Neuro-Ophthalmology 019060395X, 9780190603953

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Neuro-​Ophthalmology

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What Do I Do Now? S E R I E S C O -​E D ITORS-​I N-​C HIE F

Lawrence C. Newman, MD Director of the Headache Division Professor of Neurology New York University Langone New York, New York Morris Levin, MD Director of the Headache Center Professor of Neurology University of California, San Francisco San Francisco, California OT H E R VO L U M E S IN T HE  SE RIE S

Headache and Facial Pain Epilepsy Pain Emergency Neurology Neuroinfections Neurogenetics Neurotology Pediatric Neurology Neurocritical Care Stroke Peripheral Nerve and Muscle Disease Cerebrovascular Disease Movement Disorders Women’s Neurology Neuroimmunology

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Neuro-​Ophthalmology

SECOND EDITION Matthew J. Thurtell, MBBS, FRACP Associate Professor of Ophthalmology and Neurology Director of Neuro-​Ophthalmology Service Department of Ophthalmology and Visual Sciences University of Iowa Iowa City, IA

Robert L. Tomsak, MD, PhD Professor of Ophthalmology and Neurology Kresge Eye Institute Wayne State University Detroit, MI

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1 Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America. © Oxford University Press 2019 First Edition published in 2011 Second Edition published in 2019 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. Library of Congress Cataloging-​in-​Publication Data Names: Thurtell, Matthew J., author. | Tomsak, Robert L., author. Title: Neuro-ophthalmology / by Matthew J. Thurtell, Robert L. Tomsak. Description: Second edition. | New York, NY : Oxford University Press, [2019] | Includes bibliographical references and index. Identifiers: LCCN 2018054874 | ISBN 9780190603953 (pbk.) Subjects: | MESH: Eye Diseases—diagnosis | Nervous System Diseases—complications | Cranial Nerve Diseases | Eye Diseases—therapy | Diagnosis, Differential | Case Reports Classification: LCC RE75 | NLM WW 460 | DDC 617.7075—dc23 LC record available at https://lccn.loc.gov/2018054874 This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publisher do not accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed or incurred as a consequence of the use and/​or application of any of the contents of this material. 9 8 7 6 5 4 3 2 1 Printed by WebCom, Inc., Canada

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Robert B. Daroff, MD—​our mentor, colleague, and friend—​in recognition of his contributions to the field of neuro-​ophthalmology.

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Contents Preface  ix Acknowledgments  xi SECTION I AFFERENT DISORDERS

1 Optic Neuritis  3 2 Arteritic Ischemic Optic Neuropathy  9 3 Nonarteritic Ischemic Optic Neuropathy  15 4 Compressive Optic Neuropathy  21 5 Leber Hereditary Optic Neuropathy  25 6 Autosomal Dominant Optic Atrophy  29 7 Neuroretinitis 35 8 Papilledema 41 9 Idiopathic Intracranial Hypertension  47 10 Pseudopapilledema 55 11 Chiasmal Syndromes  61 12 Homonymous Hemianopia  67 13 Disorders of Higher Visual Function  71 14 Visual Auras, Hallucinations, and Illusions  77 15 Transient Vision Loss  83 16 Unexplained Vision Loss  89 17 Nonorganic Vision Loss  93

SECTION II EFFERENT DISORDERS

18 Third Nerve Palsy  99 19 Fourth Nerve Palsy  105 20 Sixth Nerve Palsy  111 21 Intermittent Diplopia  115

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22 Ocular Myasthenia  121 23 Infranuclear Ophthalmoplegia  127 24 Internuclear Ophthalmoplegia  133 25 Supranuclear Ophthalmoplegia  137 26 Gaze-​Evoked Nystagmus  141 27 Downbeat Nystagmus  145 28 Upbeat Nystagmus  151 29 Pendular Nystagmus  155 30 Infantile Nystagmus  161 31 Saccadic Intrusions and Dysmetria  167

SECTION III EYELID DISORDERS

32 Eyelid Ptosis  175 33 Benign Essential Blepharospasm  181

SECTION IV PUPIL DISORDERS

34 Anisocoria 187 35 Horner Syndrome  193 36 Tonic Pupil  199

SECTION V ORBITAL AND MISCELLANE O U S D I S O RD E R S

37 Thyroid Eye Disease  207 38 Syndromes of the Orbital Apex, Superior Orbital Fissure, and Cavernous Sinus  213 39 Carotid-​Cavernous Fistula  219 40 Dorsal Midbrain Syndrome  225 Index  231

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Contents

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Preface Patients with neuro-​ophthalmic conditions are commonly encountered in clinical practice, yet many clinicians feel ill prepared or uncomfortable when dealing with them. Those trained in neurology often feel uneasy when evaluating patients who have predominantly visual or ocular complaints, whereas those trained in ophthalmology often feel uncomfortable when evaluating those with predominantly neurologic complaints. Since a neuro-​ophthalmologist is not always available for consultation, the clinician might be left wondering, “What do I do now?” when encountering a challenging case. In this installment of the What Do I  Do Now? series, we aim to provide a user-​friendly manual that clinicians can reference when dealing with patients who have neuro-​ophthalmic problems. The volume is divided into five sections that cover the main subdivisions of neuro-​ophthalmic practice: (1) afferent (visual) disorders, (2) efferent (eye movement) disorders, (3) eyelid disorders, (4) pupil disorders, and (5) orbital and miscellaneous disorders. Each chapter includes a practical, case-​based discussion on how to approach and manage a patient with a particular disorder. We discuss mainly common disorders, although we also consider some less common yet important conditions, as well as neuro-​ophthalmic presentations of systemic and psychiatric disease. We have included a large number of efferent (eye movement) cases because many other handbooks focus on afferent (visual) disorders. We have based our recommendations on current evidence whenever possible. A list of key clinical points appears at the end of each chapter as well as a list of important references. In most chapters, tables and boxes summarize pertinent information. We include figures in most chapters to illustrate abnormal clinical signs or relevant imaging findings. We designed the volume as a resource for neurologists and ophthalmologists at all levels of training. We hope that it will serve as a useful handbook in caring for patients with neuro-​ophthalmic disease.

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Acknowledgments Many of the cases described in this book touch on controversial aspects of neuro-​ophthalmology. We acknowledge those experts in the field who agreed to discuss their personal approaches to such cases with us. In particular, we thank Drs. Randy H. Kardon, Michael Wall, Richard C. Allen, and Wallace L. Alward for their helpful advice. We also thank the team at Oxford University Press, Craig Panner and Tiffany Lu, for their help in bringing this volume to completion.

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SECTION I

Afferent Disorders

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1 Optic Neuritis

You are called to see a 22-​year-​old woman who has had a subacute onset of vision loss in her right eye over several days with associated pain on eye movements. She has no past medical history and denies other neurologic symptoms. Examination shows visual acuities of 20/​100 in the right eye and 20/​15 in the left eye. She can identify only the control Ishihara color plate with the right eye, but she correctly identifies all plates with the left eye. Confrontation visual fields show a central scotoma in the right eye. Her pupils are equal and react to light, but there is a right relative afferent pupillary defect. Her funduscopic examination is normal.

What do you do now?

