral optic atrophy and cortical visual impairment, posing some difficulty in determining the weighted contribution of each to the visual deficit. Also, a patient may show dorsal midbrain syndrome and bilateral sixth nerve palsy, the latter serving to reduce or mask coexisting convergence–retraction nystagmus. Light-near dissociation is difficult to ascertain in the presence of severe bilateral optic atrophy, and other signs of the dorsal midbrain syndrome should be sought before making the diagnosis. Neuro-ophthalmologic complications are most commonly encountered in the setting of aqueductal obstruction and enlargement of the third ventricle; however, they do occur in

Table 11.2 Neuro-ophthalmologic manifestations of hydrocephalus Motility abnormalities Setting sun sign (young infants) Dorsal midbrain syndrome (older children) Comitant horizontal strabismus (esotropia, exotropia) Sixth cranial nerve palsy Fourth cranial nerve palsy Third cranial nerve palsy Skew deviation A-pattern esotropia Bilateral superior oblique muscle overaction Fixation instability V-pattern pseudobobbing Bobble-headed doll syndrome Bilateral internuclear ophthalmoplegia Pupillary abnormalities Light-near dissociation Afferent pupillary defect Anterior visual pathways abnormalities Papilledema Optic atrophy Strabismic amblyopia Chiasmal syndrome (dilated third ventricle) Optic tract syndrome (damage during shunt placement or hippocampal herniation) Optociliary shunt vessels Cortical/cerebral abnormalities Cortical visual impairment Homonymous hemianopia, other visual field changes Higher cortical function disorders (e.g., constructional apraxia, dyscalculia)

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children with communicating hydrocephalus. It is useful, but not always possible, to differentiate the neuro-ophthalmologic signs arising due to the hydrocephalic process itself from those caused by associated tumors, malformations, infections, etc. It is also important to examine the parents head size, since a benign familial form of familial megalencephaly may simulate hydrocephalus.

Ocular Motility Disorders in Hydrocephalus Hydrocephalus can cause horizontal diplopia by producing either unilateral or bilateral sixth nerve palsy or comitant horizontal strabismus that is most commonly characterized by an A pattern esotropia with bilateral superior oblique muscle overaction. These findings are nonlocalizing. The sixth nerve paresis may result from a variety of causes: (1) a nonspecific response to the increased intracranial pressure, (2) traction at Dorello’s canal, or (3) as a result of shunt placement. Divergence paralysis, defined as comitant esotropia larger at a distance than near, has been reported in an adult as an early sign of aqueductal stenosis.399 In the setting of increased intracranial pressure, divergence paralysis may represent mild bilateral sixth nerve palsy, but damage to a putative divergence center usually cannot be ruled out. Unilateral or bilateral fourth nerve palsy occurs much less frequently and may be due to compression of the trochlear nerve by the tentorial margin. Bilateral fourth nerve palsy may also result from involvement of the superior medullary velum (the site of decussation of the trochlear nerves), either by tumor or by other changes brought about by the hydrocephalus itself. When bilateral fourth nerve palsy is found in the setting of nonneoplastic hydrocephalus, it may be a localizing sign of involvement of the superior medullary velum due to compression by a dilated aqueduct and/or downward pressure from an enlarged third ventricle. Such children typically show other neuro-ophthalmologic signs indicative of dorsal midbrain syndrome.373 Third nerve palsy rarely results from hydrocephalus independent of underlying causes such as tumors or infections.892 Exotropia in hydrocephalic children most commonly results from poor vision due to optic atrophy. Both comitant esotropia and exotropia are most common in children with hydrocephalus and neurodevelopmental abnormalities. The dorsal midbrain syndrome in hydrocephalus usually occurs with aqueductal stenosis and results from secondary dilation of the third ventricle or enlargement of the suprapineal recess with pressure on the posterior commissure.189,654 It is also an early sign of shunt failure. The dorsal midbrain syndrome may begin with light-near dissociation with little limitation of upgaze. The pupils are moderately enlarged and contract poorly in response to light stimulation but more fully to a near effort. Gaze paretic upbeat nystagmus then supervenes, followed by

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upgaze paralysis.202 The upgaze paralysis typically affects upward saccades more than upward pursuit, but complete paralysis of all volitional upward movements sometimes occurs. Vertical vestibulo-ocular movements are usually preserved, except in severe cases. It is important to remember that the congenital fibrosis syndrome can produce bilateral fixed downgaze with limited upward movements and jerky convergent saccades on attempted upgaze (reminiscent of convergence retraction nystagmus).118,301 The finding of bilateral ptosis rather than lid retraction helps to establish this diagnosis. The exact pathophysiology of the dorsal midbrain syndrome in hydrocephalus is unknown, but plausible explanations have been detailed by Corbett.202 The overriding factor appears to be increased periaqueductal tissue water content, due to aqueductal dilation, which results in decreased blood flow. Stretching of neural fibers may also play a role. Pupillary light-near dissociation results from dysfunction of the brachium of the superior colliculus and pretectal oculomotor fibers. Pathologic lid retraction (Collier sign) results from compression of levator inhibitory neurons within the posterior commissure from a dilated third ventricle. Paresis of upgaze results from the stretching of nerve fibers and diminished blood supply to the ventral posterior commissure (upgaze center), which in turn result from increased aqueductal size and increased periventricular water, with attendant decrease in blood flow. Convergence retraction nystagmus probably results from impairment of recurrent inhibition within the oculomotor subnuclei, which results in cofiring of the rectus muscles. It is not true nystagmus and is composed of opposing adducting saccades. A variant of convergence–retraction nystagmus that may be mistaken for ocular bobbing has been described in patients with acute obstructive hydrocephalus. This has been termed V-pattern, pretectal pseudobobbing. The typical features consist of arrhythmic, repetitive, fast downward and inward movements of the eyes (hence the V pattern designation) at a rate of 0.5–2 movements per second. The fast downward movement and the slower return render the condition readily mistakable for ocular bobbing due to pontine dysfunction, but it can be readily distinguished by the accompanying pretectal signs (e.g., abnormal pupillary light reaction, lid retraction), the intact horizontal eye movements, and a mute or stuperous (rather than comatose) patient.461 This constellation of findings occurs in acute obstructive hydrocephalus and warrants prompt neurosurgical intervention. The setting sun sign may be thought of as representing an exaggerated form of the dorsal midbrain syndrome and is unique to infants and young children. The setting sun sign is suggestive of congenital hydrocephalus and is usually diagnosed before closure of the anterior fontanelle.892 In addition to lid retraction and upgaze palsy, the eyes are conjugately deviated downward, a finding apparently unique to hydrocephalus in this age group. This suggests

a specific susceptibility of the neonatal brain to the mass effect of hydrocephalus on the downgaze center of the midbrain or a higher sensitivity of the pretectal area in infants to hydrocephalus, leading to a more profound upgaze palsy (causing the eyes to deviate downward).

Dorsal Midbrain Syndrome Although all vertical eye movements (upgaze, downgaze, reflexive, and voluntary) can be affected in the dorsal midbrain syndrome, an upgaze saccadic palsy is most frequent due to interruption of fibers of the posterior commissure.783,969 The interstitial nucleus of Cajal (INC) is the primary neural integrator for vertical gaze-holding and contributes to eye-head coordination. The rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) is considered the neural substrate for vertical saccades. The posterior commissure is comprised of a group of nuclei as well as axons from the INC, projecting to the ipsilateral as well as to the contralateral third nerve nuclear complex and fourth nerve nuclei. In addition, the posterior commissure contains fibers from the nucleus of the posterior commissure, projecting to the contralateral rostral interstitial nucleus of the MLF (riMLF) and INC that are important for upward movements. An insult to the posterior commissure can therefore result in impaired vertical eye movements, particular upward saccades, and other manifestations of the dorsal midbrain syndrome.153 Various other ocular motility signs are often associated with specific disease processes underlying the hydrocephalus. For example, both unilateral and bilateral internuclear ophthalmoplegia have been described in patients with Chiari malformations (previously discussed). Downbeat nystagmus commonly suggests Chiari malformation although it may rarely be a nonlocalizing sign of communicating hydrocephalus.686 Infants and children who develop hydrocephalus as a result of suprasellar arachnoid cysts may develop the bobble-headed doll syndrome. This consists of vertical head titubations (head nodding) that are slower (1–2 cycles per second) and larger in amplitude than those in spasmus nutans. Nystagmus is usually absent. Children with this syndrome are usually found to have a chiasmal syndrome by the time of diagnosis. They may also show nonparalytic horizontal strabismus. The head nodding resolves when the ventricular cyst is removed and the hydrocephalus is shunted. Children with frequently-revised VP shunts for hydrocephalus may develop severe bilateral enophthalmos.593 It seems plausible that the rostrocaudal brain shift accompanying the hydrocephalus may be pulling the optic nerve backward through the optic foramen.593 With recent advances in instrumentation, fiberoptic technology, and endoscopic technique, endoscopic third

Hydrocephalus

ventriculoscopy (ETV) have evolved into an excellent option in the management of third ventricular outflow obstruction.783 ETV creates an opening in the floor of the third ventricle, proximal to the site of obstruction, to allow CSF to enter the basal cistern and be absorbed through normal CSF pathways. Potential complications include arterial hemorrhage due to basilar artery injury, third cranial nerve palsy, meningitis, hemiparesis, delayed fistula closure, and hypothalamic dysfunction.193

Visual Loss in Hydrocephalus Hydrocephalus may have profound effects on the visual pathways, both anteriorly and posteriorly. A variety of visual field defects have been described in patients with hydrocephalus.481 Anterior visual pathway damage can result in unilateral or bilateral optic nerve damage, chiasmal syndrome, or optic tract injury. Many mechanisms of optic nerve damage in hydrocephalus have been reported, but the major mechanism is postpapilledema optic atrophy. A component of strabismic amblyopia may also be present. Papilledema is infrequently encountered in infants with hydrocephalus.202 In two infants, optociliary shunt vessels disappeared following a surgical procedure to normalize the intracranial pressure.262 Only 12% of 200 consecutive infants with hydrocephalus examined before shunt placement were found to have papilledema in one series.341 This paucity of papilledema has been explained by the presence of open sutures, permitting cranial enlargement, which reduces the rate of rise of intracranial pressure. However, an acute rapid elevation of intracranial pressure in an infant may overwhelm the compensatory effect of the open sutures and result in papilledema. After shunt placement, the cranial sutures fuse and subependymal fibrosis reduces ventricular compliance so that intracranial pressure increases and papilledema readily develops as a response to shunt malfunction. The papilledema that may accompany repeated bouts of shunt malfunction can eventually cause visual loss and visual field defects due to axonal attrition. Most cases of postpapilledema optic atrophy and visual loss are bilateral; they are often asymmetric but can be unilateral.158 In addition to postpapilledema atrophy, the anterior visual pathways can be damaged by distortion of normal intracranial relationships from dilated ventricles and compression of the pathways by a dilated third ventricle, adjacent arteries and veins, and adjacent basal bones. A chiasmal syndrome may result from compression of the optic chiasm from a dilated third ventricle. The anterior optic tracts are supplied by small arteries lying over bone. Pressure on these arteries has been suggested as one mechanism of visual

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loss.202 Downward herniation of the hippocampal gyrus into the tentorial notch may be another mechanism. Posterior visual pathway damage arises from posterior cerebral artery circulatory compromise, often presumably due to bilateral compression of the arteries on the tentorial edge (most common)202; from damage to the optic radiations associated with white matter loss as the posterior occipital horns enlarge; from neurosurgical damage; and from edema and swelling associated with hypoxia, meningitis, septicemia, surgical trauma, and seizures.335,832 Posterior visual pathway damage probably occurs more commonly after shunt failure than as a primary result of hydrocephalus.202 Many children with hydrocephalus show evidence of mixed anterior and posterior visual pathway damage. Even when good visual acuity is present, children with hydrocephalus share the patterns of perceptual and cognitive visual dysfunction found in children with periventricular leukomalacia.19

Effects and Complications of Treatment Untreated hydrocephalus inevitably leads to tissue damage and hemispheric atrophy. The brunt of atrophy is borne by the white matter. Hydrocephalus is usually treated by placement of a ventriculoperitoneal shunt or a ventriculoatrial shunt to divert the CSF. Timely treatment of hydrocephalus is essential to minimize the permanent neurological and ophthalmic adverse consequences. Ventricular dilation can regress completely upon early shunting. Certain neurologic abnormalities are quickly reversible upon shunting of the hydrocephalus. In some hydrocephalic children with cortical visual impairment, revision or placement of a shunt may be followed within several hours197 to a few months168 by visual improvement, possibly resulting from improved circulatory hemodynamics within the visual cortex. The setting sun sign and the various components of the dorsal midbrain syndrome ordinarily resolve shortly after shunt placement. Various electronystagmographic abnormalities continue to be detected in shunt-treated hydrocephalic children.547 Despite treatment, hydrocephalic children continue to perform below average in various neurologic and visual spheres. Rabinowicz704 examined visual perception in 100 hydrocephalic patients and found that the presence of constructional apraxia, dyscalculia, and homonymous field defects in some of the patients suggested a disorder of the posterior visual pathway and the parietal lobe. The setting sun sign usually improves quickly after shunting, but some upgaze paresis often persists. Mechanical malfunction and infection are the major complications of ventriculoperitoneal shunts.788 Ventricular shunt obstruction continues to represent a significant problem in the management of hydrocephalus, despite advances in

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materials, catheter design, new valves, and neurosurgical techniques.925 Shunt failure is usually associated with the recurrence of symptoms and signs of increased intracranial pressure (severe headache, nausea, vomiting, depressed consciousness). Newer studies showing that CSF is partially drained through perineural sheaths and lymphatics throughout the brain and nose (discussed in Chap. 3) may explain the frequent symptom of “stuffy noses” in children with shunt failure. In some children, it may manifest either as a new seizure or as recurrent seizure activity.289 Some patients may exhibit akinetic mutism and parkinsonian symptoms.80,545 Shunt malfunction is most commonly caused by occlusion of the lumen of the ventricular catheter by choroid plexus or glial tissue. The ventricles typically show enlargement upon shunt occlusion, but occasionally, increased intracranial pressure is associated with little or no ventricular enlargement. Most children with shunt failure do not have papilledema.628,688 Conversely, papilledema can sometimes be as the sole manifestation of shunt failure and cause permanent visual loss if undetected.456 Therefore, clinical signs of increased intracranial pressure should suggest shunt blockage even if the neuroimaging is unremarkable.633 In our experience, the papilledema associated with shunt failure is often associated with multiple splinter hemorrhages (Fig. 3.6). Rarely, superior oblique palsy may follow ventriculoperitoneal shunt placement.662 or endoscopic third ventriculostomy.827 When headaches occur with small ventricles (Fig. 11.25), the generic term slit-ventricle syndrome is applied.263,723 According to Rekate,721,723 the term slit ventricle syndrome, as used in clinical practice, comprises five distinct syndromes: (1) intermittent, extremely low-pressure headaches analogous to spinal headaches, (2) intermittent proximal obstruction, (3) shunt failure with small ventricles (normal volume hydrocephalus), (4) intracranial hypertension with working shunts (hydrocephalic pseudotumor), and (5) headaches unrelated to shunt function. The clinical picture is one of headache, nausea, vomiting, or lethargy.138 Mechanistically, overshunting at an early age may cause smaller head circumference and slitlike ventricles. Rather than brain growth and CSF pressure allowing for larger ventricular size and more growth of the skull, the CSF pressure is relieved by the shunt, and brain growth may not push the skull outward as it would normally. The brain then grows inward and leads to smaller ventricles. The shunt catheters are therefore more prone to malfunction because they rest up against the wall of the ventricles and obstruct more frequently within the slit-like ventricles. This process can be exacerbated by the considerable scar tissue formation in the ventricular walls (subependymal gliosis), decreasing their compliance. The initial goal is to determine whether the symptoms are caused by low or high intracranial pressure.138 Papilledema is uncommon, but postural headaches, visual field defects and optic atrophy are often found in

Fig. 11.25 Slit ventricle syndrome. Axial MR images showing slitlike ventricles in a shunted child with hydrocephalus who complained of postural headaches

these patients.253,634 Endoscopic third ventriculostomy and shunt removal has been used to treat this condition.176 Rarely, overdrainage can lead to subdural hematoma which can secondarily produce neuro-ophthalmologic signs of dorsal midbrain syndrome, such as upgaze palsy.895 “Smart” shunts with programmable valves that measure changes in pressure in the brain are being developed to avert these complications. Shunt obstruction may cause an acute rise in intracranial pressure and acute papilledema with rapid loss of vision. Loss of ventricular and cranial elasticity as the infant gets older contributes to the acute nature of symptoms and signs. Rapid shifts in the intracranial compartment may also occur, with compression of the posterior cerebral arteries and occipital infarction Children with shunt failure can develop papilledema in the absence of ventriculomegaly.610 For reasons that are poorly understood, the papilledema associated with shunt failure can have an unusually hemorrhagic appearance (Fig. 3.6). The onset of an acute headache with or without nausea and vomiting in a child with a shunt may pose a diagnostic quandary. Misinterpretation of signs and symptoms of a shunt obstruction as migraine attack delays proper revision of the shunt, and the converse leads to unnecessary surgical intervention. It is important to evaluate such a child promptly for shunt obstruction. If signs of shunt obstruction and

Vascular Lesions

increased intracranial pressure, such as papilledema, enlarging ventricular size on neuroimaging, and fourth nerve palsy, are absent, alternative diagnoses should be entertained.637 These include (1) intermittent shunt malfunction, (2) intracranial hypotension (overshunting syndrome), (3) intermittent episodes of increased intracranial pressure in the presence of normal shunt function, and (4) migraines.143 A family history of migraine, which is usually positive in up to 90% of cases of childhood migraines, should be carefully sought in such a child. If adequate shunt function can be demonstrated in such children, treatment for possible migraines should preempt operative intervention.429 A precipitous drop in intracranial pressure after shunting is rarely associated with acute visual loss.72 This is thought to arise from as yet incompletely understood vascular insufficiency at the optic disc,72 possibly related to changes in the autoregulation of the optic nerve blood flow. Intracranial hypotension secondary to overdrainage of CSF in patients with shunted hydrocephalus may be associated with symptoms and signs nearly identical to those associated with intracranial hypertension (intermittent headaches, nausea, emesis, lethargy, diplopia, strabismus, and paresis of upward gaze). However, the symptoms are usually brought about by standing and are relieved by lying down,309 which is the opposite of that observed in intracranial hypertension and blocked shunts. This disorder is usually seen shortly after shunt placement or revision and is often self-correcting within a few days.637 The major treatment options are surgical and consist of ventriculoperitoneal shunting to an implanted device or neuroendoscopy.553,722 Although rare, neuro-ophthalmologic deficits can arise as a result of direct injury to the brain during insertion of intraventricular shunts. Shults et al822 reported four such cases that showed homonymous hemianopia due to optic tract damage, esotropia, and residual bilateral facial paresis (bilateral sixth and seventh nerve palsy) from dorsal pontine injury at the level of the facial colliculi, monocular blindness from optic nerve damage, and dorsal midbrain syndrome from catheter compression in the region of the posterior commissure. Two cases of chiasmal syndrome with bitemporal hemianopia due to compression by a catheter placed in the third ventricle200 or the suprasellar cistern826 have been reported. In the latter case, the visual field loss progressed slowly over approximately 1 year. A malpositioned shunt rarely causes reversible quadrantic visual field loss due to intracerebral edema surrounding the ventricular end of the shunt.177 Direct damage to the visual pathways should always be considered in the differential diagnosis of neuro-ophthalmologic deficits in patients with intracranial shunts. Patients may also develop sixth nerve palsy after shunt placement. This is thought to be analogous to sixth nerve palsy arising after lumbar puncture, myelography,

