Optic Nerve Disorders

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3 Optic Nerve Disorders

4 Optic Nerve Disorders Diagnosis and Management, MD Associate Professor of Ophthalmology and Neurology, University of Kentucky College of Medicine, Lexington, Kentucky, USA

5 , MD Associate Professor of Ophthalmology and Neurology University of Kentucky College of Medicine Lexington, KY USA Library of Congress Control Number: ISBN: e-isbn: Printed on acid-free paper Springer Science+Business Media, LLC. 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 connection 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 respect to the material contained herein springer.com

6 This book is dedicated to my parents, Tom and Rosalie Chan especially to my mother for her unconditional love and support. I also appreciate my mentors, Drs. William F. Hoyt, John L. Keltner, and David P. Richman, who have given me guidance in my career.

7 Preface This book presents the salient features of optic nerve disorders, encompassing optic neuritis, papilledema, ischemic optic neuropathies, compressive and infiltrative optic neuropathies, traumatic optic neuropathies, nutritional and toxic optic neuropathies, hereditary optic neuropathies, and optic disc tumors. Chapters 1 to 9 outline key clinical aspects of each of these disorders. Chapter 10 illustrates some newer applications of optical coherence tomography (OCT) in monitoring optic nerve-related processes causing retinal nerve fiber layer loss and in ruling out retinal disorders. Chapter 11 discusses the adjunctive role of visual evoked potential (VEP), multifocal VEP, electroretinogram (ERG), and multifocal ERG in the diagnosis of more challenging visual problems, especially in distinguishing them from macular disorders and psychogenic etiologies. Although there are excellent textbooks covering various aspects of neuro-ophthalmology, this book is intended for any physician, including ophthalmologists, neurologists, and neurosurgeons. Fellows, residents, and medical students can acquire an up-to-date knowledge base to better help their patients with optic nerve disorders. It is a unique reference that combines the applications of some newer diagnostic techniques with the symptoms and signs approach to visual loss in a useful and practical format., MD vii

8 Contents Preface Contributors vii xi Chapter 1 Optic Neuritis Chapter 2 Ischemic Optic Neuropathies Chapter 3 Papilledema Chapter 4 Compressive and Infiltrative Optic Neuropathies Chapter 5 Traumatic Optic Neuropathies Chapter 6 Nutritional and Toxic Optic Neuropathies Chapter 7 Hereditary Optic Neuropathies Chapter 8 Congenital Disc Anomalies Chapter 9 Optic Disc Tumors Chapter 10 Optical Coherence Tomography in Optic Nerve Disorders Julio A. Rodríguez-Padilla and Thomas R. Hedges III Chapter 11 The Use of Multifocal Electroretinograms and Visual Evoked Potentials in Diagnosing Optic Nerve Disorders Donald C. Hood and Karen Holopigian Index ix

9 Contributors, MD Associate Professor of Ophthalmology and Neurology, University of Kentucky College of Medicine, Lexington, KY, USA Thomas R. Hedges III, MD Professor of Ophthalmology and Neurology, Tufts University, Director of Neuro-Ophthalmology, New England Eye Center, Tufts-New England Medical Center, Boston, MA, USA Karen Holopigian, PhD Research Associate Professor of Ophthalmology, New York University School of Medicine, New York, NY, USA Donald C. Hood, PhD James F. Bender Professor of Psychology and Professor of Ophthalmic Sciences (Ophthalmology), Columbia University, New York, NY, USA Julio A. Rodríguez-Padilla, MD Clinical Fellow in Neuro-Ophthalmology, Tufts University, Tufts-New England Eye Center, Boston, MA, USA xi