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he patient in this scenario has had a subacute onset of painful monocular vision loss and exhibits the cardinal signs of an optic neuropathy: decreased visual acuity, a central visual field defect, dyschromatopsia, and a relative afferent pupillary defect. Her presentation is classic for optic neuritis. The clinical manifestations of optic neuritis vary depending on the portion of the optic nerve that is inflamed. For example, in retrobulbar optic neuritis, the most common subtype of optic neuritis, the retrobulbar portion of the optic nerve is inflamed and there is minimal, if any, optic disc edema. However, in neuroretinitis, the optic nerve head and peripapillary retina are inflamed, giving rise to optic disc edema and changes in the macula (i.e., fluid extending into the macula initially with development of retinal exudates to form a macular star) (see Case 7). Causes for optic neuritis also vary depending on the portion of the optic nerve affected. Causes for retrobulbar optic neuritis include demyelinating diseases (e.g., multiple sclerosis [MS] and neuromyelitis optica), autoimmune diseases (e.g., systemic lupus erythematosus), inflammatory diseases (e.g., sarcoidosis), infections (e.g., Lyme disease and syphilis), and vaccinations (e.g., influenza vaccine). In many patients, however, a cause cannot be identified and the optic neuritis is considered idiopathic. Nevertheless, the first step in the evaluation of the patient described in this scenario would be to obtain further history (e.g., inquiring about recent travel, vaccinations, and tick bites). The ophthalmic and neurologic examinations should be completed, because there may be abnormalities that suggest the diagnosis. For example, the presence of granulomatous uveitis on ophthalmic examination might suggest an inflammatory disorder, such as sarcoidosis, whereas the presence of internuclear ophthalmoplegia might suggest MS. In the absence of any other significant history or abnormal examination findings, however, the optic neuritis is likely to be idiopathic. Diagnostic studies should be obtained in patients with idiopathic optic neuritis to confirm the presence of optic nerve enhancement, to evaluate for white matter lesions in the brain, and to exclude other causes for the optic neuropathy (e.g., compressive optic neuropathy; see Case 4). The most important initial diagnostic study is magnetic resonance imaging (MRI) of the orbits and brain. MRI of the orbits typically demonstrates increased signal in the affected optic nerve, with associated contrast enhancement that is best appreciated on fat-​suppressed images (Figure 1.1). However, such 4

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FIGURE 1.1.   MRI of the orbits (top row) and brain (bottom row) in a patient with optic neuritis,

demonstrating left optic nerve enhancement and multiple ovoid periventricular white matter lesions consistent with MS.

changes are nonspecific and cannot be considered diagnostic of idiopathic optic neuritis. MRI of the brain should be obtained to assess for white matter lesions, which are most obvious on the T2-​weighted and FLAIR (fluid-​attenuated inversion recovery) sequences (see Figure 1.1), because the presence of one or more lesions (especially when they have a periventricular distribution) portends an increased risk of developing MS. Laboratory investigations can be useful to screen for other causes of optic neuritis, such as neuromyelitis optica (NMO), especially in patients with atypical features to their presentation (Box 1.1). Patients with optic neuritis in the setting of NMO with NMO-​IgG (i.e., aquaporin-​4) antibodies often present with severe vision loss that can be bilateral and without associated pain, and a poor recovery of vision despite aggressive treatment. Patients 1.  Optic Neuritis

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FIGURE 1.2.   MRI of the orbits in a patient with bilateral optic neuritis in the setting of

neuromyelitis optica, demonstrating longitudinally extensive bilateral optic nerve enhancement.

with optic neuritis in the setting of NMO with myelin oligodendrocyte glycoprotein (i.e., MOG-​IgG) antibodies can also present with severe vision loss that can be bilateral with associated optic disc edema, but usually have a rapid and dramatic recovery of vision with treatment. With optic neuritis in the setting of NMO, MRI of the orbits can show longitudinally extensive optic nerve enhancement or bilateral optic nerve enhancement (Figure 1.2). Other laboratory investigations, such as antinuclear antibody, anti-​ neutrophil cytoplasmic antibodies, angiotensin-​converting enzyme level, lysozyme level, syphilis serology, and Lyme serology, are often unrevealing and, thus, unnecessary unless there are atypical features to the presentation (see Box 1.1). Cerebrospinal fluid (CSF) analysis can be useful to evaluate for other causes of optic neuritis in selected patients. However, CSF analysis

BOX 1.1   Atypical

Features for Idiopathic Optic Neuritis

Lack of pain Severe vision loss Poor recovery of vision Bilateral optic nerve involvement Systemic symptoms or signs (e.g., fever or rash) Intraocular inflammation, hemorrhages, or exudates Immunocompromised patient (e.g., transplant recipient) Longitudinally extensive optic nerve enhancement on MRI Optic nerve sheath enhancement on MRI Rapid improvement following initiation of steroids Relapsing course following withdrawal of steroids

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is not routinely required to evaluate for oligoclonal bands and other CSF markers of MS, because an increased risk of MS is more reliably predicted by the presence of white matter lesions on MRI. The recommended treatment of idiopathic optic neuritis is based on the findings of the Optic Neuritis Treatment Trial, which was a randomized controlled trial comparing outcomes in patients who received intravenous and then oral steroids, oral steroids alone, or placebo. The group receiving intravenous and then oral steroids showed a more rapid recovery of vision than the placebo group, although the final visual outcome was similar. This group also showed a lower risk of developing clinically definite MS in the first 2 years following treatment. The group receiving oral steroids alone did not show a faster recovery compared with placebo but did show an increased rate of recurrent optic neuritis attacks compared with the other two groups. Thus, the recommended treatment protocol for idiopathic optic neuritis is intravenous methylprednisone (1 g daily) for 3  days followed by oral prednisone (1 mg/​kg daily) for 11 days. The prognosis for visual recovery is excellent, with vision recovering to near normal in most patients over weeks to months, although there can be minor persisting visual deficits (e.g., in contrast and color vision) and clinical signs of optic nerve dysfunction (e.g., a relative afferent pupillary defect and optic disc pallor). In patients who have one or more white matter lesions on MRI, the risk of developing MS is greater than 65% in the 15 years following an attack of idiopathic optic neuritis, compared with 25% in patients who do not have white matter lesions. Treatment with disease-​modifying therapy for MS (e.g., beta-​interferon) can reduce the risk of developing MS in patients with idiopathic optic neuritis who have white matter lesions on MRI. Although not all optic neuritis patients with white matter lesions will develop clinically definite MS, initiation of disease-​modifying therapy should be carefully considered.

KEY POINT S TO REMEMBER

• The cardinal signs of an optic neuropathy are decreased visual acuity, a central visual field defect, dyschromatopsia, and a relative afferent pupillary defect.

1.  Optic Neuritis

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• Optic neuritis is characterized by a subacute onset of painful

monocular vision loss with a relative afferent pupillary defect; optic disc edema may or may not be present, depending on the portion of the nerve affected.

• Optic neuritis is often idiopathic but can be caused by

demyelinating disease, autoimmune disease, inflammatory disease, infections, and vaccinations.

• MRI of the orbits and brain should be obtained acutely to

confirm the presence of optic nerve enhancement, evaluate for white matter lesions in the brain, and exclude other causes of optic neuropathy.

• The 15-​year risk of developing MS is over 65% in optic neuritis patients with one or more white matter lesions on MRI versus about 25% in those with no white matter lesions.