553

or spinal anesthesia. Headache and nausea may precede the onset of esotropia and double vision. Most cases are transient, but some are permanent, requiring extraocular muscle surgery. 280 The increasing use of neuroendoscopy has led to a decreasing incidence in ventriculitis from percutaneous shunt infection. Over the last decade, endoscopic third ventriculostomy (ETV) has become the treatment of choice for noncommunicating hydrocephalus. ETV can be performed in children with aqueductal stenosis, posterior fossa tumors, fourth ventricular outflow obstruction, and spina bifida.553 ETV is most suited to treating aqueductal stenosis, with patency results reported at 80–90%. It is most effective in hydrocephalic children older than 2 years of age. ETV has remained controversial in younger children and infants, (perhaps because of the minor outflow CSF pathway that may predominate in this age group). The success of ETV in children younger than 2 years of age suffering from noncommunicating hydrocephalus seems to be dependent on both age and etiology, with better success rates seen in children with idiopathic aqueductal stenosis. It is unclear whether the persistent enlargement of the ventricles after endoscopic third ventriculostomy interferes with the mental development of patients compared with shunted patients, in whom the ventricles are usually small or even collapsed.39 Recently, third ventriculostomy with cauterization of the choroid plexus has been shown to be efficacious in the treatment of hydrocephalus associated with myelomeningocele.921

Vascular Lesions AVMs AVMs are the most common cause of spontaneous intracranial hemorrhage in children.411 Although the generally accepted view is that they are congenital lesions, the age at presentation is usually 20–40 years, suggesting a latency in the malformation’s evolution. Fewer than 10% of AVMs become symptomatic in the first decade of life. The classic AVM is presumed to represent a structural defect in the formation of the primitive arteriolar–capillary network normally interposed between brain arteries and veins.411 Histopathologically, surface AVMs appear as a conglomeration of turgid vessels covered by opacified, thickened arachnoid on the brain’s surface. The nearby cerebral convolutions show variable degrees of atrophy. Some AVMs are situated subcortically or hidden in a sulcus.411 Because of their low resistance, the tangled arteriovenous communications attract exaggerated blood flow. Over years, many AVMs gradually enlarge by increasing the size and tortuosity of their feeding

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

and drainage channels, but the number of fistulous connections probably does not increase.411 Children with AVMs may be more prone to present with a hemorrhage and to experience recurrence of the lesion after treatment.114 Humphreys411 reported a fourfold higher prevalence of AVMs than aneurysms in children with subarachnoid hemorrhage compared with that in adults.

ciated with AVM can be differentiated from migraine by the fact that it always occurs on the same side (i.e., ipsilateral to the lesion) is deeply entrenched in the literature, with scant data to support it.613 There is some controversy as to whether AVMs may also potentiate migraine in some patients, because their surgical resection sometimes leads to resolution of classic migraine headaches.730,883

Clinical Features of AVMs in Children

Natural History

AVMs are well known to produce a triad of hemorrhage, seizures, and recurrent headaches. A greater percentage of children than adults experience hemorrhage as the initial symptom, while adults are more likely to display symptoms of headache, dementia, or slowly progressive neurological dysfunction, which are presumed to be ischemic in origin.411 The prognosis in children with AVMs is less favorable than that in adults because of a higher mortality rate in younger patients due to hemorrhage.617 This discrepancy may be related to several factors: (1) there is some evidence that smaller AVMs are more likely to hemorrhage than giant ones (the larger the lesion, the longer it has been present, and the less likely it is to rupture)613; (2) some believe that hemorrhage in pediatric AVM is associated with more violent and massive bleeding than in adults169; and (3) children have a higher incidence of AVM location in the posterior fossa, where the effects of hemorrhage are more critical.411 Because bleeding may originate on the venous side of the malformation, it tends to be less torrential than with aneurysmal rupture. Terson syndrome, which may result from hyperacute elevation of intracranial pressure following aneurysmal rupture, is uncommon following hemorrhage from an AVM. AVMs can also shunt blood from adjacent brain parenchyma, resulting in relative underperfusion of the adjacent brain and in focal or generalized seizures. Cerebrovascular steal symptoms are inferred to be present when surgical excision or embolization of the AVM leads to clinical improvement in neurological function corresponding to sites that are remote from the AVM.613 Seizures are presumed to result from gliosis of brain because of chronic ischemia adjacent to the arteriovenous shunt. Estimates of the incidence of seizures as the presenting sign of AVM vary from 28 to 67%.613 These may be focal, generalized, or psychomotor, and they tend to show more variation in type and frequency than in cryptogenic or traumatic epilepsy. Many patients experience resolution of seizures following excision of the AVM. Headaches occurring in association with AVMs may be the result of dilation of the feeding arteries and, possibly, of the draining veins that involve the adjacent dura, particularly the tentorium.556 The notion that the recurrent headache asso-

Ondra et al649 prospectively studied the natural history of AVMs of the brain. They observed 160 unoperated symptomatic patients with brain AVMs for a mean follow-up period of 23.7 years. The mean interval between initial presentation and subsequent hemorrhage was 7.7 years. The rate of major rebleeding was 4.0% per year, and the mortality rate was 1.0% per year. The combined morbidity and mortality rate was 2.7% per year, and this rate remained constant over the entire period of the study. Initial presentation with or without hemorrhage did not change the incidence of rebleeding or death.

Treatment If an AVM of the brain is surgically accessible, surgical resection is the treatment of choice. Small or modest AVMs located in the frontal or polar regions are routinely treated with surgical resection because they carry significant risk of recurrent hemorrhage or progressive neurological deficit and have a low surgical morbidity and mortality.613 Larger lesions, those located in or around the motor or speech areas, lesions with arterial supply from all three vascular trees, and those involving the diencephalon, basal ganglia, or brainstem are associated with a higher risk of surgical complications. Such lesions are often treated with preoperative endovascular embolization of particulate matter into the feeding channels of AVMs prior to surgical resection to decrease the size and prevent intraoperative hemorrhage.410,613 Deep AVMs that are less than 2 cm in size can now be treated with stereotactic radiosurgery.410,557 This treatment involves focusing a collimated radiation beam on the AVM, which leads to a radiation-induced vasculitis, end-arteritis obliterans, and thrombosis of the AVM in approximately 80% of cases. Neuro-ophthalmologic manifestations of AVMs are protean (Table 11.3). Band atrophy and congenital homonymous hemianopia are associated with congenital AVMs that occupy the occipital lobe.406 Although AVMs in this location are generally believed to be congenital in origin and to produce optic atrophy via trans synaptic degeneration, some occipital

Vascular Lesions

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Table 11.3 Neuro-ophthalmologic complications from arteriovenous malformations639 Acquired visual field defects Acquired alexia with agraphia Congenital homonymous hemianopia Congenital or acquired band atrophy Papilledema Ocular motility deficits Proptosis Unformed visual hallucinations (occipital lobe epilepsy) Arteriovenous malformation of the optic nerve and retina (Bonnet–Dechaume–Blanc syndrome) Cerebral ptosis

AVMs have abnormal deep venous drainage remote from the nidus that directly involves the lateral geniculate nucleus and posterior optic tract, which could recruit blood from arteries near the optic tract and progressively injure pregeniculate axons postnatally.499 Acquired alexia with agraphia following rupture of an AVM has also been reported in an 11-year-old child.639 Papilledema may be associated with AVMs that (1) produce subarachnoid hemorrhage, (2) produce obstructive hydrocephalus by their mass effect, or (3) shunt large volumes of arterial blood into a venous sinus, resulting in venous sinus hypertension and decreased CSF absorption.142,508,601,759 Papilledema is most common in dural AVMs that drain directly into the venous sinuses454 and occur primarily in adults but may occasionally be seen in children.142 In some cases, chronic papilledema associated with AVMs can lead to progressive visual field loss.454 Proptosis in children can be the presenting manifestation of an AVM involving the galenic system.269 Remote supratentorial AVMs can also rarely produce unilateral or bilateral proptosis, presumably from direct shunting of blood into the cavernous sinus and its resultant hemodynamic changes within the orbit.565 The syndrome of unilateral retinocephalic AVM was first described by Bonnet et al98 in 1937. Six years later, WyburnMason954 added his report. Although Bonnet–Dechaume–Blanc syndrome is generally classified with the phakomatosis, cutaneous manifestations are usually subtle when present, consisting of a faint facial blush with scattered punctate red spots.115,868 In some cases, the retinocephalic malformation may also extend into the ipsilateral nasopharynx, maxilla, and mandible, producing severe epistaxis or life-threatening hemorrhage during dental extraction.131,868 The location of the AVM may lead to congenital or acquired neuro-ophthalmologic dysfunction.789 Homonymous hemianopia and cranial nerve palsies may result from hemorrhage, ischemia, or congenital replacement of neural tissue when the AVM involves the ipsilateral hemisphere or the brainstem. Ipsilateral optic atrophy occurs when the optic nerve is either replaced or honeycombed by a tangle of dilated

Fig. 11.26 Retinal photograph from patient with Bonnet–Dechaume– Blanc syndrome

vascular channels. Angiomatous involvement of the chiasm can cause band atrophy with a temporal hemianopia in the fellow eye.131 The orbital component of the retinocephalic malformation can lead to proptosis and dilation of conjunctival vessels.868,954 Over time, the retinal component of the AVM (Fig. 11.26) can progressively compromise vision by enlarging, hemorrhaging, sclerosing, or thrombosing.786 Over time, the retinal and intracranial component of the AVM can undergo spontaneous involution, leaving ghost retinal vessels in its wake.130 Effron et al271 described a 4-year-old girl with Bonnet– Dechaume–Blanc syndrome who developed a central retinal vein occlusion and neovascular glaucoma in the involved eye. Occipital AVMs can act as irritative epileptic foci and produce photopsias that can mimic the visual aura of migraine. These photopsias differ from those of classic migraine in that they begin and end abruptly, and they remain stationary rather than enlarge in a crescendo-like fashion.885 Supranuclear or infranuclear ocular motility deficits may be secondary to elevated intracranial pressure or to direct brainstem involvement.603 Dorsal midbrain syndrome can occur primarily from intrinsic midbrain involvement or secondary to compressive hydrocephalus.603 Other supranuclear disorders (gaze paresis, skew deviation, and internuclear ophthalmoplegia) may also be seen.603 Acquired progressive unilateral ptosis can be a rare manifestation of a contralateral hemispheric AVM. Lowenstein et al549 documented “cerebral ptosis” in two children who showed resolution of the ptosis following surgical removal of the AVM. They speculated that disruption of efferent fibers from the posterior frontal cortex by hemorrhage and

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

edema surrounding the AVM produced this reversible phenomenon. Children with AVMs may be more prone than adults to present with a hemorrhage and to experience recurrence of the lesion after treatment. In one study,663 61% of children with spontaneous intra-cerebral hemorrhage were found to have AVMs. Many surgeons favor resection for most AVMs and use embolization as a preoperative strategy for Grades II to V lesions treated surgically. Prehemorrhagic Grade IV and V lesions may best be treated conservatively and observed carefully for the development of symptoms.114 Although AVMs have been called the “most frequent abnormality of the intracranial circulation in childhood,”411 their natural history is poorly understood. They are generally considered congenital although some authors have recently challenged this notion.354,606 Children constitute 3–20% of patients with AVMs, and these lesions cause 30–50% of intracranial hemorrhages in children.169 Humphreys et al reported a fourfold higher prevalence of AVMs than aneurysms in children with subarachnoid hemorrhage compared with that in adults.411,829 The perioperative mortality rate was 3.7%. The recurrence rate was 5.6% over 3.3 years, consistent with rates in other pediatric series. The advent of the operating microscope and recent advances in endovascular and radiosurgical techniques (e.g., stereotactic guidance, intraoperative angiography) and have improved the success rate of treatment and offer more options for treatment of AVMs.

Cavernous Angiomas Cavernous angiomas are congenital blood vessel hamartomas composed of irregular venous sinusoidal channels separated by fibrous septae.564 They are often referred to as cryptic or occult vascular malformations because they are difficult to identify with angiography; however, they are now detected much more readily with MR imaging. Patients with cavernous angiomas may remain asymptomatic or present with seizures, intracerebral hemorrhage, or symptoms of an intracerebral mass lesion. Although rare in children, cavernous angiomas of the optic nerve and chiasm have been reported to produce visual loss.564 Chiasmal cavernous angiomas may present with insidious vision loss or acute visual loss associated with a throbbing headache (termed chiasmal apoplexy).563,564 Cavernous angiomas are now initially diagnosed by MR imaging and confirmed by biopsy. Some cavernous hemangiomas of the CNS occur in conjunction with cavernous hemangiomas of the retina and skin.331,332 When the diagnosis is established, other family members should also be examined because the conditions are often familial.564

Intracranial Aneurysms Intracranial aneurysms are uncommon in children. When they occur, aneurysms in the pediatric population are more commonly of the giant type (greater than 2.5 cm in size), and they more commonly arise peripheral to the circle of Willis than in the adult population.685 In a joint study of pediatric aneurysms, Roche et al747 found a marked sex predilection, with 70% of aneurysms arising in males. Several studies have noted an unequal topographic incidence in the circle of Willis, with 50% arising from the internal carotid bifurcation, 25% from the anterior cerebral artery, and 12.5% from the posterior cerebral artery in one study.422 Subarachnoid hemorrhage is the most common clinical presentation and may produce severe headache, vomiting, and obtundation, sometimes progressing to coma. Surgical treatment, consisting of removal of the aneurysmal sac, produces more favorable results than in adults, presumably due to cerebral plasticity and tolerance to vasospasm in children.747 Neuro-ophthalmologic signs of aneurysm in children usually result from subarachnoid hemorrhage (i.e., papilledema and sixth nerve palsy) rather than from compression. In some cases, hyperacute elevation in intracranial pressure associated with aneurysmal rupture results in Terson syndrome (papilledema with retinal and vitreous hemorrhage). Children with giant intracranial aneurysms (which constitute 20–40% of pediatric cases) may present with focal neurological symptoms and signs as a result of compression of the surrounding brain by the aneurysm.58 Posterior communicating artery aneurysms are particularly rare in children,37 but because of their immediate proximity to the third nerve, their enlargement may allow them to be diagnosed before rupture and subarachnoid hemorrhage occur, unlike other intracranial aneurysms that must reach giant size before producing signs of compression without subarachnoid hemorrhage.310 There have been only a handful of documented cases of acute third nerve palsy in children with posterior communicating artery aneurysms, all within the second decade of life.41,599,603,948 The question of whether to obtain cerebral angiography in children with acute third nerve palsy with pupillary involvement and headache but no signs of subarachnoid hemorrhage remains controversial.310 Most pediatric aneurysms are surgically clipped, but endovascular obliteration of the aneurysm can be performed in cases in which surgery is unsuccessful or when the aneurysm has no definable neck.376 Ocular hemorrhages (8% Terson syndrome and 9% other ocular hemorrhages) have been estimated to occur in 17% of patients with ruptured intracranial aneurysms.320

Strokes in Children

Isolated Venous Ectasia It is now well-recognized that orbital lymphangiomas can be accompanied by intracranial venous ectasia.455,802,906 Intraocular vascular anomalies affecting the iris or retina rarely coexist.802 The long-term prognosis and corresponding treatment implications for these intracranial venous ectasia are unknown.

Craniocervical Arterial Dissection Arterial dissection is probably an underrecognized cause of stroke in children. Rafay et al706 studied 213 children with arterial ischemic stroke and found 16 (7.5%) attributable to arterial dissection. The etiology of craniocervical arterial dissection in children was usually traumatic or idiopathic. Dissection involved the extracranial vessels in 75% and the anterior circulation in 56%. Most were treated with antithrombotic therapy. Followup showed a complete recovery in 43%, mild to moderate deficits in 44%, and severe deficits in 13%. Total occlusion had the worse prognosis for recanalization. Anterior dissection was more common in the traumatic group and posterior dissection in the spontaneous group, suggesting that the posterior circulation, especially the extracranial portion, might be more vulnerable to injury by trivial trauma, often causing there to be no associated history.706 Carotid dissection should be considered in the infant with a history of traumatic birth delivery and congenital Horner syndrome.372

Strokes in Children The advent of modern neuroimaging has led to the appreciation that childhood neurovascular disorders are more common than previously thought, perhaps approaching or exceeding childhood brain tumors in incidence.151,742 Strokes may be classified by the pathophysiologic mechanisms of the vascular dysfunction into cerebral embolism, arterial embolism, venous thrombosis, intraparenchymal hemorrhage, and subarachnoid hemorrhage. Unlike adults, in whom hypertension and atherosclerosis are the major risk factors for stroke, children have a wide array of risk factors, including vascular and metabolic etiologies (Table 11.4).797 While vascular causes of stroke have been discussed, a number of metabolic conditions warrant diagnostic consideration in the child with stroke.626,797 The pathogenesis of stroke in these disorders is not certain but may include mechanisms such as alterations in vascular endothelial wall integrity, platelet dysfunction, and alterations in cerebral perfusion

557 Table 11.4 Risk factors for pediatric cerebrovascular disease Congenital heart disease Ventricular or atrial septal defects Patent ductus arteriosus Valvular stenosis Cardiac rhabdomyoma Acquired heart disease Rheumatic heart disease Infectious endocarditis Cardiomyopathy Arrhythmia Kawasaki disease Atrial myxoma Systemic vascular disease Systemic hypertension, hypotension Diabetes Progeria Superior vena cava syndrome Vasculitis Meningitis, sepsis, varicella Systemic lupus erythematosis Polyarteritis nodosa, granulomatous angiitis Takayasu arteritis Drug abuse (cocaine) Vasculopathies Homocystinuria, Fabry disease, pseudoxanthoma elasticum Moyamoya syndrome Vasospastic disorders Migraine Vasospasm due to subarachnoid hemorrhage Hematologic disorders/hypercoagulopathies Sickle cell diseases Platelet disorders Neoplasms (e.g., leukemia) Protein C deficiency, protein S deficiency Lupus anticoagulant, anticardiolipin antibodies Antiphospholipid antibody syndrome Ornithine transcarbamylase deficiency Cerebrovascular structural anomalies Fibromuscular dysplasia Intracranial aneurysms Arteriovenous malformations Sturge–Weber syndrome Trauma Shaken baby syndrome Penetrating intracranial trauma Metabolic Cerebrotendinous xanthomatosis Familial hypercholesterolemia Hashimoto encephalitis Fabry disease Glutaric acidemia type 1 Homocystinemia Homocystinuria Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome Methylmalonic acidemia Organic-acid disorders (hyperammonemia, methylmalonic acidemia, propionic acidemia, isovaleric acidemia, glutaric aciduria) Ornithine transcarbamylase deficiency Tangier disease