10 1 Optic Neuritis Introduction Although neurologists usually diagnose and treat multiple sclerosis, the visual loss that often accompanies this disease often presents to an ophthalmologist or neuro-ophthalmologist for evaluation. It is an inflammation of one or both optic nerves resulting in (usually) temporary visual loss. It affects young to middle-aged adults between 16 and 55 years of age. The female-tomale ratio is 2 : 1. Children often are affected bilaterally, whereas adults are affected unilaterally. The annual incidence of acute optic neuritis has been estimated in population-based studies to be between 1 and 5 per 100,000. 1,2 Clinically definite multiple sclerosis (CDMS) is apparent at the onset of optic neuritis in 15% to 20% of patients with optic neuritis; another 40% will later experience a multiple sclerosis attack. 3 The clinical diagnosis and advances of understanding the pathogenesis and current recommended treatment of this disorder are outlined here. Clinical Presentation of Optic Neuritis Symptoms The loss of central vision is the major symptom reported in more than 90% of patients who have acute optic neuritis. Others who have normal visual acuity may complain of loss of peripheral vision to one side in the superior or inferior fields. The patient usually experiences mild orbital pain above or behind the eye, but the pain is mild even with severe visual loss. This dull retrobulbar pain may precede or occur concurrently with the visual loss. It also may be aggravated by upward eye movement and may occasionally last for as long as several weeks. 4 The optic nerve inflammation may stimulate the trigeminal innervation of the optic nerve sheath to cause this orbital pain. As visual acuity decreases over the next several days, the pain usually subsides when visual loss is maximal. Loss of color vision or dullness in the vision is also more commonly noticed by patients than photophobia. Other less common symptoms are perception of phosphenes (flashing lights with noise or eye movement) and decreased depth perception. 5 Signs Visual Acuity Visual acuity worsens over several hours, days, or even minutes and ranges in severity from 20/20 to no light perception. The degree of visual loss does not correlate with the final visual outcome. Visual loss usually peaks at several days to a week. Maximal improvement in visual function typically occurs within 2 to 3 weeks and at most within 6 months or more. 4 Visual Field Patients who have acute optic neuritis can present with a wide variety of visual field 1

11 2 J.W. Chan defects, most commonly a central scotoma. Less frequent defects may include an arcuate scotoma, a superior or inferior altitudinal scotoma, peripheral constriction, a cecocentral scotoma, and bitemporal or a left or right hemianopic defect. In the Optic Neuritis Treatment Trial (ONTT), this wide variety of baseline patterns of visual field loss had limited usefulness in differentiating optic neuritis from other optic nerve disorders. 6 During the recovery phase, the central scotoma reduces to a small, dim, central or paracentral defect. Occasionally, an arcuate scotoma may persist. Less severe optic neuritis may cause only blurry vision and a relative scotoma that eventually resolves. Because of the Uhthoff phenomenon, as is discussed later, patients whose optic neuritis have resolved can have large variations in visual field results on different days and at different times on the same day. 7 Contrast Sensitivity and Color Vision Contrast sensitivity and color vision are both reduced in acute optic neuritis. The loss of contrast sensitivity is often proportionate to or sometimes worse than the loss of visual acuity. 4 The color dysfunction is also usually more severe than the visual acuity level. 8 Although Ishihara color plates are most commonly used in the clinic, the Farnsworth Munsell 100-hue test has been shown to be more sensitive and specific. 9 The shortened version with caps 22 to 42 has a similar sensitivity for serial monitoring of dyschromatopsia after optic neuritis. The dyschromatopsia is related to the time course of the disease. More blue-yellow defects occur in the acute stage of optic neuritis, whereas more red-green defects occur after 6 months. 10 In the ONTT, no particular type of color vision defect was consistently associated with optic neuritis. The type of defect appeared to be inconsistent in individual patients as they recovered. The kind of color defect did seem to correlate with spatial vision at the time of testing, but the type of color defect at 6 months did not correlate with the severity of initial visual loss. 11 Patients also have decreased sensation of brightness in the affected eye. 10 Pupillary Abnormality The relative afferent pupillary defect is almost always present in anterior (swollen disc) or retrobulbar neuritis. If it is not present, then one should seriously consider other ophthalmic problems, such as a coexisting optic neuropathy in the fellow eye or other causes of visual loss unrelated to an optic neuropathy. Subclinical optic neuritis in the fellow eye is not uncommon. In the Optic Neuritis Study Group, 48% of patients who had unilateral optic neuritis and no prior optic neuritis in the fellow eye had an abnormal visual field in the asymptomatic eye. Approximately 68% of the asymptomatic fellow eyes had baseline visual field defects that mostly affected the peripheral rim or were diffuse; 62% of these visual field defects were classified as minimal. Most patients recovered normal visual field with varying pattern and location of sensitivity loss. Between 10% and 20% of these patients believed that their vision was normal, despite having abnormal visual acuity, color vision, or contrast sensitivity. 6 These clinical abnormalities are consistent with the pathological evidence of demyelination and atrophy found in the optic nerves of patients who have subclinical optic neuritis. 12,13 Fundus Findings Fundus findings also help to localize the site of the optic nerve lesion. Lesions that are adjacent to the optic nerve head cause papillitis (anterior optic neuritis) with minimal blood vessel enlargement and rarely peripapillary hemorrhages (Figure 1.1). 14 Vitritis is present in anterior optic neuritis caused by infections or inflammations (sarcoidosis, syphilis, tuberculosis, Lyme disease) and may be associated with multiple sclerosis (MS) as part of an intermediate uveitis. More posterior lesions (retrobulbar optic neuritis) do not produce papillitis. 12 Unilateral retrobulbar optic neuritis and papillitis both are part of the multiple sclerosis spectrum of presentation. 5 In retrobulbar optic neuritis, the optic disc is normal. Irrespective of the location of the lesion, 75% of patients who have MS, including those who have had a previous subclinical attack, eventually develop diffuse or