• Treatment of optic neuritis with intravenous methylprednisone (1 g daily) for 3 days and then oral prednisone (1 mg/​kg daily) for 11 days leads to a faster recovery of vision and decreased risk of developing MS in the 2 years following treatment.

Further Reading Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992;326:581–​588. Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med. 1993;329:1764–​1769. Chen JJ, Flanagan EP, Jitprapaikulsan J, et al. Myelin oligodendrocyte glycoprotein antibody (MOG-​IgG)-​positive optic neuritis: clinical characteristics, radiologic clues and outcome. Am J Ophthalmol. 2018;195:8–​15. Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-​up. Arch Neurol. 2008;65:727–​732. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–​173.

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Arteritic Ischemic Optic Neuropathy

A 75-​year-​old white woman presents to your clinic after suddenly developing vision loss in her right eye. She reports having had several brief episodes of transient vision loss in her right eye over the past week, as well as a persistent dull right-​ sided temporal headache. Examination shows visual acuities of count fingers in the right eye and 20/​25 in the left eye. She cannot identify the control Ishihara color plate with the right eye, but she correctly identifies all plates with the left eye. Her pupils are equal and react to light, but there is a right relative afferent pupillary defect. Funduscopic examination shows pallid optic disc edema in the right eye.

What do you do now?

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he acute onset of severe monocular vision loss with associated pallid optic disc edema in this older woman with temporal headaches should immediately suggest anterior ischemic optic neuropathy secondary to giant cell arteritis (GCA). Ischemic optic neuropathies occur as a result of hypoperfusion of the optic nerve. Ischemia to the retrobulbar portion of the nerve results in posterior ischemic optic neuropathy; because the anterior portion of the optic nerve is not affected, there is no associated optic disc edema. Ischemia to the anterior portion of the nerve results in anterior ischemic optic neuropathy; because the optic nerve head is affected, there is, by definition, optic disc edema, which can be hyperemic or pallid. Anterior ischemic optic neuropathy occurs more frequently than posterior ischemic optic neuropathy. It can be divided into two types: arteritic anterior ischemic optic neuropathy (AAION), in which the ischemia results from inflammatory narrowing or occlusion of the posterior ciliary arteries by vasculitis (most commonly GCA), and nonarteritic anterior ischemic optic neuropathy (NAION), in which the ischemia occurs because of other factors (see Case 3). GCA is a granulomatous vasculitis that affects medium-​to large-​sized arteries, especially the cranial branches of the aortic arch. It occurs most commonly in white women who are aged 65 years or more and does not occur in children or adults who are aged 50 years or less. Up to 50% of patients present with visual symptoms, mostly secondary to AAION. The AAION in GCA is characterized by a rapid onset of severe monocular vision loss with diffuse optic disc edema (Figure 2.1) and a dense relative afferent pupillary defect. The vision loss is often devastating, with the initial visual acuity being count fingers or worse in over 50% of patients. The optic disc edema is typically pallid, but it can be hyperemic. The optic disc edema gradually resolves over several weeks, with the optic disc ultimately becoming pale, atrophic, and cupped. In contrast with optic neuritis and NAION (see Cases 1 and 3), there is rarely any recovery of vision. AAION can sometimes be difficult to distinguish from NAION in the acute setting. The distinction is clinically important, however, because 25% to 50% of patients with AAION will develop AAION in the fellow eye within 2 weeks if left untreated. The presence of pallid optic disc edema is highly suggestive of AAION, whereas hyperemic optic disc edema with retinal nerve fiber layer hemorrhages is more characteristic of NAION (see Case 10

WHAT DO I DO NOW? Afferent Disorders

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FIGURE 2.1.   Fundus photograph demonstrating pallid optic disc edema due to AAION, with

cilioretinal artery occlusion, in a patient with GCA (left). Fluorescein angiography shows patchy choroidal nonperfusion and cilioretinal artery occlusion (right).

3). Since GCA causes inflammatory narrowing and occlusion of the posterior ciliary arteries (which supply the choroid of the eye) and the cilioretinal artery (which variably supplies the papillomacular portion of the retina), concurrent choroidal or cilioretinal ischemia is highly suggestive of GCA (see Figure 2.1). Prior to the onset of AAION, a significant proportion of patients will have episodes of transient monocular or binocular vision loss, which are typically precipitated by postural changes. Some patients experience transient diplopia, which is thought to be secondary to ischemia of the extraocular muscles. Many report systemic symptoms, such as temporal headache, jaw claudication, scalp tenderness, malaise, weight loss, and fever, which should immediately suggest GCA. However, their absence does not preclude GCA; over 20% of patients with biopsy-​proven GCA do not have systemic symptoms. For the patient in this scenario, with a dull temporal headache and severe monocular vision loss due to anterior ischemic optic neuropathy, the clinical suspicion for GCA is high. Therefore, urgent investigations and treatment are required. An erythrocyte sedimentation rate and C-​reactive protein level should be obtained immediately. Most patients with GCA have elevation of both inflammatory markers, reflecting systemic inflammation, but occasionally only one might be elevated. In patients who do not have elevated inflammatory markers, further investigations should still be obtained and empiric treatment initiated if the clinical suspicion for 2.  Arteritic Ischemic Optic Neuropathy

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GCA is high. Fluorescein angiography can be useful to demonstrate choroidal or cilioretinal ischemia, thereby helping to differentiate AAION from NAION (see Figure 2.1). However, the diagnosis can be confirmed only by identifying the characteristic histopathologic changes on temporal artery biopsy. The specimen should be at least 2 cm long and serially sectioned, to avoid a false-​negative result in the event that there are skip lesions. If the clinical suspicion is low, a negative biopsy is sufficient to exclude the diagnosis. The initiation of treatment should not be delayed while awaiting a temporal artery biopsy or its result; the histopathologic changes persist for at least several weeks after treatment is commenced. In any patient with suspected AAION, systemic corticosteroids should be administered immediately to reduce the risk of AAION occurring in the fellow eye. Although no prospective randomized study has been performed, many clinicians treat with intravenous methylprednisone (1 g daily) for 1–​ 3 days followed by high-​dose oral prednisone (1 mg/​kg daily), although some will begin with high-​dose oral prednisone alone. High-​dose oral prednisone should be continued for at least a month, until systemic symptoms have resolved and the inflammatory markers have normalized. When prednisone is used as monotherapy, its dose should be slowly tapered over 12–​18 months (e.g., by 5–​10 mg per month), provided that the patient does not have any symptoms to suggest active GCA and his or her inflammatory markers remain within normal limits. Since many patients develop significant complications and side effects from prolonged prednisone therapy (e.g., osteoporosis, steroid-​ induced diabetes, and weight gain), addition of a steroid-​sparing agent (e.g., leflunomide) should be considered. One recent trial found that therapy with tocilizumab, a monoclonal antibody to the interleukin-​6 receptor, allowed for a more rapid taper of prednisone with less serious adverse events than therapy with prednisone alone. However, long-​term follow-​up is needed to determine the durability of remission with tocilizumab and its long-​term safety.

KEY POINTS TO REMEMBER

• AAION is characterized by a rapid onset of severe monocular

vision loss with a relative afferent pupillary defect and pallid or hyperemic optic disc edema.

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• AAION occurs because of inflammatory narrowing or occlusion of the posterior ciliary arteries by vasculitis (e.g., GCA).

• GCA is a granulomatous vasculitis that most commonly occurs in older white women.