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

or metabolism caused by the accumulation of toxic metabolites.179 Hashimoto thyroid-related autoantibodies cause encephalopathy with a relapsing course and normal cerebral angiography.811 Fabry disease and homocystinuria are associated with thrombosis.608 Elevated plasma levels of homocysteine secondary to gene variants that disrupt folate metabolism can produce a thrombo-coagulative predisposition and manifest as perinatal stroke.803 In the carbohydrate-deficient glycoprotein syndromes, there is evidence of abnormal coagulation.417 The concept of “metabolic stroke,” proposed to explain the focal lesions in patients with methylmalonic acidemia, postulates that an accumulation of toxic metabolites causes infarction in the absence of hypoxia or vascular insufficiency.387,445 Organic acid disorders occur because of defects in mitochondrial metabolism, resulting in impairment of oxidative metabolism. Acute or subacute encephalopathy in the neonatal period or infancy is a common presentation, often with hyperammonemia. The clinical spectrum is broad, however, and includes progressive psychomotor retardation and seizures. Certain organic-acid disorders have been associated with stroke like episodes, including methylmalonic acidemia, propionic acidemia, isovaleric acidemia, and two forms of glutaric aciduria (Types 1 and II).113,899 Clinical features of these disorders include an extrapyramidal syndrome characterized by dystonia and tremor and pyramidal tract signs such as spastic quadriparesis. Neuroimaging shows predominant involvement of basal ganglia in cases with stroke, and diffuse deep white-matter involvement is typical.387,397 The mitochondrial encephalomyelopathies (discussed in Chap. 10) are a heterogenous group of disorders that can cause central nervous system and neuromuscular disease.797 Although any tissue in the body can be affected, brain tissue and muscle are particularly vulnerable. The syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes has seizures and strokelike episodes as prominent features (MELAS).682 The hallmark of this syndrome is the occurrence of strokelike episodes that result in hemiparesis, hemianopia, or cortical blindness. Focal or generalized seizures, recurrent migraine-like headaches, vomiting, short stature, hearing loss, and muscle weakness are common. The syndrome usually develops during childhood and has a relapsing and remitting course, with strokelike episodes separated by periods of variable resolution but resulting in neurologic dysfunction and dementia.797 The pathogenesis of strokelike episodes in patients with MELAS remains controversial. Ornithine transcarbamylase deficiency, the most common urea-cycle defect, is an X-linked disorder. The spectrum of severity of symptoms in heterozygous female carriers is broad, with some having severe symptoms. Patients may have a history of protein avoidance and complicated migraine

headaches. Recurrent strokelike episodes and seizures can be triggered by intercurrent infection and increased metabolic demand. Hyperammonemic episodes can lead to cerebral edema and increased intracranial pressure. The sequelae of severe hyperammonemic episodes includes cortical blindness, which is usually transient.18,140 The neuro-ophthalmologic complications of strokes in children are the same as those in adults, with the caveats that acquired homonymous hemianopia in children more commonly results from trauma or tumors (and their neurosurgical resection) than from vascular disease462,544 and that children tend to show greater recovery of function and superior abilities to compensate for their deficits. Disorders of higher cortical dysfunction, such as alexia without agraphia, are increasingly recognized in children with stroke.639,665 Prosopagnosia may accompany periventricular leukomalacia426,583,767 or occur as a congenital hereditary condition of unclear etiology in children.366,367

Cerebral Venous Thrombosis Cerebral venous thrombosis (CVT) is an important cause of stroke and of idopathic intracranial hypertension in children.242 CVT-venous infarction is often hemorrhagic and typically causes increased intracranial pressure.16 It affects primarily neonates and results in neurologic impairment or death in approximately 50% of cases.242 Hypoxic–ischemic encephalopathy is the most common perinatal complication.242 The occurrence of venous infarcts or seizures portends a particularly poor outcome.242 Perinatal risk factors are usually present (birth hypoxia, premature rupture of membranes, maternal infection, placental abruption), as well as gestational diabetes in neonates, infectious disorders of the head and neck, or chronic systemic diseases in older patients.242 In one study,166 the most common risk factors included mastoiditis, persistent pulmonary hypertension, cardiac malformations, and dehydration. Coagulation studies are also often abnormal (presence of anticardiolipin antibody, decreased levels of protein C, antithrombin, protein S, fibrinogen, and plasminogen, lupus anticoagulant, factor V Leiden, and G20210A prothrombin gene mutation). Deficiencies of antithrombin, protein C, and protein S are, in many cases, caused by an acquired disorder such as liver disease, nephrotic syndrome, prothrombotic drugs (asparaginase, oral contraceptives) or by disseminated intravascular coagulation.242 Children may present with decreased level of consciousness, focal neurological signs, and cranial nerve palsies, while neonates tend to present with seizures and diffuse neurological signs.242 MR imaging with MR venography (MRV) is recognized as the optimal technique for establishing the diagnosis of cerebral venous sinus

Cerebral Dysgenesis and Intracranial Malformations

thrombosis,23 but there are several pitfalls to using it. MRV may show dominance of the transverse sinus on one side and hypoplasia or atresia of transverse sinuses as variants of normal.940 Moreover, fenestrations and arachnoid granulation may simulate thrombi. For this reason, it may be advisable to perform MRV in conjunction with MR imaging with gadolinium enhancement. In neonates, CT scans may show false positive results because of increased hematocrit, decreased density of unmyelinated white matter, and slower venous flow, resulting in findings that mimic the dense-triangle sign.554 Contrary to ischemic arterial stroke, cerebral venous thrombosis carries a good neurological prognosis once the acute phase is survived.851 Lumbar puncture is important to check CSF pressure and rule out infection and carcinomatous meningitis.211 A recent multicenter study of cerebral venous sinus thrombosis in children found that predisposing factors were identifiable in (90%) of cases.924 They included infection in 40%, perinatal complications in 25%, hypercoagulable or hematologic diseases in 13%, and other conditions in 10%. Presenting features included seizures (59%), coma (30%), headache (18%), and motor weakness (22%). Hemorrhagic infarcts occurred in 40% of patients, and hydrocephalus in 10%. Transverse sinus thrombosis was more common (73%) than sagittal sinus thrombosis (35%). Fifty-five percent were younger than 6 months of age. Seizures and coma were poor prognostic indicators. Only 25% were treated with anticoagulation and thrombolysis, while 70% were treated with antibiotics and hydration. Mortality was 13% overall but 25% in neonatal cerebral venous thrombosis. Mortality is generally higher (25%) in neonatal cerebral venous thrombosis.166 Symptomatic treatment includes antiepileptic medications for treatment of seizures, antibiotics for treatment of infection (when present), and heparin for anticoagulation which, although its systematic use remains debated, has been shown to be safe even in patients with large hemorrhagic infarctions.91 Decompressive craniotomy may be needed acutely for severe cases with intractable intracranial hypertension and herniation.91

Cerebral Dysgenesis and Intracranial Malformations Malformations caused by abnormalities of cortical development comprise a heterogenous group of multifactorial disorders.660,661 These malformations can arise from derangements in neuronal or glial proliferation, neuronal migration, or subsequent cortical organization can result in a cortical malformation.47 Their causes are protean. Chromosomal mutations, destructive events arising from ischemia or infection, and tox-

559

ins (both exogenous toxins such as drugs or alcohol, or endogenous toxins in metabolic disorders) can interfere with stem cell production, radial glial development, neuronal migration, or the disengagement of neurons from radial glial fascicles and their subsequently organization.47 Destructive events, arising from ischemia or infection can damage the germinal matrix, the radial glial fibers, the molecular layer, or the overlying “pial-glial barrier.” The type, timing, and severity of injury and its potential for impact at different stages of cortical development all influence the final histopathology.660,661 Classfications of this complex group of malformations have been based on histopathology, embryological timing, or neuroimaging descriptions, and genetic aspects.660,661 Barkovich47 had classified these disorders based primarily upon the step in which cortical development is most likely perturbed. This classification system comprises disorders of stem cell proliferation or apoptosis (microcephaly with normal to thin cortex or with polymicrogyria/cortical dysplasia, hemimegalencephaly, cortical hamartomas of tuberous sclerosis, ganglioglioma/gangliocytoma); disorders of neuronal migration (lissencephaly, cortical heteroptopia); and disorders of late migration and cortical organization (polymicrogyria, schizencephaly, cortical dysplasia).47 Although they may overlap with disorders of neuronal migration such as lissencephaly,402,755 cerebellar malformations are generally classified into a discussed in a separate category. These complex classification schemes for malformations of cortical development are undergoing almost continuous revision, with a trend toward reclassifying them by causative gene, rather than by clinical phenotype, wherever possible.55,58,369,370 Clinically, malformations of cortical development are common causes of epilepsy and developmental delay that were considered idiopathic before modern neuroimaging.47,503 The availability of MR imaging has enhanced our ability to identify dysgenetic anomalies and CNS malformations in vivo and to correlate them with their associated neuro-ophthalmologic findings.66 New genes for most of the disorders have been mapped or cloned, but some cases clearly result from intrauterine ischemia or infection. Congenital or perinatal brain injury may affect the developing visual system at multiple levels. Optic disc anomalies, cortical visual loss, and homonymous hemianopia in children frequently reflect a primary dysgenesis or intrauterine injury of the developing brain. Many midline or hemispheric brain malformations directly or secondarily involve the developing visual system and produce congenital visual loss associated with small optic nerves. Other brain malformations are associated with additional malformations of one or both optic nerves at the junction with the globe, as in the morning glory disc anomaly, optic disc coloboma, and multiple malformation syndromes (e.g., Aicardi syndrome, Walker–Warburg syndrome, linear sebaceous nevus syndrome). The type of

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

optic disc malformation can often be predicted from the associated brain anomalies.117 Conversely, the appearance of the anomalous optic disc may be used in conjunction with other associated systemic and neurological abnormalities to predict that a specific constellation of CNS abnormalities will be found on neuroimaging. While considerable progress has been made in correlating malformations of the brain with those of the optic discs, little is known about the pathogenesis of each malformation complex. Depending also on their location, prenuclear and infranuclear ocular motor signs can arise from congenital malformations. As discussed in Chap. 1, children with cortical visual loss or congenital homonymous hemianopia do not generally develop nystagmus but often manifest a constant exotropia which should raise suspicion of CNS disease. Ocular motility disturbances such as periodic alternating nystagmus, A-pattern strabismus with superior oblique muscle overaction, congenital ocular motor apraxia, or skew deviation can reflect structural malformations within the posterior fossa that can disrupt the system at a pre- or postnuclear level. Ischemic injury to the developing brainstem in the intrauterine or perinatal period can even be associated with a congenital ocular motor nerve palsy. While congenital third nerve palsy may be the presenting sign of intrauterine or perinatal brainstem injury,41 congenital fourth nerve palsy and congenital sixth nerve palsy (including Duane syndrome) generally do not portend CNS malformations. In the following section, the common malformations encountered in neuro-ophthalmological practice are discussed.

Destructive Brain Lesions Destructive injuries to the developing brain include porencephaly, hydranencephaly, colpocephaly, and encephalomalacia.47 Because the fetal brain has limited capacity for astrocytic reaction, necrotic tissue is completely reabsorbed by liquefaction necrosis. The ability to mount an astrocytic response begins somewhere during the late second or early third trimester.47 Earlier injuries tend to produce porencephaly or hydranencephaly, consisting of a smooth-walled cyst, while later injuries result in encephalomalacia (with astroglial cells and an irregular wall consisting primarily of reactive astrocytes). In the mature brain, injury results in gliosis with no appreciable cystic component.

signifies localized brain injury during the first two trimesters of gestation when the brain has limited capacity to mount a glial reaction, and necrotic tissue is completely reabsorbed by liquefaction necrosis.47 On MR imaging, porencephalic cysts appear as smooth-walled cavities that are isointense to CSF on all pulse sequences (Fig. 11.27). Although porencephaly is caused by perinatal vascular insults, it may also have a genetic underpinning. Several familial cases have been described, and autosomal inheritance linked to chromosome 13q has been suggested. A recent study linked porencephaly in two families to mutations in COL4A1, an essential component of basement membrane stability that has been associated with perinatal hemorrhage or porencephaly when mutated in a mouse model.361 COL4A1 may be a major locus for genetic predisposition to perinatal cerebral hemorrhage and porencephaly in humans.111 When posterior porencephalic cysts involve the optic radiation or occipital cortex, affected patients have congenital homonymous hemianopia with homonymous hemioptic hypoplasia.406,862 Davidson et al226 documented porencephaly and optic nerve hypoplasia in four infants who were found to have neonatal isoimmune thrombocytopenic purpura.

Hydranencephaly Hydranencephaly is a devastating condition in which most of the brain mantle (cortical plate and hemispheric white matter) has been damaged, liquefied, and resorbed.47 The cerebral hemispheres are almost completely replaced by thin-walled sacs containing CSF (Fig. 11.27).315,717 The brainstem is usually atrophic, but the thalami and cerebellum are fairly well preserved.47 Although some have considered this condition to be a congenital anomaly, hydranencephaly represents a destructive process that can be conceptualized as porencephaly of the entire cerebral hemispheres. A similar condition has been induced in laboratory animals by occlusion of both cerebral hemispheres in utero. The optic nerves are formed but severely hypoplastic.388a Neurologically, children with hydranencephaly are severely developmentally delayed from birth and may be macrocephalic, normocephalic, or microcephalic, depending upon the degree of associated hydrocephalus.47 When hydranencephaly is associated with hydrocephalus, shunting does not improve intellectual development but may prevent the development of a grotesquely enlarged head.47 In other cases, severe hydrocephalus can produce extreme thinning of the cortical mantle and simulate hydranencephaly.

Porencephaly Encephalomalacia The term porencephaly refers to a smooth-walled, fluid-filled cavity that communicates with the ventricular system, the subarachnoid space, or both.5,47 The finding of porencephaly

Unlike porencephaly and hydranencephaly, encephalomalacia is characterized pathologically by astroglial proliferation and,

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Cerebral Dysgenesis and Intracranial Malformations

Fig. 11.27 Basic patterns of brain destruction. (a) porencephaly; (b) hydranencephaly; (c) encephalomalacia; (d) colpocephaly

often, septations in the area of damaged brain (Fig. 11.27).47 MR imaging shows reactive gliomas and tissue injury that are dark on T1-weighted images and bright on T2-weighted images. These findings signify injury to the mature brain, which has acquired the capacity to react to injury with significant astroglial proliferation. Neuro-ophthalmologically, encephalomalacia most often correlates with cortical visual insufficiency associated with hypoxic–ischemic injury to the visual system at term.

Colpocephaly Colpocephaly was once considered to be a distinct anatomic finding in the brain manifested by occipital horns that are disproportionately enlarged when compared with other parts of the lateral ventricles (Fig. 11.27).389 However, it is really a descriptive term with no inherent diagnostic significance. Colpocephaly is most often seen in association with agenesis of the corpus callosum, and can accompany a variety of degen-

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

erative or encephaloclastic insults to the developing brain.389 Its many causes range from destructive injuries (usually due to white matter injury in prematurity) and developmental dysgenesis (as with lissencephaly and callosal agenesis). Clinically, it is often associated with seizures, spasticity, and mental retardation, but some children are neurodevelopmentally normal.389 Colpocephaly and associated callosal agenesis may accompany a variety of congenital optic disc anomalies, most notably optic nerve hypoplasia, the morning glory disc anomaly, and other optic disc dysplasias in children with transsphenoidal encephalocele and Aicardi syndrome.163 It has also been described with bilateral cortical visual loss and with congenital homonymous hemianopia.329

insults that produce transmantle injury during the middle of the second trimester.47,530 Schizencephaly is of neuro-ophthalmologic interest primarily because of its strong association with septo-optic dysplasia.48,54,128,180,494 In some cases, this association may reflect a disruption of normal guidance mechanisms involved in the migration of both neurons and optic nerve axons in utero, preventing them from forming appropriate connections at their target sites. Alternatively, a prenatal hemispheric injury or malformation that directly involves the optic radiations can lead to transsynaptic degeneration and homonymous hemioptic hypoplasia. In some children, these two mechanisms may coexist.