12 1. Optic Neuritis 3 Figure 1.1. The left optic disc (right) is normal, but the right optic disc (left) is mildly swollen, as seen in anterior optic neuritis. (Reprinted from Spalton et al., 14 with permission from Elsevier.) temporal optic disc pallor and nerve fiber layer atrophy. 5 The optic disc swelling and the disc pallor both are nonspecific findings in optic neuritis. Peripheral retinal venous sheathing may also be seen in MS, but this finding is not specific for MS as it may also be found in sarcoidosis, pars planitis, intermediate uveitis, lymphoma, and other localized ocular conditions. This sheathing represents the visible clinical sign of perivascular lymphocytic infiltration and edema of MS lesions. The vascular inflammation occurs in a region that lacks myelin and oligodendrocytes, suggesting that the vascular endothelium may be the initial site for the formation of new lesions. The presence of peripheral retinal venous sheathing has been shown to be correlated with the development of MS. 15 Differential Diagnosis of Optic Neuritis The acute monocular visual loss suggestive of optic neuritis should alert the ophthalmologist and neurologist to consider vascular optic nerve disorders. 16 Acute ischemic optic neuropathy (AION) is an infarction of the prelaminar anterior optic nerve as a result of an occlusion of the two main posterior ciliary arteries that supply the optic nerve and choroid. The orbital pain of MS-related optic neuritis, when it is severe and when it occurs or worsens during eye movement, is often a useful feature in differentiating acute optic neuritis from anterior ischemic optic neuropathy. 17 A course that is painless and does not progress to significantly improved visual function (at least two lines of visual acuity improvement) after several weeks does not suggest optic neuritis. 4 Furthermore, altitudinal rather than generalized disc swelling, disc pallor, arterial attenuation, and peripapillary hemorrhages are features much more commonly seen in AION than in optic neuritis. 18 AION is much more common in patients who are older than 50 years and who have symptoms of giant cell arteritis and an elevated sedimentation rate. 5 It may also occur independently of giant cell arteritis. Another neuro-ophthalmic disorder to consider in the differential diagnosis of optic neuritis is Leber s hereditary optic neuropathy (LHON). Males between 15 and 35 years of age are more commonly affected than females. Impairment of ganglion cell function results in visual loss that typically begins painlessly and