• Systemic symptoms of GCA include temporal headache, jaw

claudication, scalp tenderness, malaise, weight loss, and fever.

• About 50% of patients with GCA present with vision loss, in most cases due to AAION.

• High-​dose corticosteroid treatment should be commenced

immediately whenever GCA is suspected and should not be delayed while awaiting the results of laboratory studies or temporal artery biopsy.

Further Reading González-​Gay MA, García-​Porrúa C, Llorca J, et al. Visual manifestations of giant cell arteritis: trends and clinical spectrum in 161 patients. Medicine. 2000;79:283–​292. Hayreh SS, Zimmerman B. Management of giant cell arteritis: our 27-​year clinical study: new light on old controversies. Ophthalmologica. 2003;217:239–​259. Kawasaki A, Purvin V. Giant cell arteritis: an updated review. Acta Ophthalmol. 2009;87:13–​32. Parikh M, Miller NR, Lee AG, et al. Prevalence of a normal C-​reactive protein with an elevated erythrocyte sedimentation rate in biopsy-​proven giant cell arteritis. Ophthalmology. 2006;113:1842–​1845. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-​cell arteritis. N Engl J Med. 2017;377:317–​328.

2.  Arteritic Ischemic Optic Neuropathy

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Nonarteritic Ischemic Optic Neuropathy

An overweight 58-​year-​old man presents to the emergency department after waking with vision loss in his right eye without associated pain. He has a past history of hypertension, diabetes, and erectile dysfunction, and he is taking multiple antihypertensive medications. Examination shows visual acuities of 20/​50 in the right eye and 20/​20 in the left eye. He correctly identifies 10 of 14 Ishihara color plates with the right eye and 14 of 14 plates with the left eye. Confrontation visual fields show an inferior altitudinal defect in the right eye. His pupils are equal in size and react to light, but there is a right relative afferent pupillary defect. Funduscopic examination shows superior segmental optic disc edema in the right eye and a small, structurally congested optic disc in the left eye.

What do you do now?

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he acute onset of painless monocular vision loss with associated segmental optic disc edema in this middle-​aged man with multiple vascular risk factors suggests nonarteritic anterior ischemic optic neuropathy (NAION). NAION is the most common cause of acute-​onset optic neuropathy in older adults in the Western world. It typically produces a rapid onset of painless monocular vision loss that worsens over hours to days, with a relative afferent pupillary defect and optic disc edema (Figure 3.1). An inferior altitudinal visual field defect is often present, although other visual field defects (e.g., superior altitudinal, arcuate, or central) can also occur. The optic disc edema is typically segmental (e.g., superior greater than inferior; see Figure 3.1) and gradually resolves over weeks, with the optic disc ultimately becoming pale in a segmental fashion. The visual acuity and field defects usually stabilize in the days following onset. In contrast with optic neuritis (see Case 1), there is rarely a substantial recovery of vision thereafter, although there can be a modest improvement. There is a small risk of recurrence in the affected eye, but there is a significant risk of NAION occurring in the fellow eye (15–​20% over 5 years), which patients should be warned about. NAION occurs due to hypoperfusion and ischemia of the optic nerve head. In contrast with the arteritic form (AAION; see Case 2), where vasculitis leads to narrowing and occlusion of the arteries supplying the optic

FIGURE 3.1.   Fundus photographs demonstrating optic disc edema due to NAION in the right eye

and a small, structurally congested optic disc (“disc at risk”) in the left eye.

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nerve head, the pathogenesis of NAION is not well understood. However, it is not thought to occur as a result of emboli occluding the arteries supplying the optic nerve head and, thus, a workup for an embolic source is not required. Since many affected patients have vascular risk factors, such as diabetes and hypertension, there may be atherosclerotic stenoses in the vessels supplying the optic nerve head. Many patients awake with their vision loss and, thus, nocturnal hypotension and hypoxemia from obstructive sleep apnea are thought to play an important role in the pathogenesis of NAION. Consequently, it is important to ask patients about the timing of their antihypertensive medication doses, since the use of antihypertensive medications at night might exacerbate nocturnal hypotension. A number of other factors (e.g., vasospasm and impaired vascular autoregulation) might also play a role in the pathogenesis of NAION in some patients. Consistently, however, affected patients have small, structurally congested optic discs, with a small or absent physiologic cup (see Figure 3.1); this normal variant is well established as a marker for increased risk of NAION and has been called a “disc at risk.” The “disc at risk” is more common in white patients, which might explain why there is a higher incidence of NAION in whites than in other ethnic groups. Several medications have been implicated as precipitants for NAION. Amiodarone has been reported to cause bilateral simultaneous optic neuropathies that are reminiscent of NAION. NAION may also occur in association with use of phosphodiesterase type-​5 inhibitors (sildenafil, vardenafil, or tadalafil) for erectile dysfunction. The evidence suggesting a relationship between NAION and phosphodiesterase type-​5 inhibitor use initially came from case reports or small case series, although one recent study found an approximately twofold increased risk of NAION with phosphodiesterase type-​5 inhibitor use. Consequently, it is important to ask and counsel patients about the use of these medications, because their ongoing use could increase the risk of NAION occurring in the fellow eye. NAION is a clinical diagnosis that must be differentiated from AAION, because patients with AAION can develop devastating vision loss in the fellow eye if corticosteroid therapy is not started immediately. Although AAION is also characterized by acute onset of severe monocular vision loss with optic disc edema, the patient often has other symptoms that suggest giant cell arteritis (GCA), such as headache, jaw claudication, or scalp 3.  Nonarteritic Ischemic Optic Neuropathy

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tenderness. The inflammatory markers should be checked in patients who report having symptoms that suggest GCA or are aged 50 years or more. Patients who have symptoms that suggest GCA or whose inflammatory markers are elevated should be started on corticosteroids and a temporal artery biopsy should be obtained (see Case 2). There is no effective treatment for NAION, although a number of potential therapies have been evaluated. In a multicenter randomized trial, optic nerve decompression was found to be ineffective and potentially harmful. The findings of one nonrandomized and unmasked study suggest that high-​dose prednisone treatment might result in a higher probability of improvement in visual acuity and visual field loss, compared with no treatment. However, these findings have not been replicated by other studies and, thus, use of steroids for NAION remains controversial. Furthermore, there is no proven therapy to prevent NAION from occurring in the fellow eye. The focus is therefore on reducing the risk of further events by eliminating potential precipitating factors, such as nocturnal hypotension and obstructive sleep apnea. A diagnostic sleep study should be considered, even in the absence of a history of snoring or witnessed apneic episodes. In addition, treatment of vascular risk factors and the use of antiplatelet therapy (e.g., aspirin 81 mg daily) should be considered, although there is no clinical trial evidence to suggest that these strategies prevent recurrence or fellow eye involvement.

KEY POINTS TO REMEMBER

• NAION is the most common cause of acute-​onset optic neuropathy in older adults.

• NAION causes a rapid onset of painless monocular vision loss with a relative afferent pupillary defect and segmental optic disc edema.

• NAION usually occurs in eyes with a small, structurally congested optic disc (“disc at risk”).

• NAION can occur in association with obstructive sleep apnea and nocturnal hypotension, which can be exacerbated by evening dosing of antihypertensive medications.