Hemimegalencephaly

Malformations Due to Abnormal Stem Cell Proliferation or Apoptosis Schizencephaly Schizencephaly (sometimes termed agenetic porencephaly) refers to an abnormal gray matter-lined cleft that extends through the cerebral hemisphere, from the lateral ventricle to the cortical surface (Fig. 11.28).58 The gray matter lining the cleft is usually abnormal in the form of polymicrogyria (small, irregular gyri without intervening sulci). Unlike porencephaly, however, schizencephaly is believed to result from destruction of a portion of the germinal matrix before the hemispheres form.58 Schizencephaly occurs most commonly in the parasylvian region and in the precentral and postcentral gyri.21 Schizencephaly can be unilateral or bilateral, and open-lipped (the walls of the cleft do not appose each other) or closed-lipped (the walls of the cleft do not appose each other and are often fused).530 Pathological studies suggest that it results from a hemispheric injury early in the second trimester.54 Children with schizencephaly present with seizures, hemiparesis, and variable developmental delay, with the severity of disability related to the amount of involved brain.21,47,55,362,604 Barkovich and Kjos55 reviewed neurodevelopmental records from 20 patients with schizencephaly and found bilaterality, large cleft size, and frontal lobe involvement to be associated with more severe intellectual and neurological deficits. As is the case with many malformations, schizencephaly seems to result from both genetic and acquired causes. For example, some cases may be familial363,384,746 and may be associated with mutations of the EMX2 homeobox gene, located on chromosome 10q26,139 which is expressed in the germinal matrix of the developing cerebral neocortex. Several attempts to verify EMX2 mutations in schizencephaly have heretofore been unsuccessful.591 Acquired causes include congenital CMV infection and in utero ischemic

Hemimegalencephaly (also termed unilateral megalencephaly) is a rare brain malformation characterized by congenital hamartomatous overgrowth of one cerebral hemisphere, with increased white matter volume and dilation of the lateral ventricle on the affected side (Fig. 11.28).47,244 MR imaging and histopathological examination show a wide array of migration anomalies, including pachygyria, polymicrogyria, and cortical heterotopias in the enlarged hemisphere.47,244 Hemimegalencephaly may accompany a number of neurocutaneous disorders of neuro-ophthalmologic interest; however, its frequency in the linear sebaceous nevus syndrome is particularly high.374,780 In this context, it can be associated with a variety of optic disc anomalies, including peripapillary staphyloma, 133,814 coloboma, 185,254,615 optic nerve hypoplasia,457 pseudopapilledema,159 and peripapillary chorioretinal lacunae.615,683 In retrospect, many early descriptions of unilateral “cerebral atrophy” in linear sebaceous nevus syndrome undoubtedly represented hemimegalencephaly affecting the contralateral hemisphere.133 It has been occasionally reported in neurofibromatosis,218 Klippel– Trenauney–Weber syndrome,146 and hypomelanosis of Ito,530 and linear nevus sebaceous syndrome.133 The clinical picture is usually dominated by severe, drugresistant epilepsy. Clinical features include early-onset seizures, severe encephalopathy, hemiplegia, and hemianopia.133,530 Because the affected hemisphere has essentially no function, partial or complete hemispherectomy may be indicated in children with intractable seizures and a normal contralateral hemisphere.45 Despite its high complication rate and significant mortality risk, hemispherectomy or hemispherotomy is the most effective treatment to control seizures, and it also seems to provide good results on psychomotor development when performed early.770 Patients with hemimegalencephaly actually have bilateral cerebral hemispheric abnormalities and contralateral hemimicrencephaly, which is the likely explanation for the poorer seizure control and cognitive outcomes in this group following surgical hemispherectomy.244

Cerebral Dysgenesis and Intracranial Malformations

Fig. 11.28 (a and b) Examples of abnormal stem cell proliferation. (a) Schizencephaly. Arrows denote gray matter lining bilateral schizencephalic clefts; (b) hemimegalencephaly – note larger right hemisphere with ipsilateral ventriculomegaly. (c and d) Two often coexisting malformations

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secondary to abnormal neuronal migration. (c) Lissencephaly. Note smooth, featureless cortex with thickened cortical mantle and no visible gyrations. (d) Pachygyria. Note areas of large, thickened poorly formed gyri (e) Isolated gray matter heterotopia (arrow)

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

Malformations Due to Abnormal Neuronal Migration Lissencephaly The terms lissencephaly (smooth brain) or agyria–pachygyria, are applied to several disorders of neuronal migration that result in a smooth cortex with absent sulci (agyria) or in a paucity of broad cortical gyri (pachygyria) (Fig. 11.28).3,53 In this condition, the architecture of the cortical plate is severely disturbed because of altered or arrested neuronal migration during corticogenesis.5 Lissencephaly can result from many causes, including congenital infection, (especially cytomegalovirus), impaired stem cell formation, and abnormal neuronal migration.47 Pachygyria results when neuronal migration is disrupted at a later stage. Classical lissencephaly is characterized by a thickened cortex with reduced numbers of gyri and cortical neurons (Fig. 11.28). Microscopic examination shows a thick disorganized cortex that has four layers rather than the normal six layers.530 Lissencephaly is often accompanied by areas of pachygyria, and genetic studies have confirmed that these two malformations exist on a continuum of migratory derangements caused by gene mutations.660,661 Mutations in six genes (LIS1, DCX, TUBA1A, RELN, VLDLR, and ARX) have to date been associated with lissencephaly, with mutations in LIS1 by far the most common.369 An autosomal recessive form of lissencephaly with severe abnormalities of the cerebellum, hippocampus, and brainstem has been mapped to chromosome 7q22, with mutations mapped to the RELN gene, which acts on migrating cortical neurons.370,402 A syndrome of lissencephaly with agenesis of the corpus callosum and a rudimentary dysplastic cerebellum has also recently been described.370,755 Classical lissencephaly (previously known as type 1) and cobblestone lissencephaly (previously known as type II) constitute the two major subtypes. Because of its associated ocular malformations, cobblestone lissencephaly is of greater importance to ophthalmologists. The “cobblestone cortex” of lissencephaly is characterized by multiple coarse gyri with agyric regions, a disorganized cortex of variable thickness in both the cerebral hemispheres and the cerebellum, and deficient neuronal migration.204,265,377 Other associated features include enlarged lateral ventricles, a flat brainstem, and cerebellar hypoplasia. The term lissencephaly type 2 has previously been described to characterize the brain malformation associated with Walker–Warburg syndrome.256 However, on pathologic examination, the disorganized cortical layers clearly distinguish this malformation from classic four-layered lissencephaly.204 The neuropathologic distinction of the cobblestone cortex in Walker–Warburg syndrome and muscle–eye–brain disease is based mainly on the degree of severity although additional features such as occipital enceph-

alocele, fusion of the hemispheres, and absent corpus callosum may occur in some patients with Walker–Warburg syndrome. Clinically, the cobblestone lissencephalies are characterized by hypotonia starting at birth, generalized muscle weakness, joint contractures, and associated CNS and ocular abnormalities. The three autosomal recessive disorders that share this combination of muscular dystrophy and brain malformations secondary to a neuronal migration defect are muscle–eye–brain disease, Walker–Warburg syndrome, and Fukuyama congenital muscular dystrophy. All muscle–eye– brain disease and Walker–Warburg syndrome patients present as retarded, floppy infants with suspected blindness and elevated creatine kinase values. Walker–Warburg syndrome usually causes death in infancy, while children with muscle– eye–brain disease may survive later into childhood. Ocular abnormalities are a consistent feature of Walker–Warburg syndrome and muscle–eye–brain disease. Although the phenotypic distinction between muscle–eye–brain disease and Walker–Warburg syndrome has remained controversial, these disorders are now considered to be distinct, both on clinical and genetic grounds.46,204,256,624,776,898 Walker–Warburg syndrome is an autosomal recessive disorder that is of neuro-ophthalmologic interest because of its association with hydrocephalus and optic disc anomalies and its overlap with hydrocephalus and septo-optic dysplasia. Diagnostic features consist of type II lissencephaly, cerebellar malformations, retinal abnormalities, and congenital muscular dystrophy.466 Other ocular findings include anterior chamber malformations (Peters anomaly), cataracts, persistent pupillary membrane, persistent fetal vasculature, retinal detachment, optic nerve hypoplasia, coloboma, and hypertelorism. Ophthalmologic abnormalities in Walker–Warburg syndrome have been congenital in origin and involve both the anterior and posterior segments. These include optic nerve coloboma, cataracts, microphthalmia, buphthalmos, persistent hyperplastic primary vitreous, Peters anomaly, retinal dysplasia with rosette formation, and retinal detachment.255,919,920,922 Affected infants may present with microphthalmos or buphthalmos (secondary to congenital glaucoma). Histologically, Walker–Warburg syndrome is characterized by a chaotic and unlayered cortical architecture. Hydrocephalus is attributed to proliferation of glio-mesenchymal tissue in the leptomeninges and around the brainstem, such that the subarachnoid space is often totally obliterated. MR imaging shows a smooth cerebral surface and a cortex that is abnormally thick, with absent white matter interdigitations.255 The appearance of the cortex is also distinctive, with an irregular gray matter–white matter junction, possibly reflecting the extension of bundles of disorganized cortical neurons into the underlying white matter49 and producing the classic cobblestone appearance of the cortex.47 The cerebellum is hypoplastic and usually lacks a posterior vermis. However, the posterior fossa is not enlarged, which distinguishes

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Cerebral Dysgenesis and Intracranial Malformations

Walker–Warburg syndrome from Dandy–Walker syndrome.56 The corpus callosum and septum pellucidum are frequently absent or hypoplastic.255 Aqueductal stenosis and posterior encephalocele are variable findings. The white matter is severely hypomyelinated, with a paucity of oligodendrocytes and axons. Signs of congenital muscular dystrophy include pathological changes, myopathic changes on electromyography, and elevated creatinine kinase levels.255 Because most children survive only a few months, recognition of this condition may preclude surgical treatment of associated ocular malformations such as persistent hyperplastic primary vitreous, Peters anomaly, glaucoma, or retinal detachment.46,729 Approximately 20% of affected patients have mutations in the POMT gene on chromosome 9q34, suggesting that it is genetically heterogenous.77 Muscle–eye–brain disease, described primarily in patients from Finland, presents intermediate ocular and neurologic features between the previous two conditions, with some patients requiring shunting for hydrocephalus and some having callosal dygenesis.775,776 The ocular abnormalities of muscle–eye–brain disease are characterized by coarse trabecular meshwork in the anterior chamber, predisposing to glaucoma and progressive cataracts. 691 It is linked to a mutation on chromosome 1p32–34. 203 Fukuyama Congenital Muscular Dystrophy is an autosomal recessive condition, affecting patients primarily of Japanese ancestry and associated with mutations at chromosome 9q31–33.872 Serum creatine kinase levels are elevated, and muscle biopsy shows signs of muscular dystrophy. Ocular abnormalities are less severe (myopia, nystagmus, chorioretinal degeneration),394 as are the associated hydrocephalus and callosal abnormalities.47

Gray Matter Heterotopia Heterotopia are masses of normal neurons in abnormal locations, presumably resulting from an arrest of normal neuronal migration along radial glial fibers. Heterotopia have been associated with a wide array of genetic, vascular, and environmental causes, and they may be subcortical, diffuse, or subependymal in location.51 MR diagnosis of heterotopia is based on the finding of heterotopic gray matter that is isointense, with orthotopic gray matter on all pulse sequences that does not enhance with contrast (Fig. 11.28).51 Children with heterotopic gray matter usually present with seizures.47,51 The degree and type of associated neurodevelopmental deficits are related to size, extent, and location of the heterotopias. Many cases are familial, and causative mutations have been identified. Cerebral heterotopia are subclassified into subependymal heterotopia, focal subcortical heterotopia, and band heterotopia (double cortex) may reflect different

genetic causes.47,51,813 For example, mutations in the filamin-1 gene (FLN1) at chromosome Xq28 are now known to cause subependymal heterotopias,311 and Doublecortin mutations are the most common cause of X-linked subcortical laminar heterotopia.238 Isolated optic nerve hypoplasia is the most common neuro-ophthalmologic association,128 but multisystem disorders such as Aicardi syndrome may also be found. Classical X-linked bilateral periventricular heterotopia, a specific disorder featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations, and epilepsy, is a disorder caused by mutations causing loss of function in the human filamin A gene.669

Malformations Secondary to Abnormal Cortical Organization and Late Migration Polymicrogyria Polymicrogyria is a malformation of cortical development characterized by an excessive number of small gyri with abnormal lamination (Fig. 11.29).382 It is believed to result from a midcortical ischemic necrosis predominating in layer 5 of the developing cortex.56 Macroscopically, it appears as an irregular cortical surface.530 It has a range of histopathologic appearances that are all characterized by derangement of the normal six-layered lamination of the cortex.47 With the advent of MR imaging, polymicrogyria is now recognized as one of the most common malformations of cortical development.530 Two main forms of polymicrogyria (unlayered and layered, true, or structured) have been described, but there may be considerable overlap in the same patient.530 Polymicrogyria may occur as an isolated familial condition in the setting of chromosome deletion syndromes,100,162,163,502,690,909 in metabolic disorders,530 with intrauterine ischemia,62 and cytomegalovirus infection (Fig. 1.5).47,50,530 It is a common manifestation of congenital cytomegalovirus infection.62 Polymicrogyria usually presents as an isolated malformation but may at times be accompanied by abnormalities of the corpus callosum, brain stem, and cerebellum.62,162,530 The clinical manifestations depend primarily on the location and extent of cortical involvement,47 with bilateral involvement and involvement of more than one half of a single hemisphere considered poor prognostic indicators.50 Children with focal unilateral polymicrogyria involving the frontal cortex may present with congenital unilateral hemiplegia, while focal occipital polymicrogyria may result in congenital homonymous hemianopia.891 Bilateral cases involving the occipital lobe may cause cortical visual impairment.357 Diffuse polymicrogyria is associated with microcephaly, hypotonia with subsequent appendicular spasticity, seizures (usually infantile spasms), and developmental delay.62

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

Fig. 11.29 Malformations secondary to abnormal cortical organization and late migration. (a) Polymicrogyria (arrows denote region of anomalous cortical migration); (b) Septo-optic dysplasia with mild holoprosencephaly. Note absence of septum pellucidum with anomalous

interdigitations of cerebral gray and white matter just above dilated lateral ventricles; (c) Agenesis of corpus callosum (arrow denotes position of normal corpus callosum)

A number of bilateral region-specific polymicrogyria syndromes of genetic origin have been documented.50 Most reported unilateral cases have been sporadic, but rare familial cases of unilateral polymicrogyria have also been noted.62,173,676,965 Unilateral polymicrogyria is a common cause of congenital hemiplegia.173,368,607 PAX6 mutations have been associated with absence of the pineal gland and unilateral polymicrogyria.607 The fact that isolated polymicrogyria so rarely accompanies optic nerve hypoplasia may reflect the selective involvement of gray matter that distinguishes it from most other forms of cortical dysgenesis.

Holoprosencephaly The term holoprosencephaly refers to a failure of differentiation and cleavage of the prosencephalon so that the cerebrum fails to cleave laterally into distinct cerebral hemispheres and transversely into a diencephalon and telencephalon (Fig. 11.29). Severe cases are associated with facial dysmorphism, particularly hypotelorism and midline facial clefts.47 Affected areas of brain show no definable interhemispheric fissure and no falx cerebri. Holoprosencephaly is the only nondestructive condition in which one may see the presence

Cerebral Dysgenesis and Intracranial Malformations

of the splenium of the corpus callosum and absence of the rostrum, body, and genu.47 The holoprosencephalies represent a continuum of forebrain malformation, with the anterior portions of the brain most severely affected and the posterior portions least severely affected. Although the terms alobar, semilobar, and lobar are often applied to describe the extent of involvement, no clear distinction between these categories exists.47 Holoprosencephaly is caused by both teratogens and genetic factors.748 The most common teratogen is maternal diabetes. Holoprosencephaly may be seen in children with trisomy 13 (Patau syndrome) and trisomy 18 (Edward’s syndrome).47 Mutations in at least five genetic loci have been implicated in the development of familial holoprosencephaly.47,137,748 Mutations of the sonic hedgehog gene (SHH) at the HPE3 locus, which cause an autosomal dominant form of holoprosencephaly, have been studied extensively.75 The gene product, sonic hedgehog, is a protein that is essential for the production of prechordal mesenchyme and induction of the ventral forebrain. Barkovich49 questioned whether some forms of septo-optic dysplasia with a central holoventricle and no hemispheric malformations fall within the mildest end of the spectrum of holoprosencephaly. Occasionally, cases of optic nerve hypoplasia are associated with midfacial malformations or other systemic malformations.693 Mutations in the HESX1 gene (a human homeobox gene whose mouse homologue plays a role in forebrain, midline, and pituitary development) have been demonstrated in patients with septo-optic dysplasia224,869 but are absent in most cases.693

Absence of the Septum Pellucidum Absence of the septum pellucidum may accompany a variety of cerebral malformations5,60,616; however, its frequent association with optic nerve hypoplasia has given it widespread attention in neuro-ophthalmologic circles (Fig. 11.29). Despite its numerous neuroanatomical connections with subcortical regions,779 congenital absence of the septum pellucidum in humans appears to be of no neurodevelopmental or endocrinological consequence unless concurrent abnormalities of the cerebral hemispheres (e.g., schizencephaly, periventricular leukomalacia) or pituitary infundibulum (i.e., posterior pituitary ectopia) are present.119,941 The ability of MR imaging to detect the presence or absence of these other clinically relevant anomalies now enables the neuro-ophthalmologist to predict the likelihood that hormone supplementation will be required, or that additional neurodevelopmental deficits will complicate the clinical course in the infant with optic nerve hypoplasia.119

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Hypoplasia, Agenesis, or Partial Agenesis of the Corpus Callosum The corpus callosum is the major white matter tract concerned with interhemispheric transfer and integration of information.61 Dysgenesis of the corpus callosum may occur as part of a midline malformation syndrome (e.g., in association with Dandy–Walker syndrome or transsphenoidal encephalocele). More commonly, however, it results from a wide variety of gestational or perinatal insults to the cerebral hemispheres, which secondarily affect early formation or myelination of the corpus callosum.61 Because the corpus callosum forms in an anterior-to-posterior direction with the rostrum forming last, a partially formed corpus callosum always has a genu and, less commonly, a body, while the splenium and rostrum are frequently absent.58,61 This concept is useful in distinguishing a dysgenetic corpus callosum from secondary callosal destruction that may result in a small or absent genu or body in the presence of a normal splenium or rostrum.58 Although primary agenesis of the corpus callosum has been documented, high-resolution MR imaging has demonstrated that callosal anomalies (Fig. 11.29) almost always occur in the setting of additional CNS anomalies, such as migration anomalies (schizencephaly, lissencephaly, cortical heterotopia), transsphenoidal encephalocele, holoprosencephaly, or the Dandy–Walker malformation.61 In the child with optic nerve hypoplasia, thinning of the corpus callosum is commonly seen, but complete callosal agenesis is rare.119 In this context, thinning of the corpus callosum is predictive of neurodevelopmental problems only by virtue of its frequent association with cerebral hemispheric abnormalities. The finding of callosal anomalies on MR imaging therefore necessitates a careful search for cerebral hemispheric abnormalities, which appear to be the most direct neuroimaging correlate of neurodevelopmental impairment.128 The complete callosal agenesis in Aicardi syndrome and in some of the coloboma syndromes may also reflect the severity of the associated CNS anomalies.163 An association between PAX6 mutations and callosal agenesis is now recognized.1 Agenesis of the corpus callosum can be associated with cataracts and microcephaly in the MICRO syndrome,177a and with albinism, immunodeficiency, and cardiomyopathy in the Vici syndrome.925a There seems to be a strong associate between copy number variation on chromosome 8p and agenesis of the corpus callosum, particularly for duplication at 8p.295a,421a

Focal Cortical Dysplasia Focal cortical dysplasia describes a focal disruption in the architectural lamination of the cerebral cortex, with or without

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

congregations of dysmorphic neurons or balloon cells in the cortex and subadjacent white matter.295,530,661,863 Focal cortical dysplasia is now the single most important cause of intractable epilepsy in childhood. It typically presents in a child with an otherwise normal neurological examination.47,52 Initial MR imaging is frequently interpreted as normal.470 Upon further review, subtle abnormalities in gyration and cortical thickness, or blurring of the gray/white matter junction may be the only detectable abnormality on MR imaging.530 However, its extent can range from focal involvement of a gyrus, to involvement of multiple gyri, transmantle dysplasia, lobar or hemispheric dysplasia, or even multifocal dyplasia of both hemispheres.530 Changes in white matter signal intensity, as detected on FLAIR images, are more commonly found than those in gray matter signal intensity on T2-weighted images, with both thought to represent the presence of balloon cells.530 A classification system has recently been devised661 based primarily upon the degree of dysplasia and the presence or absence of abnormal balloon cells or large dysmorphic neurons.530 Different histological types show distinct clinical and neuroimaging characteristics.492 Total removal of the lesion and any perilesional epileptigenic focus are needed for a good outcome.396 Some forms of focal cortical dysplasia can be associated with encephalomalacia and periventricular leukomalacia.492 Cortical dysplasia can accompany neuroglial tumors (dysembryonal neuroepithelial tumors),225 gangliogliomas,701 and mesial temporal sclerosis.716