13 4 J.W. Chan centrally in one eye followed by the second eye over days or months. Circumpapillary telangiectatic microangiopathy, swelling of the nerve fiber layer around the disc (pseudoedema), and absence of leakage from the disc or papillary region on fluorescein angiography are the key features distinguishing LHON from other causes of optic disc edema. 19 Genetic testing for the mitochondrial DNA mutations 11778, 3460, and can also help confirm the diagnosis of LHON. 20 Other systemic infections, granulomatous inflammations, and autoimmune diseases besides MS may present with optic disc edema as part of a neuroretinitis, posterior uveitis, or posterior scleritis. Parainfectious optic neuritis usually develops 1 to 3 weeks after the onset of a viral or bacterial infection. 21 It is more common in children than in adults and may be unilateral, but it is more often bilateral. It is usually caused by demyelination associated with swollen optic discs. It may occur with no evidence of neurological dysfunction or with a meningitis, meningoencephalitis, or encephalomyelitis. Cerebrospinal fluid is usually abnormal when neurological manifestations are present. Visual recovery after parainfectious optic neuritis is often excellent. Postviral optic neuritis may be caused by underlying adenovirus, 22 coxsackievirus, 23 hepatitis A 24 and B, 25 cytomegalovirus, 26 Epstein Barr virus (EBV), 27 human immunodeficiency virus type 1 (HIV- 1), 28 measles, 29 mumps, 30 rubella, 31 varicella zoster, 32,33 and herpes zoster. 34 Optic neuritis may also be seen in bacterial infections including anthrax, 35 beta-hemolytic streptococcal infections, 36 brucellosis, 37 cat scratch disease, 38 meningococcal infection, 39 pertussis, 40 tuberculosis, 41 typhoid fever, 42 and Whipple s disease. 43 Postvaccination optic neuritis is more often anterior and bilateral. It may develop after vaccination with Bacillus Calmette Guerin (BCG), 44 hepatitis B, 45 rabies virus, 46,47 tetanus toxoid, 48 variola virus, 49 and influenza virus. 50 However, in a recent matched case-control study of 1131 patients in the U.S. military with optic neuritis, no statistically significant associations between optic neuritis and anthrax, smallpox, hepatitis B, or influenza vaccines were observed between 1998 and In sarcoidosis, the optic neuritis may be anterior or retrobulbar; it can be the presenting feature or may occur during the course of the disease. 52 In contrast to demyelinating optic neuritis, in sarcoidosis the optic disc may have a lumpy, white appearance that suggests a granulomatous reaction and may be associated with vitritis. Unlike the course of recovery in primary demyelinating optic neuritis, which is not steroid dependent, vision may decrease again in sarcoid once steroids are tapered or stopped. This steroid-dependent course of recovery is atypical for demyelinating optic neuritis and suggests an infiltrative or nondemyelinating inflammatory process, such as sarcoidosis. 52 Both anterior and retrobulbar optic neuritis may occur in HIV-infected patients with cryptococcal meningitis, 53 cytomegalovirus (CMV) infection, 54,55 herpesvirus infection, 56 syphilis, 57 tuberculous meningitis, 58 and various fungal infections. 59 HIV is capable of invading the optic nerve itself. Opportunistic infections usually occur with a low CD 4 count. CMV papillitis is necrotizing, and CMV inclusion bodies have been isolated in the optic nerve. 60 Herpes zoster papillitis can precede outer retinal necrosis. 61 Retrobulbar optic neuritis from herpes zoster can either precede or follow acute retinal necrosis, based upon a study of six patients with central nervous system (CNS) imaging abnormalities associated with retrobulbar optic neuritis that were temporally related to acute retinal necrosis. 62 Optic neuritis related to Cryptococcus and toxoplasmosis usually presents concurrently with CNS infection. 63 Optic neuritis can be seen in patients with West Nile virus. It appears to be self-limited, and vision improves with or without corticosteroids over the course of several months. Diagnosis is based upon abnormal serum West Nile virus titers. 64 Rarely, patients with toxoplasmosis may also develop optic neuritis. 65 Optic neuritis in patients with autoimmunodeficiency syndrome (AIDS) may also represent infection of the optic nerve by HIV itself. 66,67 Regarding spirochetal infections, both anterior and retrobulbar optic neuritis may be seen in patients with Lyme disease. 68