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• No treatment has been definitively shown to improve visual

recovery, prevent recurrence, or prevent fellow eye involvement in NAION, although avoidance of precipitating factors, treatment of vascular risk factors, and antiplatelet therapy should be considered.

Further Reading Campbell UB, Walker AM, Gaffney M, et al. Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med. 2015;12:139–​151. Hayreh SS, Zimmerman MB. Non-​arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol. 2008;246:1029–​1046. Hayreh SS, Zimmerman MB, Podhajsky PA, Alward WL. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol. 1994;117:603–​624. Ischemic Optic Neuropathy Decompression Trial Research Group. Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA. 1995;273:625–​632. Palombi K, Renard E, Levy P, et al. Non-​arteritic anterior ischaemic optic neuropathy is nearly systematically associated with obstructive sleep apnoea. Br J Ophthalmol. 2006;90:879–​882. Purvin V, Kawasaki A, Borruat FX. Optic neuropathy in patients using amiodarone. Arch Ophthalmol. 2006;124:696–​701.

3.  Nonarteritic Ischemic Optic Neuropathy

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4 Compressive Optic Neuropathy

A 40-​year-​old woman presents to your clinic reporting a several-​month history of progressive painless vision loss in her right eye. Examination shows visual acuities of 20/​40 in the right eye and 20/​20 in the left eye. She correctly identifies 4 of 14 Ishihara color plates with the right eye and 14 of 14 plates with the left eye. Confrontation visual fields show a subtle central scotoma in the right eye. Her pupils are equal in size and react to light, but there is a right relative afferent pupillary defect. Funduscopic examination shows optic disc pallor in the right eye. Magnetic resonance imaging (MRI) of the orbits with contrast shows an enhancing lesion surrounding the right optic nerve.

What do you do now?

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he progressive onset of painless monocular vision loss in this patient’s right eye, with associated dyschromatopsia, a relative afferent pupillary defect, and temporal optic disc pallor, suggests a compressive optic neuropathy. Compressive optic neuropathies can be divided into anterior and posterior forms: optic disc edema is often present when the compression is anterior (i.e., intraorbital), while it is usually absent when the compression is posterior (i.e., intracranial). Both forms are characterized by progressive, and usually painless, central vision loss. The patient often has dyschromatopsia that is out of proportion to the degree of decrease in visual acuity. Formal visual field testing should be obtained to determine the extent of visual field loss; it will often demonstrate a central visual field defect, which may be subtle, and blind-​spot enlargement in patients with optic disc edema due to anterior compressive optic neuropathy. Optociliary collateral vessels may be present in patients with chronic anterior compressive optic neuropathy (Figure 4.1), and there may also be retinal folds. In contrast, patients with posterior compressive optic neuropathy have a normal optic disc initially. However, with persistent compression, they gradually develop optic disc pallor without collateral vessels or folds. Some patients with chronic posterior compressive optic neuropathy develop optic disc cupping, although they will usually have coexisting optic disc pallor and

FIGURE 4.1.   Fundus photograph demonstrating mild right optic disc edema and pallor, with

optociliary collateral vessels (left). MRI of the orbit showing a large enhancing lesion in the right orbit that has an appearance consistent with an optic nerve sheath meningioma (right).

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a normal intraocular pressure to allow for differentiation from a glaucomatous optic neuropathy. Patients with orbital pathology as the cause for their compressive optic neuropathy often have orbital signs (i.e., proptosis, chemosis, conjunctival injection, eyelid abnormalities, or limited ocular ductions). However, the absence of orbital signs does not exclude an orbital lesion as the cause for the optic neuropathy. Common causes for compressive optic neuropathy include orbital tumors (e.g., optic nerve sheath meningioma, optic glioma, capillary hemangioma, or lymphoma), intracranial tumors (e.g., pituitary adenoma, meningioma, or craniopharyngioma; see Case 11), aneurysms (e.g., internal carotid or ophthalmic artery), orbital infections (e.g., bacterial infection or fungal infection; see Case 38), and orbital inflammation (e.g., idiopathic orbital inflammation). Thyroid eye disease can also cause compressive optic neuropathy, sometimes in the absence of obvious orbital signs (see Case 37). Most causes of compressive optic neuropathy can be diagnosed with imaging. MRI of the orbits (with contrast and fat suppression) is the imaging modality of choice in most cases, although computed tomography (CT) is preferable for demonstrating calcification or if details of the bony anatomy are required (e.g., in patients with thyroid eye disease who might require orbital decompression surgery; see Case 37). Depending on the imaging findings, biopsy of the lesion may be required for definitive diagnosis. For the patient described in this scenario, MRI of the orbits has detected an enhancing lesion surrounding the right optic nerve (see Figure 4.1), which is likely to be an optic nerve sheath meningioma (ONSM). ONSMs occur most commonly in middle-​aged women and are usually unilateral. MRI shows that the lesion is extrinsic to the optic nerve and thereby allows differentiation from intrinsic tumors (e.g., optic glioma). The presence of calcification produces a characteristic “tram-​track” appearance on CT. Since the imaging findings are usually diagnostic, biopsy is rarely required. Treatment of ONSM varies depending on the severity and rate of vision loss. Patients who have minimal or no vision loss can be observed, because they may remain stable without intervention. Those with more significant or progressive vision loss, such as the patient in this scenario, are best managed with fractionated stereotactic radiotherapy, which can improve or stabilize the vision with minimal morbidity. Surgical resection is not appropriate unless there is already severe vision loss and another indication 4.  Compressive Optic Neuropathy

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for resection (e.g., severe proptosis, intractable pain), because it invariably results in severe vision loss due to interruption of the blood supply to the optic nerve.

KEY POINTS TO REMEMBER

• Compressive optic neuropathy is characterized by progressive

central vision loss, with dyschromatopsia and a relative afferent pupillary defect; the optic disc appearance varies depending on the location and chronicity of compression.

• Compressive optic neuropathy can be caused by orbital tumors, intracranial tumors (e.g., pituitary adenomas, meningiomas,

and craniopharyngiomas), aneurysms, orbital infections, orbital inflammation, and thyroid eye disease.

• MRI or CT of the orbits is usually sufficient to diagnose

the causative lesion, although biopsy and histopathologic examination may be required in some cases.

• ONSM occurs most often in middle-​aged women and is best

managed conservatively when there is minimal vision loss or with stereotactic radiotherapy when there is more severe or progressive vision loss.

Further Reading Blandford AD, Zhang D, Chundury RV, Perry JD. Dysthyroid optic neuropathy: update on pathogenesis, diagnosis, and management. Expert Rev Ophthalmol. 2017;12:111–​121. Hamilton SN, Nichol A, Truong P, et al. Visual outcomes and local control after fractionated stereotactic radiotherapy for optic nerve sheath meningioma. Ophthalmic Plast Reconstr Surg. 2018;34:217–​221. Moster ML. Detection and treatment of optic nerve sheath meningioma. Curr Neurol Neurosci Rep. 2005;5:367–​375.

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5

Leber Hereditary Optic Neuropathy

You are called to the emergency department to see a 14-​year-​old boy who has acutely developed painless vision loss in his right eye. There is a history of vision loss on the maternal side of his family. Examination shows visual acuities of 20/​200 in the right eye and 20/​15 in the left eye. He is unable to identify the control Ishihara color plate with the right eye, but he correctly identifies all plates with the left eye. Confrontation visual fields show a dense central scotoma in the right eye. His pupils are equal in size and react to light, but there is a right relative afferent pupillary defect. Funduscopic examination shows trace optic disc edema in the right eye and a normal optic disc in the left eye.