Anomalies of the Hypothalamic–Pituitary Axis Posterior Pituitary Ectopia Posterior pituitary ectopia refers to the constellation of (1) absence of the normal posterior pituitary bright spot, (2) absence of the pituitary infundibulum, and (3) an abnormal focus of hyperintense tissue at or near the tuber cinereum on T1-weighted MR images (Fig. 2.4).128 Normally, the posterior lobe of the pituitary gland is hyperintense on T1-weighted MR images, probably because of the chemical composition of the phospholipid vesicles contained in it. It is speculated that, following injury to the infundibulum, the trophic influence of continued antidiuretic hormone/neurophysin secretion at the median eminence causes an abnormal collection of posterior pituicytes to form where the upper infundibulum is normally located. This ectopic cluster of cells seems to function as a normal posterior pituitary gland, so affected patients have isolated anterior pituitary deficiency.128 In patients with optic nerve hypoplasia, the finding of posterior pituitary ectopia implicates the pituitary infundibulum as the primary site of structural dysgenesis responsible for the associated hypopituitarism.128 Posterior pituitary ectopia is often accompanied by optic nerve hypoplasia, but may also accompany isolated pituitary

dwarfism or follow traumatic transection of the pituitary stalk.128,323,468 The concurrence of posterior pituitary ectopia and isolated congenital hypopituitarism is associated with male predominance and breech delivery, indicating probable ischemic injury to the infundibulum.500,560,642,881 In contrast, posterior pituitary ectopia with optic nerve hypoplasia probably reflects hypoplasia of the pituitary infundibulum, because an increased frequency of breech delivery is not found in this setting.119,689 When absence of the infundibulum is unaccompanied by an ectopic pituitary gland, diabetes insipidus is also present.126,836 In patients with optic nerve hypoplasia, it is associated with male predominance but not with breech delivery, suggesting that it may be a sign of infundibular hypoplasia rather than traumatic transection in this setting.128 Posterior pituitary ectopia is seen in about 15% of children with optic nerve hypoplasia.128 We have found it to be a sensitive and specific neuroimaging marker for anterior pituitary hormone deficiency in children with optic nerve hypoplasia.128,610,689 Rarely, posterior pituitary ectopia can herald anterior pituitary deficiency in optic nerve aplasia.122

Empty Sella Syndrome Empty sella was first described by Busch,150 who, in an autopsy study of the sella turcica, found an incomplete diaphragma sella with an apparently empty sella and a pituitary gland flattened at the bottom in 5.5% of cases.582 The sella may be enlarged or normal in size.582 Whether an incompetent or defective diaphragma sella is an essential prerequisite for this condition is unclear.458 Pituitary surgery, pituitary apoplexy, or irradiation582 and medical treatment with bromocriptine can lead to prolapse of the optic nerves or chiasm into the empty sella, with visual loss.259 Third ventricular enlargement can also produce empty sella with chiasmal prolapse in children with aqueductal stenosis.654 In some patients with visual loss, repositioning of the optic nerves can improve vision.259 More often, it is secondary to elevated intracranial pressure, (usually from idiopathic intracranial hypertension) (Fig. 3.4). Inferior displacement of the chiasm into the sella is not seen in the latter condition. Following normalization of intracranial pressure, the pituitary gland can reexpand to fill the sella in patients with idiopathic intracranial hypertension.17,966 Notwithstanding these associations, idiopathic empty sella syndrome is infrequently seen in children.17

Encephaloceles Cephaloceles are congenital malformations consisting of herniation of an intracranial structure through a defect in the cranium and dura mater.47 Meningoencephaloceles are cepha-

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Cerebral Dysgenesis and Intracranial Malformations

loceles in which the protruding structure contains leptomeninges, brain, and CSF.625 The terms meningoencephalocele and encephalocele are often used interchangeably. The most common anatomical location of encephaloceles varies according to geographic distribution, with occipital encephaloceles most common in Europe and North America and frontoethmoidal encephaloceles most common in Russia and southeast Asia.249,625 Most encephaloceles occur on a sporadic basis and are not associated with syndromes.249 The embryology is complex and may vary according to location.900

Transsphenoidal Encephalocele Transsphenoidal encephalocele is a rare midline congenital malformation in which a meningeal pouch, often containing the chiasm and adjacent hypothalamus, protrudes inferiorly through a large round defect in the sphenoid bone (Fig. 11.30). Children with this occult basal meningocele have a wide head, flat nose, mild hypertelorism, midline notch in the upper lip and, sometimes, a midline cleft in the soft palate. The meningocele protrudes into the nasopharynx, where it may obstruct the airway. Associated brain malformations include agenesis of the corpus callosum and posterior dilatation of the lateral ventricles. Most affected children have no overt intellectual or neurological deficits, but panhypopituitarism is common. Surgery for transsphenoidal encephalocele is considered by many authorities to be contraindicated, because herniated brain tissue may include vital structures, such as the hypothalamic–pituitary system, optic nerves and chiasm, and anterior cerebral arteries, and because of the reported high postoperative mortality rate – especially in infants.963 A variety of optic disc dysplasias, particularly the morning glory disc anomaly, occur in association with transsphenoidal encephalocele.144,161 The combination of a V- or tongue-shaped zone of infrapapillary retinochoroidal depigmentation with optic disc dysplasia may be a retinal marker for transsphenoidal encephalocele.132

Orbital Encephalocele Orbital encephalocele is a rare congenital abnormality caused by a defect of the cranio-orbital bones that usually manifests soon after birth as a soft, cystic fullness in the superomedial canthal area with associated exophthalmos (Fig. 11.30).867 The globe may pulsate synchronously with the heartbeat, and crying or coughing may increase the degree of proptosis. The encephalocele can herniate through a bony orbital defect or, in some cases, through a natural opening such as the optic foramen or orbital fissures. Surgical treatment usually requires a combined orbital and intracranial approach, with use of dural flaps and bone grafts to close the defect. Most

orbital encephaloceles are isolated anomalies that do not preclude normal mental and physical development; however, posterior orbital encephaloceles may be associated with neurofibromatosis.867

Occipital Encephalocele Occipital encephaloceles account for 80% of encephaloceles in the white population of Europe and North America.59 Occipital encephaloceles may be associated with callosal anomalies, cerebral migration anomalies, Chiari malformations, and Dandy–Walker malformations.47,59,89 In children with multisystem disease, the diagnoses of Meckel–Gruber syndrome or Walker–Warburg syndrome should be considered. Occipital encephalocele is accompained by high myopia and retinal detachments in the Knobloch syndrome. The size of the defect is highly variable, ranging from a few millimeters in diameter to encephaloceles that contain most of the brain (Fig. 11.30).249 Hydrocephalus may affect the entire ventricular system or may be limited to the extracranial portion of the ventricles.625 The occipital lobes and cerebellar hemispheres may be included partially or totally in the herniated sac and show extensive vascular lesions in the form of old and recent infarction.452 The finding of meningomyelocele in 7% of children with occipital encephalocele suggests that occipital encephaloceles are related to defects in neural tube closure.625 Histopathological examination of brains with large, herniated occipital encephalocele reveals atrophic anterior visual pathways. In some cases, the optic nerves are stretched and the chiasm is postfixed, suggesting posterior traction on the anterior visual pathways as one mechanism of injury.452 The diagnosis is usually obvious clinically, and MR imaging is obtained to determine whether other severe brain abnormalities are present and whether the dural venous sinuses course within the encephalocele.59 The clinical outcome depends on the size, presence, or absence of brain herniation and the presence or absence of associated brain malformations.625 Children with small occipital meningomyeloceles do well, while those with larger lesions associated with brain herniation are totally dependent.586 Surgical correction is performed to protect the child from ulceration of the sac, which could lead to infection or hemorrhage, to prevent the sac from expanding, and to improve the cosmetic appearance.625

Cerebellar Malformations As the cerebellum is increasingly recognized for its role in cognition as well as motor control, formal classification of the cerebellar malformations has become much more

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11 Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease

Fig. 11.30 Encephaloceles. (a) Transsphenoidal encephalocele. Arrow denotes lower margin of meningeal pouch just above hard palate. Optic chiasm is split and herniated downward into defect. (b) Occipital encephalocele in a patient with modified Dandy–Walker malformation.

(c) Frontoethmoidal encephalocele pushing the right globe laterally (d) CT scan showing bony defect in the superior orbit with herniation of brain into the medial orbit

important.47 It has recently been recognized that cortical dysplasia and subcortical heterotopia can be identified in the cerebellum, as they can in the cerebrum.680 In general terms, cerebellar malformations can be classified into cerebellar hypoplasia (focal or general), and cerebellar dysplasia, which can also be focal (as in isolated vermian hypoplasia, molar tooth malformation, rhombencephalosynapsis, Lhermitte–Duclos syndrome, or focal cerebellar cortical dysplasia or heterotopia), or generalized (as in autosomal recessive lissencephaly with the RELN mutation, lissen

cephaly with agenesis of the corpus callosum and cerebellar dysplasia, or diffuse cerebral polymicrogyria).402,680,755 While cerebellar hypoplasia is usually distinguished from atrophy on the basis of progression, the neuroimaging finding of a small, well-formed cerebellum is suggestive of hypoplasia, while enlarged fissure with accentuated arborization of the individual lobes within the vermis suggests atrophy.219 Congenital ocular motor apraxia and Joubert syndrome are associated with hypoplasia of the cerebellar vermis, while ataxia telangectasia and the spinocerebellar ataxias are

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associated with atrophy. Hypoplasia of the cerebellar vermis tends to preferentially involve the inferior vermis, as is often seen in congenital ocular motor apraxia.471 The major pediatric neuro-ophthalmologic disorders associated with cerebellar vermian hypoplasia are congenital ocular motor apraxia and Joubert syndrome. All involve the ocular motor system predominantly but Joubert syndrome and spinocerebellar ataxia (SCA7) may have sensory visual loss as a salient feature, as can the rare syndrome of autosomal recessive cerebellar hypoplasia with tapetoretinal degeneration.258

Molar Tooth Malformation Patients with Joubert syndrome have a small, dysplastic cerebellar vermis with midline clefting, dysplasias and heterotopias of the cerebellar nuclei, near total absence of the pyramidal decussations.680 They also have anomalies in the structure of the inferior olivary nuclei, descending trigeminal tract, solitary fascicle and dorsal column nuclei,47,315 with probable absence of decussation of the superior cerebellar peduncles and central pontine tracts as well.955 That midline structures of the brainstem are disordered both structurally and functionally in Joubert syndrome suggests that the underlying developmental abnormality may be an inability of posterior fossa axons to cross the midline.769 Although once thought to be pathognomonic for Joubert syndrome, recent studies have shown that the molar tooth sign is seen with many associated anomalies that encompass many syndromes.347,782 The fact that some patients with Joubert syndrome have mutations on chromosome 9q34.3,766 while others do not93 further demonstrates that this finding is not diagnostic for a specific condition.47 Some patients with identical neuroimaging findings have renal anomalies (juvenile nephronophthiasis or multicystic dysplastic kidney), some have ocular anomalies (retinal dysplasias and colobomas), some have hepatic fibrosis and cysts, and some have hypothalamic hamartomas.47 A number of genetic syndromes, including Dekaban–Arima syndrome, COACH syndrome, Senior– Löken syndrome,782 Varadi–Papp syndrome,347 Joubertpolymicrogyria syndrome,347 and others,201 have been reported with identical neuroimaging findings.47 Therefore, patients with molar tooth syndrome should not be monosynaptically diagnosed with Joubert syndrome. Rather, they should be screened for supratentorial anomalies (hypothalmic hamartoma, polymicrogyria, or other malformations of cortical development) and for ocular, hepatic, and renal disease.347 On axial MR imaging, the superior cerebellar peduncles appear large, clearly horizontal, and do not cross in the dorsal midbrain (Fig. 7.7).464 The midbrain is small in its anterior–posterior diameter, particularly in its midline, probably

because of the absence of decussation of the superior cerebellar peduncles. Sagittal images show a small vermis that is situated abnormally high and a fourth ventricle that is abnormally thin. The vermian folial pattern may also be abnormal. Coronal images show a cleft in the vermian midline, yielding a triangular, “bat wing” shaped fourth ventricle.

Rhombencephalosynapsis Rhombencephalosynapsis is characterized by the absence or hypoplasia of the cerebellar vermis and fusion of the cerebellar hemispheres, dentate nuclei, and cerebellar peduncles (Fig. 11.31).47,680 Its cause is unknown. Clinical presentation ranges from mild truncal ataxia and normal cognition to severe cerebral palsy with epilepsy and mental retardation.873 Neuro-ophthalmologic abnormalities are primarily confined to the ocular motor system, consisting of prenuclear disturbances such as A-pattern strabismus with primary superior oblique overaction, and skew deviation.687 Imaging studies show dorsal fusion of the cerebellar hemispheres, absence of the vermis, and fusion of the superior cerebellar peduncles – usually in association with ventriculomegaly. Cortical malformations, hydrocephalus, abscesses of the septum pellucidem, and cranial suture synostosis can coexist.

Fig. 11.31 Rhombencephalosynapsis. T2-weighted MR image shows fusion of the cerebellar hemispheres with no intervening vermis. Note the horizontal orientation of the folia across the cerebellar midline. With permission from Phillips PH et al.687

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Lhermitte–Duclos Disease Lhermitte–Duclos disease (also known as dysplastic cerebellar gangliocytoma or diffuse hypertrophy of the cerebellar cortex) presents as a nonneoplastic mass composed of cerebellar folia expanded by hypertrophic neurons of the internal granular layer of the cerebellum.234 Neuropathologically, Lhermitte–Duclos syndrome consists of a sharply-marginated region of enlarged cerebellar cortex that usually involves one hemisphere but may extend into the vermis or the contralateral hemisphere. Microscopically, a thick layer of ganglion cells replaces the granular layer of the cerebellar cortex, and there is a thick hypermyelinated marginal layer and a thin Purkinje cell layer.315 Although it usually presents in young adults, patients may become symptomatic at any age, with signs of elevated intracranial pressure as a result of mass effect from this rare zonal form of cerebellar enlargement.597,754 Clinical evidence of cerebellar dysfunction is usually mild or inapparent. MR imaging shows hypertrophy of the cerebellar folia.47 Associated anomalies include megalencephaly, heterotopia, microgyria, polydactyly, partial gigantism, macroglossia, and multiple visceral hamartomas and neoplasms. MR imaging shows a sharply marginated cerebellar mass with T1 and T2 prolongation. Coursing through the mass are curvilinear structures of gray matter intensity that appear to be cerebellar cortex.495,719

Miscellaneous Congenital Corneal Anesthesia Congenital corneal anesthesia has been into three groups on the basis of the presence and type of associated abnormalities.712,751 In group 1, congenital corneal anesthesia occurs without associated systemic or ocular abnormalities. In group 2, corneal anesthesia is related to ectodermal or mesenchymal disorders such as Goldenhar syndrome, Möbius syndrome, VACTERL, MUCUS, Riley–Day syndrome, and congenital pain insensitivity. The sensory abnormality may be unilateral or bilateral and, generally, results from injury in early embryogenesis. Unilaterality is more common in the Golderhar group, while bilaterality is more common in the non-Goldenhar group. Group 3 is composed of patients who have corneal anesthesia without somatic malformations but with associated focal brainstem abnormalities.752 Congenital insensitivity to pain is a related group of disorders in which infants and children often bite their tongue, lips, and fingers.956 Dyck et al267 have grouped this entity into five conditions: sensory radicular neuropathy, congenital

sensory neuropathy, familial dysautonomia (Riley–Day syndrome), congenital insensitivity to pain with anhidrosis (CIPA), and congenital indifference to pain.820 The latter two types may present with self-inflicted corneal injury, keratitis, corneal ulcers, and scarring.886,896,933 A mutation in the gene encoding for the Trk/NGF receptor has been described.419,420

Reversible Posterior Leukoencephalopathy Reversible posterior leukoencephalopathy is a recently recognized syndrome characterized clinically by headache, confusion, seizure, and visual loss. Radiologic abnormalities are mainly represented by bilateral involvement of the white and gray matter in the posterior regions of the cerebral hemisphere.30,208,393,505 It is considered a reversible condition if promptly recognized and correctly treated.35,385,700 A delayed or incorrect diagnosis can lead to irreversible damage. Reversible posterior leukoencephalopathy syndrome has been reported in association with many pathologic disorders, such as malignant hypertension, toxemia of pregnancy, hemolytic uremic syndrome, acute glomerulonephritis, intravenous immunoglobulin or erythropoietin administration, blood transfusion, acute intermittent porphyria, severe hypercalcemia, and leukemia relapse. Its pathogenesis is poorly understood, but it is thought that sudden elevations in systemic blood pressure exceed the autoregulatory capabilities of the brain vasculature. Failure of autoregulation then leads to regions of vasodilatation and vasoconstriction, with breakdown of the blood–brain barrier and focal transudation of fluid into the surrounding brain tissue. In addition to resulting from hypertension, reversible posterior leukoencephalopathy can occur in immunosuppressed children following organ transplantation (particularly following liver transplantation) in children.393 Cyclosporine cortical blindness is associated with a vasogenic rather than a cytotoxic edema (i.e., damage to endothelium, not neurons and glia). It is unclear why the syndrome primarily involves the occipital lobes. When the cyclosporine is discontinued, patients will show a dramatic recovery within days. The syndrome starts with confusion, visual hallucinations, cortical blindness, homonymous hemianopia, or seizures. The findings on neuroimaging are characteristic of subcortical edema. MR imaging shows increased signal mainly in the posterior hemispheres on FLAIR and T2 but no restricted diffusion.393 The findings on neuroimaging are characteristic of subcortical edema. In children with leukemia, the combination of intrathecal methotrexate and radiation can also cause a severe leukoencephalopathy with increased signal in T2 and FLAIR in the cerebrum.

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Cerebroretinal Vasculopathies Rare disorders produce a combination of cerebrovascular retinopathy and systemic angiopathy in children.248 Vahedi et al897 recently described a syndrome of hereditary infantile hemiparesis, retinal arteriolar tortuosity and leukoencephalopathy associated with dilated perivascular spaces. Three patients also had migraine with aura. Conrath et al198 described an 11-year-old child with digestive tract and renal small-vessel hyalinosis, idiopathic nonarteriorsclerotic intracerebral calcifications, retinal ischemic syndrome, and phenotypic abnormalities. All four reported patients manifested kidney failure due to glomerular endothelial cell alterations and mesangiolysis.198 The autosomal dominant retinal vasculopathies with cerebral leukodystrophy, which generally present in adulthood.737 include cerebroretinal vasculopathy,364,878 hereditary vascular retinopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) 650,737 Unlike in Leber hereditary optic neuropathy, the (juxtafoveal, in this case) retinal telangiectasias that characterize this condition are not present in childhood and therefore cannot be used to predict that a given child in an affected kindred will be affected in adulthood.