14 1. Optic Neuritis 5 In severe acute sphenoid sinusitis, the infection may spread posteriorly to the optic nerve in the orbital apex or within the optic canal, causing retrobulbar optic neuritis and acute visual loss. 69 In neuroretinitis, intraocular inflammation itself may cause optic disc edema. Unlike the visual loss from damage to the optic nerve in demyelinating optic neuritis, the visual acuity is limited by the degree of vitreous inflammation or by secondary changes in the macula, such as cystoid macular edema, associated with optic disc edema after cataract extraction. Swelling of the peripapillary retina may be observed in patients with anterior optic neuritis. Lipid exudates in a star configuration may also develop in the macula of the affected eye. Neuroretinitis may be seen in infections involving Borrelia burgdorferi (cat scratch disease), 70 toxoplasmosis, 71 hepatitis B, 72 and influenza. 73 Syphilis can cause both neuroretinitis and optic perineuritis, which are seen more frequently as part of syphilitic meningitis 74 Coxsackievirus infection may also cause an optic neuritis or neuroretinitis. 75 In posterior uveitis, optic disc edema and profound visual loss may occur with inflammation of the retina and choroid. Posterior uveitis may be associated with some form of systemic disease. The bacterial infections include Treponema pallidum, 76 Borrelia burgdorferi, 77 Leptospira interrogans, 78 Brucella, 79 Nocardia asteroides, 80 Mycobacterium tuberculosis, 81 and Neisseria meningitides. 82 Viruses causing posterior uveitis include cytomegalovirus, 83 herpes simplex, 84 herpes zoster, 85 rubella, 86,87 rubeola, 88 and HIV. 89 Parasites, such as Toxoplasma, 90 Toxocara canis, 91 and Onchocerca volvulus, 92 and fungi, such as Candida, 93 Histoplasma capsulatum, 94 Cryptococcus neoformans, 95 Aspergillus, 96 Coccidioides immitis, 97 and Blastomyces dermatitides, 98 may also cause optic disc edema in the clinical setting of posterior uveitis. In the setting of autoimmune-related posterior uveitis, vasculitis of the optic nerve in Wegener s granulomatosis may cause optic disc edema. 99,100 Papillitis occurs in the acute phase of the posterior uveitis in at least 25% of cases of Behcet s disease and is related to microvasculitis of the arterioles feeding the optic nerve. 101 Retinopathy more often than choroidopathy is seen in systemic lupus erythematosus; the optic neuritis may occur with or without posterior uveitis. 102 Hyperemia of the optic disc and optic neuritis, in addition to uveitis, choroiditis, and exudative retinal detachments, can be seen in Vogt Koyanagi Harada disease. 103 Various malignancies may also invade the uvea and optic nerve. Up to 18% of acute leukemias and 16% of chronic leukemias have some leukemic infiltration of the optic nerve, causing optic disc edema and hemorrhage. 104 Intraocular lymphoma, malignant melanoma, and metastatic lesions may also spread to the optic nerve Regarding posterior uveitis in primary ocular disorders, severe disc edema and cystoid macular edema can be commonly seen in birdshot retinochoroiditis. 108 Papillitis occasionally may be present in acute posterior multifocal placoid pigment epitheliopathy (APMPPE) 109 and multiple evanescent white dot syndrome (MEWDS). 110 The optic nerve is usually not affected in serpiginous choroiditis, but optic neuritis has been reported so far in one patient with recurrent disease. 111 Optic disc edema may be seen in about 20% of patients with posterior scleritis, which usually presents with unilateral periocular pain and decreased vision with little or no redness. Patients more than 50 years of age usually have an associated systemic disease and are more likely to experience visual loss, mostly from macular changes or optic atrophy related to the posterior scleritis. The more common associated systemic diseases are rheumatoid arthritis, Wegener s granulomatosis, systemic vasculitis, relapsing polychondritis, and other autoimmune diseases similar to those seen in anterior scleritis, and, rarely, systemic lymphoma and multiple myeloma. 112 Less commonly, optic neuritis may be the only initial manifestation of an underlying autoimmune disease not associated with MS. Young females present with unilateral or bilateral decreased vision and usually do not have overt signs or symptoms of a preexisting collagen-vascular disease, such as systemic lupus erythematosus. Laboratory tests for antinuclear