What do you do now?

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hen a young patient has an acute onset of monocular vision loss and has clinical signs consistent with a unilateral optic neuropathy, the most likely diagnosis is idiopathic optic neuritis (see Case 1). However, the absence of pain is unusual for idiopathic optic neuritis and, therefore, atypical optic neuritis (e.g., in the setting of neuromyelitis optica) and other etiologies of optic neuropathy should be considered in this patient. Nonarteritic anterior ischemic optic neuropathy can occasionally cause an acute painless optic neuropathy in a younger patient who does not have vascular risk factors (see Case 3), but the absence of significant optic disc edema in this patient argues against that diagnosis. An acute painless optic neuropathy can also be caused by sudden optic nerve compression (see Case 4); magnetic resonance imaging (MRI) of the orbits should be obtained urgently to exclude this possibility, because recovery of vision remains possible with timely decompression. For the patient described in this case scenario, the presence of a family history of vision loss should increase suspicion for hereditary optic neuropathy. A progressive onset of painless binocular central vision loss suggests autosomal dominant optic atrophy (see Case 6), whereas an acute onset of painless monocular vision loss suggests Leber hereditary optic neuropathy (LHON). LHON is a rare disease that is caused by point mutations in the mitochondrial DNA (mtDNA). The most common causative point mutations are at positions 11778 (in about 69% of cases), 14484 (in about 14% of cases), and 3460 (in about 13% of cases) in the mtDNA; these mutations involve genes that encode subunits of complex I  of the mitochondrial respiratory chain. A number of rarer mtDNA point mutations have also been reported to cause LHON. Because LHON has a maternal inheritance, the mutation can only be passed to offspring by females. Most patients with LHON are male, with onset of symptoms typically occurring between the ages of 15 and 35 years. The typical presentation is with acute painless central vision loss in one eye, with clinical signs of a unilateral optic neuropathy. Visual field testing shows a central or ceco-​central scotoma. Funduscopic examination at the time of onset shows what appears to be trace optic disc edema, due to swelling of the retinal nerve fiber layer around the optic disc, with optic disc hyperemia and peripapillary telangiectatic vessels (Figure 5.1). These funduscopic changes eventually resolve, resulting in optic atrophy. Unfortunately, the vision loss in LHON 26

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FIGURE 5.1.   Fundus photographs demonstrating coarsening of the peripapillary retinal nerve

fiber layer, as well as optic disc hyperemia and peripapillary telangiectatic vessels, in a patient with sequential vision loss due to LHON.

is usually severe and permanent, although some patients with the 14484 mtDNA mutation have a spontaneous improvement in vision with time. However, almost all patients will develop fellow eye involvement within 1 year, often within 6–​8 weeks of their initial presentation. LHON can be diagnosed by demonstrating the presence of a causative mtDNA mutation. When testing for such mutations is unrevealing but clinical suspicion for LHON is high, whole mtDNA genome sequencing might demonstrate a rare or novel mutation. Once the diagnosis is confirmed, many patients ask if there is a way to prevent fellow eye involvement. However, factors that influence the expression of the disease remain uncertain. There is limited evidence that certain environmental factors, such as tobacco and alcohol exposure, might play a role in triggering LHON. Thus, the patient should be advised to avoid tobacco and excessive alcohol consumption. Treatment options for LHON remain limited. Many treatments have been proposed, including coenzyme Q10, succinate, and various vitamins, but there are only anecdotal reports of a beneficial effect. A  prospective randomized controlled study of idebenone (a coenzyme Q10 analog; 300 mg three times daily) showed a trend toward improvement in vision in patients with LHON. Gene therapy might ultimately prove to be effective for treating acute LHON and preventing fellow eye involvement; results 5.  Leber Hereditary Optic Neuropathy

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from clinical trials are promising. However, from a practical point of view, genetic counseling and evaluation by a low-​vision specialist are often most helpful.

KEY POINTS TO REMEMBER

• LHON demonstrates maternal inheritance and most commonly occurs in young men.

• LHON causes an acute onset of severe (and usually irreversible) painless monocular vision loss, with subsequent fellow eye involvement within 6–​12 months.

• LHON can be definitively diagnosed if a pathogenic mtDNA

point mutation is detected; the most common mutations are at positions 11778, 14484, and 3460 in the mtDNA.

• Treatment options for LHON are limited, although idebenone treatment and gene therapies hold promise.

Further Reading Carelli V, Carbonelli M, de Coo IF, et al. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J Neuroophthalmol. 2017;37:371–​381. Guy J, Feuer WJ, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: low-​and medium-​dose visual results. Ophthalmology. 2017;124:1621–​1634. Kirkman MA, Yu-​Wai-​Man P, Korsten A, et al. Gene-​environment interactions in Leber hereditary optic neuropathy. Brain. 2009;132:2317–​2326. Klopstock T, Yu-​Wai-​Man P, Dimitriadis K, et al. A randomized placebo-​controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134:2677–​2686.

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6

Autosomal Dominant Optic Atrophy

A 14-​year-​old boy presents to your clinic for evaluation of longstanding vision loss in both eyes. His vision loss was initially detected on a vision screening examination when he started school. He denies having prior episodes of acute vision loss but reports having more difficulty reading fine print over the past several years. There is a history of vision loss on the paternal side of his family. Examination shows visual acuities of 20/​40 in both eyes. He correctly identifies 4 of 14 Ishihara color plates with both eyes. Confrontation visual fields show a subtle central scotoma in both eyes. His pupils are equal in size and react to light, and there is no relative afferent pupillary defect. Funduscopic examination shows optic disc pallor in both eyes.

What do you do now?

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he patient described in this scenario reports slowly worsening central vision loss and has clinical signs suggesting bilateral optic neuropathies. There is a broad differential diagnosis for bilateral optic neuropathies, including optic neuritis (e.g., bilateral optic neuritis in multiple sclerosis; see Case 1), ischemic optic neuropathy (e.g., bilateral arteritic anterior ischemic optic neuropathy; see Case 2), compressive optic neuropathy (e.g., due to meningioma; see Case 4), nutritional optic neuropathy (e.g., due to vitamin B12 deficiency), toxic optic neuropathy (e.g., due to amiodarone toxicity; see Case 3), and traumatic optic neuropathy. The initial evaluation of a patient with bilateral optic neuropathies should therefore include a careful history to determine the temporal profile of onset of vision loss, evaluate for possible precipitating factors or events (e.g., head trauma), and ask about other neurologic symptoms. It is important to scrutinize the patient’s medication list and ask about toxin exposures; agents causing toxic optic neuropathy include methanol, ethambutol, amiodarone, and linezolid. It is also important to ask about the patient’s diet and to review the patient’s past history for conditions or procedures that might put him or her at higher risk for nutritional optic neuropathy (e.g., history of alcohol abuse, pernicious anemia, or gastric bypass surgery). Formal visual field testing should also be obtained to determine the pattern of visual field loss. In this patient, the presence of a family history of vision loss increases the possibility of hereditary optic neuropathy. The patient denies having any episodes of acute vision loss, making Leber hereditary optic neuropathy less likely (see Case 5). His history of longstanding central vision loss with gradual worsening over years is much more consistent with autosomal dominant optic atrophy (ADOA). ADOA is the most common hereditary optic neuropathy. As its name suggests, it has a dominant pattern of inheritance with an equal sex distribution. It is most often caused by mutations in the OPA1 gene on the long (q) arm of chromosome 3; the gene product has a role in various mitochondrial functions (mitochondrial fusion, membrane stabilization, and mitochondrial DNA replication) and control of apoptosis. ADOA has an incomplete penetrance and the phenotype is often quite variable within each pedigree, suggesting that other genetic and environmental factors influence disease expression.