Syndromes with Neuro-Ophthalmologic Overlap Proteus Syndrome Proteus syndrome is a rare disorder associated with multiple irregular areas of patchy tissue overgrowth involving multiple tissues and cell lineages.83 Clinical manifestations include hyperostosis (usually near the epiphyses) and impaired mobility. Hyperplastic connective tissue nevi often involve the palms and soles, producing deep grooves and a cobblestone or “cerebriform” “appearance.”83 Multiple lipomas in the abdomen and pelvis may be accompanied by a paradoxical lipoatrophy.83 Proteus syndrome is not heritary and is believed to be caused by a postzygotic somatic mutation in a gene that is lethal in the nonmosaic state.83 Its differential diagnosis includes Klippel–Trenauney–Weber syndrome, hemihyperplasia, Parkes Weber syndrome, Maffuci syndrome, NF1, linear sebaceous nevus syndrome, Bannayan Riley Ruvalcaba syndrome, and familial or symmetric lipomatosis.84 In an older child with cutaneous manifestations of NF1, the absence of Lisch nodules raises the rare possibility of Proteus syndrome, which can also produce skeletal, vis-

ceral, and cutaneous abnormalities.105 The macrocephaly, hemihypertrophy, and cutaneous tumors of Proteus syndrome can simulate neurofibromatosis, but children with Proteus syndrome lack the other neuro-ophthalmologic manifestations of neurofibromatosis.83,105 Periorbital exostosis, epibulbar tumors, and “eye enlargement” are considered to be the most characteristic ophthalmologic signs in Proteus syndrome,105 but cataract, vitreous abnormalities, myopia, and a large retinochoroidal mass have also been described.812 Long-term systemic complications that include progressive skeletal deformities, invasive lipomas, benign and malignant tumors, deep venous thrombosis, and pulmonary embolism.83

PHACE Syndrome The PHACE syndrome is a neurocutaneous syndrome that includes the following primary features: (posterior fossa malformations, facial hemangioma, arterial cerebrovascular anomalies, cardiovascular anomalies, and eye anomalies).316,592 It occurs almost exclusively in girls.316 Several recent reports have documented the association of PHACE syndrome with excavated optic disc anomalies, most notably the morning glory disc anomaly (Fig. 2.14).400,473,478 The orofacial hemangiomas seen in PHACE syndrome are characteristically large, segmental, and plaquelike.316,592 In addition to a variety of structural cardiac abnormalities and aortic coarctation, ventral developmental defects such as sternal pits, sternal clefting, and supra-abdominal raphe are common.316,592 A spectrum of posterior fossa lesions, ranging from focal cerebellar hypoplasia with or without arachnoid cyst to the Dandy–Walker complex, have been described.392 Focal dysplasia of the cerebral cortex, including pachygyria, polymicrogyria, thickening of the cerebral cortex, heterotopic gray matter, and cerebral volume loss (all occurring in the hemisphere ipsilateral to the hemangioma) is less commonly seen.392 Children with PHACE syndrome often have progressive ipsilateral stenosis, most often involving the carotid circulation, leading to cerebral infarction.148 These patients have been reported to benefit from preemptive cranial revascularization procedures.392

Goldenhar Syndrome (Oculoauriculovertebral Dysplasia) The Goldenhar syndrome comprises a complex of hemifacial microsomia, preauricular appendages, auricular abnormalities, vertebral anomalies, and epibulbar dermoids.567

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Patients with Goldenhar syndrome show a phenotypic spectrum ranging from mild facial asymmetry to severe hypoplasia of one side of the face with ipsilateral macrostoma.390,570 As a minimal sign, microtia must be present.791 Auricular abnormalities are usually unilateral and, in addition to microtia, may include malpositioning of the ear and hypoplasia of the external auditory canal, with or without hearing loss.622 Additional features are cardiac and renal anomalies, cleft lip/palate, and CNS, cervical, and radial limb anomalies.791 Colobomas and focal upper lid defects may also be present. The eye on the involved side may be microphthalmic or anophthalmic in severe cases. Gorlin et al359 now use the term oculo-auriculo-vertebral spectrum (OAVS) because of the extreme heterogeny of the condition. This nonhereditary spectrum affects males more than females, and right-sided involvement is more common and more severe.749 Neuro-ophthalmologic abnormalities include unilateral or bilateral fourth nerve palsy,10,390 congenital corneal anesthesia,612 unilateral and bilateral Duane syndrome,10,567 sixth nerve palsy,390 optic nerve hypoplasia and coloboma on the affected side,570 and ptosis.68 Amblyopia may also result from associated strabismus or anisometropia.390 The association of Goldenhar syndrome with predominantly ipsilateral cranial nerve palsies is explained by the occurrence of aplasia of the cranial nerve nuclei in this condition.10,567,612 Intelligence is usually normal, but mental retardation is more likely to be present in severe cases that are associated with ipsilateral microphthalmia or anophthalmia.570 Goldenhar syndrome may be associated with a broad array of CNS abnormalities, including hydrocephalus, Arnold–Chiari malformation, unilateral arhinencephaly, occipital and frontal encephalocele, intracranial arachnoid cyst, intracranial lipoma, holoprosencephaly, callosal hypoplasia, lissencephaly, and intracranial lipoma.791 An intracranial dermoid cyst has also been reported in a patient with Goldenhar syndrome.622 Various bony defects may also be present, including microcephaly, cranial asymmetry, platybasia, hypoplasia of the petrous and ethmoid bones, and absence of the internal auditory canals.791,946 The Wildervanck (cervico-oculo-acoustic) syndrome may be difficult to distinguish from the Goldenhar syndrome. It consists of sensorineural deafness, Klippel–Feil anomaly, and Duane syndrome (Fig. 11.32). Wildervanck syndrome is much more common in girls than in boys.127 As Duane syndrome is much more common in the Wildervanck than in the Goldenhar syndrome, its presence necessitates a search for the associated Klippel–Feil anomaly.69,209 Because many patients have overlapping features, the syndromes of Goldenhar and Wildervanck may represent different ends of a spectrum.209

Delleman (Oculocerebrocutaneous) Syndrome In 1981, Delleman and Oorthuys235 described two children with multiple intracranial cysts, orbital cysts, agenesis of the corpus callosum, periorbital skin appendages, punchlike skin defects, and skin atrophy or hypoplasia (Fig. 11.33). Numerous cases have since been described as the Delleman, or oculocerebrocutaneous, syndrome. Additional anomalies in this condition include seizures, generalized asymmetry, skull defects, rib anomalies, and mental retardation.11,947 Unilateral anophthalmos with ipsilateral orbital hypoplasia and hypoplasia of the corresponding intracranial optic nerve may also be seen.129 In some children, the clinical features of Delleman syndrome overlap those of Goldenhar spectrum, making the clinical distinction between these two entities difficult.129

Encephalocraniocutaneous Lipomatosis Encephalocraniocutaneous lipomatosis is a rare neurocutaneous syndrome characterized by lipomas of the cranium and CNS, alopecia of the scalp, and a broad range of CNS abnormalities, including unilateral intracranial cysts, cerebral migration anomalies, and cortical atrophy.480,546 Affected children have seizures, spasticity, and mental retardation. Epibulbar choristomas and small skin nodules are the most common ophthalmologic manifestations, but neuro-ophthalmologic findings including papilledema and optic disc pallor have also been reported.480 Encephalocraniocutaneous lipomatosis should be considered, along with Goldenhar syndrome and linear sebaceous nevus syndrome in the differential diagnosis of conditions with epibulbar choristomas.480

Incontinentia Pigmenti (Bloch–Sulzberger Syndrome) Incontinentia pigmenti is a rare neurocutaneous disease that affects the skin, bones, teeth, CNS, and eyes. Its almost exclusive occurrence in females is attributed to an X-linked dominant mutation that is lethal in males. Linear lesions appear at birth or soon afterward. These lesions subsequently resolve to leave a linear pattern of pigmentation. Retinal abnormalities most commonly involve the temporal equator and include vascular dilation, arteriovenous anastamosis, preretinal fibrosis, vascular proliferation, and nonperfusion of the retina temporal to the vascular abnormalities.332 These vascular changes, which resemble those of retinopathy of prematurity and sickle

Syndromes with Neuro-Ophthalmologic Overlap

575

Fig. 11.32 Wildervanck syndrome. (a) Facial photograph showing minimal esotropia in primary gaze. (b) Secondary positions of gaze showing bilateral Duane syndrome. (c) Sagittal MR image demonstrating

diffuse hypoplasia of pons and medulla. (d) Parasagittal MR imaging demonstrating foreshortening of neck and severe thoracic kyphosis. With permission from Brodsky et al127

cell disease, may lead to retinal detachment. Dragging of the retinal vessels, macular heterotopia, retinal folds, foveal hypoplasia, and retinal pigment epithelium mottling may also occur.332,350 Other ophthalmologic abnormalities may include cataract, optic atrophy, retinal dysplasia, a retrolental mass (termed pseudoglioma) secondary to extensive retinal detachment, nystagmus, and esotropia.753 Pascual-Castroviejo et al677 found MR abnormalities, including focal atrophy of the cerebrum, cerebellum, and hypoplasia of the corpus callosum, in four of eight patients with

incontinentia pigmentia. The MR abnormalities were seen only in patients who had neurological abnormalities. The CNS manifestations in incontinentia pigmenti may be ischemic in origin secondary to intracranial small vessel disease.516 Lee et al516 found the severity of retinal vascular occlusions to correlate with the degree of CNS involvement on MR imaging and suggested that retinal vascular occlusions may eventually prove to be a marker for CNS disease. The finding of optic atrophy in some children with incontinentia pigmentia may also reflect ischemic white matter injury.350

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Fig. 11.33 Delleman syndrome. (a) Note small malformed right ear, pre-auricular punch-like skin defect, skin tags, bony prominence, and malformed nose. (b) CT scan demonstrating right anophthalmos with orbital hypoplasia and large right posterior fossa cyst deforming brainstem. With permission from Brodsky et al129

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Index

A Abducens nerve palsy. See Sixth nerve palsy Abetalipoproteinemia, 487–488 Abnormal neuronal migration gray matter heterotopia, 565 lissencephaly, 563–565 Abnormal stem cell proliferation/apoptosis hemimegalencephaly, 562 schizencephaly, 562 Accommodative paresis, 362 Achiasmia, 398–400 Achromatopsia, 10, 400–401 Acute disseminated encephalomyelitis (ADE), 124–125 Addison disease, 107 Addison–Schilder disease. See X-linked adrenoleukodystrophy Adenoma sebaceum, 514–515 Adie syndrome diagnosis, 363 Horner syndrome, 364–366 iris sphincter, 363 light-near dissociation, 362 tonic pupils, 363–364 Adrenoleukodystrophy (ALD), 483–485 Aicardi syndrome, 83–85 Alagille syndrome, 140–142 Albinism Chediak–Higashi syndrome, 395 congenital hypomelanotic disorders, 394 diffuse hypopigmentation, 395 hemispheric visual evoked potentials, 397–398 optic axon distribution, 396 P gene mutations, 397 pigmentation and axonal migration, 394 positive angle kappa, 395–396 Prader–Willi syndrome, 397 zinc finger transcription factor, 396–397 Albinoidism, 395 Albinotic optic disc, 89 Alice in Wonderland syndrome, 230 Alström syndrome, 402 Alexander disease, 481 Amblyopia, 263 Anterior ischemic optic neuropathy (AION), 132–133 Apraxia of eyelid opening, 362 Arachnoid cysts, 528 Arima syndrome, 323 Arteriovenous malformation (AVM) natural history and clinical features, 554 spontaneous intracranial hemorrhage, 553 treatment, 554–556 Artificial divergence surgery, 409–410

Astrocytomas, 529 Ataxia telangiectasia autosomal recessive neurocutaneous disease, 521 breakage syndromes, 522 cerebellar hemispheric atrophy, 522–523 conjunctival telangiectasis, 522 MRE11, mutation, 523 ocular motor apraxia and palpebral fissure, 522 progressive cerebellar ataxia, 522 Athetosis, 20 Atropine (anticholinergic drugs), 233–234 Autoimmune optic neuropathy, 133 B Balint syndrome, 42 Basal ganglia disease pantothenate kinase-associated neurodegeneration, 485–486 Wilson disease, 486 Batten disease, 160, 184, 469–470 Behr syndrome, 177–178 Benign paroxysmal torticollis, 447–448 Bickerstaff’ brainstem encephalitis, 338 Bilateral schwannomas, 513 Bizarre retinochoroidal defect, 512 Blau syndrome, 120–121 Blindness, 459 Blindness, in infancy congenital causes optic nerve disorders, 10 retinal blindness, 4–5 stationary night blindness, 10 cortical visual insufficiency (CVI) (see Cortical visual insufficiency (CVI)) diagnostic algorithm, 1, 2 hereditary retinal disorders Joubert syndrome (see Joubert syndrome) Leber congenital amaurosis (LCA) (see Leber congenital amaurosis (LCA)) infantile nystagmus dynamic vestibulo-ocular reflex, 5 neurological diseases, 5 photophobia, 3–4 pupillary examination, 3 unequal nystagmus test, 6 visual evoked potential (VEP), 6 Bloch–Sulzberger syndrome. See Incontinentia pigmenti Blue cone monochromatism, 401–402 Bobble-headed doll syndrome, 457–458 Bonnet–Dechaume–Blanc syndrome, 555 Botulism, 336–337 597

598 Brain tumors adrenocorticotrophic hormone (ACTH) therapy, 526 intracranial pressure and posterior fossa tumors, 527 solid neoplasms, 525 Brainstem tumors, 533–536 Brown syndrome, 350–351 C Café au lait spots, 504 Cardiogenic embolism, 227–228 Canavan disease, 181, 478–479 Cancer-associated retinopathy (CAR), 120 Carbohydrate-deficient glycoprotein syndromes, 426 Carbon monoxide, 234 Cat scratch disease, 130–131 Cavernous angiomas, 556 Cavernous sinus lesions, 528 Cerebellar astrocytoma, 531–532 Cerebellar malformations cerebellar hypoplasia, 570 Lhermitte–Duclos disease, 572 molar tooth malformation, 571 rhombencephalosynapsis, 571 Cerebral dysgenesis and intracranial malformations, 555–556 Cerebral palsy, 310 Cerebral venous thrombosis (CVT), 558–559 Cerebroretinal vasculopathies, 573 Cerebrotendinous xanthomatosis, 482 Charcot–Marie–Tooth diseases, 186–187 Charles Bonnet syndrome, 230–231 Chediak–Higashi syndrome, 395 Chiari I malformation, 543–545 Chiari II malformation, 545–547 Chiari III malformation, 547 Chiasmal glioma, 506–509 Chronic infantile neurological cutaneous articular (CINCA), 121 Chronic progressive external ophthalmoplegia (CPEO), 326–328, 489–490 Ciancia syndrome, 415 Circadian timing systems, total blindness circadian rhythms, 43 components, 43 melanopsin, 44–45 melatonin, 44 Cobalamin C methylmalonic aciduria, 427 Cockayne syndrome, 480–481 Coloboma disc excavation, 71–73 gene mutation, 75 vs. morning glory disc anomaly, 73–75 Colocephaly, 561–562 Combined hamartomas of the retina and retinal pigment epithelium (CHRPE), 123 Complicated migraine syndromes, 217–223 Congenital bilateral mydriasis, 362 Congenital corneal anesthesia, 572 Congenital cranial dysinnervation syndromes congenital fibrosis syndrome, 344–346 congenital horizontal gaze palsy, 347 congenital ptosis, 343 Marcus Gunn jaw winking (MGJW) synkinesis, 343–344 Möbius sequence, 347–348 Congenital downbeat nystagmus, 418–419 Congenital esotropia congenital downbeat nystagmus, 418–419

Index congenital vs. acquired seesaw nystagmus, 420–421 hereditary vertical nystagmus, 419 horizontal nystagmus, 414 latent nystagmus Alexander’s law, 414 Ciancia syndrome, 415 eye movement recordings, 416 nasotemporal asymmetry, 414 treatment, 416–417 nystagmus blockage syndrome, 417 pendular vs. Jerk seesaw nystagmus, 421 periodic alternating nystagmus, 419–420 saccadic oscillations convergence-retraction nystagmus, 421 opsoclonus and ocular flutter, 421–423 seesaw nystagmus, 420 torsional nystagmus, 413 upbeating nystagmus, 417 vertical nystagmus, 417 Congenital fibrosis syndrome, 344–346 Congenital homonymous hemianopia, 451–452 asymmetric involvement, 37 exotropic deviation, 37 head turn, 37 lesions, 36 modified perimetric technique, 38 pupillary defect, 37 saccadic strategy, 37 Sturge–Weber syndrome, 36 transsynaptic degeneration, 36–37 Congenital horizontal gaze palsy, 347 Congenital hypomelanotic disorders, 394 Congenital myasthenic syndromes, 329–331 Congenital ocular motor apraxia aprataxin mutations, 321 Arima syndrome, 323 episodic tachpynea, 322 generalized neurological disorder, 321 head nodding, 459 head thrusts, 320–321 idiopathic form, 319 intermittent saccadic failure, 319 Joubert syndrome, 322–323 neurologic head turns, 452 neurometabolic causes, 321 opsoclonus/myoclonus, 459 saccadic failure, 319 Congenital optic disc anomalies Aicardi syndrome, 83–85 albinotic optic disc, 89 clinical axioms, 59 congenital optic disc pigmentation, 81–83 congenital tilted disc syndrome, 79–81 excavated optic disc anomalies, 67 megalopapilla glaucoma, 76 phenotypic variants, 75 morning glory disc anomaly computed tomography (CT) scan, 68, 69 contractile movements, 70, 72 embryogenesis, 70–71 PHACE syndrome, 70, 72 retinal detachments, 70 transsphenoidal encephalocele, 69, 70 myelinated nerve fibers, 87–88 optic disc

Index coloboma, 71–75 doubling, 85–86 dysplasia, 81, 82 optic nerve aplasia, 86–87 optic nerve hypoplasia amblyopia, 61 black optic disc, 60 CNS abnormalities, 61–64 disc size, 61 endocrinologic abnormality, 61 histopathology, 60 hypothyroidism, 62 microdisc, diagnosis, 61 prevalence, 59 pseudo-normal optic disc, 60 refractive errors, 61 retinal venous tortousity, 60 RPE and choroid, nasal pallor and extension, 60 systemic and teratogenic associations, 59–60 visual acuity, 60 optic pit vs. colobomas, 78 intraretinal fluid, 78 laser photocoagulation, 78 serous macular detachment, 77 papillorenal syndrome, 78–79 peripapillary staphyloma, 75 segmental optic nerve hypoplasia CNS injuries, 67 embryogenesis, 65–67 genetic mutations, 67 mitochondrial disease, 67 periventricular leukomalacia, 65, 68 retrogeniculate lesions, 65, 66 superior segmental optic hypoplasia, 64–65 Congenital optic disc pigmentation, 81–83 Congenital optic nerve disorders, 10 Congenital ptosis, 343, 357–358 Congenital retinal dystrophies achromatopsia, 400–401 blue cone monochromatism, 401–402 cone dystrophies, 400 leber congenital amaurosis, 402 Congenital stationary night blindness (CSNB), 10, 402–404 Congenital tilted disc syndrome, 79–81 Congenital nystagmus, 456–457 Convergence-retraction nystagmus, 421 Conversion disorder, 242 Corpus callosum, agenesis, 61, 64, 67, 69, 83, 84, 540, 541, 564–567, 570, 574 Cortical visual insufficiency (CVI) blindness proportion, 11 blindsight Balint syndrome, 42 extrageniculostriate system, 41, 42 medial temporal cortex (MT), 42 Riddoch phenomenon, 41 type I and II, 41 causes cerebral malformations, 13–15 head trauma, 14–16 herpes simplex infection, 16, 17 hydrocephalus, 16–18 meningitis, 16 metabolic and neurodegenerative causes, 16 perinatal hypoxia–ischemia, 12–13