15 6 J.W. Chan antibody (ANA) and double-stranded DNA are most useful in confirming the diagnosis of lupus. 113 Patients who have occult symptoms of rheumatic disease or who have positive family histories for collagen-vascular diseases may initially present with optic neuritis and/or transverse myelitis. The diagnosis of antiphospholipid antibody syndrome in these patients is confirmed by the presence of elevated serum immunoglobulin M (IgM) anticardiolipin antibody. 114 Another form of optic-spinal MS more commonly seen in Asians is associated with significantly high levels of antithyroid autoantibodies. It is thought that this MS variant could represent a pathogenetic link between antithyroid autoimmunity and a subgroup of opticspinal MS in Japanese that is not related to human T-cell lymphotropic virus (HTLV)-1 disease. 115 Rarely, optic nerve inflammation can be part of a paraneoplastic syndrome. Optic neuritis has been documented in cases involving bronchial carcinoma, oat cell carcinoma, and lymphoma. Pathological data have shown that inflammation and demyelination, not the carcinomatous or lymphomatous invasion of the optic nerve, cause the decreased vision (see following section on paraneoplastic optic neuropathies) Pathogenesis of Optic Neuritis Demyelination Fifty percent of MS patients have clinical evidence of having had optic neuritis (at autopsy, almost 100% have optic neuritis), and 20% of them have it as their presenting sign. 120 The initial event before demyelination is the breakdown of the blood-brain barrier through the inflammation of the vascular endothelium. With the lack of oligodendrocytes in the retina, perivenular retinal sheathing represents this vascular inflammation without demyelination. The venous sheathing occurs as a clinically silent retinal disease before the development of optic neuritis. This feature may not be visible on funduscopic examination but may be demonstrable on fluorescein angiography. 121 The basic defect in optic neuritis/ms involves demyelination of the optic nerve, which blocks or slows the conduction of axonal transmission or decreases the amplitude of the nerve action potential. Various degrees of visual loss result from this process. The perivenular demyelinating plaques from optic nerves of patients who have acute MS reveal similar pathology to the periventricular plaques found elsewhere in the brain. These plaques show a perivascular cuffing of T and B cells, edema in the myelin nerve sheaths, and subsequent myelin breakdown. In optic neuritis the axons of the optic nerve are usually spared, resulting in good clinical recovery. More advanced lesions elsewhere in the CNS white matter often involve axonal degeneration, resulting in physical or mental disability. On histopathology, macrophages engulf the degraded myelin products and glial cells proliferate to cause permanent conduction block with no clinical recovery. 122,123 Cell-Mediated Damage The neuroimmunological factors that mediate demyelination of the optic nerve involve cellmediated cytotoxicity. In one study, 76% of the patients who had optic neuritis were found to have encephalitogenic, myelin basic protein (MBP), cerebroside, and ganglioside antibodies. 124 Patients who had optic neuritis/ms and patients who had isolated optic neuritis and cerebrospinal fluid (CSF) oligoclonal bands both had encephalitogenic antibodies. Elevated T-cell-mediated cytotoxicity against the encephalitogenic peptide is a highly specific marker for demyelination in MS. Optic neuritis patients who test positive for this antigen have a greater risk of developing clinically definite MS. 125 The increased CSF MBP- and MBP-reactive B cells in patients who had optic neuritis could correlate with the process of early myelin breakdown or restoration. 126 Although magnetic resonance imaging (MRI) generally has been accepted as the marker of disease activity in patients who have MS, the concentration of MBP in CSF also has been useful as a marker during acute exacerbations of MS. It is significantly correlated with the visual acuity in patients who have optic neuritis, the Kurtzke