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Most patients with ADOA come to medical attention in the first or second decade of life after being found to have decreased visual acuities, dyschromatopsia, or optic disc pallor in both eyes (e.g., on a vision screening or routine eye examination). The vision loss is typically slowly progressive over years. Visual acuity usually ranges from 20/​20 to 20/​200 and visual field testing shows central or ceco-​central scotomas. Funduscopic examination shows a characteristic optic disc appearance with pallor, optic disc cupping, and atrophy of the papillomacular retinal nerve fiber layer (Figure 6.1). The optic disc cupping is temporal, in contrast with glaucomatous optic neuropathies, in which it is usually vertical. The severity of optic disc pallor is often much greater than would be expected on the basis of the patient’s visual function. Most patients with ADOA have no other neurologic symptoms or signs. However, up to 20% develop other deficits, which can include sensorineural hearing loss, ataxia, myopathy, peripheral neuropathy, spastic paraparesis, and chronic progressive external ophthalmoplegia (see Case 23). ADOA can be diagnosed by demonstrating the presence of an OPA1 mutation. However, an OPA1 mutation is present in only two thirds of pedigrees with ADOA and, thus, the absence of an OPA1 mutation does not exclude the diagnosis. Consequently, it can be helpful to evaluate

FIGURE 6.1.   Fundus photographs demonstrating optic disc pallor with temporal optic disc

cupping and atrophy of the papillomacular retinal nerve fiber layer in a patient with ADOA.

6.  Autosomal Dominant Optic Atrophy

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first-​degree relatives (i.e., parents and siblings) for signs of ADOA, including decreased visual acuity, dyschromatopsia, and optic atrophy. In patients who do not have a known family history of ADOA or a first-​ degree relative with signs consistent with ADOA, it is reasonable to obtain investigations (i.e., magnetic resonance imaging of the orbits with contrast and laboratory studies) to evaluate for other etiologies of bilateral optic neuropathy. There is no treatment that has been proven effective for ADOA. One small clinical trial reported a modest improvement in vision with 12 months of treatment with idebenone. Due to a lack of randomized controlled trials with long-​term follow-​up, it remains unclear if long-​term treatment with idebenone is beneficial and, thus, it should not be routinely recommended. From a practical point of view, genetic counseling and evaluation by a low-​ vision specialist should be offered. However, most patients with ADOA adapt to their vision loss and function well despite it.

KEY POINTS TO REMEMBER

• ADOA demonstrates dominant inheritance and has an equal sex distribution.

• ADOA causes slowly progressive central vision loss with associated dyschromatopsia.

• ADOA produces a characteristic optic disc appearance with pallor, temporal optic disc cupping, and atrophy of the papillomacular retinal nerve fiber layer.

• Since only two thirds of ADOA pedigrees have an OPA1

mutation, the absence of an OPA1 mutation does not exclude the diagnosis.

• Treatment options for ADOA are limited, although idebenone

treatment may give a modest improvement in visual function.

Further Reading Barboni P, Valentino ML, La Morgia C, et al. Idebenone treatment in patients with OPA1-​mutant dominant optic atrophy. Brain. 2013;136:e231.

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Cohn AC, Toomes C, Potter C, et al. Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations. Am J Ophthalmol. 2007;143:656–​662. Yu-​Wai-​Man P, Griffiths PG, Burke A, et al. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology. 2010;117:1538–​1546. Yu-​Wai-​Man P, Griffiths PG, Gorman GS, et al. Multi-​system neurological disease is common in patients with OPA1 mutations. Brain. 2010;133:771–​786.

6.  Autosomal Dominant Optic Atrophy

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7 Neuroretinitis

You are called to see a 28-​year-​old woman who has had a subacute onset of vision loss in her right eye over several days. She denies having associated pain on eye movements. She has no past medical history and denies other neurologic symptoms. Examination shows visual acuities of 20/​50 in the right eye and 20/​15 in the left eye. She correctly identifies 10 of 14 Ishihara color plates with the right eye and 14 of 14 plates with the left eye. Confrontation visual fields show a central scotoma in the right eye. Her pupils are equal and react to light, but there is a small right relative afferent pupillary defect. Funduscopic examination shows severe optic disc edema with fluid extending from the peripapillary region into the macula in the right eye.

What do you do now?

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he patient in this scenario has had a subacute onset of painless monocular vision loss and has signs suggesting an optic neuropathy, including severe optic disc edema. Although this presentation could be mistaken for a case of atypical optic neuritis (see Case 1), the presence of fluid in the macula should suggest neuroretinitis. Neuroretinitis is an inflammatory condition characterized by unilateral optic disc edema with fluid extending from the peripapillary region into the macula (Figure 7.1). The fluid can be difficult to appreciate on fundus examination but is easily demonstrated with optical coherence tomography obtained through the macula (see Figure 7.1). As the fluid resorbs with time, retinal exudates develop in a stellate configuration; this is known as a macular star (Figure 7.2). Neuroretinitis can be caused by a variety of infectious and inflammatory diseases. The most commonly identified cause is cat-​scratch disease, secondary to infection with Bartonella henselae. As its name implies, the infection is typically acquired from a cat scratch and, thus, it is important to ask the patient about a recent history of cat scratches. Patients with cat-​scratch disease often develop fevers, headaches, and lymphadenopathy prior to the onset of vision loss. Other infectious causes include bacterial infections (e.g., tuberculosis), spirochete infections (e.g., syphilis and Lyme disease), protozoal infections (e.g., toxoplasmosis), fungal infections (e.g., histoplasmosis), and viral infections (e.g., mumps). Thus, it is important to ask the patient about risk factors for these infections, such as a history of camping or tick bites. Less commonly, neuroretinitis can occur in the setting of certain inflammatory diseases, such as sarcoidosis, inflammatory bowel disease,

FIGURE 7.1.   Fundus photograph demonstrating optic disc edema with fluid in the macula in a

patient with acute idiopathic neuroretinitis (left). Optical coherence tomography of the macula from the same patient showing intraretinal fluid extending from the peripapillary region into the macula (right).