599 postnatal hypoxia–ischemia, 13 seizures, 18–19 sepsis, 16, 17 twin pregnancy, 16 ventricular shunt failure, 17–18 cerebral palsy athetosis, 20 birth injuries, 20–21 classifications, 20 dystonia, 20 hypertonia, 20 mixed motor disorders, 19 periventricular leukomalacia, 21 risk factors, 21 spastic quadriplegia, 21 cerebral visual loss, 11 classic features, 12 cortical blindness, 11 diagnostic and prognostic considerations, 25–27 hemianopic visual field defects (see Congenital homonymous hemianopia) in children, 452 injury patterns, 11 neuro-ophthalmologic signs anterior visual pathway dysfunction, 23 band atrophy, 25 congenital nystagmus, 23 horizontal conjugate gaze deviation, 23 optic atrophy, 23 transsynaptic degeneration, 24–25 subcortical visual loss, 11 visual function characteristics color identification, 22 light gazing, 22 photophobia, 22 variabilities, 21–22 visual acuity, 21 Cranial nerve palsy. See Ocular motor nerve palsies Craniocervical arterial dissection, 557 Craniopharyngioma, 164–166 Craniosynostosis syndromes, 116–117, 167, 311–312 Cyclic esotropia, 353–354 Cyclic, periodic/aperiodic disorders cyclic esotropia, 353–354 periodic alternating gaze deviation (PAGD), 354–356 periodic alternating skew deviation, 354 Cyanotic congenital heart disease, 116 Cysticercosis, 118–119 D Dandy–Walker malformation, 547–548 Delayed visual maturation (DVM) classification, 39 congenital ocular motor apraxia, 40–41 delayed myelination, 40 developmental problems, 40 optic disc appearance, 39–40 organic amblyopia and visual improvement, 39 structural cerebral abnormalities, 38–39 synapse maturation, 38 thalamic lesions, 40 vision, developmental aspects, 38 Delleman (Oculocerebrocutaneous) syndrome, 574 Dermoids, 537–538

600 Destructive brain lesions colpocephaly, 561–562 encephalomalacia, 560–561 hydranencephaly, 560, 561 porencephaly, 560 Devic disease, 126–127 Diabetic papillopathy, 111–112 Diffuse ophthalmoplegia chronic progressive external ophthalmoplegia (CPEO), 326–328 congenital myasthenic syndromes, 329–331 juvenile myasthenia, 331–335 myasthenia gravis, 328–335 transient neonatal myasthenia gravis, 328–329 Wernicke encephalopathy, 338 Diffuse unilateral subacute neuroretinitis (DUSN), 131–132 Dissociated vertical divergence (DVD), 448–449 Dominant optic atrophy (Kjer type), 172–174 Double elevator palsy, 348–350 Down syndrome, 140, 426, 450 Duane retraction syndrome classification, 290–291 embryogenesis, 291 etiology, 290 genetics, 286 lateral rectus muscle rare variants, 289–290 synergistic divergence, 288–289 upshoots and downshoots, 286–287 Y/l pattern, 287–288 surgical treatment bilateral Duane syndrome, 293 esotropia, 292 exotropia, 293 systemic associations, 290 Dysgerminoma, 166–167 E Empty sella syndrome, 568 Encephalitis, 16 Encephaloceles frontoethmoidal encephalocele, 570 occipital encephalocele, 569 orbital encephalocele, 569 transsphenoidal encephalocele, 11–12, 569 Encephalocraniocutaneous lipomatosis, 574 Encephalotrigeminal angiomatosis. See Sturge–Weber syndrome Endoscopic third ventriculostomy (ETV), 553 Enzyme replacement therapy, 493 Ependymoma, 532–533 Epidermoids, 537–538 Epilepsy, 221–227 Epileptic nystagmus, 427 Epiphora, 449 Esotropia, 29 Evoked saccadic techniques, 37 Excavated optic disc anomalies, 67 Excessive blinking in children, 358–359 Exercise-induced diplopia, 314 Eye movement tics, 357 Eyelid abnormalities congenital ptosis, 357–358 excessive blinking, 358–359 eyelid opening apraxia, 362 eyelid retraction, 360–362 hemifacial spasm, 360 Eyelid retraction, 360–362

Index F Facial telangiectasia, 518 Familial vestibulocerebellar disorder, 427 Fibrous dysplasia, 167–168 Fisher syndrome, 337–338 Fluorescein angiography, 516 Focal cortical dysplasia, 567–568 Francois syndrome, 505 Fukuyama congenital muscular dystrophy, 565 G Gangliogliomas, 529 Ganglioneuromas, 529 Gaucher disease, 473–474 Gene therapy, 493 Gliomatosis cerebri, 107, 538 Glycosylation congenital disorders, 493 GM2 type I, 471–472 GM2 type II, 472 Goldenhar syndrome, 573–574 Gray matter heterotopia, 565 H Haltia–Santavuori disease, 426, 469 Hamartin, 513–514 Head nodding autism and benign essential tremor, 458 bobble-headed doll syndrome, 457–458 cerebellar disease, 458 congenital ocular motor apraxia, 459 congenital nystagmus, 456–457 genetic syndromes, 457 infantile spasms, 458–459 neurodegenerative disorders and metabolic defects, 457 paroxysmal dystonic head tremor, 458 spasmus nutans, 456 Head nystagmus, 455 Head posture, 443 Head tilts congenital nystagmus, 447 dissociated vertical divergence, 448–449 Down syndrome, 450 noncomitant strabismus, 445–446 ocular tilt reaction, 449 paroxysmal torticollis, 447–448 photophobia and epiphora, 449 spasmodic torticollis, 450 spasmus nutans, 447 synostotic plagiocephaly, 446–447 Head trauma, 14–16 Head turns, 450–452 congenital homonymous hemianopia, 451–452 congenital ocular motor apraxia, 452 cortical visual insufficiency, 452 incomitant strabismus, 445–446 nystagmus, 455–459 seizures, 452 Hemianopia, 37 Hemianopic visual field defects (see Congenital homonymous hemianopia) Hemifacial spasm, 360 Hemimegalencephaly, 523

601

Index Hemispheric tumors astrocytomas, 529 gangliogliomas and ganglioneuromas, 529 primitive neuroectodermal tumors (PNETs), 529–530 supratentorial ependymomas, 529 Hereditary optic atrophy, 169–172 Hereditary retinal disorders Joubert syndrome (see Joubert syndrome) Leber congenital amaurosis (LCA) (see Leber congenital amaurosis (LCA)) Hereditary vertical nystagmus, 419 Holoprosencephaly, 566–567 Homocystinuria, 427, 487 Horizontal gaze palsy causes, 318–319 congenital bilateral paralysis, 319 paramedian pontine reticular formation (PPRF), 318–319 pontine glioma, 319–320 Horizontal nystagmus, 414 Horner syndrome, 364–366 Hunter syndrome, 475 Hurler syndrome, 474–475 Hydranencephaly, 560 Hydrocephalus, 169 arrested hydrocephalus, 540 cerebrospinal fluid (CSF), 539–540 clinical features, 548–549 common causes, 537 aqueductal stenosis, 541–542 Chiari I malformation, 543–545 Chiari II malformation, 545–547 Chiari III malformation, 547 congenital, genetic, and sporadic disorders, 548 Dandy–Walker malformation, 547–548 intracranial hemorrhage, 542–543 intracranial infections, 543 tumors, 541 communicating hydrocephalus, 540 dorsal midbrain syndrome, 550–551 effects and complications, treatment, 551–553 noncommunicating and normal-pressure hydrocephalus, 540 ocular motility disorders, 549–550 visual loss, 551 Hypertonia, 20 Hypnagogic hallucinations, 231 Hypothalamic–pituitary axis empty sella syndrome, 568 encephaloceles frontoethmoidal encephalocele, 570 occipital and orbital encephaloceles, 569–570 transsphenoidal encephalocele, 569, 570 posterior pituitary ectopia, 568 Hypothyroidism, 426 I Idiopathic intracranial hypertension (IIH). See also Swollen optic disc atypical IIH, 108 childhood IIH, 108 Dandy criteria, 101 neuroimaging, 102–104 pathophysiology, 101–102 primary IIH, 104 prognosis intrinsic optic disc tumors, 122–123

neurological disease, 110–111 systemic disease, 111–120 secondary IIH Addison disease, 107 bone marrow transplantation, 107 gliomatosis cerebri, 107 malnutrition, 106 neurological disease, 104–106 postinfectious stage, 108 renal transplantation, 107 severe anemia, 106–107 sleep apnea, 107–108 systemic lupus erythematosis, 108 treatment, 109 Idiopathic nystagmus, 339 Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome, 132 Immotile cilia syndrome, 548 Incomitant strabismus, 450–451 Incontinentia pigmenti, 574–575 Infantile malignant osteopetrosis, 119–120 Infantile neuroaxonal dystrophy, 426 Infantile nystagmus, 384–409, 451–457 abnormal cross-talk, defective sensory system, 383 artificial divergence surgery, 409–410 causation theories, 393–394 clinical features, 384–385 contrast sensitivity, 393 electroretinography (ERG), 388 ERG, 388eye movement recordings, 389–393 fixation, 389–390 hemispheric visual evoked potentials, 388 history, 386 medical treatment, 405 neuroimaging studies, 404 ocular stabilization systems, 392–393 onset, 385 optical treatment, 405 oscillopsia suppression, 392 pattern detection thresholds, 393 physical examination, 386–388 rectus muscle recession, acuity improvement, 409 saccadic system, 392 smooth pursuit system, 390–391 spasmus nutans, 410–412 strabismus, 389 surgical treatment torticollis improvement, 405–408 vision improvement, 408 tenotomy, 408–409 terminology, 385–386 vestibulo-ocular reflex (VOR), 391 visual disorder precipitation achiasmia, 398–400 albinism, 388, 394–398 congenital retinal dystrophies, 400–402 isolated foveal hypoplasia, 400 Intermittent esotropia, 459 Internuclear ophthalmoplegia (INO), 352–353 Intracranial aneurysms, 556 Intracranial tumor treatment complications, 538–539 Intraventricular hemorrhage (IVH), 34–35 Intrinsic optic disc tumors, 122–123 Ischemic optic neuropathy, 132–133 Isolated foveal hypoplasia, 400 Isolated venous ectasia, 557

602 J Jansky–Bielschowsky disease, 469 Joubert syndrome, 322–323, 355, 360, 425–426 vs. Arima syndrome, 9 cerebellar vermis, agenesis, 9 clinical features, 9, 10 dysgenesis/ hypoplasia, 9 eye findings, 9 genetics, 9 MR imaging, 10 ocular motor disorders, 9 Juvenile myasthenia, 331–335 Juvenile neuronal ceroid lipofuscinose. See Batten disease K Kawasaki disease, 121 Kearns–Sayre syndrome, 487, 489, 491 Kenny syndrome, 142 Kinsbourne encephalitis, 422 Klippel–Trenauney–Weber syndrome, 523–525 Knudson two-hit hypothesis, 503 Krabbe disease, 479 Krabbe’s infantile leukodystrophy, 181 L Labyrinthine fistula, 459 Latent nystagmus, 313 Alexander’s law, 414 Ciancia syndrome, 415 eye movement recordings, 416 nasotemporal asymmetry, 414 treatment, 416–417 Leber congenital amaurosis (LCA), 402 clinical features, 6 ERG, 8–9 fundus appearance, 6–7 genes, 9 MR imaging, 8 neuroimaging abnormalities, 8 neurologic disease, 7 optic discs, 7 peroxisomal dysfunction, 8 visual improvement, 7 Leber hereditary optic neuropathy (LHON), 142 cardiac abnormalities, 175 DNA (mtDNA) mutations, 175–177 misdiagnosis, 175 recessively inherited optic atrophy, 177 Leber idiopathic stellate neuroretinitis vs. anterior optic neuritis, 129–130 cat scratch disease, 130–131 diffuse unilateral subacute neuroretinitis (DUSN), 131–132 idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome, 132 infectious causes, 131 lyme disease, 131 macular star-shaped exudates, 129–130 medical evaluation, 131 posterior ischemic optic neuropathy (PION), 133 posterior scleritis, 131 retinal ischemia, 132 unilateral visual loss, 129–130 vitritis and macular star, 129–130

Index Leigh disease, 181 Leigh subacute necrotizing encephalomyelopathy, 425, 490–492 Leukemia, 414–415 Lhermitte–Duclos disease, 572 Lilliputian hallucinations, 231 Linear nevus sebaceous syndrome, 142, 523–524 Lisch nodules, 505–506 Lissencephaly, 563–565 Lysosomal diseases gangliosidoses Gaucher disease, 473–474 GM2 type I, 471–472 GM2 type II and type III, 472 Niemann–Pick disease, 472–473 mucopolysaccharidoses, 474–476 sialidosis, 476 M Macrocephaly, 509 Malaria, 120 Malignant hypertension, 112 Maple syrup urine disease, 426–427, 486–487 Marcus Gunn jaw winking (MGJW) synkinesis, 343–344, 350 Maroteaux–Lamy syndrome, 476 Medulloblastoma, 530–531 Megalopapilla glaucoma, 76 phenotypic variants, 75–76 Meningiomas, 537 Meningitis, 16, 264 Meningoepithelial angiomatosis, 518 Metabolic bypass therapy, 493–494 Metachromatic leukodystrophy, 183, 478 Metastasis, 538 Migraine amaurosis fugax, 216 complicated migraine syndromes acute confusional migraine, 217–218 acute hemiplegic migraine, 218 alternating hemiplegia, 218 benign paroxysmal vertigo, 218 cortical function disturbances, 218–219 ophthalmoplegic migraine, 219 OTC deficiency, 218 headache, 217 migraine aura, 214–216 pathophysiology, 219–221 vs. retinal vasospasm, 216–217 Mitochondrial depletion syndrome, 492 Mitochondrial encephalomyelopathies, 326–328, 488–489 Mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS), 492 Möbius sequence, 319, 347–348 Molar tooth malformation, 571 Molecular chaperone therapy, 493 Monocular elevation deficiency. See Double elevator palsy Monocular nystagmus, 413 Morning glory disc anomaly computed tomography (CT) scan, 68, 69 contractile movements, 70, 72 embryogenesis, 70–71 PHACE syndrome, 70, 72 retinal detachments, 70 transsphenoidal encephalocele, 69, 70

603

Index Morquio syndrome, 475–476 Mucopolysaccharidosis, 142 Muscle recession, 409 Muscle–eye–brain disease, 564–565 Myasthenia gravis congenital myasthenic syndromes, 329–331 juvenile myasthenia, 331–335 transient neonatal myasthenia, 328–329 Myelinated nerve fibers, 87–88 Myoclonic epilepsy, 492 Myoclonus, 459 N Nasopharyngeal disorders, 460 Neonatal adrenoleukodystrophy, 182–183 Neonatal leukodystrophy, 182–183 Neonatal opsoclonus, 342 Neonatal strabismus, 339 Neurofibromatosis (NF1) autosomal dominant disorder, 503 brainstem and cerebellar gliomas, 509 buphthalmos, 505 café au lait spots, 504 cerebrovascular abnormalities, 510 chiasmal glioma, 506–509 choroidal ganglioneuroma, 505 cognitive disability, 510 Francois syndrome, 505 freckling and hyperpigmentation, 504 Lisch nodules, 505–506 macrocephaly, 509 magnetic resonance (MR) imaging, 506 mammalian target of rapamycin (mTOR) pathways, 504 multiple focal hyperintense lesions, 506, 509 nonpulsatile proptosis, 506 optic atrophy, 506 orbital optic glioma, 506–507 plexiform neurofibroma, 504–505 pseudarthrosis and quintessential neurocristopathy, 504 radiotherapy, 509 retinal vascular abnormalities, 506 Schwann cells, 504 tumor suppressor gene, 504 Neurofibromatosis 2 (NF2) bilateral hearing loss, 510 bilateral schwannomas, 513 bilateral vestibular schwannomas, 510 genotype–phenotype correlation, 511 merlin, protein, 510–511 optic disc glioma, 511 optic nerve sheath meningiomas, 511, 513 posterior subcapsular cataracts, 511 Neurologic esotropia exercise-induced diplopia, 314 near reflex, spasm, 314 Neurologic exotropia, 315–316 Neurologic head turns, 450 Neurological nystagmus, 424–425 Neuromyelitis optica. See Devic disease Neuronal ceroid lipofuscinoses (NCLs), 184, 469–470 Batten disease, 465–466 diagnosis, 464 Haltia-Santavuori disease, 464 Jansky-Bielschowsky disease, 465 Niemann–Pick disease, 472–473

Noncomitant strabismus, 445–446 Nonmigrainous cerebrovascular disease, 228 Nutritional nystagmus, 427 Nystagmus blockage syndrome, 417 O Ocular bobbing, 424 Ocular coherence tomography (OCT), 515 Ocular neuromyotonia, 356 Ocular tilt reaction, 449 Ocular torticollis, 444 Oculo-auricular phenomenon, 351 Oculoauriculovertebral dysplasia. See Goldenhar syndrome Ocular motor nerve palsies abducens nerve palsy (see Sixth nerve palsy) fascicle, 256–257 nucleus, 256 clinical features isolated divisional oculomotor palsy, 260 isolated inferior oblique muscle palsy, 258–259 isolated inferior rectus muscle palsy, 257, 259 isolated internal ophthalmoplegia, 260 oculomotor nerve synkinesis, 260–261 active force generation test, 254–255 forced duction test and force generation test, 254–255 history, 253–254 oculomotor nerve palsy (see Third nerve palsy) trochlear nerve palsy (see Trochlear nerve palsy) Olivopontocerebellar atrophy, 336–338 Ophthalmoplegia, 326–339 Opsoclonus, 459 causes and ocular flutter, 421–423 pathophysiology, 423 Optic atrophy, 506 Behr syndrome, 177–178 carboplatin, 189 chiasmal glioma, 156, 157 Cobalamin C methylmalonic acidemia, 185–186 compressive/infiltrative intracranial lesions, 161–162 craniopharyngioma, 164–166 craniosynostoses, 167 dysgerminoma, 166–167 fibrous dysplasia, 167–168 optic glioma, 162–164 optic nerve sheath meningioma, 166 osteopetrosis, 167 pituitary adenoma, 166 congenital optic tract syndrome, 156, 158 DIDMOAD (Wolfram’s syndrome), 178–179 disc color and size, 155 epidemiology, 156–159 hereditary optic neuropathies classification, 172 dominant optic atrophy, 172–174 genetic syndromes, 170–172 types, 170 hereditary polyneuropathies Charcot–Marie–Tooth diseases, 186–187 mucopolysaccharidoses (MPS), 187 Rosenberg–Chutorian syndrome, 187 histopathology, 155 hydrocephalus, 169, 170 vs. hypoplasia, 160–161 hypoxia–ischemia, 187–188 infantile neuroaxonal dystrophy, 184

604 Optic atrophy (cont.) Leber hereditary optic neuropathy (LHON) cardiac abnormalities, 175 DNA (mtDNA) mutations, 175–177 misdiagnosis, 175 recessively inherited optic atrophy, 177 neurodegenerative disorders, 180–181 Canavan disease, 181 Krabbe’s infantile leukodystrophy, 181 metachromatic leukodystrophy, 183 neonatal adrenoleukodystrophy, 182–183 PEHO syndrome, 182 Pelizaeus–Merzbacher disease, 181–182 subacute necrotizing encephalomyelopathy, 181 X-linked adrenoleukodystrophy, 183 noncompressive causes paraneoplastic syndromes, 168–169 postpapilledema, 168 radiation optic neuropathy, 169 ophthalmoscopic appearance, 155 organic acidurias, 185 pantothenate kinase-associated neurodegeneration familial dysautonomia, 184 neuronal ceroid lipofuscinoses, 184 pediatric patient ancillary testing, 189–190 clinical examination, 189 medical history, 189 peripapillary nerve fiber layer, 155–156 propionic acidemia, 185 retinal disorders, 159–160 simple recessive optic atrophy, 177 spinocerebellar degenerations, 185–186 toxic/nutritional optic neuropathy, 179–180 traumatic optic atrophy, 188 vigabatrin, 188–189 X-linked optic atrophy, 177 Optic disc coloboma CT scan, 73 gene mutation, 75 macular detachment, 73, 74 ophthalmoscopic appearance, 74 vs. morning glory disc anomaly, 73–75 pathological findings, 73–74 uncategorizable dysplastic optic discs, 74 Optic disc drusen. See Pseudopapilledema Optic disc dysplasia, 81 Optic disc glioma, 123, 511 Optic disc hemangioma, 122 Optic glioma, 162–164 Optic nerve aplasia, 86–87 Optic nerve hypoplasia amblyopia, 61 black optic disc, 60 CNS abnormalities, 61–64 disc size, 61 endocrinologic abnormality, 61 histopathology, 60 hypothyroidism, 62 microdisc, diagnosis, 61 prevalence, 59 pseudo-normal optic disc, 60 refractive errors, 61 retinal venous tortousity, 60 RPE and choroid, nasal pallor and extension, 60 systemic and teratogenic associations, 59–60 visual acuity, 60

Index Optic nerve sheath meningioma, 166 Optic neuritis acute disseminated encephalomyelitis (ADE), 124–125 Devic disease, 126–127 history and physical examination, 124 MS, 125–126 postinfectious optic neuritis, 124 systemic evaluation, 128–129 systemic prognosis, 128 treatment, 129 visual loss and recovery, 127 Orbital hypotelorism, 142 Organic acidurias, 460 Oscillopsia, 383 Osteopetrosis, 167 P Palinopsia, 231 Pantothenate kinase-associated neurodegeneration (PKAN), 485–486 Papilledema, 555 clinical signs, 98 color vision, 99–100 fluorescein angiogram, 98, 99 idiopathic intracranial hypertension (see Idiopathic intracranial hypertension) tumors, 100–101 visual field defects, 98–99 Papillorenal syndrome, 78–79 Paraneoplastic opsoclonus, 422 Paraneoplastic syndromes, 168–169 Paroxysmal choreoathetosis, 450 Paroxysmal dystonia, 450 Paroxysmal dystonic head tremor, 458 Paroxysmal torticollis, 447–448 Pearson syndrome, 328 Peduncular hallucinosis, 231 PEHO syndrome, 182 Pelizaeus–Merzbacher disease, 181–182, 425, 457, 479–480 Perinatal hypoxia-ischemia, 12–13 Periodic alternating gaze deviation (PAGD), 354 Periodic alternating nystagmus, 419–420 Periodic alternating skew deviation, 354 Peripapillary staphyloma, 75 Periventricular leukomalacia (PVL) intraventricular hemorrhage, 34–35 pathophysiology, 33–34 perceptual difficulties, 30–33 preterm injury, 27 Peroxisomal disorders adrenoleukodystrophy (ALD), 483–485 Zellweger hepatorenal syndrome, 483 PHACE syndrome, 70, 72, 573 Phakomatosis, 503 Photophobia, 449 Pineal region tumors, 536–537 Pituitary adenomas, 166, 528 Plexiform neurofibroma, 504–505 Polymicrogyria, 565–566 Pontine glioma, 284 Porencephaly, 560 Posterior fossa tumors brainstem tumors, 533–536 cerebellar astrocytoma, 531–532 ependymoma, 532–533 medulloblastoma, 530–531

605

Index Posterior reversible encephalopathy syndrome (PRES), 231–232 Postnatal hypoxia-ischemia, 13–14 Postpapilledema optic atrophy, 168 Prader–Willi syndrome, 397 Primary oblique muscle overaction, 313 Primitive neuroectodermal tumors (PNETs), 529–530 Priventricular leukomalacia, 65, 67 Proptosis, 555 Proteus syndrome, 573 Pseudopapilledema optic disc drusen conceptual problem, 134 epidemiology, 134 fluorescein angiographic appearance, 136 growth hormone deficiency, 139 histopathology, 136–137 natural history and prognosis, 139–140 neuroimaging, 136 ocular complications, 137–139 ophthalmoscopic appearance, 134–135 pathogenesis, 137 systemic associations, 139 systemic disorders Alagille syndrome, 140–142 Down syndrome, 140 Kenny syndrome, 142 Leber hereditary neuroretinopathy, 142 linear sebaceous nevus syndrome, 142 mucopolysaccharidosis, 142 orbital hypotelorism, 142 Psychogenic visual loss categories conversion disorder, 242 possible factitious disorder, 242 true organic disease, 242 visually preoccupied child, 241 clinical profile, 239–240 management, 242–244 neuro-ophthalmologic findings, 240–241 R Radiation optic neuropathy, 169 Rathke cleft cysts, 528 Recessive optic atrophy, 177 Retinal astrocytic hamartomas, 514–516, 520 Retrobulbar tumors, 123–124 Reversible posterior leukoencephalopathy, 572 Rhombencephalosynapsis, 571 Riddoch phenomenon, 41 Riley–Day syndrome, 184 Rod-cone dystrophies, 402–404 Rosenberg–Chutorian syndrome, 187 Russell diencephalic syndrome, 412–413 S Sandhoff disease. See GM2 type II Sandifer syndrome, 455 Sanfilippo syndrome, 475 Santavuori-Haltia disease, 426 Sarcoidosis, 112–114 Scheie syndrome, 475 Schizencephaly, 562, 563 Schizophrenia, 232 Seesaw nystagmus, 420

Segmental optic nerve hypoplasia CNS injuries, 67 embryogenesis, 65–67 genetic mutations, 67–68 mitochondrial disease, 68 periventricular leukomalacia, 65, 67 retrogeniculate lesions, 65, 66 superior segmental optic hypoplasia, 64, 65 septum pellucidum, 567 Seizures, 18–19, 452 Sepsis, 16, 17 Septum pellucidum, absence of, 61, 62, 64, 565–567 Shaken baby syndrome, 116–118 Sialidosis, 476 Sixth nerve palsy benign recurrent,283 clinical algorithm, 282 congenital sixth nerve palsy, 283 Duane retraction syndrome (see Duane retraction syndrome) elevated intracranial pressure, 284 infectious sixth nerve palsy, 284–285 inflammatory, 285 pontine glioma, 284 rare causes, 285 traumatic, 283 Sjögren–Larsson syndrome, 481–482 Skew deviation, 316–318 Sleep apnea, 107–108 Slit ventricle syndrome, 552 Sls syndrome, 476 Spasmodic torticollis, 450 Spasmus nutans, 410–412, 447, 456 Spinal cord tumors, 110–111 Spongiform leukodystrophy. See Canavan disease Strabismus, neurological dysfunction bilateral superior oblique overaction, 310 cerebral palsy, 310–311 craniosynostosis syndromes, 311–312 neurologic esotropia, 313–315 neurologic exotropia, 315–316 skew deviation, 316–318 visuovestibular disorders, 311–313 Stroke in children abnormal neuronal migration, 559–562 abnormal stem cell proliferation, 562–563 cerebral dysgenesis and intracranial malformations, 559–560 cerebral venous thrombosis (CVT), 558–559 colpocephaly, 561–562 destructive brain lesions, 560 hydranencephaly, 560 ornithine transcarbamylase deficiency, 558 porencephaly, 560 risk factors, 557 vascular dysfunction, pathophysiologic mechanisms, 557 Sturge–Weber syndrome, 36 port-wine color, facial lesion, 518 tomato-catsup fundus, 519 venous dilatation, 517 Subacute sclerosing panencephalitis (SSPE), 111, 476 Subcortical visual loss. See Periventricular leukomalacia (PVL) Subependymal giant cell astrocytomas (SEGAs), 514 Subungual fibromas, 514–515 Sudanophilic leukodystrophy, 181. See Pelizaeus– Merzbacher disease Suprasellar tumors, 527–528 Supratentorial ependymomas, 529

606 Swollen optic disc, 97–142 Leber idiopathic stellate neuroretinitis anterior ischemic optic neuropathy (AION), 132–133 vs. anterior optic neuritis, 129–130 autoimmune optic neuropathy, 133 cat scratch disease, 130–131 diffuse unilateral subacute neuroretinitis (DUSN), 131–132 idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome, 132 infectious causes, 131 lyme disease, 131 macular star-shaped exudates, 129–130 medical evaluation, 131 posterior ischemic optic neuropathy (PION), 133 posterior scleritis, 131 retinal ischemia, 132 unilateral visual loss, 129–130 vitritis and macular star, 129–130 neurological disease hydrocephalus, 110 neurofibromatosis, 110 spinal cord tumors, 110–111 subacute sclerosing panencephalitis (SSPE), 111 optic neuritis acute disseminated encephalomyelitis (ADE), 124–125 Devic disease, 126–127 history and physical examination, 124 MS, 125–126 postinfectious optic neuritis, 124 systemic evaluation, 128–129 systemic prognosis, 128 treatment, 129 visual loss and recovery, 127 papilledema clinical signs, 98 color vision, 99–100 fluorescein angiogram, 98, 99 idiopathic intracranial hypertension (see Idiopathic intracranial hypertension) tumors, 100–101 visual field defects, 98–99 pseudopapilledema (see Pseudopapilledema) retrobulbar tumors, 123–124 systemic disease Blau syndrome, 120–121 chronic infantile neurological cutaneous articular (CINCA), 121 craniosynostosis syndromes, 116–117 cyanotic congenital heart disease, 116 cysticercosis, 118–119 diabetic papillopathy, 111–112 infantile malignant osteopetrosis, 119–120 Kawasaki disease,121 leukemia, 114–115 malaria, 120 malignant hypertension, 112 mucopolysaccharidosis, 119 paraneoplastic optic disc edema, 120 poststreptococal uveitis, 122 posttraumatic optic disc swelling, 121–122 sarcoidosis, 112–114 shaken baby syndrome, 117–118 uveitis, 120–121 Synostotic plagiocephaly, 446–447 Systemic disease Blau syndrome, 120–121

Index chronic infantile neurological cutaneous articular (CINCA), 121 craniosynostosis syndromes, 116–117 cyanotic congenital heart disease, 116 cysticercosis, 118–119 diabetic papillopathy, 111–112 infantile malignant osteopetrosis, 119–120 Kawasaki disease,121 leukemia, 114–115 malaria, 120 malignant hypertension, 112 mucopolysaccharidosis, 119 paraneoplastic optic disc edema, 120 poststreptococal uveitis, 122 posttraumatic optic disc swelling, 121–122 sarcoidosis, 112–114 shaken baby syndrome, 117–118 uveitis, 120–121 Systemic lupus erythematosis, 107 Systemic disorders aortic regurgitation, 459–460 cobalamin C methylmalonic aciduria and homocystinuria, 427 Down syndrome, 426 endocrine and metabolic disturbances, 460 epileptic nystagmus, 427 hypothyroidism, 427 maple syrup urine disease, 426–427 nasopharyngeal disorders, 460 nutritional nystagmus, 427 organic acidurias, 460 T Tay–Sachs disease. See GM2 type I Third nerve palsy acquired oculomotor nerve palsy cryptogenic third nerve palsy, 266 inflammatory causes, 267 meningitis, 264 neoplastic causes, 267 ophthalmoplegic migraine, 264–266 recurrent isolated third nerve palsy, 266 Transient unilateral oculomotor nerve palsy, 267 traumatic third nerve palsy, 263–264 vascular causes, 266 clinical anatomy fascicle, 256–257 nucleus, 256 clinical features isolated divisional oculomotor palsy, 260 isolated inferior oblique muscle palsy, 258–259 isolated inferior rectus muscle palsy, 257, 259 isolated internal ophthalmoplegia, 260 oculomotor nerve synkinesis, 260–261 congenital third nerve palsies amblyopia, 263 cyclic oculomotor palsy, 263 left oculomotor nerve palsy,262, 263 PHACE syndrome, 263 unusual facial-oculomotor synkinesis, 261, 262 differential diagnosis congenital fibrosis of the extraocular muscles (CFEOM), 267–268 internuclear ophthalmoplegia, 268 myasthenia gravis, 267

607

Index orbital blowout fracture, 268 type II Duane syndrome, 268 evaluation, clinical algorithm, 262 management amblyopia, 268 ocular alignment, 269 ptosis, 270 Tick paralysis, 338 Todd’s paralysis, 19 Tonic downgaze, 339–341 Tonic upgaze, 341–342 Torsional nystagmus, 413 Torticollis head posture, 443 neuromuscular causes, 453–455 ocular torticollis, 444 paroxysmal torticollis, 447–448 refractive causes, 453 systemic causes, 455 wryneck/caput obstipum, 443 Transient idiopathic nystagmus, 339 Transient neonatal myasthenia, 328–329 Transient neonatal strabismus, 339 Transient ocular motor disturbances, infancy idiopathic nystagmus, 339 neonatal opsoclonus, 342 neonatal strabismus, 339 tonic downgaze, 339–341 tonic upgaze, 341–342 transient vertical strabismus, 342 Transient vertical strabismus, 342 Transient visual loss Alice in Wonderland syndrome, 230 anomalous optic discs, 229 cannabinoid, 233 cardiogenic embolism, 227–228 Charles Bonnet syndrome, 230–231 entoptic images, 229 epilepsy ictal cortical blindness, 225 vs. migraine,225–227 postictal blindness, 225 seizure aura, 223–225 vigabitrin, 227 genetics, 221–222 hallucinogenic drug, 232–233 hypnagogic hallucinations, 231 lilliputian hallucinations,231 media opacities, 230 migraine amaurosis fugax, 216 complicated migraine syndromes, 217–219 headache, 217 migraine aura, 214–216 pathophysiology, 219–221 vs. retinal vasospasm, 216–217 multiple sclerosis, 232 neurodegenerative disease, 232 nonmigrainous cerebrovascular disease, 228 obscurations, 228–229 palinopsia, 231 peduncular hallucinosis, 231 phosphenes, 230 posterior reversible encephalopathy syndrome (PRES), 231–232 posttraumatic transient cerebral blindness, 227

retinal circulation, 229 schizophrenia, 232 sequelae, 222 toxic and nontoxic drug effects antimetabolites and cancer therapy, 233 atropine (anticholinergic drugs), 233–234 carbon monoxide, 234 clinical approach, 234–235 digitalis,233 erythropoietin, 233 laboratory evaluation, 235 treatment, 222–223 Uhthoff symptom, 230 Trigemino-oculomotor synkinesis. See Marcus Gunn jaw winking (MGJW) synkinesis Trochlear nerve palsy bilateral trochlear nerve palsy, 273–274 clinical anatomy, 270–271 congenital trochlear nerve palsy causes, 277–278 facial asymmetry, 275–277 large vertical fusional vergence amplitudes, 275 differential diagnosis, 278–279 head posture, 271–272 isolated trochlear nerve palsy, 274 three-step test, 272–273 traumatic trochlear nerve palsy, 275 treatment, 279–280 vertical diplopia, 270 Tuberin, 514 Tuberous sclerosis, 122–123 adenoma sebaceum, 514–515 chromosome 16p13, 514 chromosome 9q34, 513 CNS lesions, 516 diagnosis, 514 giant cell astrocytomas, 516 renal cysts, 514 retinal astrocytic hamartomas, 514–516 SEGAs, 514 subcortical and cortical tubers, 516 subungual fibromas, 514–515 Twin pregnancy, 16 U Uhthoff symptom, 230 Unexplained visual loss. See Visual loss, unexplained Unilateral schwannoma, 513 Upbeating nystagmus, 417 Uveitis, 120–121 V Vacant optic disc. See Papillorenal syndrome Vascular lesions AVMs, 553–556 cavernous angiomas, 556 craniocervical arterial dissection, 557 intracranial aneurysms, 556 isolated venous ectasia, 557 Ventricular shunt failure, 17–18 Vertical gaze palsies downgaze palsy, 324–325 rostral interstitial nucleus of medial longitudinal fasciculus (riMLF), 324

608 Vertical gaze palsies (cont.) supranuclear, 323–324 upgaze palsy, 325–326 Vertical head postures, 452–453 Vertical nystagmus, 417–419 Vestibular schwannomas, 512 Vigabitrin-associated visual field loss, 227 Visual disorders achiasmia, 398–400 albinism, 394–398 congenital retinal dystrophies, 400–402 isolated foveal hypoplasia, 400 rod-cone dystrophies, 402–404 Visual loss, unexplained causes cornea, 236 refractive abnormalities, 236 transient amblyogenic factors, 235–236 optic nerve, 237–238 retina, 236–237 Visuovestibular disorders, 311–313 Voluntary nystagmus, 423–424 von Hippel–Lindau disease 2A phenotype, 521 cerebellar hemangioblastomas, 520 inheritance, 519 low spontaneous mutation rate, 520 renal carcinoma, 521 retinal capillary hemangiomas, 520 types 1 and 2B, 521

Index vanillylmandelic acid (VMA), 521 VHL gene, 520 W Walker–Warburg syndrome, 564 Wegener granulomatosis, 338 Wernicke encephalopathy, 338 White matter disorders Alexander disease, 481 Canavan disease, 478–479 cerebrotendinous xanthomatosis, 482 Cockayne syndrome, 480–481 Krabbe disease, 479 metachromatic leukodystrophy, 478 Pelizeus–Merzbacher disease, 479–480 Sjögren–Larsson syndrome, 481–482 Wildervanck syndrome, 574–575 Wilson disease, 486 Wolfram syndrome, 178–179 X X-linked adrenoleukodystrophy, 183 X-linked optic atrophy, 177 Z Zellweger hepatorenal syndrome, 483 Zinc finger transcription factor, 396–398