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FIGURE 7.2.   Fundus photograph demonstrating optic disc edema and retinal exudates forming a

macular star in a patient with Bartonella neuroretinitis.

and polyarteritis nodosa. Neuroretinitis is usually a self-​limited condition, with gradual resolution over about 6–​8 weeks. However, some patients with idiopathic neuroretinitis have recurrent attacks that occur months or sometimes years apart. Although neuroretinitis is a clinical diagnosis, diagnostic studies should be obtained to evaluate for potential infectious etiologies and underlying inflammatory disease, depending on the history and clinical picture. In particular, serology studies for the common infectious causes (i.e., cat-​scratch disease, syphilis, and Lyme disease) should be obtained, as this will influence the choice of treatment. Diagnostic studies for inflammatory disease should also be considered, including anti-​neutrophil cytoplasmic antibodies, angiotensin-​ converting enzyme level, lysozyme level, and chest x-​ray or computed tomography of the chest to evaluate for signs of pulmonary sarcoidosis. Magnetic resonance imaging (MRI) of the orbits typically shows enhancement of the optic nerve head acutely but is otherwise unrevealing and, thus, is usually not necessary. Since there is no association between neuroretinitis and multiple sclerosis, an MRI of the brain is not routinely indicated. The prognosis for recovery of vision is variable. In most patients, there is an excellent recovery of vision, although many have subtle persistent visual 7. Neuroretinitis

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deficits from residual optic nerve dysfunction. Patients with severe vision loss or a moderate to large relative afferent pupillary defect at presentation have a poorer prognosis for recovery of vision. Likewise, patients with recurrent neuroretinitis have a poorer prognosis for recovery of vision. Treatment of neuroretinitis should be tailored depending on the cause. In patients with a history of a recent cat-​scratch, empiric antibiotic therapy (e.g., with azithromycin, ciprofloxacin, or doxycycline) is indicated, although some studies have reported a benefit from corticosteroid therapy in combination with antibiotics. In patients with an underlying inflammatory disease or idiopathic neuroretinitis, treatment with corticosteroids (e.g., oral prednisone 1 mg/​kg daily) should be considered. The prednisone dose can be rapidly tapered once the optic disc edema has resolved (typically about 4–​6 weeks following initial presentation). In patients with recurrent (noninfectious) neuroretinitis, treatment with oral prednisone (1 mg/​kg daily) should be offered acutely and long-​term immunosuppressive therapy (e.g., azathioprine or mycophenolate) should be considered to reduce the frequency of further attacks.

KEY POINTS TO REMEMBER

• Neuroretinitis is an inflammatory condition characterized by unilateral optic disc edema with fluid extending from

the peripapillary region into the macula and subsequent development of retinal exudates forming a macular star.

• Neuroretinitis can be caused by a variety of infectious and

inflammatory diseases; the most commonly identified cause is cat-​scratch disease, due to infection with Bartonella henselae.

• There is a good prognosis for recovery of vision, although

patients with severe vision loss or a significant relative afferent pupillary defect at presentation tend to have a poorer recovery.

• Patients with cat-​scratch neuroretinitis should be treated with antibiotics, whereas those with inflammatory

disease or idiopathic neuroretinitis should be treated with corticosteroids.

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• In patients with recurrent neuroretinitis, long-​term

immunosuppressive therapy should be considered to reduce the frequency of further attacks.

Further Reading Chi SL, Stinnett S, Eggenberger E, et al. Clinical characteristics in 53 patients with cat scratch optic neuropathy. Ophthalmology. 2012;119:183–​187. Habot-​Wilner Z, Trivizki O, Goldstein M, et al. Cat-​scratch disease: ocular manifestations and treatment outcome. Acta Ophthalmol. 2018;96:e524–​532. Purvin V, Sundaram S, Kawasaki A. Neuroretinitis: review of the literature and new observations. J Neuroophthalmol. 2011;31:58–​68. Sundaram SV, Purvin VA, Kawasaki A. Recurrent idiopathic neuroretinitis: natural history and effect of treatment. Clin Exp Ophthalmol. 2010;38:591–​596.

7. Neuroretinitis

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8 Papilledema

A 32-​year-​old man presents to your clinic with a several-​month history of increasing headaches. He also reports that his vision is blurred. His wife reports some subtle changes in his personality over the past few years. Otherwise, he is healthy and does not take any medications. Examination shows visual acuities of 20/​25 in both eyes. With pinhole, his visual acuities improve to 20/​20 in both eyes. He correctly identifies all Ishihara color plates with both eyes. Confrontation visual fields are full in both eyes. His pupils are equal in size and react to light, and there is no relative afferent pupillary defect. Eye movements are normal. Funduscopic examination shows bilateral optic disc edema.

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he patient in this scenario presents with symptoms and signs of increased intracranial pressure (ICP). Headache is the most frequent symptom of increased ICP and is typically a daily holocranial headache, which awakens the patient and is exacerbated by maneuvers that increase ICP, such as coughing or straining. However, headache is a nonspecific symptom that can be caused by many other disorders. Consequently, it is important to inquire about other symptoms of increased ICP, such as pulse-​synchronous tinnitus; this is a common symptom that is usually not volunteered by the patient and is seldom present in patients with other causes of headache. Visual symptoms are common in patients with increased ICP and are often secondary to papilledema, which is the term used to describe optic disc edema that is caused by increased ICP. Papilledema is usually symmetric (Figure 8.1) but can be unilateral or asymmetric in some patients (e.g., in Foster Kennedy syndrome, where there is ipsilateral optic atrophy due to optic nerve compression by a tumor and contralateral papilledema due to increased ICP). Patients with papilledema often report brief episodes of vision loss that are precipitated by postural changes and Valsalva-​like maneuvers, with rapid recovery (within seconds) back to baseline between episodes. These episodes, called transient visual obscurations, are thought to occur because of transient ischemia of the edematous optic nerve head. Papilledema can also cause progressive irreversible visual field loss and optic atrophy. Enlargement of the physiologic blind spot is the earliest visual field change to occur (see Figure 8.1). If papilledema is persistent or severe, nasal (often inferonasal) defects, arcuate defects, and, ultimately, visual field constriction can develop. However, the vision loss might go unnoticed by the patient until severe, because visual acuity is usually not affected until the visual field loss is advanced. Visual acuity can be affected early if there is macular pathology (e.g., edema) or a change in refractive error (e.g., hyperopic shift) due to posterior globe flattening or chorioretinal folds. Other common visual symptoms of increased ICP include binocular horizontal diplopia due to unilateral or bilateral sixth nerve palsy. Increased ICP can have a number of sinister causes (Box 8.1). Many causes of increased ICP, such as intracranial mass lesions and hydrocephalus, can be detected on imaging. Unless contraindicated, the imaging study of choice is magnetic resonance imaging (MRI) of the brain with 42

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FIGURE 8.1.   Fundus photographs demonstrating bilateral papilledema in a patient with increased

ICP (top row). Automated perimetry shows enlarged blind spots in both eyes (bottom row).

BOX 8.1   Causes

of Increased ICP

Mass lesions (e.g., benign and malignant tumors, intracerebral hemorrhage) Obstruction of ventricular system (e.g., aqueduct stenosis, third-​ventricular  tumor) Obstruction of venous outflow (e.g., cerebral venous sinus thrombosis) Decreased CSF absorption (e.g., meningitis, subarachnoid hemorrhage) Increased CSF secretion (e.g., choroid plexus tumor) Diffuse cerebral edema (e.g., post–​head injury) Medications (e.g., tetracyclines, retinoids, lithium) Idiopathic intracranial hypertension

4

contrast. Although cerebral venous sinus thrombosis (CVST) is usually evident on MRI of the brain with contrast, magnetic resonance venography (MRV) of the head with contrast should be obtained if there is a concern for CVST. If no cause for the increased ICP is identified on MRI or MRV, the next step is to perform a lumbar puncture in the lateral decubitus position in order to measure the cerebrospinal fluid (CSF) opening pressure (normal in adults is